Panorama of Emergency Medicine PoEM is an international peer-reviewed independent journal dedicated to advancing knowledge and practice in emergency medicine.
The Digital Stethoscope: Harnessing Artificial Intelligence in Pediatric Emergency Medicine
Dear Editor, Artificial Intelligence (AI) is increasingly recognized as a transformative force in healthcare, with Pediatric Emergency Medicine (PEM) standing to benefit significantly from its adoption. Children often present with subtle, atypical signs, making timely recognition of critical illness challenging. AI-driven tools are being applied in triage, predictive monitoring, diagnostic imaging, and resuscitation support, while also enhancing education through simulation and personalized learning. For global health, AI offers opportunities to reduce disparities by extending decision support to resource-limited settings. However, challenges such as data bias, ethical oversight, and the need for clinician training remain critical considerations. AI should be viewed not as a replacement for pediatric emergency physicians but as an augmentation of human expertise, amplifying decision-making, enhancing safety, and expanding access to quality care. This letter to the editor reflects on the promise, pitfalls, and potential of AI in PEM, advocating for its thoughtful and equitable integration into practice and education. Why AI matters in pediatrics emergencies Children are unique individuals with dynamic physiology. Their developmental stages influence clinical presentations, and emergencies can quickly become critical. Traditional triage and diagnostic tools, primarily designed for adults, often fail to meet the specific needs of pediatric care [1]. AI offers a transformative solution by providing rapid risk stratification and pattern recognition that surpasses human intuition, all while maintaining clinician oversight. Just as pulse oximetry revolutionized patient monitoring decades ago, AI is poised to become an indispensable tool in pediatric triage. Diagnostics and resuscitation : AI as an ally Machine learning systems are already making strides in predicting sepsis, respiratory failure, and unrecognized deterioration [2, 3]. In the realm of cardiac arrest, AI-driven rhythm interpretation and chest compression feedback are being tested as digital "coaches" [4]. This evolution mirrors the transformation brought about by Automated External Defibrillators (AEDs), which were once met with skepticism but are now indispensable worldwide. Similarly, AI can enhance the role of the CPR coach or even act as a resuscitation co-lead by providing evidence-based prompts, allowing leaders to maintain their focus on team dynamics. Education and simulation : Extending the classroom Rare pediatric emergencies, like congenital heart lesions or toxin ingestions, are infrequent in training but essential to master. While simulation addresses this gap, it is often resource-intensive and reliant on faculty. AI-enhanced virtual patients and adaptive case generators offer scalable solutions [5]. Just as flight simulators revolutionized aviation training, AI-enabled simulation could democratize access to high-quality pediatric emergency training worldwide. Additionally, natural language processing tools that analyze debriefings can help novice faculty provide structured, personalized feedback [6]. Global equity : Narrowing the gap or widening it? In low- and middle-income countries, where pediatric emergency subspecialists are scarce, AI-assisted decision-support tools embedded in mobile platforms have the potential to dramatically improve outcomes. These tools can provide rapid, evidence-based guidance to healthcare providers, helping them make critical decisions in real-time. However, there is a significant risk that algorithms trained on data from high-income populations may not perform accurately in different contexts, potentially leading to misclassification and inappropriate treatment decisions. This could exacerbate existing health inequities rather than alleviate them [7, 8]. The lesson from global vaccination campaigns is instructive: technology alone is insufficient to address complex health challenges. Successful implementation requires deliberate inclusion of diverse populations in the development and testing of AI tools, local adaptation to ensure relevance and effectiveness, and equitable distribution to ensure that all communities benefit. Without these measures, the promise of AI in improving pediatric emergency care may remain unfulfilled, and the gap between high- and low-income countries could widen further [9,10]. Challenges: Navigating bias, trust and integration AI, like any new diagnostic tool, faces significant barriers. Data bias is particularly problematic when pediatric datasets are small and heterogeneous. Blackbox algorithms that clinicians cannot interrogate risk eroding trust. Integration into workflows must be seamless; otherwise, clinicians may abandon tools that slow rather than support their practice. Lessons from electronic health record implementation highlight how poorly integrated systems can frustrate providers and compromise safety. The way forward AI in Pediatric Emergency Medicine should be viewed not as "artificial" intelligence but as “an augmented intelligence partner” that enhances human expertise without replacing it. The analogy to the stethoscope is fitting: a tool once controversial, now indispensable, but only effective in the hands of a trained clinician. The same will hold for AI. Preparing the workforce through faculty development, establishing ethical oversight, and ensuring equitable design are essential next steps. Author contributions All authors contributed equally and validated the final version of record. Declarations Conflicts Of Interests The Author declares that there is no conflict of interest. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Registration No registration applicable. Data availability statement The data that support the findings of this study are available from the corresponding author upon reasonable request. Ethical approval Ethical approval for this study was not required. References 1. Kauppi W, Imberg H, Herlitz J, Molin O, Axelsson C, Magnusson C. Advancing a machine learning-based decision support tool for pre-hospital assessment of dyspnoea by emergency medical service clinicians: a retrospective observational study. BMC Emerg Med. 2025 Jan 5;25(1):2. https://doi.org/10.1186/s12873-024-01166-9 2. Muralitharan S, Nelson W, Di S, McGillion M, Devereaux P, Barr NG, et al. Machine Learning–Based Early Warning Systems for Clinical Deterioration: Systematic Scoping Review. J Med Internet Res. 2021 Feb 4;23(2):e25187. https://doi.org/10.2196/25187 3. Jahandideh S, Ozavci G, Sahle BW, Kouzani AZ, Magrabi F, Bucknall T. Evaluation of machine learning-based models for prediction of clinical deterioration: a systematic literature review. Int J Med Inform. 2023 Jul 1;175:105084. https://doi.org/10.1016/j.ijmedinf.2023.105084 4. Chikatimalla R, Trivedi YV, Chigurupati HD, Faheem MSB, Naveed MA, Sattar Y, et al. From prediction to precision: Artificial intelligence and emerging technologies in cardiopulmonary resuscitation. Prog Cardiovasc Dis. 2025 Sep 1;92:97–107. https://doi.org/10.1016/j.pcad.2025.09.004 5. Díaz-Guio DA, Henao J, Pantoja A, Arango MA, Díaz-Gómez AS, Gómez AC. Artificial intelligence, applications and challenges in simulation-based education. Colomb J Anesthesiol. 2024;52(1). 6. Shaik T, Tao X, Li Y, Dann C, McDonald J, Redmond P, et al. A Review of the Trends and Challenges in Adopting Natural Language Processing Methods for Education Feedback Analysis. IEEE Access. 2022;10:56720–39. https://doi.org/10.1109/ACCESS.2022.3177752 7. Mir MM, Mir GM, Raina NT, Mir SM, Mir SM, Miskeen E, et al. Application of artificial intelligence in medical education: current scenario and future perspectives. J Adv Med Educ Prof. 2023 Jul;11(3):133. https://doi.org/10.30476/jamp.2023.98655.1803 8. Ejaz H, McGrath H, Wong BL, Guise A, Vercauteren T, Shapey J. Artificial intelligence and medical education: a global mixedmethods study of medical students’ perspectives. Digit Health. 2022 May;8:20552076221089099. https://doi.org/10.1177/20552076221089099 9. Chin MH, Afsar-Manesh N, Bierman AS, Chang C, Colón-Rodríguez CJ, Dullabh P, et al. Guiding principles to address the impact of algorithm bias on racial and ethnic disparities in health and health care. JAMA Netw Open. 2023 Dec 1;6(12):e2345050. https://doi.org/10.1001/jamanetworkopen.2023.45050 10. Nazer LH, Zatarah R, Waldrip S, Ke JX, Moukheiber M, Khanna AK, et al. Bias in artificial intelligence algorithms and recommendations for mitigation. PLOS Digit Health. 2023 Jun 22;2(6):e0000278. https://doi.org/10.1371/journal.pdig.0000278
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Proceedings of the Qatar Paediatric Emergency Medicine 2026 Conference - Selected Abstracts
Welcome to this issue of Panorama of Emergency Medicine (POEM) dedicated to the 10th Qatar Paediatric Emergency Medicine (Q-PEM) International Conference which was organised and hosted by Sidra Medicine (Doha, Qatar) and held online from January 16 to 18, 2026. Since its first iteration in 2017, Q-PEM has steadily evolved into an international forum for clinicians, educators, and researchers involved in the acute care of children to exchange knowledge, reflect on clinical practice, and share emerging research in paediatric emergency medicine. In 2025, the conference welcomed 2,000 online delegates from 22 countries and the programme included over 55 speakers [1]. Adopting a similar format, with 3 parallel sessions covering different important and contemporary topics, the event proved as popular in its 2026 edition with nearly identical numbers, yet we marked an important milestone for the Q-PEM community. Building on the success of previous years, the meeting again attracted a large international audience with multidisciplinary participation from physicians, nurses, pharmacists, allied health professionals, and trainees involved in paediatric emergency care. Similar to previous editions, the scientific programme combined plenary sessions, focused tracks, and research presentations to provide practical, evidence-based updates relevant to frontline emergency care. The conference was designed to enhance recognition and management of serious illness and injury in children, promote patient safety, and facilitate the translation of evidence into everyday clinical practice. Emergency Medicine is still a relatively young specialty, yet it is important to recognise that it includes a number of subspecialisations with clinicians of different professions each with their specific skill sets and knowledge to match the needs of the distinctive patient groups they care for [2]. Emergency Medicine continues to expand into highly specialized domains requiring multidisciplinary expertise. Paediatric Emergency Medicine represents one of the most demanding of these areas, where clinicians must rapidly recognize critical illness, manage complex physiological responses in children, and coordinate care within dynamic team environments. Q-PEM was established to support this evolving field by providing a platform for clinicians to share experiences, explore best practices and discuss emerging challenges in paediatric emergency care. A new and welcome development in the 2026 conference was the introduction of a call for abstracts, allowing delegates to contribute directly to the scientific programme. A total of 23 abstracts were received, all of which were reviewed by a panel of experienced clinicians from various countries. It resulted in 19 abstracts being presented during the conference in the form of e-posters. The abstracts presented reflect several important themes within contemporary paediatric emergency practice. We are now pleased to publish Open Access a selection of the accepted poster abstracts in collaboration with the journal POEM. Topics ranged from a systematic review exploring the use of simulation in training paramedics caring for paediatric patients [3] to the development of a prehospital paediatric sepsis screening tool designed to improve early recognition and referral pathways [4]. These contributions highlighted the diversity of ongoing work within paediatric emergency medicine, spanning clinical research, quality improvement initiatives, and educational innovation. They also illustrate the growing emphasis on early detection of critical illness, multidisciplinary education, and system level approaches to improving outcomes for children in emergency settings. The presenters of the top 3 abstracts [5-7] as ranked by the review panel were invited to deliver short oral presentations during the conference. Plenary Sessions The plenary sessions provided a broader perspective on the evolving challenges facing paediatric emergency medicine globally. International experts explored topics such as advances in resuscitation science, systems-based approaches to emergency care, and the integration of evidence-based protocols into busy emergency departments. Several plenary discussions emphasized the realities of decision-making under pressure—particularly in overcrowded departments where clinicians must balance speed, accuracy, and team coordination. Themes such as cognitive load, team leadership during resuscitation, and the importance of structured decision frameworks were recurrent throughout these sessions. Speakers also highlighted emerging tools that support clinical decision-making, including cognitive aids, simulation-based training, and digital health innovations. Collectively, the plenary sessions reinforced the importance of structured resuscitation approaches, effective team communication, and continuous professional development in improving outcomes for critically ill children presenting to emergency departments. Conference Tracks To allow deeper exploration of specific domains within paediatric emergency medicine, the Q-PEM 2026 scientific programme was structured around several parallel thematic tracks, each addressing key clinical and professional areas relevant to modern paediatric emergency practice. Paediatric emergency medicine core track The PEM core track focused on the fundamental clinical presentations encountered in paediatric emergency departments, including acute respiratory illness, shock states, neurological emergencies, and metabolic crises. Sessions emphasized structured clinical reasoning and the application of evidence based management pathways for common but potentially life-threatening conditions. Participants gained updated perspectives on recognizing early clinical deterioration in children and applying standardized approaches to diagnosis and stabilization. The track reinforced the importance of maintaining strong clinical fundamentals while adapting to evolving evidence and guidelines. Learning outcomes included: • Improved recognition of early warning signs of serious illness in children. • Application of evidence-based pathways in common paediatric emergencies. • Strengthening clinical reasoning in time-critical decision-making. Critical care and resuscitation track The Critical Care and Resuscitation track addressed the management of high-acuity paediatric emergencies, including septic shock, traumatic injury, cardiac arrest, and respiratory failure. Sessions highlighted advances in resuscitation science, high performance team dynamics, and post-resuscitation care. Speakers emphasized the role of structured resuscitation algorithms, coordinated multidisciplinary teamwork, and rapid escalation pathways. Discussions also explored the challenges of maintaining clinical clarity during high-stress scenarios and the strategies that support effective leadership during resuscitation events. Learning outcomes included: • Updated approaches to paediatric resuscitation and shock management. • Improved understanding of high-performance team communication during resuscitation. • Recognition of the importance of early stabilization and escalation of care. Toxicology track The Toxicology track explored acute poisoning and toxic exposures in children, a frequent yet often complex presentation in paediatric emergency departments. Sessions addressed the identification of high-risk ingestions, emerging toxicological threats, and evidence-based management strategies. Presenters discussed practical approaches to risk assessment, antidote use, and supportive care, while also highlighting the role of poison control systems and multidisciplinary collaboration in managing toxicological emergencies. Learning outcomes included: • Recognition of red-flag features in paediatric toxicology presentations. • Evidence-based approaches to managing common and high-risk ingestions. • Improved coordination with toxicology specialists and poison centres. Academic and research track The Academic and Research track focused on advancing scholarship within paediatric emergency medicine, including clinical research methodologies, quality improvement initiatives, and innovations in medical education. Sessions encouraged participants to critically evaluate evidence, translate research findings into practice, and contribute to the growing academic foundation of the specialty. The introduction of abstract presentations during Q-PEM 2026 further strengthened this academic component by providing a platform for clinicians and trainees to share original work with an international audience. Learning outcomes included: • Strengthening research literacy among clinicians. • Encouraging participation in quality improvement and scholarly work. • Promoting evidence-based practice in paediatric emergency medicine. Communication and patient-safety track Recognizing that safe paediatric emergency care extends beyond clinical decision-making, this track focused on communication, teamwork, and patient safety within emergency systems. Topics included medication safety, safeguarding pathways, digital safety tools, and strategies for reducing system errors. Speakers emphasized that improving outcomes for children often requires not only clinical expertise but also well-designed systems, effective interprofessional communication, and a culture of safety within healthcare teams. Learning outcomes included: • Improved communication strategies in high-stress clinical environments. • Identification of common patient safety risks in paediatric emergency care. • Integration of safety frameworks into daily clinical practice. Nursing track The Nursing track highlighted the critical role of paediatric emergency nurses in frontline resuscitation, patient monitoring, and family communication. Sessions addressed practical clinical care, nursing leadership during emergencies, and strategies for improving multidisciplinary collaboration. By focusing on the perspectives and expertise of nursing professionals, this track reinforced the importance of a truly team-based approach to paediatric emergency care. Learning outcomes included: • Strengthening nursing leadership during emergencies. • Enhancing collaboration between physicians and nursing teams. • Improving patient-centred care in the paediatric emergency environment. Looking ahead Across the programme, a consistent message emerged: clinicians value practical, evidence-informed education that directly supports bedside decision-making. Delegates particularly appreciated sessions that combined clinical evidence with real-world experience, interactive discussion, and multidisciplinary perspectives. The introduction of the abstract programme further strengthened the academic dimension of the conference and provided an opportunity for clinicians to share their work with the wider paediatric emergency medicine community. We are very thankful for everyone’s contribution to the success of Q-PEM 2026. As interest in the conference continues to grow, future editions of Q-PEM will aim to expand opportunities for research dissemination, skills-based learning, and global collaboration, notably through the likely reiteration of a call for abstracts in 2027. Author contributions All authors contributed equally and validated the final version of record. Acknowledgements Special thanks to the abstract submitters and reviewers for their input to the conference programme and to Panorama of Emergency Medicine for supporting the Open Access publication of a selection of the accepted Q-PEM 2026 abstracts. For more information about Q-PEM, please visit: https://q-pem.com/ Declarations Conflicts Of Interests The Authors declare that there is no conflict of interest. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Registration No registration applicable. Data availability statement The data that support the findings of this study are available from the corresponding author upon reasonable request. Ethical approval Ethical approval for this study was not required. References 1. Blackie B, Al Ansari K, Alinier G, Haidar N, Huda S, Adeola R, Akram S, Reid L, Sendad N. (2024). The Qatar Pediatric Emergency Medicine International Conference – Knowledge Translation Successes and Challenges. Proceedings of the Qatar Health Congress 2023 and 3rd Public Health Conference. Manara - Qatar Research Repository. Conference contribution. https://doi.org/10.57945/manara.25709457 2. Heymann EP, Lim R, Maskalyk J, Pulfrey S, Chun S, Osei-Ampofo M, Desouza K, Landes M, Lang E. Emergency medicine: a global perspective on its past, evolution, and future. Internal and Emergency Medicine. 2025,20(6):1917-21. https://doi.org/10.1007/s11739-024-03812-3 3. Al Badawi AK, Tomeh B, Alinier N, Alinier G. Literature review of the use of simulation for the training of paramedics in relation to caring for pediatric patients. Panorama of Emergency Medicine. 2026,4(2) https://doi.org/ 10.26738/poem.v4i2.6 4. Naidoo V, Ashou R, Gueddes A. Development and Implementation of a Prehospital Paediatric Sepsis Screening Tool: Enhancing Early Recognition, Resuscitation, and Referral. Panorama of Emergency Medicine. 2026,4(2) https://doi.org/ 10.26738/poem.v4i2.7 5. Ali N, Shakeel E, Raheem A, Ather H, Bano S. Risk Factors of Peri-intubation Cardiac Arrest in Critically Ill Pediatric Patients Presenting to the Emergency Department of a Low-Middle-Income Country: A Case-Control Study. Panorama of Emergency Medicine. 2026,4(2) https://doi.org/ 10.26738/poem.v4i2.3 6. Fatahi M, Shahidi R. Diagnostic accuracy of ultrasound findings for distinguishing complicated appendicitis from simple appendicitis in pediatric patients: A systematic review and meta-analysis. Panorama of Emergency Medicine. 2026,4(2) https://doi.org/ 10.26738/poem.v4i2.8 7. Fahmi A, Al-Kuwari S, Al-Ansari A, Hashem S, Kamal M. Reversal of Bradycardia through Nutritional Rehabilitation in Paediatric Anorexia Nervosa: A Retrospective Study from Qatar. Panorama of Emergency Medicine. 2026,4(2) https://doi.org/10.26738/poem.v4i2.1
Literature review of the use of simulation for the training of paramedics in relation to caring for pediatric patients
Background Paramedics face unique challenges when managing paediatric emergencies due to limited clinical exposure, insufficient training, the unpredictable prehospital environment, and scarce resources [1]. These factors increase anxiety and medical error risk, especially during rare, high-stakes events [2]. Simulation-based education (SBE) provides a safe, controlled environment that bridges the gap between knowledge and practice by allowing learners to rehearse decision-making and technical skills. Aim This review assesses the current state of paediatric simulation literature, evaluates the effectiveness of SBE in paramedic training using the Kirkpatrick evaluation framework, and identifies directions for future research. Methods A comprehensive search was conducted across PubMed, PsycINFO, CINAHL, ERIC, and Scopus for studies published between 2003 and 2023, using keywords and MeSH terms related to paramedics, prehospital care, paediatrics, and simulation. The review followed PRISMA 2020 guidelines, and methodological quality was appraised using the Joanna Briggs Institute checklists. Studies were categorised according to the four Kirkpatrick levels. Findings A total of 227 articles were identified, and upon removing duplicates, 184 were screened, and 60 were assessed for eligibility, following which 46 were excluded. In the remaining 14 studies, the use of SBE was generally reported to have had a positive impact on paramedics’ confidence and competence in performing several procedures (Table 1). Several studies reported that paramedics often felt uncomfortable providing care to children, made fewer errors, and wished they had more such training opportunities. No studies reported on how the training interventions contributed to improving actual patient care to fulfil the criteria of Kirkpatrick level 4. The full details of the findings have recently been reported [3]. Conclusion Simulation shows promise in improving paramedics' readiness for paediatric emergencies, especially knowledge, skills, and confidence. Future studies should use longitudinal designs to determine whether simulation training improves patient safety and clinical outcomes. Author contributions All authors contributed equally and validated the final version of record. Acknowledgements This work was primarily conducted by the first author as part of his Master in Medical Education with Dundee University, Scotland Declarations Conflicts Of Interest The Authors declare that there is no conflict of interest. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Registration No registration applicable. Data availability statement The data that support the findings of this study are available from the corresponding author upon reasonable request. Ethical approval Ethical approval for this study was not required. References 1. Yuknis ML, Weinstein E, Maxey H, Price L, Vaughn SX, Arkins T, et al. Frequency of pediatric emergencies in ambulatory practices. Pediatrics. 2018;142(2). https://doi.org/10.1542/peds.2017-3082 2. Der Sahakian G, Buléon C, Alinier G. Chapter 14 – Educational Foundations of Instructional Design Applied to Simulation-Based Education. In: Chiniara G, editor. Clinical Simulation (Second Edition). Academic Press. 2019:185–206. https://doi.org/10.1016/B978-0-12-815657-5.00014-0 3. Al Badawi AK, Alinier G, Nashwan AJ, Kunjavara J, Tomeh B. Effectiveness of paediatric simulation in paramedic education: a literature review. International Paramedic Practice. 2025 Aug 2;15(2):43–51. https://doi.org/10.12968/ippr.2025.0001
Diagnostic accuracy of ultrasound findings for distinguishing complicated appendicitis from simple appendicitis in pediatric patients: A systematic review and meta-analysis
Background Acute appendicitis is the most common surgical emergency in children. While up to 85% of pediatric appendicitis cases are uncomplicated, the rate of complicated appendicitis can be significant, ranging from approximately 30% overall to as high as 50–75% in certain cohorts [1]. Ultrasound (US) is a first-line imaging modality, yet its diagnostic performance in accurately identifying these complications remains uncertain [2]. Methods Following PRISMA [3], we searched PubMed, Embase, Web of Science, and Scopus from inception. Risk of bias was assessed with QUADAS-2. Bivariate random effect model pooled sensitivity and specificity; heterogeneity was summarized using I² and Q; small-study effects were evaluated using Deeks’ test. Clinical utility was illustrated using a Fagan nomogram, and overall accuracy was assessed using a summary receiver-operating characteristic (SROC) curve. Results Twenty-one studies met the inclusion criteria. Nearly all procedures were conducted by specialists or residents in radiology. The age range for the pediatric population was between 0 to 18 years old. Pooled US sensitivity for identifying complicated appendicitis was 0.52 (95% CI 0.41–0.62), and specificity was 0.90 (0.84–0.94) (Figure 1). The area under the curve was 0.80 (0.76–0.83) (Figure 2), and the summary operating point mirrored the pooled estimates. Deeks’ test suggested no significant asymmetry (p=0.08). Assuming a pre-test probability of 25%, a positive US result (LR+ = 5) increased the post-test probability to ~64%, whereas a negative result (LR–=0.54) reduced it to ~15%. Conclusion In pediatric appendicitis, US demonstrates high specificity but moderate sensitivity for discriminating complicated from simple disease. A positive scan can “rule in” complication and support expedited, targeted management; a negative scan cannot exclude complication and should be interpreted alongside clinical findings, laboratory data, and, when indicated, adjunct imaging. Future studies should standardize sonographic criteria and report per feature performance to refine thresholds and reduce heterogeneity. Author contributions All authors contributed equally and validated the final version of record. Declarations Conflicts Of Interest The Authors declare that there is no conflict of interest. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Registration No registration applicable. Data availability statement The data that support the findings of this study are available from the corresponding author upon reasonable request. Ethical approval Ethical approval for this study was not required. References 1. Benabbas R, Hanna M, Shah J, Sinert R. Diagnostic accuracy of history, physical examination, laboratory tests, and point‐of‐care ultrasound for pediatric acute appendicitis in the emergency department: a systematic review and meta‐analysis. Acad Emerg Med. 2017 May;24(5):523–51. https://doi.org/10.1111/acem.13181 2. Badlis M, Amari K, Alkheshi M, Alolaby K, Alsaid B. Ultrasound and computed tomography in differentiating between simple and complicated appendicitis in pediatric patients. Pediatr Surg Int. 2024 Nov 9;40(1):299. https://doi.org/10.1007/s00383-024-05880-0 3. Sarkis-Onofre R, Catalá-López F, Aromataris E, Lockwood C. How to properly use the PRISMA Statement. Syst Rev. 2021 Apr 19;10(1):117. https://doi.org/10.1186/s13643-021-01671-z
Development and Implementation of a Prehospital Paediatric Sepsis Screening Tool: Enhancing Early Recognition, Resuscitation, and Referral
Background Paediatric sepsis remains a leading cause of preventable morbidity and mortality, contributing to 11 million deaths annually, including 1.2 million children [1, 2]. Early recognition is critical, yet prehospital identification is hindered by subtle presentations, age-related physiological variability, and limited diagnostic capability [1, 3]. Currently, no validated prehospital paediatric sepsis screening tool exists. The aim of this project was to develop and implement an evidence-based prehospital paediatric sepsis screening tool for paramedics. Methods The development process included a targeted literature review and formal stakeholder engagement with Hamad Medical Corporation Ambulance Service (HMCAS) and Sidra Medicine. The iterative tool refinement was informed by international guidelines, aligned with Sidra Medicine pathways, and adapted to support HMCAS clinical practice guidelines. Age-specific physiological thresholds were calibrated using Advanced Paediatrc Life Support vital-sign parameters within the sepsis context. Implementation was supported by a blended educational model comprising 4 hours of online preparatory modules, 7 hours of face-to-face workshops, and simulation-enhanced active learning sessions. Results The final screening tool integrated infection-risk assessment, high-risk clinical criteria, age-specific vital-sign thresholds, and key physiological indicators, supported by an algorithm (Figure 1). A corresponding prehospital sepsis care bundle (Figure 2) was incorporated to standardise timely recognition, intervention, and escalation, aligned with the “Sepsis Golden Hour” and “Sepsis 6” principles [1, 3]. Clinical validation and alignment were provided through expert review by paediatric sepsis specialists from Sidra Medicine. Case-based learning, deliberate practice, and simulations supported the application of the tool for operational practice. Conclusion The Prehospital Paediatric Sepsis Screening Tool was successfully developed and implemented, supported by structured educational preparation to strengthen early recognition and clinical decision-making. By the end of Quarter 1, 2025, 1,513 HMCAS staff (89%) had completed the training. Future study with ongoing evaluation should examine the tool’s impact on recognition accuracy, timeliness of intervention, and patient outcomes across the prehospital paediatric sepsis pathway. Author contributions All authors contributed equally and validated the final version of record. Declarations Conflicts Of Interests The Authors declare that there is no conflict of interest. Funding No financial support or sponsorship was received for the development or implementation of the Prehospital Paediatric Sepsis Screening Tool. Registration No registration applicable. Data availability statement The data that support the findings of this study are available from the corresponding author upon reasonable request. Ethical approval Ethical approval for this study was not required. References 1. World Sepsis Day [Internet]. [cited 2025 Nov 18]. Sepsis facts. Available from: https://www.worldsepsisday.org/sepsisfacts 2. Zick, Marvin. Global Sepsis Alliance Joins WHO’s Acute Care Action Network (ACAN) [Internet]. Global Sepsis Alliance; 2024 [cited 2024 Dec 12]. Available from: https://globalsepsisalliance.org/news/2024/10/21/global-sepsis-alliance-joins-whos-acute-care-action-network-acan 3. Labib A, Ashour R. Qatar National Paediatric Sepsis Program: Where are we? Qatar Med J. 2019 Nov 7;2019(2):65. https://doi.org/10.5339/qmj.2019.qccc.65
Impact of Interprofessional Simulation-Based Training on Enhancing Non-Technical Skills and Team Readiness in Pediatric Resuscitation
Background Effective pediatric resuscitation relies on both technical proficiency and non-technical skills, including leadership, communication, and teamwork [1]. These skills enhance role clarity, situational awareness, and coordinated interprofessional responses under pressure [2]. Combined with technical performance, they improve outcomes, build confidence, and foster collaboration. Simulation-based training provides a structured environment to strengthen decision-making, task delegation, and closed-loop communication [3]. This study assessed the impact of interprofessional simulation-based pediatric resuscitation training on non-technical skills and team readiness. Methods A pre/post interventional study was conducted at Al Wakra Hospital over 10 months starting December 2024, included 75 participants, comprising physicians and pediatric nurses, who were randomized into 12 teams with a designated leader for each team. 2.5-3 hours program following Advanced Life Support Group (ALSG) Guidelines, included a 1-hour interactive presentation and 1.5-2 hours of simulation scenarios, with 2–3 leaders trained per session with their teams. Each leader led a 10-15-minute pediatric resuscitation scenario with structured debriefing and faculty feedback. Pre-training scores were collected immediately before, and post-training scores after completion of entire mass training. Outcomes were measured using a validated 30-item non-technical skills checklist scored by independent observers with each item rated as 1 if demonstrated and 0 if not demonstrated (maximum possible score = 30), covering leadership, teamwork, and communication. Team readiness was assessed by post-training self-reported survey. Pre–post differences were analyzed with Wilcoxon signed-rank test. Results Descriptive and inferential data analysis of normalized mean scores (0–1 scale, with 1 representing the maximum possible score: leadership = 10, teamwork = 14, communication = 6) demonstrated significant improvements in leadership (0.32 → 0.90, p<0.01), teamwork (0.71 → 0.92, p=0.02), and communication (0.20 → 0.88, p<0.01) (Table 1). Participants likewise reported enhanced team readiness (Figure 1). Conclusion Interprofessional simulation-based training markedly improved non-technical skills and team readiness in pediatric resuscitation. Author contributions All authors contributed equally and validated the final version of record. Acknowledgements We would like to express our sincere appreciation to the administration of the Hamad International Training Center (HITC) for their continuous guidance and support, Ms. Khulud Maghraby for her input and to the administration of Al Wakra Hospital, along with the Nursing Education Team and the Pediatric Division, for their invaluable cooperation and contributions throughout this project. Declarations Conflicts Of Interests The Authors declare that there is no conflict of interest. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Registration No registration applicable. Data availability statement The data that support the findings of this study are available from the corresponding author upon reasonable request. Ethical approval The study was approved as Quality improvement project by Director of HITC and was exempted from ethical approval. References 1. Friedlaender RF, Gubert EM, Fernandes CMB, Mello RG, Coelho ICMM. Evaluation of acquisition and retention of non-technical skills of residents submitted to interprofessional simulation-based training in pediatric cardiopulmonary resuscitation. J Pediatr (Rio J). 2025 Feb 26;101(3):394–9. https://doi.org/10.1016/j.jped.2024.12.003 2. Matlhaba K. Managing Complex Situations. In: Enhancing Clinical Competence of Graduate Nurses. 1st ed. Springer Cham; 2025. p. 161–72. https://doi.org/10.1007/978-3-031-81407-5 3. Rehman U, Sarwar MS, Jarvis S, Oeppen RS, Brennan PA. The critical importance of non-technical skills in developing surgical teams in the digital era. Surgery (Oxford). 2025 Mar 1;43(3):171–7. https://doi.org/10.1016/j.mpsur.2025.01.005
Enhancing Paediatric & Adult Resuscitation Performance Through Flowchart Driven Targeted Training in the Critical First Five Minutes
Background Early recognition of cardiac arrest and delivery of high-quality early resuscitation are critical for survival [1]. Performance during this phase remains inconsistent in healthcare settings [2]. Simulation-based multidisciplinary team (MDT) training has shown superior outcomes compared to traditional lecturing, especially when monitored by measurable key performance indicators (KPIs) [3]. Data collected by Resuscitation Officers from the Hamad International Training Centre revealed KPIs not being met (Table 1), prompting a revised training method at Hamad Medical Corporation’s (HMC) hospitals, in Qatar. This study aimed to evaluate the introduction of a MDT training program integrating response algorithms emphasizing the first five minutes on resuscitation KPIs in simulated clinical settings. Methods A pre-/post-intervention study was conducted with 80 participants randomly allocated from newly formed MDT as per the shift roster at a newly opened HMC hospital providing diverse services. Each MDT consisted of two physicians and six nurses with defined roles, all with over 5 years of post-registration experience and qualified in Immediate Life Support or Paediatric Life Support. (European Resuscitation Committee 2021 guidelines). Performance was evaluated before and after the introduction of the revised training model. The initial sessions were skills-based (90 minutes of Basic Life Support airway and defibrillation) followed by a cardiac arrest simulation (30 minutes), latter sessions of the same duration were entirely simulation-based with coaching and emphasis on rapid assessment, timely recognition, and prompt initiation of interventions within the first five minutes of collapse, reinforced by the implementation of response algorithms (Figure 1). Data collection focused on six KPIs (Table 1). Results Implementation of the MDT training program and response pathway algorithms replacing solely skills training, resulted in improvements across all KPIs (Table 1). Conclusion This training with algorithms improved performance across KPIs highlighting the significance of integrating clear response pathways and defined roles. Author contributions All authors contributed equally and validated the final version of record. Acknowledgements We would like to express our sincere appreciation to, Dr. M HA Nasser ALamri Snr. Con. Paeds for their continuous guidance and support. We also extend our gratitude to the leadership team and staff of Aisha Bint Hamad al Attiyah Hospital for their invaluable cooperation throughout this project. Declarations Conflicts Of Interests The Authors declare that there is no conflict of interest. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Registration No registration applicable. Data availability statement The data that support the findings of this study are available from the corresponding author upon reasonable request. Ethical approval The study was approved as Quality improvement project by Director of Hamad International Training Centre. References 1. Advanced Life Support Group (ALSG). Advanced Paediatric Life Support: A Practical Approach to Emergencies, 7th Edition. Smith S, editor. Wiley-Blackwell; 2023. 528 p 2. Chapman SM. Recognition of Clinical Deterioration in Children. In: DeVita MA, editor. Textbook of Rapid Response Systems: Concept and Implementation [Internet]. Cham: Springer Nature Switzerland; 2024. p. 489–97. Available from: https://doi.org/10.1007/978-3-031-67951-3_42 3. Aboudonya ME, Tobin J, Peter VL, Mahadiva A, Almomani EA, Karic E, et al. Enhancing preparedness and competence of front-line healthcare providers to manage maternal cardiac arrest: a quantitative observational study. BMJ Open Quality. 2025;14(Suppl 2):A1. https://doi.org/10.1136/bmjoq-2025-IHI.1
Risk Factors of Peri-intubation Cardiac Arrest in Critically Ill Pediatric Patients Presenting to the Emergency Department of a Low-Middle-Income Country: A Case-Control Study
Background Peri-intubation cardiac arrest is defined as cardiac arrest that occurs within 20 minutes of airway management [1]. Incidence in the pediatric population ranges from 0.7% to 1.7% [2, 3]. Identifying pre-intubation risk factors may improve preparedness and outcomes during emergency intubations. This study aims to identify clinical and physiological predictors associated with peri-intubation cardiac arrest in pediatric patients undergoing emergency airway management in a tertiary care emergency department. Methods A retrospective case-control study was conducted at the emergency department of a tertiary care hospital in Karachi, Pakistan, from January 2019 to June 2023. Pediatric patients (<18years) who experienced cardiac arrest within 20 minutes of intubation were included as cases. For each case, four controls were randomly selected from the same cohort who were intubated without arrest. Pre-intubation clinical data, laboratory parameters, and vital signs were analyzed. Multivariable logistic regression was used to identify independent predictors of peri-intubation cardiac arrest. Results A total of 125 pediatric patients were included, 25 cases and 100 controls. Multivariate analysis identified several independent predictors of peri-intubation cardiac arrest. Age less than one year (aOR:10.97; p=0.028), hypoxemia (SpO₂<92%) (aOR:5.48; p=0.047), elevated heart rate (aOR:2.88; p=0.029), low systolic blood pressure (aOR:6.16; p=0.043), elevated shock index (≥1.2) (aOR:5.52; p=0.046), modified shock index ≥1.3 (aOR:11.11; p=0.048), lactate ≥2 mmol/L (aOR:15.64; p=0.023), and capillary refill time >3 seconds (aOR:7.55; p=0.042), were found to be independent predictors of peri-intubation cardiac arrest (Table 1). Conclusion Pre-intubation physiological instability is strongly associated with peri-intubation cardiac arrest in pediatric patients. Early recognition of high-risk features such as hypoxemia, tachycardia, hypotension, elevated lactate levels, delayed capillary refill time, and elevated shock indices may allow for better preparation and resuscitation planning. These findings support the need for structured pre-intubation assessment protocols in emergency settings. Declarations Conflicts Of Interests The Authors declare that there is no conflict of interest. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Registration No registration applicable. Data availability statement The data that support the findings of this study are available from the corresponding author upon reasonable request. Ethical approval The research has been approved by the Ethical Review Committee of the Aga Khan University Hospital, Karachi, Pakistan (2023-8659-24735). References 1. Esangbedo ID, Byrnes J, Brandewie K, Ebraheem M, Yu P, Zhang S, et al. Risk factors for peri-intubation cardiac arrest in pediatric cardiac intensive care patients: a multicenter study. Pediatr Crit Care Med. 2020 Dec 4;21(12):e1126–33. https://doi.org/10.1097/pcc.0000000000002472 2. Pek JH, Ong GY. Emergency intubations in a high-volume pediatric emergency department. Pediatr Emerg Care. 2018 Dec 1;34(12):852–6. https://doi.org/10.1097/pec.0000000000001355 3. Long E, Sabato S, Babl FE. Endotracheal intubation in the pediatric emergency department. Paediatr Anaesth. 2014 Dec;24(12):1204–11. https://doi.org/10.1111/pan.12490
The Emergence of Excellence: Proposing the Paediatric Transport Reflective Improvement and Simulation-based Education (PaeTRISE) Framework for the Western Cape, South Africa
Background: Inter-facility transport of critically ill children in the Western Cape, in South Africa, poses significant risks, often contributing to preventable morbidity.1 While specialised teams exist, many transfers are undertaken by non-specialist personnel. South African literature confirms this gap, noting that paediatric critical care retrieval is often absent as a formal, stand-alone course in tertiary curricula and that transfers are handled by personnel with variable baseline training.2 This lack of standardised, continuous professional development creates a gap between theoretical knowledge and clinical application. Methods: We developed the Paediatric Transport Reflective Improvement and Simulation-based Education (PaeTRISE) framework, informed by literature on simulation, reflective practice, and transport medicine. PaeTRISE is founded on two pillars: Reflective Improvement (structured debriefing to critically analyse clinical experiences) and Simulation-based Education (safe practice of high-acuity, low-occurrence events.3 The framework integrates these pillars into a continuous cycle of learning, reflection, and adaptation, tailored to the geo-historical and socio-cultural realities of the Western Cape healthcare system. Results: PaeTRISE has the potential to cultivate emergent excellence. By coupling simulation with reflective practice, it transcends procedural training to enhance adaptive decision-making, teamwork, and resilience. From a critical realist perspective, PaeTRISE functions as a causal mechanism to activate practitioners’ latent capacity. Crucially, it directly addresses the documented absence of a formalised, standardised learning structure for this high-risk activity, proposing a scalable, contextually relevant model for continuous professional development. The explicit integration of reflection and simulation represents a novel contribution to standardising paediatric transport education in South Africa. Conclusion: PaeTRISE offers a theoretically grounded, practical framework to strengthen the quality and safety of paediatric transport. Adoption of this model may empower healthcare providers, improve patient outcomes, and foster a culture of reflective excellence Author contributions All authors contributed equally and validated the final version of record. Declarations Conflicts Of Interests The Authors declare that there is no conflict of interest. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Registration No registration applicable. Data availability statement The data that support the findings of this study are available from the corresponding author upon reasonable request. Ethical approval Ethical approval for this study was not required. References 1. Abdullah N, Majiet N, Sobuwa S. The prehospital paediatric emergency care burden managed by a public ambulance service in the Western Cape, South Africa. BMC Emerg Med. 2024 Dec 18;24(1):234. https://doi.org/10.1186/s12873-024-01146-z 2. Williams W, Theron E, Khan W, Stassen W. Developing a South African curriculum for education in neonatal critical care retrieval: An initial exploration. PLoS One. 2023 Aug 31;18(8):e0290972. https://doi.org/10.1371/journal.pone.0290972 3. Alinier G, Al Shaikh L, Campbell C, Fawzy I, Meyer J. Board# 200-Program Innovation Development of a Multi-disciplinary Simulation-based Training Course for the Safe High Acuity Adult Retrieval Programme (SHAARP) (Submission# 9978). Simulation in Healthcare. 2014 Dec 1;9(6):439. https://doi.org/10.1097/01.SIH.0000459339.11544.33
Reversal of Bradycardia through Nutritional Rehabilitation in Paediatric Anorexia Nervosa: A Retrospective Study from Qatar
Background Anorexia nervosa (AN) is a severe mental health disorder characterized by persistent energy intake restriction, intense fear of weight gain, and a distorted body image. AN affects nearly every organ system, with the cardiovascular system being affected in up to 80% of cases [1]. AN carries the highest mortality among psychiatric disorders, with sudden cardiac death as a major cause [2]. Bradycardia is the most common cardiovascular manifestation in AN.1 Nutritional rehabilitation reverses these abnormalities, but rapid weight gain can pose risks such as electrolyte imbalance and arrhythmias. Early detection and monitoring of bradycardia are therefore crucial [3]. Methods We conducted a retrospective cohort study using data from Sidra Medicine and Hamad General Hospital in Qatar. Patients admitted between December 2016 and June 2024 with AN and bradycardia (Heart Rate (HR) <60 beats per minute (bpm)) were included. Patientswith incomplete records were excluded. Ethical approval was obtained from the institutional review board of Sidra Medicine (IRB 1929504). Data were extracted and analyzed by independent reviewers. Results Of 222 screened patients (aged 10–18 years), 46 met the inclusion criteria. The majority were female (91.3%), with a mean age of onset at 14 years and a percentile of median BMI for age (%mBMI) of 9.1% (z-score -2.36) (Table 1). The average admission HR was 49.96bpm, confirming bradycardia as a frequent complication. All patients underwent nutritional rehabilitation with caloric intake starting from around 1200kCal/day and increasing by 200kCal/day/day. At 1–2 weeks follow-up, the mean HR improved significantly to 78.63bpm (Table 1). Figure 1 shows the correlation between %mBMI and the change in HR (R2=0.07, p=0.133). Conclusion This study highlights the burden of bradycardia among adolescents with AN in Qatar. Nutritional rehabilitation was effective in restoring HR, emphasizing the need for early recognition and careful monitoring. Future studies with larger sample size are needed to validate these findings and improve generalizability. Declarations Conflicts Of Interests The Authors declare that there is no conflict of interest. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Registration No registration applicable. Data availability statement The data that support the findings of this study are available from the corresponding author upon reasonable request. Ethical approval This study was approved by the Institutional Review Board of Sidra Medicine (1929504). References 1. Casiero D, Frishman WH. Cardiovascular complications of eating disorders. Cardiol Rev. 2006 Sep 1;14(5):227–31. https://doi.org/10.1097/01.crd.0000216745.96062.7c 2. Yahalom M, Spitz M, Sandler L, Heno N, Roguin N, Turgeman Y. The significance of bradycardia in anorexia nervosa. Int J Angiol. 2013 June;22(2):83–94. https://doi.org/10.1055/s-0033-1334138 3. Proulx-Cabana S, Metras ME, Taddeo D, Jamoulle O, Frappier JY, Stheneur C. To Improve the Initial Inpatient Management of Adolescents Admitted with Severe Anorexia Nervosa: A Narrative Review and a Convenient Protocol. Nutrients. 2022 Jan;14(1):229. https://doi.org/10.3390/nu14010229
All for one and one for all: Scaling mountains for a good cause. SDG 4: quality education awareness campaign
How it all started? In the mountains, I discover a profound inner tranquility, revitalizing my mind and fortifying myself to confront life’s obstacles. Hiking has deeply transformed my life, igniting a passion to push the boundaries of my physical capabilities, enabling me to venture further and ascend higher. In 2017, during my inaugural hiking expedition, I seized the opportunity to spotlight the issue of burnout, a struggle I was personally overcoming. Amidst inquiries about how I managed time for training and hiking, I found a platform to raise awareness and advocate for self-care amidst life’s demands.In July 2023, fueled by a Law school course on the significance of international organizations and inspired by the UAE’s designation of 2023 as the year of sustainability, I resolved to amplify awareness around Sustainable Development Goal (SDG) 3: Health. In the four days leading up to my departure, I delved into research, crafted social media campaigns, and hand-painted banners bearing meaningful messages, each destined to be showcasing varying altitudes throughout my journey. Remarkably, this preparatory work alleviated the stress that typically accompanies summit preparations. It transformed the purpose of my expedition from a solitary pursuit of reaching the peak to a collective endeavor of championing a noble cause. This shift not only mitigated stress but also infused each hiking day with embedded purpose, as I ascended to new altitudes, unveiling campaign banners—a tangible representation of progress and a triumph in itself. Why SDG 4: Quality Education? In January 2024, I proudly attained my Law degree, a decision not taken lightly, especially after completing medical school, obtaining board certification in two demanding specialties, and earning three master’s degrees, all while juggling numerous professional commitments such as speaking engagements, research endeavors, and educational pursuits. The four years spent as a Law student profoundly transformed me, deepening my gratitude for the educational system that afforded me the opportunity for such high-quality learning experiences. As a celebration of my Law school graduation, I embarked on a journey to conquer Aconcagua, standing at a staggering 6,992 meters above sea level, the tallest peak in South America renowned for its unforgiving weather conditions. This expedition served as a well-deserved respite following the rigorous four-year commitment of being a full-time student while simultaneously managing roles as a clinician, researcher, educator, avid mountain hiker, and long-distance runner. As John Dewey rightly said, “Education is not preparation for life; education is life itself,” and, therefore, in recognition of the educational opportunities afforded to me, I dedicated the Aconcagua expedition to raising awareness for Sustainable Development Goal #4: Quality Education. SDG 4. Definition and the role of technology in achieving it The primary objective of the initial message was to introduce the United Nations Sustainable Development Goal 4, which aims to guarantee inclusive and equitable access to quality education while fostering lifelong learning opportunities for all individuals (Figure 1) [1]. SDG 4 is only achievable by international, national, induvial efforts and collaborations. On the second day the message brought attention to the role of artificial Intelligence (AI) to address SDG 4. Artificial Intelligence (AI) can contribute significantly by leveraging personalized learning platforms, virtual tutoring, and data-driven insights to improve educational outcomes and accessibility. Moreover, AI-driven tools can play a pivotal role in tracking progress, pinpointing learning deficiencies, and tailoring content to individual needs, thereby nurturing inclusivity within the realm of education<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"WRt04oa4","properties":{"formattedCitation":"[2]","plainCitation":"[2]","noteIndex":0},"citationItems":[{"id":4260,"uris":["http://zotero.org/users/1172831/items/PESNQXGB"],"itemData":{"id":4260,"type":"webpage","title":"Exploring the potential of artificial intelligence to accelerate the progress towards SDG 4 -Education 2030 - UNESCO Digital Library","URL":"https://unesdoc.unesco.org/ark:/48223/pf0000367373","accessed":{"date-parts":[["2024",3,17]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[2]<!-- [if supportFields]><![endif]-->. Importance of Role models as source of inspiration Role models serve as beacons of inspiration, lighting the way with the trails they blaze for us. In the rich tapestry of the United Arab Emirates' history, Sheikh Muhammad bin Saeed bin Ghubash Al Marri (1899-1968) emerges as a luminous figure (Figure 2). As the first Emirati university graduate, he defied the constraints of limited educational opportunities in the Emirates during his time, embarking on a journey of learning that spanned continents. His educational journey commenced in local Quranic schools, where he immersed himself in the study of the Quran, Hadith, and religious sciences. Despite the challenges, he persevered, spending five formative years at the Rajbani School in Ras Al Khaimah. Undeterred by barriers, he ventured further, seeking knowledge at the Taimiyyah Al Mahmoudiya School in Sharjah in 1907, before pursuing his studies at the Athariyah School in Qatar in 1917. In 1926, his quest for enlightenment led him to Egypt, where he delved into Islamic sciences at the prestigious Al-Azhar University. Upon his return, armed with wisdom and experience, he dedicated himself to service. Initially serving in the judiciary, he adorned the robe of justice as a judge in Ras Al Khaimah, adjudicating disputes with fairness and integrity until 1951. Sheikh Muhammad bin Saeed bin Ghubash Al Marri's legacy illuminates the power of resilience, determination, and unwavering pursuit of knowledge. His remarkable journey not only symbolizes personal triumph but also serves as a testament to the transformative potential of education, inspiring generations to strive for excellence and chart their own paths toward enlightenment and progress. Later in his career, he expanded his horizons, lending his expertise to Saudi Arabia and Qatar. Tragically, in 1969, his journey was cut short by a fatal traffic accident. Among his notable works, Sheikh Muhammad bin Saeed bin Ghubash Al Marri left behind a legacy of written treasures. One such manuscript, "Benefits in the History of the Emirates," meticulously chronicles the rich history and genealogy of several Emirati tribes and families, offering invaluable insights into their origins and lineage. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"uvRDvx0P","properties":{"formattedCitation":"[3]","plainCitation":"[3]","noteIndex":0},"citationItems":[{"id":4262,"uris":["http://zotero.org/users/1172831/items/YXM52SZZ"],"itemData":{"id":4262,"type":"webpage","abstract":"في الأول من ديسمبر 2014 كرّم صاحب السمو الشيخ محمد بن راشد آل مكتوم نائب رئيس دولة الإمارات العربية المتحدة، رئيس مجلس الوزراء، حاكم دبي في احتفال كبير ب","language":"en","title":"محمد بن سعيد بن غباش.. أول خريج جامعي من مواطني الإمارات","URL":"https://alay.am/p/5zjj","accessed":{"date-parts":[["2024",3,17]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[3]<!-- [if supportFields]><![endif]-->. Among the esteemed figures from the distant annals of UAE history stands Ahmad bin Majid bin Muhammad (1418-1501 CE), an illustrious navigator and geographer hailing from Julphar, now known as Ras Al Khaimah. Revered for his mastery of astronomy, navigation, and geography, he was bestowed with the epithet "Asad al-Bahr" (Lion of the Sea), a testament to his unparalleled prowess on the waters. Ahmad bin Majid emerged as one of the foremost Arab navigators of the latter half of the 15th century, leaving an impactful mark on maritime exploration. Under the tutelage of his father, Majid bin Muhammad Al Saadi, and other seasoned sailors, Ahmad bin Majid received his early education. Immersing himself in their gatherings and debates, he developed his skills, surpassing the knowledge of his predecessors. Through relentless self-study, he mastered celestial navigation, meticulously measuring and observing stars, understanding their celestial movements, and deciphering their influence on maritime seasons. Ahmad bin Majid's drive for knowledge transcended conventional boundaries. He meticulously scrutinized and rectified numerous inaccuracies in existing navigational data, enriching it with his own practical insights and experiences. Documenting his profound wisdom in poetic compositions, he not only disseminated his expertise but also safeguarded it from the ravages of time. Ahmad bin Majid's legacy endures as a beacon of enlightenment, illuminating the path for future generations of navigators and scholars, and immortalizing his contributions to the advancement of maritime exploration and knowledge dissemination. Ahmad bin Majid's ingenuity extended to the invention of the magnetic needle, famously referred to as the "qibla," which revolutionized maritime navigation by providing a reliable means to ascertain directions during sea voyages. This compass, a testament to his innovative spirit, played a pivotal role in simplifying and enhancing navigation techniques for sailors of his time. Beyond his groundbreaking contributions to maritime exploration, Ahmad bin Majid distinguished himself as a prolific writer and poet. His literary legacy comprises approximately forty works, predominantly in poetic form. Among his notable literary achievements is the prose work titled "Kitab al-Fawaid fi Usul Ilm al-Bahr wa al-Qawa'id” (“The Book of Benefits in the Principles of the Science of the Sea and the Rules”), a comprehensive treatise shedding light on the fundamental principles of maritime science and navigational rules. Through his array of talents as a navigator, writer, and poet, Ahmad bin Majid left an indelible mark on both the realms of exploration and literature, solidifying his legacy as a Renaissance figure of his era. Ahmad bin Majid's legacy resonates through his array of contributions, notably his invention of the magnetic needle, dubbed the “qibla,” a pivotal tool in maritime navigation. This ingenious compass revolutionized sea journeys by offering a reliable means to determine directions, thereby streamlining navigation processes. Utilizing poetry as a vessel for documenting his ideas, culture, knowledge, and practical experiences during sea voyages, Ahmad bin Majid ensured accessibility of his insights to fellow navigators and sailors. His literary level served as an invaluable resource for maritime enthusiasts and scholars alike. Ahmad bin Majid's enduring legacy as a navigator, geographer, and writer is truly etched into maritime and UAE history, a testament to his profound impact on the exploration of the seas and the preservation of invaluable maritime knowledge for generations to come <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"ZGcUv569","properties":{"formattedCitation":"[4], [5]","plainCitation":"[4], [5]","noteIndex":0},"citationItems":[{"id":4264,"uris":["http://zotero.org/users/1172831/items/JQ6478NK"],"itemData":{"id":4264,"type":"webpage","abstract":"Away and close to the political news, at the same time, I followed a while ago an input posted by the Ruler of the Emirate of Sharjah, in the UAE, Sheikh Dr. Sultan Al Qasimi, requesting reconsideration and review of some of the topics educated within the educational curricula in the UAE.","container-title":"The Personal Website of H.H. Sheikh Dr. Sultan bin Muhammad Al Qasimi","language":"en-GB","title":"Was Seaman Ibn Majid A Traitor?","URL":"https://sheikhdrsultan.ae/Portal/en/media-center/ruler-in-their-pens/15/3/2014/هل-خان-البحار-ابن-ماجد.aspx","accessed":{"date-parts":[["2024",3,17]]},"issued":{"date-parts":[["2014",3,15]]}}},{"id":4266,"uris":["http://zotero.org/users/1172831/items/SDM9S87A"],"itemData":{"id":4266,"type":"webpage","abstract":"Ahmad ibn Majid was one of the greatest and most illustrious Arab navigators and cartographers of all times. He gained fame in the West as the man who guided Vasco da Gama to find his way from the east coast of Africa to India around the Cape of Good Hope. His wide knowledge of the seas greatly impressed the Portuguese and, in their writings, they referred to him as the \"Master of Astrological Navigation.\"","language":"en-EN","title":"Ahmad ibn Majid","URL":"https://prabook.com/web/ahmad.ibn_majid/3720561","accessed":{"date-parts":[["2024",3,17]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[4], [5]<!-- [if supportFields]><![endif]-->. Undoubtedly, both role models showcase an exceptional talent for making the most of the educational resources within reach. Their successes highlight the significance of determination and resilience, qualities that hold profound importance for the advancement and well-being of a nation. Defining interdisciplinary education and its importance On Day four, the message centered on promoting interdisciplinary education, which involves the integration of two or more academic, scientific, or artistic disciplines. Interdisciplinary learning or training empowers individuals to blend diverse subjects, fostering innovative thinking and addressing intricate challenges. Throughout history, scientists have embraced interdisciplinary approaches, transcending narrow specializations to yield groundbreaking inventions and advancements that have reshaped human civilization. Three exemplary interdisciplinary scientists are Jabir ibn Hayyan, Ibn Sina, and Marie Curie. Jabir ibn Hayyan, an Arab Muslim scientist, demonstrated exceptional proficiency in a wide array of fields including chemistry, astronomy, engineering, metallurgy, philosophy, medicine, and pharmacy. Revered as the pioneer of practical chemistry, his contributions laid the foundation for modern chemical science. Ibn Sina, also known as Avicenna, was a distinguished Muslim scholar and physician. Renowned for his profound insights into medicine and philosophy, he made significant strides in advancing both fields, leaving an indelible mark on intellectual history. Finally, Marie Curie, a renowned physicist and chemist, epitomized interdisciplinary excellence with her groundbreaking work in radioactivity. Her interdisciplinary approach bridged the realms of physics and chemistry, leading to transformative discoveries that earned her two Nobel Prizes and revolutionized our understanding of the natural world. These exemplary figures exemplify the transformative potential of interdisciplinary collaboration, inspiring future generations to embrace diverse perspectives and forge new pathways of knowledge and innovation<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"OnxCMB77","properties":{"formattedCitation":"[6]","plainCitation":"[6]","noteIndex":0},"citationItems":[{"id":4268,"uris":["http://zotero.org/users/1172831/items/8QFK5GMW"],"itemData":{"id":4268,"type":"article-journal","container-title":"Annals of Saudi Medicine","DOI":"10.5144/0256-4947.2007.53","ISSN":"0256-4947","issue":"1","journalAbbreviation":"Ann Saudi Med","note":"PMID: null\nPMCID: PMC6077026","page":"52-53","source":"PubMed Central","title":"Jabir ibn Hayyan","volume":"27","author":[{"family":"Amr","given":"Samir S."},{"family":"Tbakhi","given":"Abdelghani"}],"issued":{"date-parts":[["2007"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[6]<!-- [if supportFields]><![endif]-->. Ibn Sina, widely known as the "Prince of Physicians" in the Western world, wrote over 200 books covering a diverse range of subjects, with a significant focus on philosophy and medicine. His magnum opus, "The Canon of Medicine," stood as the definitive reference in the medical field for an astounding seven consecutive centuries. Notably, Ibn Sina's pioneering contributions include the precise description of meningitis, the identification of jaundice causes, the delineation of bladder stones symptoms, and the acknowledgment of psychological treatment's therapeutic efficacy in healing processes <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"SeJs8DxW","properties":{"formattedCitation":"[7]","plainCitation":"[7]","noteIndex":0},"citationItems":[{"id":4271,"uris":["http://zotero.org/users/1172831/items/8IIG8YPU"],"itemData":{"id":4271,"type":"webpage","title":"Ibn Sina (Avicenna): The Prince Of Physicians - PMC","URL":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6077049/","accessed":{"date-parts":[["2024",3,17]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[7]<!-- [if supportFields]><![endif]-->. Marie Curie (1867–1934) was a pioneering scientist in the fields of physics and chemistry. Her groundbreaking research on radioactivity led to the discovery of the element’s polonium and radium, significantly advancing our understanding of radiation's properties <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"qejZzOnN","properties":{"formattedCitation":"[8]","plainCitation":"[8]","noteIndex":0},"citationItems":[{"id":4273,"uris":["http://zotero.org/users/1172831/items/KJNYMWEH"],"itemData":{"id":4273,"type":"webpage","abstract":"The Nobel Prize in Physics 1903 was divided, one half awarded to Antoine Henri Becquerel \"in recognition of the extraordinary services he has rendered by his discovery of spontaneous radioactivity\", the other half jointly to Pierre Curie and Marie Curie, née Skłodowska \"in recognition of the extraordinary services they have rendered by their joint researches on the radiation phenomena discovered by Professor Henri Becquerel\"","container-title":"NobelPrize.org","language":"en-US","title":"The Nobel Prize in Physics 1903","URL":"https://www.nobelprize.org/prizes/physics/1903/marie-curie/biographical/","accessed":{"date-parts":[["2024",3,17]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[8]<!-- [if supportFields]><![endif]-->. Indeed, interdisciplinary education and active learning opened the door for innovation. As Gyan Nagpal said “Breakthrough innovation occurs when we bring down boundaries and encourage disciplines to learn from each other.” UAE as a role modeling in achieving SDG 4 Day five of the campaign was dedicated to expressing gratitude to the UAE and the educational institutions that played a crucial role in shaping my life journey (Figure 3). The UAE provided me with invaluable opportunities for quality education, including two scholarships that allowed me to pursue medicine at Arabian Gulf University in Bahrain from 1996 to 2002, followed by specialization in Emergency Medicine and Critical Care at McGill University in Montreal, Canada, from 2005 to 2011. These experiences not only nurtured my growth as a medical professional but also enriched my personal development, enforcing in me a commitment to continuous learning and exploration of diverse disciplines to tackle current and future healthcare challenges. In my quest for knowledge and skills enhancement, I pursued further academic endeavors, including a Master's in Quality and Safety in Healthcare from RCSI-Dubai in 2014, followed by a Master's in Organ Donation and Transplantation from the University of Barcelona in 2017. Subsequently, I completed an Executive MBA at Hult University in Dubai in 2019, and culminated my educational journey with a Bachelor of Law from Al Ain University in 2023. Reflecting on the vision of H.H. Shaikh Zayed Bin Sultan Al Nahyan, the founding Father of the UAE, who emphasized the role of education in advancing a nation, I was inspired by his belief that the progress of societies is intricately tied to the level and accessibility of education. His unwavering support for education, regardless of gender, has contributed significantly to the UAE's remarkable literacy rate, which soared from 58% in 1975 to a record breaking 98% in 2021! (Figure 4). The UAE has implemented various literacy initiatives, catering to diverse demographics. For instance, the Elderly education program, with its flexible design, allows seniors to attend literacy sessions. Additionally, government entities offer incentives to employees pursuing education. Furthermore, legislative measures, such as Law No. 11 of 1972 on Compulsory Education, mandate parents or legal guardians to ensure their children attend school. Under the leadership's commitment to education accessibility, schooling is provided free of charge to the entire population. In 2012, the UAE Cabinet introduced a new federal law on compulsory education, updating the previous legislation and refining the stages of compulsory education. This law mandates that all children aged between six and 18 years must be enrolled in school, reaffirming the nation's dedication to universal education. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Zc00m0TC","properties":{"formattedCitation":"[9]","plainCitation":"[9]","noteIndex":0},"citationItems":[{"id":4275,"uris":["http://zotero.org/users/1172831/items/AKY9D3TX"],"itemData":{"id":4275,"type":"webpage","title":"4. Quality education | The Official Portal of the UAE Government","URL":"https://u.ae/en/about-the-uae/leaving-no-one-behind/4qualityeducation","accessed":{"date-parts":[["2024",3,17]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[9]<!-- [if supportFields]><![endif]-->. In 2016, the UAE introduced the National Reading Law, establishing a comprehensive legislative framework and specific government responsibilities aimed at fostering lifelong learning for the UAE population<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"7GKhet05","properties":{"formattedCitation":"[10]","plainCitation":"[10]","noteIndex":0},"citationItems":[{"id":4278,"uris":["http://zotero.org/users/1172831/items/TKHWQIDQ"],"itemData":{"id":4278,"type":"webpage","title":"National Literacy Strategy | The Official Portal of the UAE Government","URL":"https://u.ae/en/about-the-uae/strategies-initiatives-and-awards/strategies-plans-and-visions/human-resources-development-and-education/national-literacy-strategy","accessed":{"date-parts":[["2024",3,17]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[10]<!-- [if supportFields]><![endif]-->. What can individuals do to support SDG 4? In its final message, the campaign highlights the power of individual actions in collectively advancing the global goals outlined in SDG 4 (Figure 5). Whether through advocacy, volunteering, or supporting educational initiatives, individuals play a crucial role in promoting quality education for all. By volunteering with organizations that provide educational resources to underserved communities, individuals can help improve access to education. Similarly, empowering others through teaching, by volunteering as tutors or mentors, can make a significant difference. Embracing a culture of lifelong learning for oneself and encouraging others to do the same fosters continuous personal and societal growth. Active engagement with educational institutions, such as participating in parent-teacher associations or supporting local school initiatives, is another effective way to contribute. Additionally, advocating for education, especially for girls and women, and leveraging social media platforms to share information about the importance of education and ongoing initiatives can amplify impact. In conclusion, education is a fundamental human right, and it is imperative that we collectively strive to make quality education accessible to everyone, everywhere. Although SDG 4 presents a formidable challenge, it is achievable through united efforts by all and for all. Conclusion In summary, combining my passion for public education, humanitarian work and mountain hiking works well for all three purposes as well as taking the summit stress out completely out of the equation. As I share the messages day by day and feel the interaction with the public, my attention shifts to the public oriented goal more than my personal mountain Goal and the summit becomes secondary rather than the primary goal of the trip. Declarations Author contributions All authors contributed equally and validated the final version of record. Conflicts Of Interest The Author(s) declare(s) that there is no conflict of interest. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Registration No registration applicable Data availability statement The data that support the findings of this study are available from the corresponding author upon reasonable request. Ethical approval Ethical approval for this study was not required. References 1. Project Everyone. The Global Goals. [cited 2024 Mar 17]. Goal 4: Quality education. Available from: https://globalgoals.org/goals/4-quality-education/ 2. UNESCO Executive Board. Exploring the potential of artificial intelligence to accelerate the progress towards SDG 4 -Education 2030 [Internet]. Paris: UNESCO; 2019 Mar [cited 2024 Mar 17] p. 4. Report No.: 206 EX/44 REV. + CORR. Available from: https://unesdoc.unesco.org/ark:/48223/pf0000367373 3. عبدالله المدني. Alayam. 2022 [cited 2024 Mar 17]. محمد بن سعيد بن غباش.. أول خريج جامعي من مواطني الإمارات. Available from: https://alay.am/p/5zjj 4. The Personal Website of H.H. Sheikh Dr. Sultan bin Muhammad Al Qasimi [Internet]. 2014 [cited 2024 Mar 17]. Was Seaman Ibn Majid A Traitor? Available from: https://sheikhdrsultan.ae/Portal/en/media-center/ruler-in-their-pens/15/3/2014/%D9%87%D9%84-%D8%AE%D8%A7%D9%86-%D8%A7%D9%84%D8%A8%D8%AD%D8%A7%D8%B1-%D8%A7%D8%A8%D9%86-%D9%85%D8%A7%D8%AC%D8%AF.aspx 5. Prabook [Internet]. [cited 2024 Mar 17]. Ahmad ibn Majid. Available from: https://prabook.com/web/ahmad. ibn_majid/3720561 6. Amr SS, Tbakhi A. Jabir ibn Hayyan. Ann Saudi Med. 2007 Jan 1;27(1):52–3. https://doi.org/10.5144/0256-4947.2007.53. 7. Amr SS, Tbakhi A. Ibn Sina (Avicenna): the prince of physicians. Ann Saudi Med. 2007 Mar;27(2):134–5. https://doi.org/10.5144/0256-4947.2007.134. 8. The Nobel Prize [Internet]. [cited 2024 Mar 17]. The Nobel Prize in Physics 1903. Available from: https://www.nobelprize.org/prizes/physics/1903/marie-curie/biographical/ 9. The Official Portal of the UAE Government [Internet]. [cited 2024 Mar 17]. 4. Quality education | The UN’s 2030 Agenda. Available from: https://u.ae/en/about-the-uae/leaving-no-one-behind/4qualityeducation 10. The Official Portal of the UAE Government [Internet]. [cited 2024 Mar 17]. National Literacy Strategy. Available from: https://u.ae/en/about-the-uae/strategies-initiatives-and-awards/strategies-plans-and-visions/human-resources-development-and-education/national-literacy-strategy
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Unilateral optic disc swelling: an atypical presentation for a large frontal meningioma
Intracranial masses pose frequent diagnostic dilemmas for community facing physicians especially in patients presenting with neurological or ophthalmological signs. We describe a case of a large meningioma in a 47-year-old man presenting with left sided optic disc swelling and right visual field disturbance alongside atypical headaches, and mild behavioural disturbance. Neuroimaging demonstrated a large mass with signs of raised intracranial pressure (ICP) and parenchymal herniation. He underwent surgical debulking and biopsy, confirming the suspected diagnosis. Post-operative course was complicated by day one hemiparesis due to venous strokes, with full subsequent motor recovery. Whilst raised ICP is classically thought to cause bilateral optic disc swelling, unilaterality does not exclude this. Careful assessment and use of red flag indicators are therefore needed in determining need for neuroimaging. Declining utility of fundoscopy in non-specialists creates an additional barrier to diagnosis in these presentations and warrants increased research or training to bridge this gap. Introduction Primary brain tumours (BT) are common cancers in those under 65 but are uncommon when pooled across cancers in all ages. Despite this, they demonstrate disproportionately higher morbidity and mortality rates, even among non-malignant cases. Meningiomas represent the commonest non-malignant primary BT, with data from the United States demonstrating that they account for 53% of cases 1. Symptoms associated with intracranial masses include headaches, new focal neurology, visual acuity (VA) changes, persistent vomiting, new onset seizures or behavioural changes (including reduced energy, apathy, executive dysfunction and disinhibition) (2– 4). Symptoms such as these are commonplace, but as BT remain a rare cause each symptom, correctly diagnosing a brain tumour from such symptoms can be troublesome 3. For instance, at least 50% of headaches are attributed to primary causes: tensiontype, migraine and trigeminal neuralgia 5. Intracranial masses represent an important differential in these presentations. The challenge to community facing physicians is stratifying which patients require more investigation. Studies advocate for the utilisation of ‘red flag’ indicators in headache presentations. These include changes in severity from orthostatic/Valsalva manoeuvres, acute change in existing headaches, new headache in those >50 years, progressive change in headache over days/weeks, focal neurology or prior malignancy history 4. Fundoscopic assessment for raised optic discs should form a part of this diagnostic workup but, through multiple factors regarding training and healthcare professionals’ perceptions of this component, it’s utility by non-specialists, has been declining 6. Case report In September 2024, a 47-year-old man with a history of hypercholesterolaemia and hypertension was referred to the emergency department (ED) by his optician, having noted new left sided optic disc swelling compared to two months prior. This review was due to patient concerns of new progressive right eye visual disturbance despite a recent new glasses prescription. He denied loss of vision, diplopia or photophobia. The patient also reported intermittent, severe headaches with bilateral cervical to frontal radiation. He denied diurnal, orthostatic or Valsalva exacerbations and reported only a single, isolated episode of vomiting. He had achieved moderate control of these headaches with the use of simple analgesia, physiotherapy exercises and heat packs. He denied weight loss, fevers, change in energy levels or seizure activity during this time. The patient’s family raised concerns of cognitive changes including mild intermittent delays in responses to questions. Ophthalmological assessment demonstrated no diplopia, no visual field loss, normal conjugate gaze, normal pupillary light reflexes, no change in colour vision and no periorbital, cranial or cervical skin changes or tenderness. He was orientated to time, place and person with preserved attention and memory with his wife corroborating the history. With his new glasses prescription, right eye VA was 6/30 and left eye VA was 6/6. Following pupillary dilation using topical tropicamide drops, left sided optic disc swelling was visualised on fundoscopy with a normal appearing right optic disc. Further examination demonstrated preserved power (MRC grade 5/5) in all limbs, preserved reflexes, no loss to light touch sensation and no signs of cerebellar dysfunction. The ophthalmology team suggested computerised tomography (CT) imaging of the brain was indicated and, if negative for acute pathology, the patient could be reviewed as an outpatient. The neurology team also suggested a CT brain and, if this were negative, no further neurology input would be needed at this time. A CT angiogram demonstrated a large (52mm TR x 50mm AP x 49mm CC) right, homogenously hyperdense paraclinoid frontal lobe mass (Figure 1). Involvement of multiple intracranial arterial vessels was noted including narrowing and medial displacement of the right supraclinoid internal carotid artery (ICA), posteromedial displacement of the right M1 middle cerebral artery (MCA), non-enhancement of right M2 MCA (with surrounding collateral vessel enhancement) and displacement of the anterior cerebral arteries (ACA). This scan also demonstrated compression of the right optic nerve, global sulcal effacement, right lateral ventricle effacement, anterior and posterior clinoid process erosions and 14mm left midline shift. Given the appearance and location, a sphenoid wing meningioma was suspected. Given these findings, this patient was discussed with the neurosurgical on call team. He was commenced on oral dexamethasone and transferred urgently to the tertiary neurosurgical centre for urgent review. Magnetic Resonance Imaging (MRI) (Figure 2) of his brain and orbits detailed further significant vascular involvement, including invasion of the right cavernous sinus, encasement of the right supraclinoid ICA, proximal right M1 MCA and foetal posterior cerebral artery (PCA). The A1 ACA segment was absent or occluded and the right M1 MCA was severely stenosed. The mass directly abutted the lateral surface of the right optic nerve but without evidence of involvement or chronic nerve atrophy (Figure 3). Formal ophthalmology assessment noted improvement in his VA to 6/6 bilaterally with grade 1-2 optic disc swelling in the left eye without evidence of vascular changes and normal appearance of the right optic disc. Operative management involved craniotomy with dissection of the tumour, retrograde to the direction of the MCA. Gradual tumour bulk removal allowed for visualisation of the optic nerve, ICA, ACA, MCA, posterior communicating artery (PCOM) and anterior communicating artery. Despite the operation’s success in removing the majority of the tumour bulk, the mass was closely adherent to the MCA (and associated perforators), avernous sinus and right posterior communicating artery. These sections were unable to be completely excised. Biopsies were taken, demonstrating tissue consistent with World Health Organisation (WHO) grade 1 meningioma without invasion into brain parenchyma. Post-operative recovery was complicated with day one dense left hemiparesis. A CT stroke code identified an acute right MCA territory infarct with a subsequent MRI identifying acute infarcts of the right basal ganglia and caudate head. As perforator arteries were thought to be culprit, the patient was managed conservatively, where, over the following week, he made a full neurological recovery. This rapid symptomatic improvement suggested that the observed infarcts were likely related to venous strokes. On discharge, the patient had regained power, was mobilising independently and remained fully cognisant. He was planned for reviews from neurosurgical, endocrinology, ophthalmology and physiotherapy perspectives. Discussion This case demonstrates a rare and important presentation for community facing clinicians when assessing individuals for raised ICP, both regarding the discordance in findings between eyes and the atypical secondary symptoms. Presentation with unilateral optic disc swelling was the main diagnostic dilemma, especially given the contralateral changes in reported vision. Classically, an intracranial mass large enough to precipitate raised ICP and therefore optic disc swelling is thought to do so bilaterally7. Unilateral optic disc swelling usually suggests local pathologies (AION, ON and, by extension, multiple sclerosis) or with concomitant contralateral optic nerve atrophy (Foster-Kennedy syndrome (FKS)) 8. FKS may have offered an explanation in the mismatch between optic disc appearance and VA changes. Though, without direct evidence of optic nerve involvement or atrophy, this case would not match this conditions usual phenotype 8. Pathophysiological studies demonstrated that development of raised optic discs is not directly due to raised ICP, rather consequential disruptions in axoplasmic flow within the optic nerve sheath causing cellular oedema and extracellular fluids accumulation. These studies also demonstrated that supratentorial masses would initially lead to a unilateral or asymmetrical raised optic disc but, importantly, affecting the optic nerve ipsilateral to the mass – contrary to this case 7. Case reports detailing individuals presenting with unilateral optic disc swelling are sparse with the majority of these attributed to idiopathic intracranial hypertension (IIH) 9. Knowledge of this atypical presentation is therefore crucial to avoid premature exclusion of raised ICP. The additional symptoms in this patient’s presentation were also not stereotypical for an intracranial mass. His headache lacked the orthostatic variation and persistent vomiting consistent with raised ICP. Secondly, the behavioural changes reported by his family were not fully consistent with those usually found in frontal brain tumours (apathy, disinhibition, executive dysfunction or anergy) 2. Bedside fundoscopy remains an important component of these assessments 7. Despite this, clinical utilisation by non-specialists has been declining. Contributory factors to this include lack of equipment or knowledge to perform the examination, perceived disapproval from seniors and low perceived clinical utility 6.Bedside ocular ultrasound (BOUS) has been shown to be a useful non-invasive clinical adjunct to assess for the presence of optic disc swelling, demonstrating sensitivities between 90-100% and may offer an alternative approach to this part of the assessment 10. Conclusion Intracranial masses remain an important differential for those presenting with visual changes, headaches and changes in behaviour. With the ever-increasing utilisation of CT imaging in the ED, investigating such pathologies is becoming more straightforward. This case demonstrates the importance of a comprehensive assessment in those with symptoms consistent with raised ICP, with specific focus on lesser assessed and atypical features. This, combined with screening for red flag symptoms, are key to stratifying these patients, allowing for early identification of potentially life threatening diagnoses. The linchpin in this case was the ophthalmoscopy findings, as without this, he may have presented later in his disease course. Given the noted decline in fundoscopy in non-specialists, without work into increasing its utility or incorporating alternative tools, patients such as this, may be missed. Declarations Author contributions All authors contributed equally and validated the final version of record. Conflicts Of Interest The Author(s) declare(s) that there is no conflict of interest. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Registration No registration applicable Data availability statement The data that support the findings of this study are available from the corresponding author upon reasonable request. Ethical approval Written informed consent was given by the patient about which this case was written. Details of the history have been anonymised and any imaging for this report have been deidentified. Ethics approval for this case report has been granted by the local hospital ethics committee. ERM: 114100. References 1. Miller KD, Ostrom QT, Kruchko C, Patil N, Tihan T, Cioffi G, et al. Brain and other central nervous system tumor statistics, 2021. CA Cancer J Clin. 2021 Sep 24;71(5):381–406. https://doi.org/10.3322/caac.21693 2. Cabrera S, Edelstein K, Mason WP, Tartaglia MC. Assessing behavioral syndromes in patients with brain tumors using the frontal systems behavior scale (FrSBe). Neurooncol Pract. 2016 Jun 1;3(2):113–9. https://doi.org/10.1093/nop/npv055 3. Comelli I, Lippi G, Campana V, Servadei F, Cervellin G. Clinical presentation and epidemiology of brain tumors firstly diagnosed in adults in the Emergency Department: a 10-year, single center retrospective study. Ann Transl Med. 2017 Jul;5(13):269. https://doi.org/10.21037/atm.2017.06.12 4. Palmieri A, Valentinis L, Zanchin G. Update on headache and brain tumors. Cephalalgia. 2021 Apr 28;41(4):431–7. https://doi.org/10.1177/0333102420974351 5. Viera AJ, Antono B. Acute Headache in Adults: A Diagnostic Approach. Am Fam Physician. 2022 Sep;106(3):260–8. 6. Dunn HP, Kang CJ, Marks S, Dunn SM, Healey PR, White AJ. Optimising fundoscopy practices across the medical spectrum: A focus group study. PLoS One. 2023;18(1):e0280937. https://doi.org/10.1371/journal.pone.0280937 7. Hayreh SS. Pathogenesis of optic disc edema in raised intracranial pressure. Prog Retin Eye Res. 2016 Jan;50:108–44. https://doi.org/10.1016/j.preteyeres.2015.10.001 8. Hata M, Miyamoto K. Causes and Prognosis of Unilateral and Bilateral Optic Disc Swelling. Neuroophthalmology. 2017 Apr 10;41(4):187–191. https://doi.org/10.1080/01658107.2017.1299766 9. Huna–Baron R, Landau K, Rosenberg M, Warren FA, Kupersmith MJ. Unilateral swollen disc due to increased intracranial pressure. Neurology. 2001 Jun 12;56(11):1588–90. https://doi.org/10.1212/wnl.56.11.1588 10. Carter SB, Pistilli M, Livingston KG, Gold DR, Volpe NJ, Shindler KS, et al. The role of orbital ultrasonography in distinguishing papilledema from pseudopapilledema. Eye (Lond). 2014 Dec 5;28(12):1425–30. https://doi.org/10.1038/eye.2014.210
Peritoneal carcinomatosis presenting as a mimic for DVT
Unilateral leg swelling poses a diagnostic challenge with a myriad of potential differential diagnosis, including deep vein thrombosis (DVT), Baker's cyst, and cellulitis. As some of these causes can be benign and easily treatable, other causes may be more severe and even life threatening. This article highlights the critical need for healthcare professionals to expand their differential diagnosis when common causes have been excluded, recognizing that some rare etiologies may signify severe underlying conditions. We present the case of a 55-year-old female with a two-month history of right leg swelling, initially attributed to erysipelas due to negative DVT findings. Upon closer examination, an abdomino-pelvic CT scan revealed diffuse peritoneal carcinomatosis, obstructing the right external iliac vein and elucidating the unilateral lower limb edema. This case focuses the importance of considering atypical causes, especially in patients with a history of cancer, and the potential life-threatening nature of rare etiologies. The article emphasizes the significance of a multidisciplinary approach, comprehensive laboratory assessments, and advanced imaging techniques in achieving accurate and timely diagnoses, ultimately guiding effective patient management. Introduction Unilateral leg swelling can be attributed to various factors, with deep vein thrombosis (DVT), Baker's cyst, and cellulitis being the most prevalent causes. It is particularly crucial for healthcare professionals to promptly diagnose DVT, due to its potential life-threatening complication of pulmonary embolism (1). When ruling out these more common etiologies, it is important to recognize that numerous less common causes of unilateral leg swelling exist, spanning a spectrum from benign to potentially serious conditions. Therefore, clinicians should be mindful of rare etiologies, such as arterial insufficiency, lymphatic or venous obstruction, or systemic diseases like vasculitis (2). Conditions like popliteal artery entrapment syndrome, lymphangioleiomyomatosis, or Behçet's disease may present with unilateral leg swelling, posing diagnostic challenges due to their infrequent occurrence (3). Furthermore, certain rare genetic disorders, such as hereditary angioedema or Milroy's disease, can manifest as unilateral leg swelling (4). These conditions, though infrequent, underscore the importance of considering a broad differential diagnosis. In fact, any lesion or disease process that mechanically obstruct major abdominal veins, can potentially present as unilateral or bilateral leg swelling, mimicking DVT, ranging from cysts, malignancies, even abscesses (5). This article presents a never yet reported case of upstream venous obstruction, due to diffuse peritoneal carcinomatosis obstructing at the level of the right external vein, in a patient with 2-month history of unilateral leg swelling, with negative workup for DVT and no improvement with antibiotics. Case presentation This is the case of a 55-year-old female patient, known to have breast carcinoma in 2010 status post remission after chemotherapy and radiotherapy, and endometrial cancer in 2019 status post hysterectomy and bilateral oophorectomy, presented to the emergency room for unilateral right leg pain and swelling of two months duration. The history goes back to multiple visits to her primary care physician for the same complaint; ultrasound was conducted at that time and eliminated a DVT of the lower extremity, or the presence of a cyst. The patient was then prescribed antibiotics, assuming erysipelas was the etiology of the clinical presentation. After a 7 days course of treatment, the patient noticed no amelioration, therefore she presented to the emergency department. Upon presentation, the patient was tachycardic, afebrile and in pain. Physical exam was unremarkable, except for non-pitting right lower limb edema extending to the mid-thigh, with minimal erythema and positive pedal pulses (Figure 1). Review of personal history was non-significant except for the previously mentioned oncologic disorder, and recent ablation of a cutaneous lesion on right leg that was found benign on histology; review of family history and review of systems were insignificant. Laboratory workup were ordered and showed an elevated D-Dimer (3120 ng/ml with a reference value of <500 ng/ml) and CRP (22 mg/L), with a negative white blood cells count, normal creatinine and normal liver enzymes. In light of a negative DVT workup, and elevated D-Dimer, malignancy was suspected, and therefore an abdominal-pelvic CT with injection was ordered. Surprisingly, the report showed diffuse peritoneal carcinomatosis, with an intra-peritoneal speculated lesion, lateral to the bladder on the right, compressing the right external iliac vein that could explain the unilateral lower limb swelling. After seeking surgical, gynecologic and oncologic consults, the plan was to admit the patient and put her on prophylactic anticoagulation, waiting for further investigations and management, including chest CT scan, MRI of the pelvis, biopsies. Verbal consent was taken from the patient to publish these data anonymously. Discussion This case highlights the imperative need for healthcare professionals to maintain a broad and comprehensive approach when confronted with unilateral leg swelling, particularly when common etiologies like deep vein thrombosis (DVT), Baker's cyst, and cellulitis have been ruled out. Although rare etiologies can be benign and non-life threatening, others can be more serious, and can be the superficial, visible tip of an iceberg, hiding underneath the surface a very serious condition, that needs prompt investigations and management. For instance, the case of unilateral lower limb edema, depicted in this report, unveiled a hidden malignancy and introduces a rare etiology of venous obstruction, although mechanical obstruction due to compression by a mass is relatively a common cause of edema and swelling (6), having peritoneal carcinomatosis as the cause of the presentation is not documented in the literature yet. In fact, obstruction related to peritoneal carcinomatosis have been reported mainly as small bowel occlusion (highlighting the distinctiveness of this case report (7-8). Furthermore, this patient had strong risk factors and signs for DVT: unilateral leg swelling, 2 months duration, elevated D-Dimer, history of breast and endometrial cancer, no improvement on antibiotics, and was tachycardic upon presentation (which could be a sign of consequences of DVT such as pulmonary embolism), which could easily lead to a bias in diagnosis; but the negative Doppler Ultrasound mead the physicians in the emergency department into further investigation. Given her past medical history, other diagnosis could be thought of such as idiopathic lymphedema, heart failure, kidney failure, pulmonary hypertension … all of which were eliminated by the physical exam, laboratory workup and imaging done in the ER. The delayed diagnosis in this case demonstrates the potential life-threatening nature of rare etiologies and the importance of promptly identifying and addressing them, even though Peritoneal Carcinomatosis (PC) is a late-stage manifestation of several gastrointestinal and gynecological malignancies, and is usually a sign of metastatic disease and has a poor prognosis (9). Finally, it is important to note that, in low-resource settings, the practical challenges of investigating lower limb edema can be significant. Relying on expensive imaging techniques like CT scans may not be realistic due to the high costs involved and limited access to such technology. This can make it difficult for healthcare providers to accurately diagnose the underlying cause of a similar presentation and develop an appropriate treatment plan. In these settings, healthcare providers may need to rely on less expensive and more readily available diagnostic tools, such as physical exams and basic laboratory tests, which can lead to misdiagnosis. The multidisciplinary approach taken, involving surgical, gynecologic, and oncologic consultations, exemplifies the complexity of managing such cases. The decision to initiate anticoagulation while awaiting additional investigations reflects a cautious approach given the potential complications associated with venous obstruction, including a chest CT to rule out any potential pulmonary embolisms. Further investigations are in order, including MRI, biopsies with histological and pathological studies to assess the extent of the disease and potentially the source of PC. Conclusion This case underscores the significance of broadening the differential diagnosis for unilateral leg swelling beyond common causes. Clinicians should remain vigilant for rare etiologies, recognizing their potential to be life threatening or indicative of more extensive and serious underlying conditions. A multidisciplinary approach, comprehensive laboratory assessments, and advanced imaging techniques are essential in ensuring timely and accurate diagnoses, thereby facilitating appropriate and effective patient management. References 1. Brice G, Mansour S, Ostergaard P, Connell F, Jeffery S, Mortimer P. Milroy disease. In: Adam M, Ardinger H, Pagon R, Wallace S, Bean L, Stephens K, et al., editors. GeneReviews(®) [Internet]. Seattle (WA): University of Washington, Seattle; 1993. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1239/ 2. Davis DD, Shaw PM. Popliteal artery entrapment syndrome. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK441965/ 3. Demarest K, Lavu H, Collins E, Batra V. Comprehensive Diagnosis and Management of Malignant Bowel Obstruction: A Review. J Pain Palliat Care Pharmacother. 2023 Jan 2;37(1):91–105. https://doi.org/10.1080/15360288.2022.2106012 4. Elgendy IY, Lo MC. Unilateral lower extremity swelling as a rare presentation of non-Hodgkin’s lymphoma. BMJ Case Rep. 2014 Jan 13;2014:bcr2013202424. https://doi.org/10.1136/bcr-2013-202424 5. Gasparis AP, Kim PS, Dean SM, Khilnani NM, Labropoulos N. Diagnostic approach to lower limb edema. Phlebology. 2020 Oct 1;35(9):650–5. https://doi.org/10.1177/0268355520938283 6. Ijaz M, Sakam S, Ashraf U, Marquez JG. Unusual Presentation of Recurrent Pyogenic Bilateral Psoas Abscess Causing Bilateral Pulmonary Embolism by Iliac Vein Compression. Am J Case Rep. 2015;16:606–610. https://doi.org/10.12659/ajcr.894206 7. Santangelo ML, Grifasi C, Criscitiello C, Giuliano M, Calogero A, Dodaro C, et al. Bowel obstruction and peritoneal carcinomatosis in the elderly. A systematic review. Aging Clin Exp Res. 2017 Feb 1;29(1):73–8. https://doi.org/10.1007/s40520-016-0656-9 8. Stone J, Hangge P, Albadawi H, Wallace A, Shamoun F, Knuttien MG, et al. Deep vein thrombosis: pathogenesis, diagnosis, and medical management. Cardiovasc Diagn Ther. 2017 Dec 21;7(Suppl_3):S276–84. https://doi.org/10.21037/cdt.2017.09.01 9. Szadkowska MA, Pałucki J, Cieszanowski A. Diagnosis and treatment of peritoneal carcinomatosis – a comprehensive overview. Pol J Radiol. 2023;88:89–97. https://doi.org/10.5114/pjr.2023.125027
Elderly patient with late diagnosed metastatic bone lytic lesions
Low back pain is a frequent reason for emergency department visits, pain management and screening for red flags should be considered for every patient, especially in elderly even with reassuring physical exam. In this case report, we discuss a case of an elderly patient who visited the emergency department many times with low back pain. His physical exam was reassuring. A low suspicion threshold, and a prompt history taking were the keys for diagnosis of bone-destroying lesions with multiple fractures and metastases. The patient had history of liver cirrhosis post hepatitis B, Alpha foetoprotein was high and he was diagnosed with metastatic hepatocarcinoma with extensive bone metastasis. Persistent pain, especially in older adults with progressive back pain, should be thoroughly investigated for serious conditions like bone metastases. Remember the "red flags" for lower back pain and note that physical exams may appear normal even with advanced bone issues. Introduction Acute back pain is one of the main reasons for emergency department (ED) presentations, and constitutes 4.4% of emergency department applications worldwide [1]. Advanced age places the patient at higher risk and requires further investigation [4]. Malignancies and related metastatic bone lesions form a small part of people who present to the emergency department with low back pain [4]. However, it should not be forgotten in elderly people with low back pain [3]. Emergency physicians should utilize red flag screening methods to detect those with serious diseases and, thus, patients who need to be investigated [2,3]. History of malignancy and cancer risk factors are considered among the serious red flags, since bone tissue appears as a frequent region in terms of metastasis. The presence of bone metastases is an indicator of poor prognosis in cancer patients. Prostate and breast cancers frequently metastasize to the skeletal system. Bone metastases occur much more often than primary bone cancers, especially in adults. The overall incidence of bone metastasis is unknown. The presence of bone metastases may cause severe pain as well as pathological fractures, limitation of mobility, bone marrow aplasia, compression of the spinal cord, and hypercalcemia [5]. In this case report, we present a patient with extensive bony lytic lesions who were mobile despite having many pathological fractures and metastatic lesions that caused almost complete disappearance of one-half of the pelvis. The institution's approval was obtained from Medical Research Center (CIRC-RDB-43-12-2022), and written informed consent was obtained from the patient. The paper was presented at the World Academic Congress of Emergency Medicine in Antalya, Türkiye, from October 28 to 31, 2023. Case Presentation A sixty-seven-year-old male presented to the emergency department with a complaint of lower back pain for 4 months. There was no history of trauma. The pain was on and off, radiating to his right hip and gluteal region, worsening for the last two weeks, and associated with walking difficulty for the last ten days. Within this period, the patient was seen multiple times in primary health care services and at the ED. Detailed neurological examination was reported as normal. Non-steroidal anti-inflammatory drugs were prescribed at various times at the health center and ED, but the patient's complaints gradually increased, although there was no reduction in his pain during these four months. He had a past medical history of hypertension, chronic gastritis, and liver cirrhosis post hepatitis B, with no regular follow-up for the last three years. During the last ED visit, the patient’s vitals were stable. On physical assessment, motor and sensory examination results were normal. There was tenderness in the right gluteal region and the lower back. At the same time, it was seen that the anal sphincter tone was normal. There was no saddle anesthesia or signs of dropping foot. The X-ray of the pelvis and thoracic spine showed a compression fracture of thoracic (T) 9 vertebra, absence of right pedicle of lumbar (L) 4 vertebra, destruction of bilateral pubic rami and ischial tuberosity, a large pelvic bone lytic lesion accompanied by a secondary pathological fracture, as well as a large soft tissue component eroding the adjacent part of the sacrum (Figure 1). Thoracolumbar spine and pelvis computed tomography (CT) performed and showed multiple lytic lesions in the thoracic and lumbar spine involving both vertebral bodies and posterior elements of the spine. Bilateral pelvic bones multifocal lytic lesions with pathological fractures are seen (Figure 2). Magnetic resonance imaging (MRI) of the spine showed multiple expansile osteolytic lesions along the axial skeleton, including the thoracic and lumbar vertebrae, ribs, and pelvic bones. A large expansile lesion involving the posterior neural element of the (T3) vertebra with intraspinal epidural soft tissue component compressing the posterior aspect of the upper thoracic cord was noted. Another expansile lesion, as seen in the (T6) and (T7) vertebra with a large soft tissue component totally occluding the neural canal, was noted (Figure 3). The patient was admitted to the neurosurgery department for pain management and further workup. Alpha fetal protein (AFP) level was 12,244 IU/ml (AFP normal level 0-6 IU/ml). Pan CT showed extensive bony lesions with soft tissue components through the cervical spine, cirrhotic liver with portal hypertension, and extensive portosystemic collateral formation, metastases involving the liver and the lung parenchyma. The most likely diagnosis was hepatocellular carcinoma with metastases. The case was discussed in the oncology team meeting, and a decision for palliative radiotherapy was made considering the patient’s status and the cancer stage. The patient was discharged after one week, and a rapid appointment with the radiotherapy clinic was arranged. Discussion In this case report, we presented a patient who came to the emergency department with back pain and had metastatic bone lesions with failure to diagnose early, even after multiple visits to the hospital. It was quite surprising that the patient had osteolytic lesions, causing severe destruction, and yet, was mobile. We have not encountered a patient presentation with such advanced lesions and are still mobile in the literature. We tried to emphasize that advanced age is a red flag for low back pain. In addition, it should be kept in mind that the neurologic examination may be normal despite advanced vertebral lesions. Back pain is one of the common reasons for emergency presentation; it is a condition that seriously affects people's daily activities and comfort [1]. Our patient visited health care facilities frequently despite taking his analgesics properly. During the last days preceding the last visit, he had walking difficulties affecting his daily routine. Low back pain is often defined as nonspecific or mechanical low back pain and constitutes 90% of the cases. Usually, the condition is self-limited and resolves within 4 to 6 weeks [3]. Rarely, patients may have serious pathologies, and critical diagnoses are often missed at the first presentation because of cognitive errors, lack of knowledge, and overlooked signs and symptoms [3]. Considering the frequency of patients presenting with back pain, it is necessary to comprehensively evaluate patients with lumbar complaints to keep patients with overlooked serious pathology to a minimum. The alarming signs should be figured out, and a detailed systemic investigation and examination should be carried out. Failure to notice these symptoms promptly can lead to a poor patient outcome. Getting a comprehensive history is particularly important in this stage. Our patient had history of liver cirrhosis post hepatitis B with no follow up for three years. This detail in history should alert the treating physician to consider further investigation considering the well-known risk of hepatocarcinoma in cirrhotic patients [6]. A complete physical examination following this will guide clinicians in recognizing the danger signs [7]. For this purpose, red flag scanning methods have been developed. While taking the history, age, history of surgery, trauma, immunosuppression, intravenous drug use, and sexual dysfunction should be questioned. In addition, the patient should be asked about any history of fever, anticoagulant use, urinary retention, epidural injection, decrease in anal sphincter tone, lower extremity motor weakness, and saddle anesthesia [8]. Serious pathologies can be revealed from the patient's history or by identifying abnormal musculoskeletal systems and abnormal neurological examination findings. In general, progression, change in character, or persistence of symptoms are alarming and may indicate serious pathology [8]. The presence of acute back pain in patients under the age of 18 or over the age of 50 should be a cause of concern. In young patients, congenital defects, spondylolysis, or vertebral fractures may be the cause of low back pain [9]. In patients over 50 years of age, new-onset back pain may be associated with intra-abdominal processes such as tumor, infection, abdominal aortic aneurysm, pancreatitis, or kidney stone. Osteoporosis accelerates with age progression. The decrease in the strength of bone tissue with osteoporosis may cause fractures in the bone tissue without trauma or with minor traumas. These fractures can be in the whole bone tissue as well as in the vertebrae. Therefore, vertebral fractures should be investigated in elderly patients presenting with acute onset low back pain. In addition, malignancy and metastatic bone lesions can be seen in both adolescents and the elderly, the presence of night pain and weight loss together with back pain requires investigation for malignancy [10]. Bone metastases are much more common than primary bone cancers, especially in adults [5]. Once cancer has spread to the bones, it is rarely curable, but treatments are used to slow the progression of the disease. Bone metastases may be osteolytic, osteoblastic, or mixed [5]. Our patient had extensive osteolytic lesions, interestingly, his physical exam was reassuring and did not identify any neurological compromise. However, he had walking difficulties but was still ambulating with walking aid despite the extensive pelvic lesions with pathological fracture. This could be explained by the fact that body movement is multifactorial and does not depend only on bone integrity. Interactions between bones, muscles and joints play a major role in maintaining movements including the capacity of walking [11]. Osteolytic metastases are characterized by osteoclast-mediated destruction of normal bones. The main malignancies in which osteolytic metastases are seen are multiple myeloma, renal cell carcinoma, melanoma, non-small cell lung cancer, non-Hodgkin lymphoma, thyroid cancer, and Langerhans cell histiocytosis [12]. Osteoblastic metastases are characterized by new bone deposition. The main malignancies are prostate cancer, carcinoid, small cell lung cancer, Hodgkin lymphoma, or medulloblastoma [13]. Mixed metastases are malignancies in which both osteolytic and osteoblastic lesions are seen. The main causes are breast cancer, gastrointestinal cancer, and squamous cancers [14]. Bone metastasis in hepatocarcinoma are predominately osteolytic like in our case report, however osteoblastic or mixed lesions are possible [15]. Uncomplicated acute lower back pain and/or radiculopathy of less than six weeks is considered a self-limiting and benign low back pain and does not require any imaging studies. However, further investigation should be carried out to determine if malignancy or infection is suspected clinically by red flags or pathological markers. In the presence of severe, progressive neurological deficits, diagnostic imaging, and laboratory tests are recommended to guide treatment. Although the systemic examination is completely normal, initial investigation efforts should begin with X-ray, metastases and malignant tumors come to mind, especially if bone lesions are seen in advanced ages. For this reason, the age of patients with suspected bone tumors or metastasis at the time of presentation is of great importance [16]. For elderly patients with persistent back pain and advanced bone lesions, a comprehensive treatment plan is essential. Medications such as bone-building drugs (e.g., bisphosphonates), pain medications, steroids, hormone therapy, and chemotherapy play a crucial role in managing symptoms and reducing pain [6]. Radiation therapy, including intravenous radiation for multiple bone metastases and external beam radiation for localized pain relief, is also recommended [14]. Surgical interventions, such as curettage and bone grafting for benign lesions, marginal resection or wide resection for aggressive lesions, and minimally invasive spine stabilization for spinal involvement, are important treatment options [8]. Palliative care techniques, like percutaneous cryoablation and embolization, help manage pain and improve quality of life [14]. Early diagnosis through imaging techniques like X-rays, CT scans, and MRIs, along with a multidisciplinary approach and patient education, is vital for effective management and improved prognosis [16]. Conclusion This case highlights the need for thorough evaluation in elderly patients with persistent back pain, especially when standard treatments fail. Despite extensive bone lesions and fractures, the patient's mobility was preserved, stressing the importance of considering malignancy, even with a reassuring physical exam. Physical exams can appear normal despite advanced lesions, hence a low threshold of suspicion for serious conditions like bone metastases should be maintained especially in elderly patients. Comprehensive diagnostic workups, starting with X-rays and progressing to CT scans, MRIs, and lab tests, are crucial for early detection and management, enhancing symptom control and overall prognosis. Declarations Author contributions All authors contributed equally and validated the final version of record. Conflicts Of Interest The Author(s) declare(s) that there is no conflict of interest. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Registration No registration applicable Data availability statement The data that support the findings of this study are available from the corresponding author upon reasonable request. Ethical approval The institution’s approval was obtained from Medical Research Center (CIRC-RDB-43-12-2022), and written informed consent was obtained from the patient. References 1. Coombs DM, Machado GC, Richards B, Wilson R, Chan J, Storey H, et al. Healthcare costs due to low back pain in the emergency department and inpatient setting in Sydney, Australia. Lancet Reg Health West Pac. 2021 Jan 29;7:100089. https://doi.org/10.1016/j.lanwpc.2020.100089 2. Traeger A, Buchbinder R, Harris I, Maher C. Diagnosis and management of low-back pain in primary care. CMAJ. 2017 Nov 13;189(45):E1386–E1395. https://doi.org/10.1503/cmaj.170527 3. DePalma MG. Red flags of low back pain. JAAPA. 2020 Aug;33(8):8–11. https://doi.org/10.1097/01.jaa.0000684112.91641.4c 4. Saes-Silva E, Vieira YP, Saes MO, Meucci RD, Aikawa P, Cousin E, et al. Epidemiology of chronic back pain among adults and elderly from Southern Brazil: a cross-sectional study. Braz J Phys Ther. 2021 May-Jun;25(3):344–351. https://doi.org/10.1016/j.bjpt.2020.12.005 5. Macedo F, Ladeira K, Pinho F, Saraiva N, Bonito N, Pinto L, et al. Bone Metastases: An Overview. Oncol Rev. 2017 May 9;11(1):321. https://doi.org/10.4081/oncol.2017.321 6. Shiffman ML. Approach to the patient with chronic hepatitis B and decompensated cirrhosis. Liver Int. 2020;40(Suppl. 1):22–26. https://doi.org/10.1111/liv.14359 7. Oliveira CB, Maher CG, Pinto RZ, Traeger AC, Lin CC, Chenot JF, et al. Clinical practice guidelines for the management of non-specific low back pain in primary care: an updated overview. Eur Spine J. 2018 Nov;27(11):2791–2803. https://doi.org/10.1007/s00586-018-5673-2 8. Verhagen AP, Downie A, Popal N, Maher C, Koes BW. Red flags presented in current low back pain guidelines: a review. Eur Spine J. 2016 Sep;25(9):2788–802. https://doi.org/10.1007/s00586-016-4684-0 9. Casazza BA. Diagnosis and treatment of acute low back pain. Am Fam Physician. 2012 Feb 15;85(4):343–50. 10. O'Sullivan P, Smith A, Beales D, Straker L. Understanding Adolescent Low Back Pain from a Multidimensional Perspective: Implications for Management. J Orthop Sports Phys Ther. 2017 Oct;47(10):741–751. https://doi.org/10.2519/jospt.2017.7376 11. Lu TW, Chang CF. Biomechanics of human movement and its clinical applications. Kaohsiung J Med Sci. 2012 Feb 1;28(2S):S13–25. https://doi.org/10.1016/j.kjms.2011.08.004 12. Della-Giustina D. Evaluation and treatment of acute back pain in the emergency department. Emerg Med Clin North Am. 2015 May;33(2):311–26. https://doi.org/10.1016/j.emc.2014.12.005 13. Taube T, Elomaa I, Blomqvist C, Beneton MNC, Kanis JA. Histomorphometric evidence for osteoclast-mediated bone resorption in metastatic breast cancer. Bone. 1994 Mar 1;15(2):161–6. https://doi.org/10.1016/8756-3282(94)90703-X 14. Coleman RE. Metastatic bone disease: clinical features, pathophysiology, and treatment strategies. Cancer Treat Rev. 2001 Jun;27(3):165–76. https://doi.org/10.1053/ctrv.2000.0210 15. Yuan X, Zhuang M, Zhu X, Cheng D, Liu J, Sun D, et al. Emerging Perspectives of Bone Metastasis in Hepatocellular Carcinoma. Front Oncol. 2022 Jun 29;12:943866. https://doi.org/10.3389/fonc.2022.943866 16. Coleman RE, Seaman JJ. The role of zoledronic acid in cancer: Clinical studies in the treatment and prevention of bone metastases. Semin Oncol. 2001 Apr 1;28:11–6. https://doi.org/10.1016/S0093-7754(01)90260-X
The Killer Wound; Early Diagnosis and Management of Necrotizing Fasciitis Utilizing Point-of-Care Ultrasound: A Case Repor
Background: Necrotizing fasciitis (NF) is a rapidly progressive and life-threatening infection of the fascia and subcutaneous tissues. Early diagnosis and prompt surgical intervention are critical to reducing morbidity and mortality. This case report highlights the importance of point-of-care ultrasound (PoCUS) in the rapid diagnosis of NF. Case Presentation: A 34-year-old male carpenter presented to the Emergency Department of Casey Hospital, with a 48-hour history of increasing swelling and pain in his right arm and chest. Two weeks prior, he sustained an open wound to his right wrist from a rusty nail. Initial management by his family doctor focused on musculoskeletal injury without antibiotics. On ED presentation, the patient exhibited signs of systemic infection and gross swelling of the right upper limb and chest. PoCUS demonstrated characteristic findings of NF, including cobble stoning and subcutaneous air with dirty shadowing, leading to an expedited surgical consultation and immediate intervention. Management and Outcome: The patient underwent multiple debridements, antibiotic therapy, and hyperbaric oxygen therapy. Post-surgical rehabilitation showed substantial gains in function and mobility. Discussion: This case underscores the crucial role of PoCUS in the early diagnosis and management of NF. PoCUS allows for rapid bedside imaging, enabling timely surgical consultation and intervention, thereby improving patient outcomes. The multidisciplinary approach, involving emergency physicians, surgeons, and intensivists, is essential for optimal management of NF. Conclusion: Early recognition and treatment, facilitated by PoCUS, are key to reducing the high morbidity and mortality. Key Messages * Early surgical intervention and antibiotic therapy are crucial in reducing morbidity and mortality in Necrotizing Fasciitis. * Multidisciplinary coordination is required for patient stabilization and rapid transfer from the Emergency Department to the operating theatre, as surgical debridement is the definitive treatment. * Utilization of Point-of-Care Ultrasound (PoCUS) is essential for the early diagnosis and management of Necrotizing Fasciitis and associated complications, significantly impacting patient outcomes. Presentation In November 2022, a 34-year-old male carpenter presented to the Emergency Department (ED) of Casey Hospital, Monash Health, a 229-bed facility providing comprehensive health services, including ICU, to Melbourne’s outer-east communities. The patient reported increased swelling and pain in his right arm and chest over the past 48 hours. Two weeks prior, he sustained an open wound to the dorsum of his right wrist from a rusty nail at work. He did not seek medical treatment and only cleaned the wound with a Betadine wash. Three days before presenting to the ED, he visited his family doctor due to feeling unwell with right arm swelling and right-sided chest pain. He was managed as a musculoskeletal (MSK) injury with analgesia, including non-steroidal anti-inflammatory drugs (NSAID), and rest. The day before his ED presentation, he revisited his family doctor with worsening pain and lethargy. An X-ray and MSK ultrasound were planned, and the NSAID was discontinued. No antibiotics were considered at that time. Initial ED Assessment and Management Upon ED presentation, he was tachycardic at 139/min, borderline tachypneic at 28 breaths per minute, apyrexial at 36.7°C, with an initial blood pressure of 115/78 mmHg. Examination revealed gross swelling of the right upper limb and chest, a 2 cm sloughy, partially healed open wound on the posterior aspect of the right forearm with surrounding erythema, and no purulent discharge (Figure 1). No palpable subcutaneous emphysema was noted. A C6 dermatomal sensation deficit was observed, likely secondary to inflammation and swelling. Capillary refill time (CRT) was greater than 5 seconds with a palpable radial pulse. The patient reported increasing pain, intermittent fevers, anorexia, and anuria for the past two days1. His social history revealed he was a non-smoker, social drinker, and did not use illicit drugs. ED Investigations and Initial Management He was triaged as category 2 (ATS; to be seen within 10 minutes) and self-mobilized to a resuscitation cubicle after identification of his critical condition. Observations and monitoring were applied, and two large-bore 18G IV cannulas were inserted into his left arm. An ECG (Figure 2) showed sinus tachycardia. Pathology tests, including a venous blood gas, inflammatory markers, UECs, LFTs, coagulation screen, and troponin, were taken2. His VBG indicated respiratory acidosis (pH 7.09, pCO2 65) and profound hyperlactatemia of 10.5. It also noted a haemoglobin of 166, potentially being indicative of dehydration/sepsis. His electrolytes were noted to be mildly deranged (Na 133, K 5.1, Cl 97). With a provisional diagnosis of sepsis, resuscitation with crystalloid intravenous fluids (NaCl) was initiated. Point-of-Care Ultrasound (PoCUS) demonstrated cobblestoning and subcutaneous air with dirty shadowing of the entire upper limb and right-side chest wall3 (Figure 3), suspicious for Necrotizing Fasciitis, as well as a non-compressible proximal part of the axillary vein suspicious for concurrent thrombus (Figure 4), likely secondary to swelling and immobility. Extended PoCUS showed a hyperdynamic heart without effusion, LV dysfunction, or significant right heart strain. Triple antibiotics, including clindamycin, piperacillin/tazobactam, and vancomycin, were commenced according to therapeutic guidelines4, followed by surgical and plastics consultation for urgent debridement5 in the operating theatre (OT) and post-op ICU admission. During transport to OT, he became hypotensive with septic shock and was managed with peripheral metaraminol with a good temporary response. Operative and Post-ED Management Upon arrival to the theatre, he was intubated, and invasive access for monitoring and management, including arterial and central venous lines, was established. Initial debridement found a large collection of pus under the pectoral, with pustular tracts noted between the pectoral major and minor towards the axilla. The fascia was healthy. Further exploration later that night revealed pus collections in the acromioclavicular and sternoclavicular joints, requiring washouts. Tissue samples were sent for microscopy and culture. Triple antibiotic therapy continued, and he was transferred to the ICU at Casey Hospital. With a confirmed diagnosis of Necrotizing Fasciitis intraoperatively, he was transferred to the Alfred Hospital, a metropolitan tertiary centre, for hyperbaric oxygen therapy and ongoing care. At the Alfred Hospital, he underwent two further debridements. His antibiotics were changed to cefepime, benzylpenicillin, and clindamycin, aligned with intraoperative tissue sample antibiogram sensitivities. Nasogastric feeds commenced, and he weaned off vasopressor support. Bilateral pleural effusions secondary to sepsis were found, and intercostal catheters were placed after bronchoscopy. He was transferred back to Monash Health (Dandenong Hospital) for ongoing management under plastics surgery care. Due to ongoing fevers and concerns for an empyema, his antibiotic therapy was escalated to include ciprofloxacin, linezolid, metronidazole, and micafungin4. Surgical Timeline D0: Initial debridement of the right upper limb/chest wall with biopsies concerning for Necrotizing Fasciitis. D2: Secondary debridement of the right arm/axilla/chest wall. D4: Third debridement with change of VAC dressing right upper limb and chest wall. D7: Fourth debridement and VAC change right arm, axilla, and chest. D14: VAC change and re-washout (assisted by Cardiothoracic Surgical team). D16: VAC change right chest wall. D21: Right axilla debridement and VAC change. Discussion Diagnosis of Necrotizing Fasciitis Necrotizing Fasciitis is a rapidly progressive, life-threatening infection of the fascia and subcutaneous tissues that requires immediate medical and surgical intervention. Early diagnosis is crucial to prevent significant morbidity and mortality. Clinical diagnosis can be challenging due to its variable presentation and overlap with other less severe soft tissue infections. Typical symptoms include severe pain, swelling, erythema, and systemic signs of sepsis such as fever, tachycardia, and hypotension. However, these symptoms can be nonspecific and may lead to initial misdiagnosis, as seen in this case, where the patient was initially treated for a musculoskeletal injury6. Diagnostic imaging plays a pivotal role in the early detection and management of Necrotizing Fasciitis. Radiographic imaging such as X-rays may show soft tissue gas, while computed tomography (CT) and magnetic resonance imaging (MRI) can provide more detailed information regarding the extent of infection. However, these modalities can be time-consuming, and may delay critical treatment. Utility of Point-of-Care Ultrasound (PoCUS) in Diagnosis Point-of-Care Ultrasound (PoCUS) has emerged as a valuable tool in the rapid diagnosis of Necrotizing Fasciitis, especially in the emergency department setting. PoCUS allows for bedside imaging, which can significantly reduce the time to diagnosis and subsequent treatment. In this case, PoCUS was instrumental in identifying the hallmark features of Necrotizing Fasciitis, including cobblestoning, subcutaneous air with dirty shadowing, and non-compressible veins suggesting thrombus formation7. These findings prompted immediate surgical consultation and expedited surgical intervention. The utility of PoCUS extends beyond diagnosis to include ongoing management and monitoring of disease progression. It provides real-time information about the extent of infection and can be used to guide fluid resuscitation, identify complications, such as abscess formation, and monitor the effectiveness of therapeutic interventions. Additionally, PoCUS can be used to evaluate cardiac function and detect hemodynamic instability, as was done in this case6. Antibiotic Stewardship The Australian Therapeutic Guidelines (ETG) is a leading source of independent, evidence based, practical treatment advice to assist practitioners with decision making at the point-of care. The content is regularly updated, based on the latest international literature, interpreted by Australia’s most respected experts, with input from an extensive network of general practitioners, pharmacists and other users. Thus, becoming the standard of practice in Australasia and most other countries like the United Kingdom and the United States of America. As per ETG, three antibiotics are required for empirical therapy for necrotizing skin Infections; Either meropenem or piperacillin/tazobactam, plus vancomycin, plus either clindamycin or lincomycin can be commenced4. This regime provides appropriate gram-positive and gram-negative aerobic cover, as well as coverage for anaerobes and MRSA. Decision for Limb Sparing Surgery In many instances there is a preference to preserve limbs whilst performing surgical intervention if possible. This coincides with the desire to avoid amputation in order to best return the patient to as close to return of function as possible8. Even though there is a deficit in published studies to support this claim, it was the preferred choice of the patient and the surgical team. Role of Multi-Disciplinary Intervention The initial suspicion and subsequent diagnosis of Necrotizing Fasciitis was completed by the Emergency Department team. Prompt inclusion of the intensive care, surgical/plastics team was required for definitive and post operative supportive treatment9. Post operative care included allied health involvement (physiotherapy, hand therapy, occupational therapy and social work). A multi-disciplinary approach provided the best outcome for this patient, giving him the greatest chance for return to function. Conclusion This case highlights the critical importance of early diagnosis and multidisciplinary management in patients with Necrotizing Fasciitis. Point-of-Care Ultrasound (PoCUS) proved to be a rapid, effective diagnostic tool that facilitated prompt surgical intervention and appropriate medical management, ultimately improving patient outcomes10. Early recognition and aggressive treatment, including the use of PoCUS for rapid bedside assessment, are key to reducing the high morbidity and mortality associated with Necrotizing Fasciitis. Patient Outcome Following surgical interventions, antibiotic therapy, and rehabilitation, the patient has made significant gains in function and mobility. Almost two years post-initial presentation, he has not fully returned to baseline but continues to make progress (Figure 5). References 1. Stevens DL, Bryant AE, Goldstein EJ. Necrotizing soft tissue infections. Infect Dis Clin North Am. 2021;35(1):135–155. https://doi.org/10.1016/j.idc.2020.10.004 2. Fernando SM, Tran A, Cheng W, Rochwerg B, Kyeremanteng K, Seely AJE, et al. Necrotizing Soft Tissue Infection: Diagnostic Accuracy of Physical Examination, Imaging, and LRINEC Score: A Systematic Review and Meta-Analysis. Ann Surg. 2019;269(1):58–65 https://doi.org/10.1097/SLA.0000000000002774 3. Marks A, Patel D, Sundaram T, Johnson J, Gottlieb M. Ultrasound for the diagnosis of necrotizing fasciitis: a systematic review of the literature. Am J Emerg Med. 2023;65:31–35. https://doi.org/10.1016/j.ajem.2022.12.037 4. Therapeutic Guidelines [Internet]. 2024 [cited 2024 Dec 9]. Therapeutic Guidelines | Independent, reliable, relevant and respected. Available from: https://www.tg.org.au/ 5. Wong CH, Yam AK, Tan AB, Song C. Approach to debridement in necrotizing fasciitis. Am J Surg. 2008;196(3):e19–e24. https://doi.org/10.1016/j.amjsurg.2007.08.076 6. Goh T, Goh LG, Ang CH, Wong CH. Early diagnosis of necrotizing fasciitis. Br J Surg. 2014;101(1):e119–e125. https://doi.org/10.1002/bjs.9371 7. Kohen B, Halperin M, Felix G, Dixon T, Montenegro M, Patel F. Sonographic crepitus, a point-of-care ultrasound finding. POCUS J. 2022;7(1):129–130 https://doi.org/10.24908/pocus.v7i1.15406 8. Misiakos EP, Bagias G, Patapis P, Sotiropoulos D, Kanavidis P, Machairas A. Current concepts in the management of necrotizing fasciitis. Front Surg. 2014;1:36. https://doi.org/10.3389/fsurg.2014.00036 9. Marchesi A, Marcelli S, Parodi PC, Perrotta RE, Riccio M, Vaienti L. Necrotizing fasciitis in aesthetic surgery: a review of the literature. Aesthetic Plast Surg. 2017;41(2):352–358. https://doi.org/10.1007/s00266-016-0754-2 10. Raj S, Williams EM, Davis MJ, Abu-Ghname A, Luu BC, Buchanan EP. Cost-effectiveness of multidisciplinary care in plastic surgery: a systematic review. Ann Plast Surg. 2021;87(2):206–210. https://doi.org/10.1097/SAP.0000000000002931
Assessment of Relatives’ Satisfaction in the Emergency Department
Introduction: Emergency departments (EDs) are high-pressure environments where both patients and their relatives face numerous challenges. While patient satisfaction has been widely studied, the satisfaction of relatives remains underexplored, despite their crucial role in supporting patient care and decision-making. Recognizing relatives as key actors in the care process helps improve communication and reduce stress. This study aimed to assess the satisfaction of relatives of patients treated in the ED. Methods: A prospective, descriptive study was conducted at the ED of the Mahmoud Yaacoub Center for Urgent Medical Assistance in Tunis from October 2023 to January 2024. Satisfaction was assessed using a 25-item structured questionnaire. Included participants were adult relatives directly involved in patient care who gave informed consent. Assessed dimensions included reception and management, information provided and overall satisfaction. Results: The study included 165 relatives (mean age 41 ± 13 years, 52.1% female). Relationships included parents (26%), offspring (18.9%), and siblings (14.8%). Overall satisfaction was high: 78% were satisfied with the overall care, 82% with the initial reception, 74% with waiting times, 80% with accessibility, and 77% with information clarity. No significant associations were found between age or education and overall satisfaction. However, relatives from healthcare or paramedical backgrounds showed significantly higher satisfaction (85%) with the registration process compared to non-healthcare relatives (62%) (p = 0.043). Conclusion: The study supports strengthening the involvement of relatives in strategies aimed at improving ED care quality Introduction Emergency Departments (EDs) are high-pressure, overcrowded environments where skilled professionals provide care for critically ill patients [1,2]. The fast-paced, overcrowded, and unfamiliar ED environment can cause stress and frustration for patients and families, often leading to feelings of alienation and reduced involvement in care. Recognizing relatives’ as integral to the critical care process, and striving to support both patients and their loved ones has been proven to be a crucial aspect of comprehensive patient care [3–6]. Understanding and addressing the needs, emotions, and expectations of relatives of critically ill patients, along with gathering their feedback, helps ED professionals improve communication, enhance care quality, build trust, and reduce distress or aggressive behavior [7,8]. Factors influencing family satisfaction in the ED include the clarity and frequency of communication with healthcare professionals, the perceived empathy and responsiveness of the care team, and logistical considerations, such as waiting times and access to information. Negative experiences in these areas can lead to significant dissatisfaction, potentially undermining trust in the healthcare system and discouraging future engagement with healthcare services. Conversely, positive interactions characterized by clear communication, empathy, and a supportive care environment can enhance the family’s understanding of the patient’s condition, foster greater cooperation with healthcare providers, and contribute to a more favorable overall experience. However, there is a notable gap in research focusing on ED, where the unique dynamics of acute care can significantly impact patient and relatives’ experience. Moreover, the satisfaction of relatives of patients in the ED has been even less frequently assessed, despite their crucial role in supporting patient care and decision-making. While patient satisfaction has been extensively studied, the satisfaction of patients' relatives, particularly within the high-pressure environment of the ED, remains under-explored [9]. In the ED, where patients frequently present with acute, often life-threatening conditions, the patient may be unable to actively participate in their care, placing greater importance on the involvement and perspectives of their relatives [10]. This study aimed to assess the satisfaction of patients' relatives in a Tunisian ED and to identify the factors influencing their satisfaction. Methods Study design This study was a monocentric, prospective, observational, descriptive study conducted at the ED of Mahmoud Yaacoub Center for Urgent Medical Assistance in Tunis. The study was conducted over a four-month period, from October 2023 to January 2024. The study targeted adult relatives, aged 18 years or older, who were directly involved in the care of a patient during their visit to the ED. Eligible participants included parents, offspring, spouses, siblings, other family members, friends, or neighbors accompanying the patient. Relatives were not included if they were under 18, declined to participate, were accompanying incarcerated patients, or were related to patients who passed away during their ED stay. Surveys were excluded if they had a non-response rate exceeding 20%, defined as more than five unanswered items out of the 25-question survey. Additionally, responses related to patients who left the ED before completing their care were excluded from the final analysis. Informed consent was obtained from all participating relatives after explaining the study's purpose. Explicit verbal consent was also obtained from patients to allow accompanying relatives to receive medical information during the ED visit. Study Protocol A comprehensive family satisfaction survey was specifically developed for this study to assess the experience of relatives in the ED. The survey was inspired from existing surveys in other departments and was designed for a local context. It was validated by a committee of practitioners [11–14] . The survey consisted of 25 items grouped into four main domains: relative’s background information, reception and management by the healthcare team, information provided to the relative and overall satisfaction (appendix 1). The first domain collected demographic and contextual data such as age, sex, relationship to the patient, educational level, frequency of ED visits, healthcare employment status, distance to the hospital, and reason for the visit. The second domain assessed aspects of care delivery including reception and consultation delays, registration procedures, length of stay, staff accessibility, interaction quality, and understanding of healthcare roles. The third domain focused on the information provided to relatives, evaluating clarity, honesty, satisfaction with communication from doctors and paramedics, and consistency of information. The final domain addressed overall satisfaction with the reception, management, and care provided to the patient. Most items were rated on a 4-point Likert scale ranging from "V ery D issatisfied" to "V ery S atisfied," while four items were structured as yes/no questions. The survey was developed in formal Arabic and French to enhance accessibility and administered at the end of the patient's ED care, with only one relative per patient invited to participate. On-call physicians or paramedical staff explained the study, obtained informed consent, guided respondents through the process, and ensured confidentiality and anonymity. The survey was administered after the patient's condition was stabilized and before the patient’s discharge from the ED. In this study, relatives were defined as individuals accompanying the patient to the ED, including immediate or extended family members, friends, neighbors, or any primary caregiver involved in the patient's support. Age groups were categorized based on the World Health Organization (WHO) classification: Adolescents and Young Adults (15–24 years), Adults (25–64 years), and Older Adults or Seniors (65 years and older) [15]. The study received approval from the institutional ethics committee prior to initiation. Statistical analysis Statistical analysis was conducted using SPSS software, version 25.0, with a significance level set at p < 0.05. Descriptive statistics included frequencies, percentages, means, standard deviations, medians, interquartile ranges, and overall range. Analytical methods involved correlation and regression analyses to explore potential associations between various factors and levels of satisfaction among relatives. Results Descriptive study A total of 169 relatives were included in our study (Figure 1). The participants' ages ranged from 18 to 73 years, with a mean age of 41 ± 13 years (52.1% female). Table 1 summarized the demographic characteristics of the population. Reception and Management by the Healthcare Team The average reception delay reported by participants was 4.82 ± 4.18 minutes, with the majority 142 respondents (84.%) reportedly being attended to in less than 10 minutes. When asked about their familiarity with the role of each healthcare provider involved in the patient's care, 95 participants (56.2%) responded affirmatively (Figure 2). Information Provided to the Patient's Relative Most of the participants (94.7%) stated they had received information regarding the patient’s care. However, 12 participants (7.1%) reported inconsistencies or contradictions in the information provided (Figure 3). Overall Satisfaction Satisfaction in the domain of reception and management was high, with 89.7% of participants expressing full satisfaction. Similarly, 87.4% were satisfied with the information received. The overall satisfaction domain recorded the highest satisfaction, with 93.9% of respondents expressing a positive evaluation (Table 2). Factors Associated with Satisfaction of Patients’ Relatives in the ED Multivariate analysis showed significantly higher registration satisfaction among healthcare workers compared to non-healthcare participants (p = 0.043; OR = 2.64; 95% CI: 1.03–6.77) No significant associations were found between age, sex, or educational background and satisfaction in reception and management, information provided, or overall satisfaction (Table 3). Discussion This prospective study aimed to assess the satisfaction of patients’ relatives in the ED of Mahmoud Yaacoub Center for Urgent Medical Assistance. The study found high satisfaction levels across most domains, including overall care (96.4%), reception (89.3%), and belief that the best care was provided (95.9%). In the Tunisian context, medical confidentiality is protected by the Penal Code and the Medical Code of Ethics [16] [17]. Disclosure of information to relatives requires the patient’s explicit consent, which must be distinguished from mere accompaniment. However, recent legal provisions permit the medical team to inform relatives in life-threatening emergencies requiring immediate medical intervention. Our finding that 94.7% of relatives received information suggests that ED staff are effectively navigating these ethical and legal requirements, likely by obtaining consent when possible, or acting under these emergency provisions. The demographic characteristics of the study population, with a mean age of 41 ± 13 years and slight female predominance, aligned with previous studies on relatives in ED/ICU settings [10,18,19]. The distribution of relationships to the patient, showing high involvement of parents, offspring, and siblings, also corresponds with other research findings [18,20,21]. The high proportion of participants with secondary or university education was consistent with observations regarding family involvement in care decisions [20–22]. Our analytical study revealed a significant difference in satisfaction with the registration procedure between healthcare and non-healthcare employees, with the former expressing higher satisfaction (85% vs 62%, p=0.043). This may be attributed to their greater familiarity with hospital administrative processes, supporting prior research [23]. Unlike evaluation of relatives’ satisfaction with healthcare, the evaluation of patient satisfaction has been extensively studied in healthcare settings [24] , particularly in I ntensive C are U nits (ICUs) and P ediatric D epartments [25–27]. It is a well-established indicator of healthcare quality, routinely measured through surveys designed to identify areas for improvement and enhance service delivery [11,28] . These surveys have become integral to the patient-centered approach that dominates modern healthcare, allowing providers to align their services more closely with patient needs and expectations [12]. Studies on relatives' satisfaction in ICUs have emphasized the importance of fostering understanding, as relatives often navigate complex emotions and interactions with healthcare providers during critical moments of care [29,30]. Similarly, in pediatric settings, research has emphasized the impact of communication and empathy on parental satisfaction. However, in the ED, where rapid decision-making and high patient turnover are common, the satisfaction of relatives has not been sufficiently assessed. This gap in literature suggests a need for targeted research to better understand and improve the experiences of both patients and their families in the emergency care environment. In our study, the high satisfaction with reception and management by healthcare providers [6,26], including short reception delays for the majority, and high satisfaction with consultation delay [22,23,31] , registration [9], availability, and relationships [22,23,31] , aligned with the importance of timely reception in emergency settings. However, the observed dissatisfaction regarding the honesty of information provided (39.6% unsatisfied) suggests potential gaps in transparency, corroborating studies where families felt information was withheld, particularly in critical cases [25,27]. We also found that 7.1% of respondents reported receiving conflicting information, which aligned with findings from other studies that emphasize the impact of inconsistent messaging [25,32]. Interestingly, unlike some other studies, our study found no significant association between age, sex, or educational background and overall satisfaction, which is consistent with literature reporting inconsistent associations between demographic factors and parent satisfaction [33]. This could suggest that the ED's practices are effective across diverse demographics or may be influenced by the homogeneity of the specific study population [10,25,34,35]. Our findings, particularly the high overall satisfaction rates, can be interpreted in light of specific cultural norms in Tunisia, where strong family involvement in patient care is deeply ingrained and expected. The significant proportions of relatives accompanying patients for 'transport' (40.2%) and fulfilling 'cultural/family/social obligations' (45.6%) underscore this active family presence. This societal expectation might contribute to higher satisfaction when families feel included and informed. Additionally, cultural perceptions of medical authority and the public's trust in healthcare providers could play a role in the generally positive satisfaction levels observed. Strengths and Limitations To the best of our knowledge, this is the first study in Tunisia to assess the satisfaction of relatives in the ED, specifically focusing on adult family members, an often-overlooked perspective in patient-centered care. Using a structured scoring system, we evaluated key factors influencing satisfaction, including reception, clarity of communication, and overall experience. The prospective design further strengthens the reliability of the data collected in real-time clinical settings. We acknowledge several limitations: the small, single-center sample may limit generalizability, and findings may not reflect other regions or settings. Larger, multicenter, and longitudinal studies are needed to enhance validity and assess changes in satisfaction over time. Recommendations Based on the findings of our study, several strategies are recommended to improve the satisfaction of relatives in EDs. First, administrative procedures should be simplified and streamlined, especially for non-healthcare users, with consideration given to digital solutions such as pre-registration platforms. Second, providing real-time updates on waiting times and offering comfort measures in waiting areas could help reduce stress and improve the overall experience. Third, ED staff should be trained and encouraged to communicate clearly, compassionately, and consistently with patients' relatives. This research highlights the importance of improving communication with patients' relatives to reduce frustration that may lead to aggression, and to strengthen their support for the patient, ultimately enhancing the quality of care in the ED. Conclusion Our findings highlight that while overall satisfaction of patients’ relatives was high in the ED, areas like the registration process require targeted improvement, especially for those unfamiliar with healthcare systems. Our study underscores the importance of clear communication, streamlined administrative processes, and a supportive environment. These insights contribute valuable information for developing family-centered care strategies that could lead to enhanced patient outcomes and a more supportive emergency care environment. Declarations Author contributions All authors contributed equally and validated the final version of record. Conflicts Of Interest The Author(s) declare(s) that there is no conflict of interest. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Registration No registration applicable Data availability statement The data that support the findings of this study are available from the corresponding author upon reasonable request. Ethical approval The study received approval from the institutional ethics committee prior to initiation. References 1. Brysiewicz P, Emmamally W. Focusing on families in the emergency department. Int Emerg Nurs. 2017 Jan 1;30:1–2. https://doi.org/10.1016/j.ienj.2016.08.002 2. Batista M, Vasconcelos P, Miranda R, Amaral T, Geraldes J, Fernandes A. Family presence during emergency situations: the opinion of nurses in the adult emergency department. Revista de Enfermagem Referência. 2017 Jun 14;IV Série:83–92. https://doi.org/10.12707/RIV16085 3. Rosland AM. Sharing the Care: The Role of Family in Chronic Illness [Internet]. California HealthCare Foundation; 2009 [cited 2025 Jun 11]. Available from: https://docslib.org/doc/10595523/sharing-the-care-the-role-of-family-in-chronic-illness 4. Hardicre J. Meeting the needs of families of patients in intensive care units. Nurs Times. 2003 Jul;99(27):26–7 5. Chesla CA. Do Family Interventions Improve Health? J Fam Nurs. 2010 Nov 1;16(4):355–77. https://doi.org/10.1177/1074840710383145 6. Redley B, Beanland C. Revising the Critical Care Family Needs Inventory for the Emergency Department. J Adv Nurs. 2004 Jan 1;45(1):95–104. https://doi.org/10.1046/j.1365-2648.2003.02865.x 7. Paavilainen E, Salminen-Tuomaala M, Kurikka S, Paussu P. Experiences of counselling in the emergency department during the waiting period: importance of family participation. J Clin Nurs. 2009 Aug 1;18(15):2217–24. https://doi.org/10.1111/j.1365-2702.2008.02574.x 8. Innes K, Jackson D, Plummer V, Elliott D. Care of patients in emergency department waiting rooms – an integrative review. J Adv Nurs. 2015 Dec 1;71(12):2702–14. https://doi.org/10.1111/jan.12719 9. Zohrevandi B, Tajik H. A survey of patients’ satisfaction in emergency department of Rasht Poursina Hospital. Emerg (Tehran). 2014;2(4):162–5 10. Redley B, Phiri LM, Heyns T, Wang W, Han CY. Family needs during critical illness in the Emergency Department: A retrospective factor analysis of data from three countries. J Clin Nurs. 2019 Aug 1;28(15–16):2813–23. https://doi.org/10.1111/jocn.14857 11. Atari M, Atari M. Brief Emergency Department Patient Satisfaction Scale (BEPSS); Development of a New Practical Instrument. Emerg (Tehran). 2015;3(3):103–8. 12. Hoonakker PLT, Carayon P, Brown RL, Werner NE. A Systematic Review of the Consumer Emergency Care Satisfaction Scale (CECSS). J Nurs Care Qual. 2022;37(4):349–55. https://doi.org/10.1097/NCQ.0000000000000636 13. Heyland DK, Tranmer JE, for the Kingston General Hospital ICU Research Working Group. Measuring family satisfaction with care in the intensive care unit: The development of a questionnaire and preliminary results. J Crit Care. 2001 Dec 1;16(4):142–9. https://doi.org/10.1053/jcrc.2001.30163 14. Molter NC. Needs of relatives of critically ill patients: a descriptive study. Heart Lung. 1979 Mar-Apr;8(2):332-9 15. World (WHO 2000-2025) Standard - Standard Populations - SEER Datasets [Internet]. National Cancer Institute; [cited 2025 Mar 26]. Available from: https://seer.cancer.gov/stdpopulations/world.who.html 16. Code de deontologie medicale tunisien [Internet]. May 17, 1993. Available from: https://studylibfr.com/doc/790942/code-de-deontologie-medicale-tunisien 17. Article 254: Code pénal [Internet]. Imprimerie Officielle de la République Tunisienne; Available from: https://9anoun.tn/fr/kb/codes/code-penal/code-penal-article-254
Admission Criteria and Successful Care of Adults in a Tertiary Care Pediatric Hospital During the COVID-19 Pandemic
Objective The study assessed the health outcomes of adult patients admitted on Pediatric Wards and Intensive Care Unit (PICU) of the Montreal Children’s Hospital (MCH) in Canada during the first and second waves of the COVID-19 pandemic. Methods This retrospective chart review analyzed data regarding all adult patients hospitalized at the MCH on pediatric units between March 14, 2020 and March 31, 2021. Results Forty (40) adults were admitted to MCH pediatric units. The median age was 28.5 years. There were 26 females and 14 males. The average length of stay (LOS) at the MCH was 6.3 days. There were 32 consultations from adult medical consultants performed at the MCH. Seventeen (17) incident reports were completed. There were no in-hospital deaths, but 6 in-hospital incidents were reported. Within the first seven days post discharge from the pediatric units, 1/24 (4%) patients returned to the adult emergency room and an additional 4 patients (16,6%) returned within 30 days. Conclusion With clear admission criteria, careful planning, and well-planned supportive resources treating adult patients within a pediatric care facility by pediatric care teams, also caring for pediatric patients in the same units, could be considered as a safe contingency plan in a time of crisis. Furthermore, admitting and treating adult patients on several pediatric units (PICU) may provide a larger variety of options for admission of adult patients. Introduction The COVID-19 pandemic put a significant stress on the healthcare systems leading to a shortage of hospital beds and equipment, disproportionally affecting older adults compared to the pediatric population1. In response to the critical rise in adult care demands, and considering that very few children required hospitalization due to COVID-19, innovative collaborations were developed to expand adult care capacity. Pediatric medical staff from children’s hospitals and pediatric centres worldwide stepped up to support their adult colleagues. Pediatric institutions employed different strategies to address this challenge, including the admission of adults on pediatric care units 2,3. Others adopted a hybrid model of care 4-6, or entirely repurposed their units to exclusively care for adults 7-9. In most cases, pediatric patients were either consolidated onto other units within the same hospital, transferred to standalone pediatric hospitals, or referred to community centres when specialized care was not required. The first COVID-19 positive case in Canada was reported on January 25, 2020, and on February 27, 2020 in Quebec10-11. On March 14 of the same year, the Quebec government declared state of health emergency12. Rapidly, Montreal became the epicentre of COVID-19 in Canada with the most cases during the first wave13. The Montreal Children’s Hospital (MCH), part of the Glen site of the McGill University Health Center (MUHC) was the first Canadian pediatric centre to admit adult patients within its own walls during the COVID-19 pandemic. There is limited knowledge on the occurrence of adverse events for adult patients admitted in pediatric hospitals, and on adult patients being treated by hospitalist pediatricians in Canada. The objective of this study was to assess outcomes of adult patients admitted on pediatric wards and intensive care unit (PICU) of the Montreal Children’s Hospital (MCH) during the first and second waves of the COVID-19 pandemic. Methods Study Design and Setting In this retrospective study, a thorough medical chart review of adult patients hospitalized on the MCH units (PICU, pediatric medicine, and pediatric surgery) during the first and second wave of the COVID-19 pandemic between March 14, 2020 and March 31, 2021 was conducted. The first wave occurred between March 14, 2020 and August 31, 2021 whereas the second wave took place from September 1, 2021 through March 31, 2021. The MCH is an urban tertiary care pediatric hospital and one of the four physically joint care facilities that form the MUHC, which is situated in Montreal, Canada. Admission criteria were developed carefully during the pandemic by a multidisciplinary group of pediatric and adult health providers and were used to select the adults to be admitted on pediatric units (Table 1). Data Collection Medical charts were reviewed by one researcher. The data was recorded in an excel spreadsheet, specifically designed for this study. The collected data included: patient demographics, primary diagnosis (as reported on the hospitalization summary), length of stay, location of the hospitalization, number of consultants from the adult medical staff involved, whether transfers occurred at any point during hospitalization on pediatric units (from pediatric wards to PICU and from pediatric units to adult units), disposition, and patient health outcomes (including: Code Blue activations, in-hospital deaths, incident reports, unplanned return visits to any of the MUHC emergency departments). Data analysis The study is descriptive, and no comparison groups were included. Descriptive statistics, encompassing the mean, standard deviation, and interquartile range (IQR), were computed to analyze various aspects of the dataset, such as patient age, length of stay and the involvement of adult consultants. Additionally, frequency tabulations were utilized to analyze primary diagnoses and patient health outcomes such as transfers, code blue activations, in-hospital deaths, incident reports, dispositions, and unplanned return visits. Ethical Considerations The MUHC Research Ethics Board approved the study protocol (#2022-7761) which was conducted in accord with the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans 2 (2018), as well as in respect of the requirements set out in the applicable standard operation procedures of the MUHC Research Institute. Anonymity and confidentiality were maintained throughout the study. Results This retrospective chart review identified a total of 40 admissions of adult patients to the MCH pediatric medical and surgical wards, as well as the PICU. These patients were cared for by a pediatric team on shared units alongside regular pediatric patients. The patients were mostly young, healthy adults, with a median age of 28.5 years. Among them, 26 were females and 14 were males ( Table 2). The average length of stay for all adult patient admissions was 6.3 days at the MCH and 22.2 days overall for those who were transferred back to the adult site when bedspace became available to complete their hospitalization. As demonstrated in Table 2, the 40 adult patients included in the study received a total of 132 consultations from adult medical consultants, with the number of consultations per patient ranging from 0 to 16. Of note, only 32 consultations occurred during the hospitalization on the pediatric units, divided amongst 22 patients. Among those, 15 consultations were in follow-up to the initial non-MCH phase of admission, while 17 were initiated by the pediatric medical staff to address evolving healthcare needs of patients during their stay on the pediatric units. Seventeen (17) incident reports were completed during admission at the MCH. There were no in-hospital deaths reported, and 6 in-hospital complications occurred: 1 line infection; 1 code blue activation; 1 accidental extubation, and 3 cases of ventilator-associated pneumonia. Following discharge from the MCH, most adult patients (n=24) returned home, while others were transferred to various healthcare facilities (n=16). Within 7 days post discharge from the pediatric units, 1 out of 24 patients (4%) returned to the adult emergency room, and an additional 4 patients (16.6%) returned within 30 days. Reasons for return visits varied and included new or worsening symptoms, post-operative complications, therapeutic interventions, or equipment dysfunctions. These findings are detailed in Table 4. Discussion A MUHC-wide strategy was implemented to provide the necessary capacity for adult patients while continuing to care for pediatric patients. During the first and second waves of the pandemic, this strategy involved admissions of adult patients on the PICU as well as the pediatric medicine and surgical wards of the MCH. The MCH opted to implement a hybrid model of care, wherein adults received treatment alongside children, administered by the same pediatric medical staff and within the same facility. Admissions originated from various sources and encompassed diverse primary diagnoses, resulting in positive and safe patient health outcomes. A pivotal factor contributing to this success was the collaborative development of clear admission criteria. Indeed, these criteria were developed by a multidisciplinary committee mandated to elaborate patient care trajectories and admission guidelines for adults on the different pediatric units ( Table 1). The selection of adult cases that were not excessively complex ensured favorable health outcomes for these adult patients admitted to pediatric units while also ensuring safety of the admitted pediatric patients. The study by Deep & colleagues4 described solely a hybrid pediatric and adult critical care unit without involvement of other pediatric units. The identification of adult patients for admission to the hybrid critical care unit was determined by a tactical lead from the adult team who would discuss individual patients for admission with the pediatric critical care lead. No predetermined admission criteria were reported. Sinha et al reported that 7 PICUs in England repurposed their space, equipment, and staff to care for a total of 145 critically ill adults during the first wave of the pandemic. The adults admitted were older (median age ranging from 57 to 62 years old in the different PICUs) as well as their in-patient mortality rate. Indeed, 20 of 145 (14%) adult patients admitted died in the PICU vs 0 in-patient deaths in all the pediatric units caring for adult patients at the Montreal Children’s hospital. In addition, the study did not publish any specific admission criteria for adults care for the 7 PICUs. Our experience at the MUHC reported in this study highlights both the effectiveness and safety of pediatric teams caring for adult patients in the PICU, as well as on pediatric surgical and medical wards. Collaboration and communication between the pediatric and adult medical teams as well as careful elaboration of admission criteria were instrumental in the success of the strategy. Whilst being very safe, the strict criteria established that adult patients infected with COVID-19 and requiring ICU level care had to be aged 30 years old or less to be considered for admission on the PICU. This significantly limited the number of potential adult PICU admissions. Return visits to the emergency room after discharge were only assessed at the MUHC and not in other nearby hospitals. In addition, the findings of this study may not apply to adult and pediatric facilities that are not located inside the same building. In such contexts, support from adult health providers may not be readily available and transport of patients from one hospital to the other may cause delays to admission. Conclusion With clear admission criteria, careful planning, and well-planned supportive resources, treating adult patients within a pediatric care facility by pediatric care teams, also caring for pediatric patients in the same units, could be considered as a safe contingency plan in a time of crisis. Furthermore, admitting and treating adult patients on several pediatric units (PICU, pediatric medicine ward, and pediatric surgical ward) may provide a larger variety of options for admission of adult patients. It would be ideal for healthcare facilities, without such experience, to prepare a similar strategy before the next pandemic strikes. Future research could assess if a similar strategy would be safe in other contexts, such as mass casualty incidents, natural, or manmade disasters. Acknowledgements: Additional contribution: We extend our appreciation to David Iannuzzi for providing research assistance during data collection, Karine Jones for her support in manuscript preparation, and Lindsay Hales for her excellent librarian support. Declarations Author contributions All authors contributed equally and validated the final version of record. Conflicts Of Interest The Author(s) declare(s) that there is no conflict of interest. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Registration No registration applicable Data availability statement The data that support the findings of this study are available from the corresponding author upon reasonable request. Ethical approval Ethical approval for this study was not required. References 1. Guan W, Ni Z, Hu Y, Liang W, Ou C, He J, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020 Apr 30;382(18):1708–20. https://doi.org/10.1056/NEJMoa2002032 2. Dong Y, Mo X, Hu Y, Qi X, Jiang F, Jiang Z, et al. Epidemiology of COVID-19 among children in China. Pediatrics. 2020 Jun;145(6):e20200702. https://doi.org/10.1542/peds.2020-0702 3. Lu X, Zhang L, Du H, Zhang J, Li YY, Qu J, et al. SARS-CoV-2 Infection in Children. N Engl J Med. 2020 Apr 23;382(17):1663–5. https://doi.org/10.1056/NEJMc2005073 4. Deep A, Knight P, Kernie SG, D’Silva P, Sobin B, Best T, et al. A Hybrid Model of Pediatric and Adult Critical Care During the Coronavirus Disease 2019 Surge: The Experience of Two Tertiary Hospitals in London and New York. Pediatr Crit Care Med. 2021 Feb;22(2):e125–34. https://doi.org/10.1097/PCC.0000000000002584 5. Sinha R, Aramburo A, Deep A, Bould EJ, Buckley HL, Draper ES, et al. Caring for critically ill adults in paediatric intensive care units in England during the COVID-19 pandemic: planning, implementation and lessons for the future. Arch Dis Child. 2021 Jun 1;106(6):548–557. https://doi.org/10.1136/archdischild-2020-320962 6. Osborn R, Doolittle B, Loyal J. When Pediatric Hospitalists Took Care of Adults During the COVID-19 Pandemic. Hosp Pediatr. 2021 Jan 1;11(1):e15–8. https://doi.org/10.1542/hpeds.2020-001040 7. Yager PH, Whalen KA, Cummings BM. Repurposing a Pediatric ICU for Adults. N Engl J Med. 2020;382(22):e80. https://doi.org/10.1056/NEJMc2014819 8. Philips K, Uong A, Buckenmyer T, Cabana MD, Hsu D, Katyal C, et al. Rapid Implementation of an Adult Coronavirus Disease 2019 Unit in a Children’s Hospital. J Pediatr. 2020 Jul 1;222:22–7. https://doi.org/10.1016/j.jpeds.2020.04.060 9. Joyce CL, Howell JD, Toal M, Wasserman E, Finkelstein RA, Traube C, et al. Critical Care for Coronavirus Disease 2019: Perspectives From the PICU to the Medical ICU. Crit Care Med. 2020;48(11):1553–5. https://doi.org/10.1097/CCM.0000000000004543 10. Berry I, Soucy JPR, Tuite A, Fisman D. Open access epidemiologic data and an interactive dashboard to monitor the COVID-19 outbreak in Canada. CMAJ. 2020 Apr 14;192(15):E420. https://doi.org/10.1503/cmaj.75262 11. Santé et Services sociaux. Cas confirmé de COVID-19 au Québec [Internet]. Quebec: Gouvernement du Québec; 2020 [cited 2021 Mar 1]. Available from: https://www.quebec.ca/nouvelles/actualites/details/cas-confirme-de-covid-19-au-quebec 12. Santé et Services sociaux. Pandémie de COVID-19 - Le gouvernement du Québec déclare l’état d’urgence sanitaire, interdit les visites dans les centres hospitaliers et les CHSLD et prend des mesures spéciales pour offrir des services de santé à distance [Internet]. Quebec: Gouvernement du Québec; 2020 [cited 2021 Mar 1]. Available from: https://www.quebec.ca/nouvelles/actualites/details/pandemie-de-covid-19-le-gouvernement-du-quebec-declare-letat-durgence-sanitaire-interdit-les-visites-dans-les-centres-hospitaliers-et-les-chsld-et-prend-des-mesures-speciales-pour-offrir-des-services-de-sante-a-distance 13. Health Canada [Internet]. Quebec: Government of Canada; 2020. Epidemiological summary of COVID-19 cases in Canada. Available from: https://health-infobase.canada.ca/covid-19/epidemiological-summary-covid-19-cases.html
Adherence to Screening Recommendations for Diabetic Nephropathy in Lebanese Patients With Diabetes
Background: Diabetic nephropathy (DN) is a debilitating microvascular complication of diabetes mellitus that often progresses before becoming symptomatic, highlighting the importance of screening during comprehensive diabetes management. Therefore, we captured a snapshot of DN screening in a country caught in the whirlwind of a pandemic and a severe economic crisis limiting access to healthcare facilities and adherence to screening schedules. Methods: We conducted a cross-sectional study that assessed the adherence of 258 Lebanese patients with diabetes to the recommended DN screening guidelines in a tertiary medical center. Medical records were analyzed for patient demographics, medication profile and laboratory indicators of glycemic control, e.g. glycated hemoglobin (HbA1c), and kidney function. Results: Less than half of patients in our cohort screened for DN with almost two-thirds recording abnormal markers of kidney function. Only half of the screened cohort underwent follow-up testing. Multivariate analysis revealed that lower HbA1c, lower age, outpatient status and year of first abnormal HbA1c were independently associated with DN screening. Conclusion: National-scale interventions through funding an annual screening and awareness campaign, while institutional-level interventions by implementing a quality improvement process to detect and address gaps in practice, are needed to increase adherence to screening recommendations. Key Messages · What is already known on this topic– Diabetic Nephropathy (DN) is a rapidly progressive condition often detected at late stages, due to limited screening practices. Screening for DN has never been investigated in Lebanon, and the impact of the country’s multifaceted crisis on regular check-ups and screening practices remains unaddressed. · What this study adds – This study is the first to describe DN screening practices in Lebanon across times of crisis. · How this study might affect research, practice or policy- Both national campaigns and institutional quality improvement interventions are required to increase adherence to DN screening guidelines. Introduction Diabetic Nephropathy (DN) is one of the most common and debilitating complications of diabetes mellitus (DM), affecting approximately 20-40% of patients with DM. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"j0um2rpv","properties":{"formattedCitation":"[1]","plainCitation":"[1]","noteIndex":0},"citationItems":[{"id":"DP3umt2Q/o9tpfnQb","uris":["http://zotero.org/users/6348749/items/3MV3HB4L"],"itemData":{"id":50,"type":"article-journal","container-title":"Diabetes Care","DOI":"10.2337/diacare.28.1.164","ISSN":"0149-5992, 1935-5548","issue":"1","journalAbbreviation":"Diabetes Care","language":"en","page":"164-176","source":"DOI.org (Crossref)","title":"Diabetic Nephropathy: Diagnosis, Prevention, and Treatment","title-short":"Diabetic Nephropathy","volume":"28","author":[{"family":"Gross","given":"J. L."},{"family":"Azevedo","given":"M. J.","non-dropping-particle":"de"},{"family":"Silveiro","given":"S. P."},{"family":"Canani","given":"L. H."},{"family":"Caramori","given":"M. L."},{"family":"Zelmanovitz","given":"T."}],"issued":{"date-parts":[["2005",1,1]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[1]<!-- [if supportFields]><![endif]--> DN is defined as increased urinary albumin excretion in the absence of any other renal disease. It is a chronic condition characterized sequentially by glomerular hypertrophy, transient hyperfiltration, proteinuria, renal fibrosis, and ultimately a decrease in glomerular filtration rate and albuminuria. DN can result in end-stage renal disease, eventually necessitating renal replacement therapy. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"DIopnn6z","properties":{"formattedCitation":"[2]","plainCitation":"[2]","noteIndex":0},"citationItems":[{"id":"DP3umt2Q/RAEkIEhk","uris":["http://zotero.org/users/6348749/items/PW49YZR3"],"itemData":{"id":48,"type":"chapter","container-title":"Comprehensive Physiology","event-place":"Hoboken, NJ, USA","ISBN":"978-0-470-65071-4","language":"en","note":"DOI: 10.1002/cphy.c100049","page":"c100049","publisher":"John Wiley & Sons, Inc.","publisher-place":"Hoboken, NJ, USA","source":"DOI.org (Crossref)","title":"Pathophysiology of the Diabetic Kidney","URL":"http://doi.wiley.com/10.1002/cphy.c100049","editor":[{"family":"Terjung","given":"Ronald"}],"author":[{"family":"Vallon","given":"Volker"},{"family":"Komers","given":"Radko"}],"accessed":{"date-parts":[["2021",2,17]]},"issued":{"date-parts":[["2011",7]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[2]<!-- [if supportFields]><![endif]--> According to the American Diabetes Association (ADA), patients with type I DM should be screened for DN yearly starting five years after the diagnosis, whereas patients with type II DM should be screened at diagnosis and yearly afterwards. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"s0TiBSav","properties":{"formattedCitation":"[3]","plainCitation":"[3]","noteIndex":0},"citationItems":[{"id":"DP3umt2Q/aXqkhk1A","uris":["http://zotero.org/users/6348749/items/LCL5QG8A"],"itemData":{"id":5821,"type":"article-journal","container-title":"Diabetes Care","DOI":"10.2337/diacare.27.2007.S79","ISSN":"0149-5992","issue":"suppl_1","journalAbbreviation":"Diabetes Care","page":"s79-s83","source":"Silverchair","title":"Nephropathy in Diabetes","volume":"27","author":[{"literal":"American Diabetes Association"}],"issued":{"date-parts":[["2004",1,1]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[3]<!-- [if supportFields]><![endif]--> Recommended initial DN workup involves measurement of albumin in a spot sample of urine. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"CQENL3oV","properties":{"formattedCitation":"[3]","plainCitation":"[3]","noteIndex":0},"citationItems":[{"id":"DP3umt2Q/aXqkhk1A","uris":["http://zotero.org/users/6348749/items/LCL5QG8A"],"itemData":{"id":5821,"type":"article-journal","container-title":"Diabetes Care","DOI":"10.2337/diacare.27.2007.S79","ISSN":"0149-5992","issue":"suppl_1","journalAbbreviation":"Diabetes Care","page":"s79-s83","source":"Silverchair","title":"Nephropathy in Diabetes","volume":"27","author":[{"literal":"American Diabetes Association"}],"issued":{"date-parts":[["2004",1,1]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[3]<!-- [if supportFields]><![endif]--> Twenty-four-hour urine collection is also possible, but less practical for patients and less accurate compared to spot urine samples. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"dIDWWHup","properties":{"formattedCitation":"[3]","plainCitation":"[3]","noteIndex":0},"citationItems":[{"id":"DP3umt2Q/aXqkhk1A","uris":["http://zotero.org/users/6348749/items/LCL5QG8A"],"itemData":{"id":5821,"type":"article-journal","container-title":"Diabetes Care","DOI":"10.2337/diacare.27.2007.S79","ISSN":"0149-5992","issue":"suppl_1","journalAbbreviation":"Diabetes Care","page":"s79-s83","source":"Silverchair","title":"Nephropathy in Diabetes","volume":"27","author":[{"literal":"American Diabetes Association"}],"issued":{"date-parts":[["2004",1,1]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[3]<!-- [if supportFields]><![endif]--> Measured albumin values can be presented as urinary albumin concentrations or urinary albumin-to-creatinine ratio (ACR). <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"sRILDmYb","properties":{"formattedCitation":"[4]","plainCitation":"[4]","noteIndex":0},"citationItems":[{"id":3617,"uris":["http://zotero.org/users/8309088/items/7F5UJ6AZ"],"itemData":{"id":3617,"type":"article-journal","container-title":"Diabetic Medicine","issue":"9","note":"ISBN: 0742-3071\npublisher: Wiley Online Library","page":"716-730","title":"A desktop guide to type 2 diabetes mellitus","volume":"16","author":[{"family":"European Diabetes Policy Group","given":"1999"}],"issued":{"date-parts":[["1999"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[4]<!-- [if supportFields]><![endif]--> Abnormal albumin values should be followed by two other sample collections within three to six months. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"bGM555pt","properties":{"formattedCitation":"[3]","plainCitation":"[3]","noteIndex":0},"citationItems":[{"id":"DP3umt2Q/aXqkhk1A","uris":["http://zotero.org/users/6348749/items/LCL5QG8A"],"itemData":{"id":5821,"type":"article-journal","container-title":"Diabetes Care","DOI":"10.2337/diacare.27.2007.S79","ISSN":"0149-5992","issue":"suppl_1","journalAbbreviation":"Diabetes Care","page":"s79-s83","source":"Silverchair","title":"Nephropathy in Diabetes","volume":"27","author":[{"literal":"American Diabetes Association"}],"issued":{"date-parts":[["2004",1,1]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[3]<!-- [if supportFields]><![endif]--> Alternatively, proteinuria can be assessed via protein-to-creatinine ratio (PCR). <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"WO7xYZCz","properties":{"formattedCitation":"[5]","plainCitation":"[5]","noteIndex":0},"citationItems":[{"id":3618,"uris":["http://zotero.org/users/8309088/items/YCICVMBY"],"itemData":{"id":3618,"type":"article-journal","abstract":"The spot (random) urine protein to creatinine ratio (P/C ratio) is an alternative, fast and simple method of detecting and estimating the quantitative assessment of proteinuria. The aim of the work was to review the literature concerning the usefulness of spot urine P/C ratio evaluation in the diagnosis of proteinuria in the course of kidney disease, hypertension, gestational hypertension, preeclampsia, immunological diseases, diabetes mellitus, and multiple myeloma, and in the diagnosis of proteinuria in children. We searched the PubMed and Google Scholar databases using the following keywords: proteinuria, spot urine protein to creatinine ratio, spot urine P/C ratio, protein creatinine index, PCR (protein to creatinine ratio), P/C ratio and methods, Jaffe versus enzymatic creatinine methods, urine protein methods, spot urine protein to creatinine ratio versus ACR (albumin to creatinine ratio), proteinuria versus albuminuria, limitations of the P/C ratio. More weight was given to the articles published in the last 10–20 years. A spot urine P/C ratio >20 mg/mmol (0.2 mg/mg) is the most commonly reported cutoff value for detecting proteinuria, while a P/C ratio value >350 mg/mmol (3.5 mg/mg) confirms nephrotic proteinuria. The International Society for the Study of Hypertension in Pregnancy recommends a P/C ratio of 30 mg/mmol (0.3 mg/mg) for the classification of proteinuria in pregnant women at risk of preeclampsia. A high degree of correlation was observed between P/C ratio values and the protein concentration in 24-h urine collections. The spot urine P/C ratio is a quick and reliable test that can eliminate the need for a daily 24-h urine collection. However, in doubtful situations, it is still recommended to assess proteinuria in a 24-h urine collection. The literature review indicates the usefulness of the spot P/C ratio in various disease states; therefore, this test should be available in every laboratory. However, the challenge for the primary care physician is to know the limitations of the methods used to determine the protein and creatinine concentrations that are used to calculate the P/C ratio. Moreover, the P/C ratio cutoff used should be determined in individual laboratories because it depends on the patient population and the laboratory methodologies.","container-title":"Critical Reviews in Clinical Laboratory Sciences","DOI":"10.1080/10408363.2020.1723487","ISSN":"1040-8363","issue":"5","note":"publisher: Taylor & Francis\n_eprint: https://doi.org/10.1080/10408363.2020.1723487\nPMID: 32058809","page":"345-364","source":"Taylor and Francis+NEJM","title":"Diagnostic utility of protein to creatinine ratio (P/C ratio) in spot urine sample within routine clinical practice","volume":"57","author":[{"family":"Kamińska","given":"Joanna"},{"family":"Dymicka-Piekarska","given":"Violetta"},{"family":"Tomaszewska","given":"Justyna"},{"family":"Matowicka-Karna","given":"Joanna"},{"family":"Koper-Lenkiewicz","given":"Olga Martyna"}],"issued":{"date-parts":[["2020",7,3]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[5]<!-- [if supportFields]><![endif]--> DN may progress long before symptoms become evident, accounting for its increased associated mortality, reaching as high as 31.1% of DN cases. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"oN1G0n09","properties":{"formattedCitation":"[6]","plainCitation":"[6]","noteIndex":0},"citationItems":[{"id":"DP3umt2Q/0od5Hhm4","uris":["http://zotero.org/users/6348749/items/DLW3FTLX"],"itemData":{"id":52,"type":"article-journal","container-title":"Journal of the American Society of Nephrology","DOI":"10.1681/ASN.2012070718","ISSN":"1046-6673, 1533-3450","issue":"2","journalAbbreviation":"JASN","language":"en","page":"302-308","source":"DOI.org (Crossref)","title":"Kidney Disease and Increased Mortality Risk in Type 2 Diabetes","volume":"24","author":[{"family":"Afkarian","given":"Maryam"},{"family":"Sachs","given":"Michael C."},{"family":"Kestenbaum","given":"Bryan"},{"family":"Hirsch","given":"Irl B."},{"family":"Tuttle","given":"Katherine R."},{"family":"Himmelfarb","given":"Jonathan"},{"family":"Boer","given":"Ian H.","non-dropping-particle":"de"}],"issued":{"date-parts":[["2013",2]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[6]<!-- [if supportFields]><![endif]--> Therefore, early detection and intervention are key, since these have been shown to improve prognosis. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"i3Ni5ZhK","properties":{"formattedCitation":"[7]","plainCitation":"[7]","noteIndex":0},"citationItems":[{"id":"DP3umt2Q/NB2CMxKd","uris":["http://zotero.org/users/6348749/items/22UYI7KK"],"itemData":{"id":44,"type":"article-journal","issue":"3","language":"en","page":"11","source":"Zotero","title":"Diabetic Nephropathy for the Primary Care Provider: New Understandings on Early Detection and Treatment","volume":"14","author":[{"family":"Kowalski","given":"Andrew"},{"family":"Krikorian","given":"Armand"},{"family":"Lerma","given":"Edgar V"}],"issued":{"date-parts":[["2014"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[7]<!-- [if supportFields]><![endif]--> Nonetheless, despite clear screening recommendations, DN remains substantially underdiagnosed and/or sub-optimally followed up. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"a5FC3vDa","properties":{"formattedCitation":"[8]","plainCitation":"[8]","noteIndex":0},"citationItems":[{"id":"DP3umt2Q/SNqwGbxF","uris":["http://zotero.org/users/6348749/items/GDJ636UN"],"itemData":{"id":5804,"type":"article-journal","container-title":"Mayo Clinic Proceedings","DOI":"10.1016/S0025-6196(11)60786-6","ISSN":"1942-5546","issue":"12","journalAbbreviation":"Mayo Clin Proc","language":"eng","note":"PMID: 19046557","page":"1373-1381","source":"PubMed","title":"Rationale and strategies for early detection and management of diabetic kidney disease","volume":"83","author":[{"family":"Radbill","given":"Brian"},{"family":"Murphy","given":"Barbara"},{"family":"LeRoith","given":"Derek"}],"issued":{"date-parts":[["2008",12]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[8]<!-- [if supportFields]><![endif]--> One of the reasons is the lack of proper provider adherence to screening guidelines. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"QQfLn3Ns","properties":{"formattedCitation":"[9]","plainCitation":"[9]","noteIndex":0},"citationItems":[{"id":3705,"uris":["http://zotero.org/users/8309088/items/5HYUNLDM"],"itemData":{"id":3705,"type":"article-journal","abstract":"BACKGROUND: Recent European Society of Cardiology (ESC)/European Association for the Study of Diabetes (EASD) guidelines provide recommendations for detecting and treating chronic kidney disease (CKD) in diabetic patients. We compared clinical practice with guidelines to determine areas for improvement.\nMETHODS: German database analysis of 675,628 patients with type 1 or type 2 diabetes, with 134,395 included in this analysis. Data were compared with ESC/EASD recommendations.\nRESULTS: This analysis included 17,649 and 116,747 patients with type 1 and type 2 diabetes, respectively. The analysis showed that 44.1 and 49.1 % patients with type 1 and type 2 diabetes, respectively, were annually screened for CKD. Despite anti-diabetic treatment, only 27.2 % patients with type 1 and 43.5 % patients with type 2 achieved a target HbA1c of < 7.0 %. Use of sodium-glucose transport protein 2 inhibitors (1.5 % type 1/8.7 % type 2 diabetes) and glucagon-like peptide-1 receptor agonists (0.6 % type 1/5.2 % type 2 diabetes) was limited. Hypertension was controlled according to guidelines in 41.1 and 67.7 % patients aged 18-65 years with type 1 and 2 diabetes, respectively, (62.4 vs. 68.4 % in patients > 65 years). Renin angiotensin aldosterone inhibitors were used in 24.0 and 40.9 % patients with type 1 diabetes (micro- vs. macroalbuminuria) and 39.9 and 47.7 %, respectively, in type 2 diabetes.\nCONCLUSIONS: Data indicate there is room for improvement in caring for diabetic patients with respect to renal disease diagnosis and treatment. While specific and potentially clinically justified reasons for non-compliance exist, the data may serve well for a critical appraisal of clinical practice decisions.","container-title":"BMC nephrology","DOI":"10.1186/s12882-021-02394-y","ISSN":"1471-2369","issue":"1","journalAbbreviation":"BMC Nephrol","language":"eng","note":"PMID: 34011313\nPMCID: PMC8135159","page":"184","source":"PubMed","title":"Guidelines adherence in the prevention and management of chronic kidney disease in patients with diabetes mellitus on the background of recent European recommendations - a registry-based analysis","volume":"22","author":[{"family":"Bramlage","given":"Peter"},{"family":"Lanzinger","given":"Stefanie"},{"family":"Tittel","given":"Sascha R."},{"family":"Hess","given":"Eva"},{"family":"Fahrner","given":"Simon"},{"family":"Heyer","given":"Christoph H. J."},{"family":"Friebe","given":"Mathias"},{"family":"Buschmann","given":"Ivo"},{"family":"Danne","given":"Thomas"},{"family":"Seufert","given":"Jochen"},{"family":"Holl","given":"Reinhard W."}],"issued":{"date-parts":[["2021",5,19]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[9]<!-- [if supportFields]><![endif]--> In Lebanon, there have been no national DN screening or awareness campaigns. Additionally, no prior study has attempted to quantify the frequency of DN and adherence to DN screening guidelines. Given the proven cost-effectiveness of population-based screening measures in reducing disease burden <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2mVvPHw1","properties":{"formattedCitation":"[10]","plainCitation":"[10]","noteIndex":0},"citationItems":[{"id":4587,"uris":["http://zotero.org/users/8309088/items/EPF6RL5V"],"itemData":{"id":4587,"type":"article-journal","abstract":"Background\nDespite the majority of patients with chronic kidney disease (CKD) live in low- and middle-income countries, most evidence on screening strategies is derived from high-income countries, where the contexts differ significantly. This study aims to assess the cost-effectiveness of population-based CKD screening strategies in both the general population and adults with diabetes in China.\nMethods\nA validated microsimulation model of CKD was developed to evaluate the costs and health consequences of population-based CKD screening strategies from a societal perspective. A cohort of the population aged 45 years in China was simulated over their lifetime. Model parameters were estimated based on the existing literature and various data sources in China. Main outcomes included the averted number of cases with cardiovascular disease (CVD) and kidney failure with replacement therapy (KFRT) under the population-based screening strategy compared with usual care, and the incremental cost-effectiveness ratios (ICERs). CKD screening with different frequencies and for different age groups in both the general population and adults with diabetes were considered. One-way sensitivity analyses were performed to assess the robustness of the results.\nFindings\nThe ICER of annual screening starting at 45 years of age was $10,588 per quality-adjusted life year (QALY) for the general population and $9184 per QALY for adults with diabetes. Other screening strategies were also cost-effective compared to usual care, with ICERs less than three times the per-capita gross domestic product of China ($35,501). The most prominent absolute decrease in lifetime incidence of KFRT and CVD were also observed with the annual screening strategy in both the general population and in adults with diabetes. Specifically, the decreases were 1.88 and 8.55 per 1000 individuals for KFRT, and 35.07 and 19.92 per 1000 individuals for CVD, respectively.\nInterpretation\nCKD screening in both the general population and adults with diabetes is cost-effective and could avert substantial numbers of KFRT and CVD cases in China.\nFunding\nThis study was supported by grants from National Natural Science Foundation of China (72125009), National Key Research and Development Program of China (2022YFF1203001), National High Level Hospital Clinical Research Funding (State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, 24QZ007), Peking University Medicine Sailing Program for Young Scholars’ Scientific & Technological Innovation (BMU2023YFJHMX014), Young Elite Scientists Sponsorship Program by CAST (2022QNRC001), and CAMS Innovation Fund for Medical Sciences (2019-I2M-5–046).","container-title":"The Lancet Regional Health - Western Pacific","DOI":"10.1016/j.lanwpc.2025.101493","ISSN":"2666-6065","journalAbbreviation":"The Lancet Regional Health - Western Pacific","page":"101493","source":"ScienceDirect","title":"Cost-effectiveness of population-based screening for chronic kidney disease among the general population and adults with diabetes in China: a modelling study","title-short":"Cost-effectiveness of population-based screening for chronic kidney disease among the general population and adults with diabetes in China","volume":"56","author":[{"family":"Wen","given":"Fengyu"},{"family":"Wang","given":"Jinwei"},{"family":"Yang","given":"Chao"},{"family":"Wang","given":"Fulin"},{"family":"Li","given":"Yan"},{"family":"Zhang","given":"Luxia"},{"family":"Pagán","given":"José A."}],"issued":{"date-parts":[["2025",3,1]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[10]<!-- [if supportFields]><![endif]-->, it has become imperative to draw a baseline for DN frequency and screening practices. Such data will help highlight the public health significance of DN, and guide the development of targeted interventions to address existing gaps, with the goal of reducing costs of treatment for end-stage renal disease. Financially smart preventive measures are now critical more than ever, in light of Lebanon’s financial crisis, that ranked among the highest in the world. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"qxyQjAHk","properties":{"formattedCitation":"[11]","plainCitation":"[11]","noteIndex":0},"citationItems":[{"id":4387,"uris":["http://zotero.org/users/8309088/items/HCDSNF57"],"itemData":{"id":4387,"type":"book","abstract":"The Lebanese banking sector has for long been supporting the Lebanese economy by funding its sovereign debt. However, a few missteps characterized by the non-diversification of the banks’ investments and serving governmental debt (through investing in Treasury bills and Eurobonds) funded from their agents’ deposits, coupled with deteriorating macro-environmental factors, have led to a severe financial crisis and placed Lebanese banks on the front lines of the crisis.","source":"ResearchGate","title":"LEBANESE BANKS: A FACTOR OF THE CURRENT LEBANESE FINANCIAL CRISIS (2019-2020)","title-short":"LEBANESE BANKS","author":[{"family":"Elia","given":"Jean"}],"issued":{"date-parts":[["2020",5,15]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[11]<!-- [if supportFields]><![endif]--> Therefore, we attempted to quantify the frequency of DN, and adherence to DN screening and follow-up testing in patients with DM over a period of three years. We were also interested in understanding the factors that affected DN screening practices. This study is the first to depict the frequency of DN, and attempts to establish a baseline for understanding DN screening practices in a country crippled by a severe economic crisis that has limited access to proper preventive medicine. This crisis further contributed to a shift in priorities away from preventive health maintenance and towards combating a pandemic, which, in turn, has also restricted access to healthcare facilities for non-urgent care. Methods We conducted a retrospective longitudinal study, since we collected pre-existing data to look back from a defined starting point i.e., first abnormal glycated hemoglobin (HbA1c), and examined data over time e.g., time to first DN screening and follow-up. Although our data was collected from a static database, the temporal structure and statistical methods reflect a longitudinal design. The study did not involve direct contact with patients and carried minimal risk to patients, hence waiver of informed consent was provided by the Institutional Review Board after it approved this study. We followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"sBSWPKRA","properties":{"formattedCitation":"[12]","plainCitation":"[12]","noteIndex":0},"citationItems":[{"id":4509,"uris":["http://zotero.org/users/8309088/items/276UELNN"],"itemData":{"id":4509,"type":"article-journal","abstract":"Poor reporting of research hampers assessment and makes it less useful. An international group of methodologists, researchers, and journal editors sets out guidelines to improve reports of observational studies","container-title":"BMJ (Clinical research ed.)","DOI":"10.1136/bmj.39335.541782.AD","ISSN":"1756-1833","issue":"7624","journalAbbreviation":"BMJ","language":"eng","note":"PMID: 17947786\nPMCID: PMC2034723","page":"806-808","source":"PubMed","title":"Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies","title-short":"Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement","volume":"335","author":[{"family":"Elm","given":"Erik","non-dropping-particle":"von"},{"family":"Altman","given":"Douglas G."},{"family":"Egger","given":"Matthias"},{"family":"Pocock","given":"Stuart J."},{"family":"Gøtzsche","given":"Peter C."},{"family":"Vandenbroucke","given":"Jan P."},{"literal":"STROBE Initiative"}],"issued":{"date-parts":[["2007",10,20]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[12] <!-- [if supportFields]><![endif]-->Study Design A retrospective study was performed to assess the rate of adherence to DN screening and follow-up testing among a sample of Lebanese patients with DM from a tertiary university medical center. The patient population was selected by looking at laboratory results of HbA1c measurements taken between January 2019 and June 2021. Inclusion criteria were: age > 18 years, and HbA1c ≥ 6.5% as per the 2021 ADA guidelines. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"ebNrNjIZ","properties":{"formattedCitation":"[13]","plainCitation":"[13]","noteIndex":0},"citationItems":[{"id":"DP3umt2Q/TGoY0LGs","uris":["http://zotero.org/users/6808417/items/IUQAZ9LP"],"itemData":{"id":180062,"type":"article-journal","container-title":"Diabetes Care","DOI":"10.2337/dc21-S002","ISSN":"0149-5992, 1935-5548","issue":"Supplement 1","language":"en","note":"publisher: American Diabetes Association\nsection: Standards of Care\nPMID: 33298413","page":"S15-S33","source":"care.diabetesjournals.org","title":"2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes—2021","title-short":"2. Classification and Diagnosis of Diabetes","volume":"44","author":[{"family":"Association","given":"American Diabetes"}],"issued":{"date-parts":[["2021",1,1]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[13]<!-- [if supportFields]><![endif]--> Patients were further stratified into three groups, based on the degree of DM control: <8% (Group 1), eight – 10% (Group 2), and >10% (Group 3). Other parameters indicative of DM control (i.e., fasting blood sugar (FBS) at the date of first abnormal HbA1c and a random blood glucose measurement) were also collected. The dataset was further divided into three groups based on the year of the first abnormal HbA1c: 2019, 2020, and 2021. Primary outcomes Nephropathy screening upon the first abnormal HbA1c after 2019 was the primary outcome we sought in this study. To determine nephropathy screening status, patients’ laboratory data were followed longitudinally until December 20, 2022. The first laboratory testing after the first abnormal HbA1c post-2019 was considered as initial DN screening. Sequential testing was a DN screening follow-up. Dates of DN screening and up to four follow-up testings – along with those of the first abnormal HbA1c post-2019 – were recorded and time intervals were calculated in days. Those whose time interval between first abnormal HbA1c and DN screening was zero were considered to be patients with a prior diagnosis of DN. Using medical records and clinical archives, we checked whether patients were tested for albumin in spot urine (cut-off: <2 mg/dL), ACR (cut-off: <30 mg/g creatinine), 24-hour urine protein (cut-off: <150 mg/24hrs), and/or PCR (cut-off: <200 mg/g). Abnormal lab values were noted and corresponding two follow-up testings were categorized into expected (< six months) and late (> six months). Covariables Risk factors as well as protective factors for DM and DN were chosen a priori as covariables. Information was retrieved from medical records and included: age, gender, in/outpatient status, smoking history, and comorbidities such as hypertension and dyslipidemia. Medication profiles were collected and grouped into four categories: antihyperglycemic agents (insulin, metformin, sodium-glucose transport protein 2 (SGLT2) inhibitors, sulfonylureas, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor agonists (GLP1-RA), meglitinides), antihypertensives (angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), beta blockers, calcium channel blockers, diuretics), antilipidemic (statins, fenofibrates), renoprotective medications (ACE inhibitors/ARBs, SGLT2 inhibitors and GLP1-RA). <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"iiCiCOpU","properties":{"formattedCitation":"[14\\uc0\\u8211{}16]","plainCitation":"[14–16]","noteIndex":0},"citationItems":[{"id":"DP3umt2Q/Zq2mPwur","uris":["http://zotero.org/users/6348749/items/V93RQESS"],"itemData":{"id":5848,"type":"article-journal","container-title":"Cardiovascular Diabetology","DOI":"10.1186/s12933-020-01163-9","ISSN":"1475-2840","issue":"1","journalAbbreviation":"Cardiovasc Diabetol","language":"eng","note":"PMID: 33222693\nPMCID: PMC7680601","page":"196","source":"PubMed","title":"Renoprotection with SGLT2 inhibitors in type 2 diabetes over a spectrum of cardiovascular and renal risk","volume":"19","author":[{"family":"Giorgino","given":"Francesco"},{"family":"Vora","given":"Jiten"},{"family":"Fenici","given":"Peter"},{"family":"Solini","given":"Anna"}],"issued":{"date-parts":[["2020",11,22]]}},"label":"page"},{"id":"DP3umt2Q/Ze1cPSDk","uris":["http://zotero.org/users/6348749/items/82QMZV5M"],"itemData":{"id":5876,"type":"article-journal","container-title":"Clinical and Experimental Nephrology","DOI":"10.1007/s10157-020-02007-2","ISSN":"1437-7799","issue":"4","journalAbbreviation":"Clin Exp Nephrol","language":"eng","note":"PMID: 33409761","page":"365-375","source":"PubMed","title":"Renoprotective effect of GLP-1 receptor agonist, liraglutide, in early-phase diabetic kidney disease in spontaneously diabetic Torii fatty rats","volume":"25","author":[{"family":"Yamada","given":"Shohei"},{"family":"Tanabe","given":"Jun"},{"family":"Ogura","given":"Yuji"},{"family":"Nagai","given":"Yoshio"},{"family":"Sugaya","given":"Takeshi"},{"family":"Ohata","given":"Keiichi"},{"family":"Natsuki","given":"Yasunori"},{"family":"Ichikawa","given":"Daisuke"},{"family":"Watanabe","given":"Shiika"},{"family":"Inoue","given":"Kazuho"},{"family":"Hoshino","given":"Seiko"},{"family":"Kimura","given":"Kenjiro"},{"family":"Shibagaki","given":"Yugo"},{"family":"Kamijo-Ikemori","given":"Atsuko"}],"issued":{"date-parts":[["2021",4]]}},"label":"page"},{"id":3681,"uris":["http://zotero.org/users/8309088/items/JQAM7N5I"],"itemData":{"id":3681,"type":"article-journal","abstract":"BACKGROUND: The role of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) reducing risk of cardiovascular events (CVEs) and preserving kidney function in patients with chronic kidney disease is well-documented. However, the efficacy and safety of these agents in dialysis patients is still a controversial issue.\nMETHODS: We systematically searched MEDLINE, Embase, Cochrane Library and Wanfang for randomized trials. The relative risk (RR) reductions were calculated with a random-effects model. Major cardiovascular events, changes in GFR and drug-related adverse events were analyzed.\nRESULTS: Eleven trials included 1856 participants who were receiving dialysis therapy. Compared with placebo or other active agents groups, ARB therapy reduced the risk of heart failure events by 33% (RR 0.67, 95% CI 0.47 to 0.93) with similar decrement in blood pressure in dialysis patients. Indirect comparison suggested that fewer cardiovascular events happened during treatment with ARB (0.77, 0.63 to 0.94). The results indicated no significant differences between the two treatment regimens with regard to frequency of myocardial infarction (1.0, 0.45 to 2.22), stroke (1.16, 0.69 to 1.96), cardiovascular death (0.89, 0.64 to 1.26) and all-cause mortality (0.94, 0.75 to 1.17). Five studies reported the renoprotective effect and revealed that ACEI/ARB therapy significantly slowed the rate of decline in both residual renal function (MD 0.93 mL/min/1.73 m2, 0.38 to 1.47 mL/min/1.73 m2) and urine volume (MD 167 ml, 95% CI 21 ml to 357 ml). No difference in drug-related adverse events was observed in both treatment groups.\nCONCLUSIONS: This study demonstrates that ACE-Is/ARBs therapy decreases the loss of residual renal function, mainly for patients with peritoneal dialysis. Overall, ACE-Is and ARBs do not reduce cardiovascular events in dialysis patients, however, treatment with ARB seems to reduce cardiovascular events including heart failure. ACE-Is and ARBs do not induce an extra risk of side effects.","container-title":"BMC nephrology","DOI":"10.1186/s12882-017-0605-7","ISSN":"1471-2369","issue":"1","journalAbbreviation":"BMC Nephrol","language":"eng","note":"PMID: 28666408\nPMCID: PMC5493067","page":"206","source":"PubMed","title":"Effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on cardiovascular events and residual renal function in dialysis patients: a meta-analysis of randomised controlled trials","title-short":"Effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on cardiovascular events and residual renal function in dialysis patients","volume":"18","author":[{"family":"Liu","given":"Youxia"},{"family":"Ma","given":"Xinxin"},{"family":"Zheng","given":"Jie"},{"family":"Jia","given":"Junya"},{"family":"Yan","given":"Tiekun"}],"issued":{"date-parts":[["2017",6,30]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[14–16]<!-- [if supportFields]><![endif]--> Medications with renoprotective properties work to optimally maintain kidney function. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"d4vJKhba","properties":{"formattedCitation":"[17]","plainCitation":"[17]","noteIndex":0},"citationItems":[{"id":3714,"uris":["http://zotero.org/users/8309088/items/QL5VKIE5"],"itemData":{"id":3714,"type":"article-journal","container-title":"Kidney International","DOI":"10.1111/j.1523-1755.2005.09716.x","ISSN":"0085-2538","journalAbbreviation":"Kidney International","language":"English","note":"publisher: Elsevier","page":"S95-S101","source":"www.kidney-international.org","title":"The future of renoprotection","volume":"68","author":[{"family":"Perico","given":"Norberto"},{"family":"Codreanu","given":"Igor"},{"family":"Schieppati","given":"Arrigo"},{"family":"Remuzzi","given":"Giuseppe"}],"issued":{"date-parts":[["2005",8,1]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[17] <!-- [if supportFields]><![endif]-->Study Size and Patient Involvement Given the proportion of type-two DM in our population – 11.2% in 2019 based on the International Diabetes Federation (IDF) <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"OxmmrfLY","properties":{"formattedCitation":"[18]","plainCitation":"[18]","noteIndex":0},"citationItems":[{"id":949,"uris":["http://zotero.org/users/8309088/items/DU5Q8AML"],"itemData":{"id":949,"type":"article-journal","container-title":"Dunia: IDF","title":"IDF diabetes atlas ninth","author":[{"family":"International Diabetes Federation","given":""}],"issued":{"date-parts":[["2019"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[18]<!-- [if supportFields]><![endif]-->, the sample size was calculated using the single population proportion formula (fig 1) where n is the sample size, Z is the Z-score for a 95% confidence level (1.96), p is the estimated prevalence (0.112), and d is the margin of error (0.05). A minimum of 239 patients should be included in this study. We randomly selected a total of 298 patients with abnormal HbA1c ≥ 6.5% between January 2019 and June 2021, from our laboratory archives. A total of 40 patients were excluded from the study due to the following: 34 were duplicates and six were <18 years old. Our final cohort comprised 258 patients with DM. Patients with DM were not involved in study design, implementation, reporting, or dissemination plans of our work. Statistical Analysis The data was analyzed using SPSS (Statistical Package for Social Sciences) software, version 28.0. For descriptive analysis, frequency and percentage were used for categorical variables. Mean and standard deviation were employed for quantitative variables. The distribution of these variables was considered normal using visual inspection of the histogram while the skewness and kurtosis were lower than one. For the bivariate analysis of continuous variables, the Student’s T-test was used to compare the means between two groups and ANOVA to compare between three groups or more, after checking for homogeneity of variances using Levene’s test. In case the variances are not homogenous, the corrected T-Test and the Kruskal-Wallis test were used, respectively. Moreover, a univariate Cox regression was conducted to take into account time to screening. As for the multivariate analysis, a multiple Cox regression analysis was conducted, and adjusted Hazard Ratio were calculated as exponential betas. Independent variables introduced in the models were sociodemographic, and other independent variables of clinical importance. In all cases, a p-value lower than .05 was considered significant. Given having missing data inherent to the retrospective data collection from health records, we did not perform missing values replacement. However, we conducted two models for multivariate analysis: one without variables that had missing values (Model one) and the other with these variables (Model two), which could be considered as a sensitivity analysis. Results Our sample comprised 258 patients with a mean age of 67.64 (± 12.9) years, and reflected a male predominance (n=163; 63.2%). At the time of abnormal HbA1c detection, 78 patients (30.2%) were admitted to the hospital, while the remainder of our sample (n=180; 69.8%) consisted of outpatients. The average HbA1c was 7.98 ± 1.49 % with 172 (66.7%) patients having an HbA1c below eight %, 61 (23.6%) patients between eight %-10%, and 25 (9.7%) patients greater than 10%. Other measures of glycemic control assessed were FBS (171.78 ± 76.24 mg/dL) and point of care blood glucose (195.13 ± 94.74mg/dL) for inpatients. More than half of patients were taking antihyperglycemic medications (n=146, 56.6%). It is difficult to determine whether the remaining 43.4% of patients were diet treated, or were taking no medication at all. Approximately 70% of patients (n=181; 73.3%) had a history of hypertension, with more than half (n=145, 56.2%) taking antihypertensive medications. Dyslipidemia was another comorbid condition present in 147 (59.5%) patients, and of those, 40.3% (n=104) were taking lipid lowering medications. Around one third of patients were taking a renoprotective medication (n=85, 32.9%). The majority of patients did not smoke (n=161; 62.4%) (Table 1). A total of 113 (43.8%) patients were screened for DN, out of which almost 40% had elevated albumin or protein in urine (n=44). Follow-up testing for DN was conducted in more than half of tested patients (n=64; 56.6%). Among those with abnormal DN screening who attempted follow-up testing, nine out of 44 patients (20.45%) were tested again in the expected first six months after the abnormal reading. The tests ordered for DN screening and follow-up testing included urine microalbumin spot (n=167; 54.2%), ACR (n=104; 33.8%), PCR (n=22; 7.1%), and 24-hour urine protein (n=15; 4.9%). The patients who screened for DN were younger (64.72 ± 13.95 years) and had lower HbA1c levels (7.77 ± 1.23 %) than those who did not undergo screening (P < .05) (Table 2). Hospitalization status was also significantly associated with DN screening, whereby outpatients at the time of their abnormal HbA1c had a higher likelihood of pursuing DN screening (χ², 11.044; P, .001) (Table 3). Nonetheless, there was no significant difference in FBS levels and point of care glucose values between patients who underwent DN screening and those who did not (P > .05) (Table 2). Similarly, sex, comorbid conditions (i.e., hypertension and dyslipidemia), smoking status, HbA1c levels, and medication profile were not significantly associated with DN screening (P > .05) (Table 3). Time between the first abnormal HbA1c and DN screening was significantly shorter for patients with abnormal DN workup (Mean, 48.43; SD, 173.37 days) compared to those with normal DN workup (Mean, 193.41; SD, 295.09 days) (Effect size, .073; P, .004) (Table 4). As such, abnormality in DN workup was a significant risk factor for initiation of DN screening (HR, 1.566; 95% CI, 1.051 to 2.333; P, .027) (Table 5). Subsequent time intervals between DN screening and follow-up testing did not significantly differ between those with normal versus abnormal DN screening results (P > .05) (Table 4). Patients who had their first abnormal HbA1c detected in 2020 and 2021 were less likely to screen for DN compared to those whose abnormal HbA1c was detected in 2019 (χ², 34.235; P, < .001 / 2019 vs 2020: HR, .568; 95% CI, .354 to .911; P, .019 / 2019 vs 2021: HR, .289; 95% CI, .181 to .460; P, < .001). Conversely, HbA1c level did not affect the cumulative probability of DN screening (P > .05) (Table 5). In multivariate model one, lower HbA1c (HR, .768; 95% CI, .619 to .952; P, .016), younger age (HR, .950; 95% CI, .927 to .974; P, < .001), outpatient status (HR, .513; 95% CI, .267 to .985; P, .045) and year of first abnormal HbA1c (2019 vs 2021: HR, 8.387; 95% CI, 4.127 to 17.043; P, < .001 / 2020 vs 2021: HR, 2.763; 95% CI, 1.300 to .875; P, .008) were independently associated with DN screening. Patterns of associations with DN screening were not preserved when variables with missing values were included in multivariate model two, wherein screening for DN remained independently associated with the year at which the first abnormal HbA1c was recorded (2019 vs 2021: HR, 9.441; 95% CI, 3.056 to 28.982; P, < .001 / 2020 vs 2021: HR, 3.428; 95% CI, 1.017 to 11.554; P, .047), while a significant negative association was revealed in hyperlipidemic patients (HR, .331; 95% CI, .120 to .909; P, .032) (Table 6). Discussion In this study, we sought to determine the frequency of screening for DN amongst patients in a university tertiary medical center. We found that less than half of the patients in our sample were screened for DN, with nearly 40% of them having abnormal markers of kidney function. Patients with lower HbA1c levels presenting to our hospital for outpatient laboratory testing were more likely to undergo DN screening, especially if their first abnormal HbA1c was in 2019 compared to later years. Conversely, patients with comorbid dyslipidemia were less likely to screen for DN. The DN screening rate observed in this study falls within the values reported in the literature that ranged from 11 to 86 %. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Zk35RurR","properties":{"formattedCitation":"[19\\uc0\\u8211{}21]","plainCitation":"[19–21]","noteIndex":0},"citationItems":[{"id":3684,"uris":["http://zotero.org/users/8309088/items/J33CPNY2"],"itemData":{"id":3684,"type":"article-journal","abstract":"BACKGROUND: Chronic kidney disease (CKD) is a public health problem, while data from developing countries are limited. We sought to investigate the epidemiological features of kidney damage in metropolis-residing Chinese adults (>40 years old), and to determine the associated factors of CKD.\nMETHODS: Two thousand three hundred and fifty-three residents in one district of Beijing were interviewed and tested for albuminuria, reduced renal function, haematuria and pyuria. The associations between demographic characteristics, health characteristics and indicators of kidney damage were examined.\nRESULTS: Albuminuria was detected in 6.2% of subjects; reduced renal function was found in 5.2% of subjects; haematuria was found in 0.8% and non-infective pyuria was found in 0.09%. Approximately, 11.3% (95% confidence interval: 10.0-12.8%) of subjects had at least one indicator of kidney damage. The awareness rate of CKD was only 7.2%. Systolic blood pressure and diabetes were independently associated with albuminuria. Age, diastolic blood pressure, hypercholesteraemia, hypertriglyceridaemia and hyperuricaemia were independently associated with reduced renal function.\nCONCLUSIONS: This is the first report on the prevalence of CKD in a community-based population within a developing country, determined using protocols recommended by kidney disease improving global outcomes (KDIGO). The prevalence of CKD in our population was close to the levels observed in developed countries, and the spectrum of CKD and associated factors were similar to developed countries. Results from this study suggest that strategies aimed at an intervention of hypertension and other metabolic disorders might prove effective in controlling the pandemic of CKD in China, as well as other developing countries.","container-title":"Nephrology, Dialysis, Transplantation: Official Publication of the European Dialysis and Transplant Association - European Renal Association","DOI":"10.1093/ndt/gfl763","ISSN":"0931-0509","issue":"4","journalAbbreviation":"Nephrol Dial Transplant","language":"eng","note":"PMID: 17210584","page":"1093-1099","source":"PubMed","title":"Community-based screening for chronic kidney disease among populations older than 40 years in Beijing","volume":"22","author":[{"family":"Zhang","given":"LuXia"},{"family":"Zuo","given":"Li"},{"family":"Xu","given":"GuoBin"},{"family":"Wang","given":"Fang"},{"family":"Wang","given":"Mei"},{"family":"Wang","given":"ShuYu"},{"family":"Lv","given":"JiCheng"},{"family":"Liu","given":"LiSheng"},{"family":"Wang","given":"HaiYan"}],"issued":{"date-parts":[["2007",4]]}}},{"id":3687,"uris":["http://zotero.org/users/8309088/items/ZKNG6Z2M"],"itemData":{"id":3687,"type":"article-journal","container-title":"Brussels: International Society of Nephrology","title":"Global Kidney Health Atlas: a report by the International Society of Nephrology on the global burden of end-stage kidney disease and capacity for kidney replacement therapy and conservative care across world countries and regions","author":[{"family":"Bello","given":"A. K."},{"family":"Levin","given":"A."},{"family":"Lunney","given":"M."},{"family":"Osman","given":"M. A."},{"family":"Ye","given":"F."},{"family":"Ashuntantang","given":"G."},{"family":"Bellorin-Font","given":"E."},{"family":"Benghanem","given":"G. M."},{"family":"Ghnaimat","given":"M."},{"family":"Harden","given":"P."}],"issued":{"date-parts":[["2019"]]}}},{"id":3690,"uris":["http://zotero.org/users/8309088/items/N4PZJQ9X"],"itemData":{"id":3690,"type":"article-journal","abstract":"AIMS: To estimate the prevalence of chronic kidney disease (CKD) in patients with type 2 diabetes (T2D) in Finnish primary healthcare, and to evaluate the screening for CKD and the proportions of patients receiving antihyperglycemic and cardiovascular preventive medication.\nMATERIAL AND METHODS: T2D patients treated at the Rovaniemi Health Center, Finland during the years 2015-2019. Data included patient characteristics, blood pressure, HbA1c, lipid levels, kidney function and albuminuria, and medications prescribed. CKD was defined as estimated glomerular filtration rate (eGFR) <60 ml/min/1.72 m2 and/or albuminuria.\nRESULTS: The study population comprised of 5112 T2D patients with a mean (SD) age of 66.7 (13.0) years. Of these, 60.2% were screened for CKD with both eGFR and albuminuria, and 30.1% of these patients had CKD. The prevalence of moderately increased and severely increased albuminuria was 19.6% and 3.2%, respectively. A total of 57.0% of the study population received angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB).\nCONCLUSIONS: Screening for CKD with both recommended measures (eGFR and albuminuria) was insufficiently performed among this T2D population. Additionally, just over half of the study population had been prescribed ACE inhibitors or ARB. These results suggest an incongruity between the gold standard of diabetes care and real-world clinical practice.","container-title":"Primary Care Diabetes","DOI":"10.1016/j.pcd.2020.05.005","ISSN":"1878-0210","issue":"6","journalAbbreviation":"Prim Care Diabetes","language":"eng","note":"PMID: 32527663","page":"639-644","source":"PubMed","title":"The prevalence of chronic kidney disease and screening of renal function in type 2 diabetic patients in Finnish primary healthcare","volume":"14","author":[{"family":"Hagnäs","given":"Maria"},{"family":"Sundqvist","given":"Henry"},{"family":"Jokelainen","given":"Jari"},{"family":"Tumminia","given":"Andrea"},{"family":"Vinciguerra","given":"Federica"},{"family":"Loreto","given":"Carla"},{"family":"Frittitta","given":"Lucia"},{"family":"Russo","given":"Giuseppina T."},{"family":"Mikkola","given":"Ilona"}],"issued":{"date-parts":[["2020",12]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[19–21]<!-- [if supportFields]><![endif]--> Amidst the scarcity of data on DN screening in our country, comparable data on low to middle income countries in 2019 reveals underscreening in our sample, with around 44 % of patients undergoing screening versus 86% in other cohorts. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"FQ3uwvXp","properties":{"formattedCitation":"[20]","plainCitation":"[20]","noteIndex":0},"citationItems":[{"id":3687,"uris":["http://zotero.org/users/8309088/items/ZKNG6Z2M"],"itemData":{"id":3687,"type":"article-journal","container-title":"Brussels: International Society of Nephrology","title":"Global Kidney Health Atlas: a report by the International Society of Nephrology on the global burden of end-stage kidney disease and capacity for kidney replacement therapy and conservative care across world countries and regions","author":[{"family":"Bello","given":"A. K."},{"family":"Levin","given":"A."},{"family":"Lunney","given":"M."},{"family":"Osman","given":"M. A."},{"family":"Ye","given":"F."},{"family":"Ashuntantang","given":"G."},{"family":"Bellorin-Font","given":"E."},{"family":"Benghanem","given":"G. 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Individuals who visit our laboratories as outpatients are more likely to undergo screening than those admitted to the hospital. Evidently, patients who are admitted are dealing with more urgent issues, however given the paucity of outpatient screening, this may be a missed opportunity to improve the care of these patients. Unfortunately, current insurance policies in our country do not cover DN screening during inpatient services, which drives patients to do these tests as outpatient. Patients with co-morbid dyslipidemia were less likely to undergo DN screening, despite their increased risk of developing nephropathy. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"YLEkHtcJ","properties":{"formattedCitation":"[23]","plainCitation":"[23]","noteIndex":0},"citationItems":[{"id":3708,"uris":["http://zotero.org/users/8309088/items/NMQUWM53"],"itemData":{"id":3708,"type":"article-journal","abstract":"Diabetic nephropathy is the leading cause of end-stage renal disease. Patients with diabetic nephropathy have a high cardiovascular risk, comparable to patients with coronary heart disease. Accordingly, identification and management of risk factors for diabetic nephropathy as well as timely diagnosis and prompt management of the condition are of paramount importance for effective treatment. A variety of risk factors promotes the development and progression of diabetic nephropathy, including elevated glucose levels, long duration of diabetes, high blood pressure, obesity, and dyslipidemia. Most of these risk factors are modifiable by antidiabetic, antihypertensive, or lipid-lowering treatment and lifestyle changes. Others such as genetic factors or advanced age cannot be modified. Therefore, the rigorous management of the modifiable risk factors is essential for preventing and delaying the decline in renal function. Early diagnosis of diabetic nephropathy is another essential component in the management of diabetes and its complications such as nephropathy. New markers may allow earlier diagnosis of this common and serious complication, but further studies are needed to clarify their additive predictive value, and to define their cost-benefit ratio. This article reviews the most important risk factors in the development and progression of diabetic nephropathy and summarizes recent developments in the diagnosis of this disease.","container-title":"The review of diabetic studies: RDS","DOI":"10.1900/RDS.2015.12.110","ISSN":"1614-0575","issue":"1-2","journalAbbreviation":"Rev Diabet Stud","language":"eng","note":"PMID: 26676664\nPMCID: PMC5397986","page":"110-118","source":"PubMed","title":"Diabetic Nephropathy: New Risk Factors and Improvements in Diagnosis","title-short":"Diabetic Nephropathy","volume":"12","author":[{"family":"Tziomalos","given":"Konstantinos"},{"family":"Athyros","given":"Vasilios G."}],"issued":{"date-parts":[["2015"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[23]<!-- [if supportFields]><![endif]--> This questions our DN screening practices as evidence from a retrospective observational study on 15,362 patients with DM from the database of the Italian Association of Clinical Diabetologists showed decreased high-density lipoprotein concentration and elevated triglycerides to be independent predictors of DN development. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"TNlfmxeF","properties":{"formattedCitation":"[24]","plainCitation":"[24]","noteIndex":0},"citationItems":[{"id":3699,"uris":["http://zotero.org/users/8309088/items/G69ZBHPX"],"itemData":{"id":3699,"type":"article-journal","abstract":"OBJECTIVE: Despite the achievement of blood glucose, blood pressure, and LDL cholesterol (LDL-C) targets, the risk for diabetic kidney disease (DKD) remains high among patients with type 2 diabetes. This observational retrospective study investigated whether diabetic dyslipidemia-that is, high triglyceride (TG) and/or low HDL cholesterol (HDL-C) levels-contributes to this high residual risk for DKD.\nRESEARCH DESIGN AND METHODS: Among a total of 47,177 patients attending Italian diabetes centers, 15,362 patients with a baseline estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2, normoalbuminuria, and LDL-C ≤130 mg/dL completing a 4-year follow-up were analyzed. The primary outcome was the incidence of DKD, defined as either low eGFR (<60 mL/min/1.73 m2) or an eGFR reduction >30% and/or albuminuria.\nRESULTS: Overall, 12.8% developed low eGFR, 7.6% an eGFR reduction >30%, 23.2% albuminuria, and 4% albuminuria and either eGFR <60 mL/min/1.73 m2 or an eGFR reduction >30%. TG ≥150 mg/dL increased the risk of low eGFR by 26%, of an eGFR reduction >30% by 29%, of albuminuria by 19%, and of developing one abnormality by 35%. HDL-C <40 mg/dL in men and <50 mg/dL in women were associated with a 27% higher risk of low eGFR and a 28% risk of an eGFR reduction >30%, with a 24% higher risk of developing albuminuria and a 44% risk of developing one abnormality. These associations remained significant when TG and HDL-C concentrations were examined as continuous variables and were only attenuated by multivariate adjustment for numerous confounders.\nCONCLUSIONS: In a large population of outpatients with diabetes, low HDL-C and high TG levels were independent risk factors for the development of DKD over 4 years.","container-title":"Diabetes Care","DOI":"10.2337/dc16-1246","ISSN":"1935-5548","issue":"12","journalAbbreviation":"Diabetes Care","language":"eng","note":"PMID: 27703024","page":"2278-2287","source":"PubMed","title":"Plasma Triglycerides and HDL-C Levels Predict the Development of Diabetic Kidney Disease in Subjects With Type 2 Diabetes: The AMD Annals Initiative","title-short":"Plasma Triglycerides and HDL-C Levels Predict the Development of Diabetic Kidney Disease in Subjects With Type 2 Diabetes","volume":"39","author":[{"family":"Russo","given":"Giuseppina T."},{"family":"De Cosmo","given":"Salvatore"},{"family":"Viazzi","given":"Francesca"},{"family":"Pacilli","given":"Antonio"},{"family":"Ceriello","given":"Antonio"},{"family":"Genovese","given":"Stefano"},{"family":"Guida","given":"Pietro"},{"family":"Giorda","given":"Carlo"},{"family":"Cucinotta","given":"Domenico"},{"family":"Pontremoli","given":"Roberto"},{"family":"Fioretto","given":"Paola"},{"literal":"AMD-Annals Study Group"}],"issued":{"date-parts":[["2016",12]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[24]<!-- [if supportFields]><![endif]--> The clinical correlation of this observation raises concern for potential underscreening of these patients. Notably, patients who screened for DN had increased use of antilipidemic medications – albeit statistically insignificant due to low event rate – reflecting closer control of comorbid health issues which could justify fewer screening efforts. Conversely, the co-presence of hypertension did not significantly impact DN screening, even though hypertension is associated with an increased risk of DN and albuminuria. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"68EhWF2x","properties":{"formattedCitation":"[23]","plainCitation":"[23]","noteIndex":0},"citationItems":[{"id":3708,"uris":["http://zotero.org/users/8309088/items/NMQUWM53"],"itemData":{"id":3708,"type":"article-journal","abstract":"Diabetic nephropathy is the leading cause of end-stage renal disease. Patients with diabetic nephropathy have a high cardiovascular risk, comparable to patients with coronary heart disease. Accordingly, identification and management of risk factors for diabetic nephropathy as well as timely diagnosis and prompt management of the condition are of paramount importance for effective treatment. A variety of risk factors promotes the development and progression of diabetic nephropathy, including elevated glucose levels, long duration of diabetes, high blood pressure, obesity, and dyslipidemia. Most of these risk factors are modifiable by antidiabetic, antihypertensive, or lipid-lowering treatment and lifestyle changes. Others such as genetic factors or advanced age cannot be modified. Therefore, the rigorous management of the modifiable risk factors is essential for preventing and delaying the decline in renal function. Early diagnosis of diabetic nephropathy is another essential component in the management of diabetes and its complications such as nephropathy. New markers may allow earlier diagnosis of this common and serious complication, but further studies are needed to clarify their additive predictive value, and to define their cost-benefit ratio. This article reviews the most important risk factors in the development and progression of diabetic nephropathy and summarizes recent developments in the diagnosis of this disease.","container-title":"The review of diabetic studies: RDS","DOI":"10.1900/RDS.2015.12.110","ISSN":"1614-0575","issue":"1-2","journalAbbreviation":"Rev Diabet Stud","language":"eng","note":"PMID: 26676664\nPMCID: PMC5397986","page":"110-118","source":"PubMed","title":"Diabetic Nephropathy: New Risk Factors and Improvements in Diagnosis","title-short":"Diabetic Nephropathy","volume":"12","author":[{"family":"Tziomalos","given":"Konstantinos"},{"family":"Athyros","given":"Vasilios G."}],"issued":{"date-parts":[["2015"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[23]<!-- [if supportFields]><![endif]--> More than half of our patients were taking anti-hypertensive medication; however, little information was available about the duration and control of their hypertension. Despite not reaching statistical significance for the aforementioned reasons, the magnitude and direction of effect size suggests a meaningful clinical impact wherein patients with comorbid hypertension are at higher risk for DN and screen more closely. We noticed the absence of a significant difference in medication profile between those who were screened for DN and those who were not. As such, medications profiles do not seem to reflect the complexity of the clinical status of screening patients. This finding was also reported in a cross-sectional sample of 378 non-insulin dependent patients with DM, which concluded that aggressive treatment measures did not affect DN screening. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"ISosdlns","properties":{"formattedCitation":"[25]","plainCitation":"[25]","noteIndex":0},"citationItems":[{"id":3692,"uris":["http://zotero.org/users/8309088/items/JRJIWBJM"],"itemData":{"id":3692,"type":"article-journal","abstract":"OBJECTIVE: To examine physician and patient adherence to prevention guidelines in non-insulin-dependent diabetes mellitus (NIDDM) with attention to possible differences in adherence by patient race or ethnicity.\nRESEARCH DESIGN AND METHODS: We performed a cross-sectional chart review study of prevention practices, complications, and risk factors in 378 NIDDM patients (at least 5 years known duration) who were Permanente Medical Care Program, Oakland, CA. There were 232 blacks, 81 whites, 29 Hispanics, and 36 members of other races/ethnicities.\nRESULTS: Age- and duration-adjusted prevalence of 14 complications was low and, with the exception of diabetic retinopathy, did not differ significantly by race. An eight-point prevention score that reflected recommended use of glucose, HbA1c, high-density lipoprotein/total cholesterol, blood pressure and proteinuria testing, ophthalmology a and foot examinations, and diabetes education during a 2-year period did not differ by race/ethnicity (P = 0.36). The mean score (4.9 +/- 1.6) indicated that on average, five of eight guidelines were performed appropriately. Compliance was poorest for annual proteinuria checks (32.2%). No differences were noted by race/ethnicity in referrals to ophthalmology, weight reduction, or smoking cessation or in missed appointments or failure to keep referral visits.\nCONCLUSIONS: The absence of racial differences in either prevention practices or complication rates in this insured prepaid setting suggests that improved access to preventive services may be effective in reducing such differences nationally. However, adherence to several guidelines was < or = 50%, indicating that physicians are not sufficiently convinced of the necessity for these prevention measures.","container-title":"Diabetes Care","DOI":"10.2337/diacare.18.8.1124","ISSN":"0149-5992","issue":"8","journalAbbreviation":"Diabetes Care","language":"eng","note":"PMID: 7587847","page":"1124-1132","source":"PubMed","title":"Physician and patient prevention practices in NIDDM in a large urban managed-care organization","volume":"18","author":[{"family":"Martin","given":"T. L."},{"family":"Selby","given":"J. V."},{"family":"Zhang","given":"D."}],"issued":{"date-parts":[["1995",8]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[25]<!-- [if supportFields]><![endif]--> Compared with cross-sectional real-world data on more than 80,000 patients from both high- and low-income Asian countries between 2007 and 2012, patients in this study were less likely to be taking antihypertensive (56.2% vs 90%) and antilipidemic (40.3% vs 77%) medications, <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"NO9Ah07F","properties":{"formattedCitation":"[26]","plainCitation":"[26]","noteIndex":0},"citationItems":[{"id":3676,"uris":["http://zotero.org/users/8309088/items/IZ28RI5T"],"itemData":{"id":3676,"type":"article-journal","abstract":"AIMS/HYPOTHESIS: Diabetes is the leading cause of kidney disease worldwide. There is limited information on screening, treatment and control of kidney disease in patients with diabetes in low-to-middle-income countries (LMICs).\nMETHODS: The International Diabetes Management Practices Study is an ongoing, non-interventional study of clinical profiles and practices among patients receiving outpatient care mainly by internal medicine physicians and endocrinologists in LMICs. We examined screening, prevalence, treatment and control of kidney disease across seven waves (W) of data collection between 2005 and 2017.\nRESULTS: Among 15,079 patients with type 1 and 66,088 patients with type 2 diabetes, screening for kidney disease increased between W2 and W3 followed by a plateau (type 1 diabetes: W2, 73.7%; W3, 84.1%; W7, 83.4%; type 2 diabetes: W2, 65.1%; W3, 82.6%; W7, 86.2%). There were also decreasing proportions of patients with microalbuminuria (type 1 diabetes: W1, 27.1%; W3, 14.7%; W7, 13.8%; type 2 diabetes: W1, 24.5%; W3, 12.6%; W7, 11.9%) and proteinuria (type 1 diabetes: W1, 14.2%; W3, 8.7%; W7, 8.2%; type 2 diabetes: W1, 15.6%; W3, 9.3%; W7, 7.6%). Fewer patients were reported as receiving dialysis for both type 1 diabetes (W2, 1.4%; W7, 0.3%) and type 2 diabetes (W2, 0.9%; W7, 0.2%) over time. While there was no change in mean HbA1c or prevalence of diagnosed hypertension (type 1 diabetes: W1, 22.7%; W7, 19.9%; type 2 diabetes: W1, 60.9%; W7, 66.2%), the use of statins had increased among patients diagnosed with dyslipidaemia (type 1 diabetes: W1, 77.7%; W7, 90.7%; type 2 diabetes: W1, 78.6%; W7, 94.7%). Angiotensin II receptor blockers (type 1 diabetes: W1, 18.0%; W7, 30.6%; type 2 diabetes: W1, 24.2%; W7, 43.6%) were increasingly used over ACE inhibitors after W1 (type 1 diabetes: W1, 65.0%; W7, 55.9%; type 2 diabetes: W1, 55.7%, W7, 41.1%) among patients diagnosed with hypertension.\nCONCLUSIONS/INTERPRETATION: In LMICs, real-world data suggest improvement in screening and treatment for kidney disease in patients with type 1 and type 2 diabetes attending non-nephrology clinics. This was accompanied by decreasing proportions of patients with microalbuminuria and proteinuria, with fewer patients who reported receiving dialysis over a 12-year period.","container-title":"Diabetologia","DOI":"10.1007/s00125-021-05406-6","ISSN":"1432-0428","issue":"6","journalAbbreviation":"Diabetologia","language":"eng","note":"PMID: 33594476\nPMCID: PMC8099838","page":"1246-1255","source":"PubMed","title":"Screening, prevalence, treatment and control of kidney disease in patients with type 1 and type 2 diabetes in low-to-middle-income countries (2005-2017): the International Diabetes Management Practices Study (IDMPS)","title-short":"Screening, prevalence, treatment and control of kidney disease in patients with type 1 and type 2 diabetes in low-to-middle-income countries (2005-2017)","volume":"64","author":[{"family":"Mbanya","given":"Jean Claude"},{"family":"Aschner","given":"Pablo"},{"family":"Gagliardino","given":"Juan J."},{"family":"İlkova","given":"Hasan"},{"family":"Lavalle","given":"Fernando"},{"family":"Ramachandran","given":"Ambady"},{"family":"Chantelot","given":"Jean-Marc"},{"family":"Chan","given":"Juliana C. N."}],"issued":{"date-parts":[["2021",6]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[26]<!-- [if supportFields]><![endif]--> both of which were linked with decreased progression of diabetic kidney disease. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"QRxqCgeR","properties":{"formattedCitation":"[16,27]","plainCitation":"[16,27]","noteIndex":0},"citationItems":[{"id":3681,"uris":["http://zotero.org/users/8309088/items/JQAM7N5I"],"itemData":{"id":3681,"type":"article-journal","abstract":"BACKGROUND: The role of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) reducing risk of cardiovascular events (CVEs) and preserving kidney function in patients with chronic kidney disease is well-documented. However, the efficacy and safety of these agents in dialysis patients is still a controversial issue.\nMETHODS: We systematically searched MEDLINE, Embase, Cochrane Library and Wanfang for randomized trials. The relative risk (RR) reductions were calculated with a random-effects model. Major cardiovascular events, changes in GFR and drug-related adverse events were analyzed.\nRESULTS: Eleven trials included 1856 participants who were receiving dialysis therapy. Compared with placebo or other active agents groups, ARB therapy reduced the risk of heart failure events by 33% (RR 0.67, 95% CI 0.47 to 0.93) with similar decrement in blood pressure in dialysis patients. Indirect comparison suggested that fewer cardiovascular events happened during treatment with ARB (0.77, 0.63 to 0.94). The results indicated no significant differences between the two treatment regimens with regard to frequency of myocardial infarction (1.0, 0.45 to 2.22), stroke (1.16, 0.69 to 1.96), cardiovascular death (0.89, 0.64 to 1.26) and all-cause mortality (0.94, 0.75 to 1.17). Five studies reported the renoprotective effect and revealed that ACEI/ARB therapy significantly slowed the rate of decline in both residual renal function (MD 0.93 mL/min/1.73 m2, 0.38 to 1.47 mL/min/1.73 m2) and urine volume (MD 167 ml, 95% CI 21 ml to 357 ml). No difference in drug-related adverse events was observed in both treatment groups.\nCONCLUSIONS: This study demonstrates that ACE-Is/ARBs therapy decreases the loss of residual renal function, mainly for patients with peritoneal dialysis. Overall, ACE-Is and ARBs do not reduce cardiovascular events in dialysis patients, however, treatment with ARB seems to reduce cardiovascular events including heart failure. ACE-Is and ARBs do not induce an extra risk of side effects.","container-title":"BMC nephrology","DOI":"10.1186/s12882-017-0605-7","ISSN":"1471-2369","issue":"1","journalAbbreviation":"BMC Nephrol","language":"eng","note":"PMID: 28666408\nPMCID: PMC5493067","page":"206","source":"PubMed","title":"Effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on cardiovascular events and residual renal function in dialysis patients: a meta-analysis of randomised controlled trials","title-short":"Effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on cardiovascular events and residual renal function in dialysis patients","volume":"18","author":[{"family":"Liu","given":"Youxia"},{"family":"Ma","given":"Xinxin"},{"family":"Zheng","given":"Jie"},{"family":"Jia","given":"Junya"},{"family":"Yan","given":"Tiekun"}],"issued":{"date-parts":[["2017",6,30]]}},"label":"page"},{"id":3680,"uris":["http://zotero.org/users/8309088/items/PP8CYSWG"],"itemData":{"id":3680,"type":"article-journal","container-title":"British journal of diabetes","issue":"1","note":"ISBN: 2397-6241","page":"7-13","title":"Cardiovascular outcomes trials with statins in diabetes","volume":"18","author":[{"family":"Naeem","given":"Fariha"},{"family":"McKay","given":"Gerard"},{"family":"Fisher","given":"Miles"}],"issued":{"date-parts":[["2018"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[16,27]<!-- [if supportFields]><![endif]--> Further weakening the strength of medication profiles as a variable reflective of disease severity and quality of patient follow-up. The time interval between the first abnormal HbA1c and DN screening is shorter in those who eventually had abnormal DN values, potentially indicating that first evidence of DN prompted patients to undergo screening before the annual checkup milestone. Clinically, this suggests that DN screening in Lebanon often follows clinical suspicion of disease progression rather than primary screening, which highlights the lack of current preventive measures. Additionally, screening figures showed a decreasing trend over the years (from 2019 to 2021) in which the first abnormal HbA1c was detected, which could be attributed to the soaring economic crisis that is considered one of the most severe crises since the mid-nineteenth century. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"jszyuHMH","properties":{"formattedCitation":"[28]","plainCitation":"[28]","noteIndex":0},"citationItems":[{"id":3319,"uris":["http://zotero.org/groups/4546179/items/VIUHHH5P"],"itemData":{"id":3319,"type":"webpage","abstract":"According to the latest World Bank Lebanon Economic Monitor, the economic and financial crisis is likely to rank in the top 10, possibly top 3, most severe crises episodes globally since the mid-nineteenth century. In the face of colossal challenges, continuous policy inaction and the absence of a fully functioning executive authority threaten already dire socio-economic conditions and a fragile social peace with no clear turning point in the horizon.","language":"en","title":"Lebanon Sinking into One of the Most Severe Global Crises Episodes, amidst Deliberate Inaction","URL":"https://www.worldbank.org/en/news/press-release/2021/05/01/lebanon-sinking-into-one-of-the-most-severe-global-crises-episodes","author":[{"family":"World Bank","given":""}],"accessed":{"date-parts":[["2022",3,13]]},"issued":{"date-parts":[["2021"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[28]<!-- [if supportFields]><![endif]--> In the study of Parikh et al. (2014), responses of 11,274 participants from the Centers for Disease Control Behavioral Risk Factor Surveillance Survey in the United States revealed financial barriers to be linked with fewer medical check-ups, HbA1c measurements, ophthalmologic and diabetic foot exams, and more vascular morbidity. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"G4bTxXIk","properties":{"formattedCitation":"[29]","plainCitation":"[29]","noteIndex":0},"citationItems":[{"id":4589,"uris":["http://zotero.org/users/8309088/items/FRQQT5RX"],"itemData":{"id":4589,"type":"article-journal","abstract":"BACKGROUND: The prevalence and consequences of financial barriers to health care among patients with multiple chronic diseases are poorly understood.\nOBJECTIVE: We sought to assess the prevalence of self-reported financial barriers to health care among individuals with diabetes and coronary heart disease (CHD) and to determine their association with access to care, quality of care and clinical outcomes.\nDESIGN: The 2007 Centers for Disease Control Behavioral Risk Factor Surveillance Survey.\nPARTICIPANTS: Diabetic patients with CHD.\nMAIN MEASURES: Financial barriers to health care were defined by a self-reported time in the past 12 months when the respondent needed to see a doctor but could not because of cost. The primary clinical outcome was vascular morbidity—a composite of stroke, retinopathy, nonhealing foot sores or bilateral foot amputations.\nKEY RESULTS: Among the 11,274 diabetics with CHD, 1,541 (13.7 %) reported financial barriers to health care. Compared to individuals without financial barriers, those with financial barriers had significantly reduced rates of medical assessments within the past 2 years, hemoglobin (Hgb) A1C measurements in the past year, cholesterol measurements at any time, eye and foot examinations within the past year, diabetic education, antihypertensive treatment, aspirin use and a higher prevalence of vascular morbidity. In multivariable analyses, financial barriers to health care were independently associated with reduced odds of medical checkups (Odds Ratio [OR], 0.61; 95 % Confidence Intervals [CI], 0.55–0.67), Hgb A1C measurement (OR, 0.85; 95 % CI, 0.77–0.94), cholesterol measurement (OR, 0.76; 95 % CI, 0.67–0.86), eye (OR, 0.85; 95 % CI, 0.79–0.92) and foot (OR, 0.92; 95 % CI, 0.84–1.00) examinations, diabetic education (OR, 0.93; 95 % CI, 0.87–0.99), aspirin use (OR, 0.88; 95 % CI, 0.81–0.96) and increased odds of vascular morbidity (OR, 1.23; 95 % CI, 1.14–1.33).\nCONCLUSIONS: In diabetic adults with CHD, financial barriers to health care were associated with impaired access to medical care, inferior quality of care and greater vascular morbidity. Eliminating financial barriers and adherence to guideline-based recommendations may improve the health of individuals with multiple chronic diseases.","container-title":"Journal of General Internal Medicine","DOI":"10.1007/s11606-013-2635-6","ISSN":"1525-1497","issue":"1","journalAbbreviation":"J Gen Intern Med","language":"eng","note":"PMID: 24078406\nPMCID: PMC3889957","page":"76-81","source":"PubMed","title":"The impact of financial barriers on access to care, quality of care and vascular morbidity among patients with diabetes and coronary heart disease","volume":"29","author":[{"family":"Parikh","given":"Puja B."},{"family":"Yang","given":"Jie"},{"family":"Leigh","given":"Steven"},{"family":"Dorjee","given":"Kunchok"},{"family":"Parikh","given":"Roopali"},{"family":"Sakellarios","given":"Nicholas"},{"family":"Meng","given":"Hongdao"},{"family":"Brown","given":"David L."}],"issued":{"date-parts":[["2014",1]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[29]<!-- [if supportFields]><![endif]--> As such, restricting the effects of financial hurdles on the application of optimal medical care can help reduce the rate of diabetic complications through interventions targeted towards financially challenged groups. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"BQDdNWAu","properties":{"formattedCitation":"[25]","plainCitation":"[25]","noteIndex":0},"citationItems":[{"id":3692,"uris":["http://zotero.org/users/8309088/items/JRJIWBJM"],"itemData":{"id":3692,"type":"article-journal","abstract":"OBJECTIVE: To examine physician and patient adherence to prevention guidelines in non-insulin-dependent diabetes mellitus (NIDDM) with attention to possible differences in adherence by patient race or ethnicity.\nRESEARCH DESIGN AND METHODS: We performed a cross-sectional chart review study of prevention practices, complications, and risk factors in 378 NIDDM patients (at least 5 years known duration) who were Permanente Medical Care Program, Oakland, CA. There were 232 blacks, 81 whites, 29 Hispanics, and 36 members of other races/ethnicities.\nRESULTS: Age- and duration-adjusted prevalence of 14 complications was low and, with the exception of diabetic retinopathy, did not differ significantly by race. An eight-point prevention score that reflected recommended use of glucose, HbA1c, high-density lipoprotein/total cholesterol, blood pressure and proteinuria testing, ophthalmology a and foot examinations, and diabetes education during a 2-year period did not differ by race/ethnicity (P = 0.36). The mean score (4.9 +/- 1.6) indicated that on average, five of eight guidelines were performed appropriately. Compliance was poorest for annual proteinuria checks (32.2%). No differences were noted by race/ethnicity in referrals to ophthalmology, weight reduction, or smoking cessation or in missed appointments or failure to keep referral visits.\nCONCLUSIONS: The absence of racial differences in either prevention practices or complication rates in this insured prepaid setting suggests that improved access to preventive services may be effective in reducing such differences nationally. However, adherence to several guidelines was < or = 50%, indicating that physicians are not sufficiently convinced of the necessity for these prevention measures.","container-title":"Diabetes Care","DOI":"10.2337/diacare.18.8.1124","ISSN":"0149-5992","issue":"8","journalAbbreviation":"Diabetes Care","language":"eng","note":"PMID: 7587847","page":"1124-1132","source":"PubMed","title":"Physician and patient prevention practices in NIDDM in a large urban managed-care organization","volume":"18","author":[{"family":"Martin","given":"T. L."},{"family":"Selby","given":"J. V."},{"family":"Zhang","given":"D."}],"issued":{"date-parts":[["1995",8]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[25]<!-- [if supportFields]><![endif]--> Another factor that likely contributed to decreased DN screening is the Covid pandemic, whereas decreased outpatient clinic visits were reported during this period, and the routine, non-urgent care of patients suffered greatly. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"FO91rhQ2","properties":{"formattedCitation":"[30]","plainCitation":"[30]","noteIndex":0},"citationItems":[{"id":3711,"uris":["http://zotero.org/users/8309088/items/Q3H54GLX"],"itemData":{"id":3711,"type":"article-journal","abstract":"OBJECTIVES: 1) To explore the possible impact of the pandemic on the health seeking behavior of the patients, 2) To explore the relation of socio-demographics on the utility of health-care facilities.\nMETHODS: This cross-sectional study was conducted by enrolling all patients ≥15 years of age presenting to the Out-Patient-Department of three main public-hospitals after obtaining ethical committee approval. A questionnaire with validated Urdu translation was filled by each participant that included socio-demographic data, pre-Covid and Covid-19 era health seeking behaviors and the impact of the pandemic on the utilization of healthcare facilities. Data was analyzed using SPSS V.19.\nRESULTS: A total of 393 patients were enrolled with a male preponderance (72%) and a median age range of 31-45 years. Fifty-eight percent of the study population was unemployed and 47.3% were seeking follow up care. The frequency of ER and multiple (>4 times) OPD visits were significantly decreased in the Covid-19 times whereas, the laboratory and radiology services were largely unaffected. A significant number of patients were not satisfied with the current healthcare facilities that was seen irrespective of the socio-demographic status. Emergency Room and radiology services were largely unaffected whereas, elective procedures and laboratory facilities were reported to be severely affected or delayed in relation to socio-demographic variables.\nCONCLUSIONS: Healthcare inequalities have widened and depression has shown a sharp rise during this pandemic. The over-burdened healthcare facilities at the verge of collapse may miss out on the chronic non-Covid patients which would ultimately lead to increased morbidity and mortality.","container-title":"Pakistan Journal of Medical Sciences","DOI":"10.12669/pjms.37.2.3536","ISSN":"1682-024X","issue":"2","journalAbbreviation":"Pak J Med Sci","language":"eng","note":"PMID: 33679953\nPMCID: PMC7931298","page":"576-581","source":"PubMed","title":"Amid COVID-19 pandemic, are non-COVID patients left in the lurch?","volume":"37","author":[{"family":"Alam","given":"Laima"},{"family":"Kazmi","given":"Syed Kumail Hasan"},{"family":"Alam","given":"Mafaza"},{"family":"Faraid","given":"Varqa"}],"issued":{"date-parts":[["2021"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[30]<!-- [if supportFields]><![endif]--> Park et al. (2022) studied 51,471 patients with diabetes from the Korea Community Health Survey and found that the degree of exposure to Covid was negatively associated with screening for complications of DM. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"rjPszlsL","properties":{"formattedCitation":"[31]","plainCitation":"[31]","noteIndex":0},"citationItems":[{"id":4591,"uris":["http://zotero.org/users/8309088/items/CBIF2JSP"],"itemData":{"id":4591,"type":"article-journal","abstract":"This study aimed to investigate the implementation of diabetes complications screening in South Korea during the coronavirus disease (COVID-19) outbreak. Data from the Korea Community Health Surveys conducted in 2019 and 2020 were used. This study included 51,471 participants. Multiple level analysis was used to investigate the relationships between screening for diabetic retinopathy and diabetic nephropathy and variables of both individual- and community-level factors in 2019 and 2020, before and after the COVID-19 outbreak. Diabetes nephropathy complications screening in 2020 had a lower odds ratio. However, regions heavily affected by COVID-19 showed a negative association with diabetes complications screening after the COVID-19 outbreak. For those being treated with medication for diabetes, there was a significant negative association with diabetic nephropathy screening after the outbreak. The COVID-19 outbreak was associated with a reduction in the use of diabetes nephropathy complications screening. Additionally, only regions heavily affected by COVID-19 spread showed a negative association with diabetes complications screening compared to before the COVID-19 outbreak. In this regard, it appears that many patients were unable to attend outpatient care due to COVID-19. As such, these patients should be encouraged to visit clinics for diabetes complications screening. Furthermore, alternative methods need to be developed to support these patients. Through these efforts, the development of diabetes-related complications should be prevented, and the costs associated with these complications will be reduced.","container-title":"International Journal of Environmental Research and Public Health","DOI":"10.3390/ijerph19095436","ISSN":"1661-7827","issue":"9","journalAbbreviation":"Int J Environ Res Public Health","note":"PMID: 35564832\nPMCID: PMC9104609","page":"5436","source":"PubMed Central","title":"Screening for Diabetes Complications during the COVID-19 Outbreak in South Korea","volume":"19","author":[{"family":"Park","given":"Yu","dropping-particle":"shin"},{"family":"Kim","given":"Soo Young"},{"family":"Park","given":"Eun-Cheol"},{"family":"Jang","given":"Sung-In"}],"issued":{"date-parts":[["2022",4,29]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[31]<!-- [if supportFields]><![endif]--> In Lebanon, one fifth of patients with DM could not maintain regular follow-up with their physicians because of the compounded effects of the economic crisis and Covid pandemic <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"gp3gLER5","properties":{"formattedCitation":"[32]","plainCitation":"[32]","noteIndex":0},"citationItems":[{"id":4344,"uris":["http://zotero.org/users/8309088/items/UM3TZ8PN"],"itemData":{"id":4344,"type":"article-journal","abstract":"Against the backdrop of Lebanon’s escalating multifaceted crisis which resulted in medication shortages for chronic diseases and unaffordable healthcare services, the current study endeavors to shed light on a critical yet overlooked facet of the Lebanese economic crisis– its profound impact on the health-seeking behaviors of patients with hypertension and diabetes mellitus.","container-title":"BMC Public Health","DOI":"10.1186/s12889-024-18116-6","ISSN":"1471-2458","issue":"1","journalAbbreviation":"BMC Public Health","page":"628","source":"BioMed Central","title":"Unveiling the unseen toll: exploring the impact of the Lebanese economic crisis on the health-seeking behaviors in a sample of patients with diabetes and hypertension","title-short":"Unveiling the unseen toll","volume":"24","author":[{"family":"Cherfane","given":"Michelle"},{"family":"Boueri","given":"Myriam"},{"family":"Issa","given":"Elio"},{"family":"Abdallah","given":"Racha"},{"family":"Hamam","given":"Ali"},{"family":"Sbeity","given":"Kassem"},{"family":"Saad","given":"Anthony"},{"family":"Abi-Gerges","given":"Aniella"}],"issued":{"date-parts":[["2024",2,27]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[32]<!-- [if supportFields]><![endif]-->, ultimately affecting DN screening. The main obstacles to screening were the predominance of expensive private health institutions in care delivery, and high costs of private insurance <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"SHjnEQ17","properties":{"formattedCitation":"[33]","plainCitation":"[33]","noteIndex":0},"citationItems":[{"id":4599,"uris":["http://zotero.org/users/8309088/items/CIBBRR6F"],"itemData":{"id":4599,"type":"article-journal","abstract":"Lebanon, an Eastern Mediterranean country with a lower-middle income status, that once boasted a health care system that was functional despite its challenges and complexity. However, it has faced a series of crises—economic, an influx of refugees, political instability, and recent sanctions—that have significantly impacted its aim, principles and values that has impacted upon its ability to function. The objective of this study is to delve into the health service delivery within the Lebanese system and conduct a SWOT analysis (assessing strengths, weaknesses, opportunities, and threats).","container-title":"BMC Health Services Research","DOI":"10.1186/s12913-024-11593-w","ISSN":"1472-6963","issue":"1","journalAbbreviation":"BMC Health Services Research","page":"1122","source":"BioMed Central","title":"Healthcare delivery in Lebanon: a critical scoping review of strengths, weaknesses, opportunities, and threats","title-short":"Healthcare delivery in Lebanon","volume":"24","author":[{"family":"Aoun","given":"Nour"},{"family":"Tajvar","given":"Maryam"}],"issued":{"date-parts":[["2024",9,27]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[33]<!-- [if supportFields]><![endif]-->, amidst inability of the Ministry of Public Health to cover care costs due to budget cuts. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"VmxHDnmV","properties":{"formattedCitation":"[34]","plainCitation":"[34]","noteIndex":0},"citationItems":[{"id":4434,"uris":["http://zotero.org/users/8309088/items/SIHSB889"],"itemData":{"id":4434,"type":"article-newspaper","abstract":"Lebanon's healthcare system is crumbling amid an economic crisis that has led to an exodus of thousands of doctors and nurses, forced private hospitals to close some departments and put further strains on the already stretched state sector.","container-title":"Reuters","language":"en","section":"Middle East","source":"www.reuters.com","title":"Lebanon's healthcare on brink of collapse amid crisis, says minister","URL":"https://www.reuters.com/world/middle-east/lebanons-healthcare-brink-collapse-amid-crisis-says-minister-2022-01-20/","author":[{"family":"Azhari","given":"Timour"},{"family":"Bassam","given":"Laila"},{"family":"Saad","given":"Maya"}],"accessed":{"date-parts":[["2024",6,9]]},"issued":{"date-parts":[["2022",1,20]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[34]<!-- [if supportFields]><![endif]--> Current trends of DN screening highlight the need for additional measures to improve adherence with screening guidelines, while keeping careful consideration for the underserved socioeconomic context of the country. As such, a funded national screening campaign can be organized yearly to diagnose DN earlier, which offers a monetary advantage that relies on low-cost interventions to circumvent the need for high-cost national expenditure on treatment of advanced kidney disease. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"VtWnZmIc","properties":{"formattedCitation":"[35,36]","plainCitation":"[35,36]","noteIndex":0},"citationItems":[{"id":3694,"uris":["http://zotero.org/users/8309088/items/89LGK3G5"],"itemData":{"id":3694,"type":"article-journal","abstract":"IMPORTANCE: Kidney disease is a substantial worldwide clinical and public health problem, but information about available care is limited.\nOBJECTIVE: To collect information on the current state of readiness, capacity, and competence for the delivery of kidney care across countries and regions of the world.\nDESIGN, SETTING, AND PARTICIPANTS: Questionnaire survey administered from May to September 2016 by the International Society of Nephrology (ISN) to 130 ISN-affiliated countries with sampling of key stakeholders (national nephrology society leadership, policy makers, and patient organization representatives) identified by the country and regional nephrology leadership through the ISN.\nMAIN OUTCOMES AND MEASURES: Core areas of country capacity and response for kidney care.\nRESULTS: Responses were received from 125 of 130 countries (96%), including 289 of 337 individuals (85.8%, with a median of 2 respondents [interquartile range, 1-3]), representing an estimated 93% (6.8 billion) of the world's population of 7.3 billion. There was wide variation in country readiness, capacity, and response in terms of service delivery, financing, workforce, information systems, and leadership and governance. Overall, 119 (95%), 95 (76%), and 94 (75%) countries had facilities for hemodialysis, peritoneal dialysis, and kidney transplantation, respectively. In contrast, 33 (94%), 16 (45%), and 12 (34%) countries in Africa had facilities for hemodialysis, peritoneal dialysis, and kidney transplantation, respectively. For chronic kidney disease (CKD) monitoring in primary care, serum creatinine with estimated glomerular filtration rate and proteinuria measurements were reported as always available in only 21 (18%) and 9 (8%) countries, respectively. Hemodialysis, peritoneal dialysis, and transplantation services were funded publicly and free at the point of care delivery in 50 (42%), 48 (51%), and 46 (49%) countries, respectively. The number of nephrologists was variable and was low (<10 per million population) in Africa, the Middle East, South Asia, and Oceania and South East Asia (OSEA) regions. Health information system (renal registry) availability was limited, particularly for acute kidney injury (8 countries [7%]) and nondialysis CKD (9 countries [8%]). International acute kidney injury and CKD guidelines were reportedly accessible in 52 (45%) and 62 (52%) countries, respectively. There was relatively low capacity for clinical studies in developing nations.\nCONCLUSIONS AND RELEVANCE: This survey demonstrated significant interregional and intraregional variability in the current capacity for kidney care across the world, including important gaps in services and workforce. Assuming the responses accurately reflect the status of kidney care in the respondent countries, the findings may be useful to inform efforts to improve the quality of kidney care worldwide.","container-title":"JAMA","DOI":"10.1001/jama.2017.4046","ISSN":"1538-3598","issue":"18","journalAbbreviation":"JAMA","language":"eng","note":"PMID: 28430830\nPMCID: PMC5470418","page":"1864-1881","source":"PubMed","title":"Assessment of Global Kidney Health Care Status","volume":"317","author":[{"family":"Bello","given":"Aminu K."},{"family":"Levin","given":"Adeera"},{"family":"Tonelli","given":"Marcello"},{"family":"Okpechi","given":"Ikechi G."},{"family":"Feehally","given":"John"},{"family":"Harris","given":"David"},{"family":"Jindal","given":"Kailash"},{"family":"Salako","given":"Babatunde L."},{"family":"Rateb","given":"Ahmed"},{"family":"Osman","given":"Mohamed A."},{"family":"Qarni","given":"Bilal"},{"family":"Saad","given":"Syed"},{"family":"Lunney","given":"Meaghan"},{"family":"Wiebe","given":"Natasha"},{"family":"Ye","given":"Feng"},{"family":"Johnson","given":"David W."}],"issued":{"date-parts":[["2017",5,9]]}}},{"id":3697,"uris":["http://zotero.org/users/8309088/items/J8GDJZQ3"],"itemData":{"id":3697,"type":"article-journal","abstract":"BACKGROUND: Preventive care for adults with diabetes has improved substantially in recent decades. We examined trends in the incidence of diabetes-related complications in the United States from 1990 through 2010.\nMETHODS: We used data from the National Health Interview Survey, the National Hospital Discharge Survey, the U.S. Renal Data System, and the U.S. National Vital Statistics System to compare the incidences of lower-extremity amputation, end-stage renal disease, acute myocardial infarction, stroke, and death from hyperglycemic crisis between 1990 and 2010, with age standardized to the U.S. population in the year 2000.\nRESULTS: Rates of all five complications declined between 1990 and 2010, with the largest relative declines in acute myocardial infarction (-67.8%; 95% confidence interval [CI], -76.2 to -59.3) and death from hyperglycemic crisis (-64.4%; 95% CI, -68.0 to -60.9), followed by stroke and amputations, which each declined by approximately half (-52.7% and -51.4%, respectively); the smallest decline was in end-stage renal disease (-28.3%; 95% CI, -34.6 to -21.6). The greatest absolute decline was in the number of cases of acute myocardial infarction (95.6 fewer cases per 10,000 persons; 95% CI, 76.6 to 114.6), and the smallest absolute decline was in the number of deaths from hyperglycemic crisis (-2.7; 95% CI, -2.4 to -3.0). Rate reductions were larger among adults with diabetes than among adults without diabetes, leading to a reduction in the relative risk of complications associated with diabetes. When expressed as rates for the overall population, in which a change in prevalence also affects complication rates, there was a decline in rates of acute myocardial infarction and death from hyperglycemic crisis (2.7 and 0.1 fewer cases per 10,000, respectively) but not in rates of amputation, stroke, or end-stage renal disease.\nCONCLUSIONS: Rates of diabetes-related complications have declined substantially in the past two decades, but a large burden of disease persists because of the continued increase in the prevalence of diabetes. (Funded by the Centers for Disease Control and Prevention.).","container-title":"The New England Journal of Medicine","DOI":"10.1056/NEJMoa1310799","ISSN":"1533-4406","issue":"16","journalAbbreviation":"N Engl J Med","language":"eng","note":"PMID: 24738668","page":"1514-1523","source":"PubMed","title":"Changes in diabetes-related complications in the United States, 1990-2010","volume":"370","author":[{"family":"Gregg","given":"Edward W."},{"family":"Li","given":"Yanfeng"},{"family":"Wang","given":"Jing"},{"family":"Burrows","given":"Nilka Rios"},{"family":"Ali","given":"Mohammed K."},{"family":"Rolka","given":"Deborah"},{"family":"Williams","given":"Desmond E."},{"family":"Geiss","given":"Linda"}],"issued":{"date-parts":[["2014",4,17]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[35,36]<!-- [if supportFields]><![endif]--> Campaigns can also provide awareness on the importance of controlling risk factors for kidney disease, including blood pressure and glycemic control which were linked with decreased morbidity in the literature. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"fYrho11z","properties":{"formattedCitation":"[37,38]","plainCitation":"[37,38]","noteIndex":0},"citationItems":[{"id":3673,"uris":["http://zotero.org/users/8309088/items/77ECTRDB"],"itemData":{"id":3673,"type":"article-journal","container-title":"Diabetes care","issue":"6","note":"ISBN: 0149-5992\npublisher: Am Diabetes Assoc","page":"977-982","title":"Effects of structured versus usual care on renal endpoint in type 2 diabetes: the SURE study: a randomized multicenter translational study","volume":"32","author":[{"family":"Chan","given":"Juliana C."},{"family":"So","given":"Wing-Yee"},{"family":"Yeung","given":"Chun-Yip"},{"family":"Ko","given":"Gary T."},{"family":"Lau","given":"Ip-Tim"},{"family":"Tsang","given":"Man-Wo"},{"family":"Lau","given":"Kam-Piu"},{"family":"Siu","given":"Sing-Chung"},{"family":"Li","given":"June K."},{"family":"Yeung","given":"Vincent T."}],"issued":{"date-parts":[["2009"]]}}},{"id":3674,"uris":["http://zotero.org/users/8309088/items/LYCW2HIC"],"itemData":{"id":3674,"type":"article-journal","container-title":"British journal of clinical pharmacology","issue":"5","note":"publisher: Wiley-Blackwell","page":"643","title":"The UK prospective diabetes study (UKPDS): clinical and therapeutic implications for type 2 diabetes","volume":"48","author":[{"family":"King","given":"Paromita"},{"family":"Peacock","given":"Ian"},{"family":"Donnelly","given":"Richard"}],"issued":{"date-parts":[["1999"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[37,38]<!-- [if supportFields]><![endif]--> Based on our findings, interventions should target young patients at an early stage of their DM course, ideally before DN progresses. At the institutional level, a quality improvement process, involving interprofessional cooperation, can greatly increase compliance with screening guidelines for kidney disease. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"PfQzlF4n","properties":{"formattedCitation":"[39]","plainCitation":"[39]","noteIndex":0},"citationItems":[{"id":3675,"uris":["http://zotero.org/users/8309088/items/SHYJGH2E"],"itemData":{"id":3675,"type":"article-journal","container-title":"Applied Nursing Research","note":"ISBN: 0897-1897\npublisher: Elsevier","page":"148-153","title":"Screening for diabetic kidney disease in primary care for the underinsured: a quality improvement initiative","volume":"30","author":[{"family":"Hughes-Carter","given":"Della L."},{"family":"Hoebeke","given":"Roberta E."}],"issued":{"date-parts":[["2016"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[39]<!-- [if supportFields]><![endif]--> This process involves reflection over gaps in medical practice in order to formulate actionable goals to improve DN screening. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"H1Pie8RF","properties":{"formattedCitation":"[39]","plainCitation":"[39]","noteIndex":0},"citationItems":[{"id":3675,"uris":["http://zotero.org/users/8309088/items/SHYJGH2E"],"itemData":{"id":3675,"type":"article-journal","container-title":"Applied Nursing Research","note":"ISBN: 0897-1897\npublisher: Elsevier","page":"148-153","title":"Screening for diabetic kidney disease in primary care for the underinsured: a quality improvement initiative","volume":"30","author":[{"family":"Hughes-Carter","given":"Della L."},{"family":"Hoebeke","given":"Roberta E."}],"issued":{"date-parts":[["2016"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[39]<!-- [if supportFields]><![endif]--> Both the incidence of DN in our cohort and scarcity of screening in Lebanon bolster the importance of applying ADA clinical practice guidelines for DN screening. The financial interference in our findings imparts economic considerations on these practice guidelines, i.e., stringent application of guidelines should apply to high-risk patients with more lenience on low-risk groups. Based on our findings, patients with higher HbA1c, dyslipidemia, and of older age are high-risk groups. As such, healthcare providers should give greater attention to these patients. Moreover, institutions can optimize DN screening cards/checklists for patients with diabetes, especially given siloed care delivery in Lebanon amidst decentralized and inconsistent initiation of care by primary care physicians. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"l1PjSv0T","properties":{"formattedCitation":"[40]","plainCitation":"[40]","noteIndex":0},"citationItems":[{"id":4594,"uris":["http://zotero.org/users/8309088/items/VHAPLUQ6"],"itemData":{"id":4594,"type":"article-journal","abstract":"Primary Health Care (PHC), as defined by the World Health Organization (WHO), aims to ensure optimal health and wellbeing by adopting a whole-of-socie","container-title":"Journal of Community Medicine & Public Health","ISSN":"2577-2228","language":"en","note":"publisher: Gavin Publishers","source":"www.gavinpublishers.com","title":"Bridging the Gap in Primary Healthcare: Identifying Gaps and Recommendations to Enhancing the Utilization of PHC Services in Lebanon: A Qualitative Study","title-short":"Bridging the Gap in Primary Healthcare","URL":"https://www.gavinpublishers.com/article/view/bridging-the-gap-in-primary-healthcare--identifying-gaps-and-recommendations-to--enhancing-the-utilization-of-phc-services-in-lebanon-a-qualitative-study","author":[{"family":"Tabaja","given":"Malak"},{"family":"Naccahe","given":"Mirna"},{"family":"Kapuria","given":"Bhrigu"},{"family":"Mazloum","given":"Farah"},{"family":"Corm","given":"Joelle El"},{"family":"ElKhoury","given":"Christina"},{"family":"Aung","given":"Kyaw"},{"family":"Syed","given":"Sabin"},{"family":"Hamadeh","given":"Randah"}],"accessed":{"date-parts":[["2025",5,16]]},"issued":{"date-parts":[["2024",4,5]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[40]<!-- [if supportFields]><![endif]--> Limitations Our medical center is an academic health center with relatively expensive pricing of laboratory tests, which may make it less appealing for routine workups. As a result, we may not have a comprehensive view of DN screening rates if patients who previously underwent testing at our center have shifted to other centers due to the ongoing financial crisis and Covid pandemic. This could lead to an underestimation of DN screening rates and challenge the external validity of our study to the entire population. Furthermore, our data was solely obtained retrospectively from our center's medical records, which could have been incomplete, inaccurate, or inconsistently recorded, since we did not have access to physicians' paper charts that could have included more detailed information on DN screening status and other factors related to DM control. Access to this information via electronic medical records could have enhanced our analysis. Selection bias is another limitation in this study due to the possible loss of follow-up of some patients. Moreover, residual confounding is a potential limitation since we could not take account of all potential confounders in our analysis. Finally, male predominance in our cohort is another potential confounder, however - despite no statistical significance - we have no explanation why men were more likely to be screened than women beyond increased DM frequencies in males. Conclusion This retrospective longitudinal study aimed to assess the rate of adherence to DN screening and follow-up testing among a sample of patients with DM from a university medical center. We demonstrated that less than 50% of patients with DM were screened for nephropathy, which is less than in countries of equivalent income, with numbers further declining throughout the years likely due to the financial crisis and the impact of the Covid pandemic on quality of outpatient care. We suggest the establishment of a national screening and awareness campaign to favor those suffering from the financial crisis, as screening would be more cost-effective than treatment once DN has been established. Factors found to be associated with better DN screening include lower HbA1c, younger age, hospitalization, and year of first abnormal HbA1c. On the other hand, no link was found between medication profile and the tendency to screen for DN. Declarations Author contributions All authors contributed equally and validated the final version of record. Conflicts Of Interest The Author(s) declare(s) that there is no conflict of interest. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Registration No registration applicable Data availability statement The data that support the findings of this study are available from the corresponding author upon reasonable request. 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Diabetes Care. 2016 Dec;39(12):2278–87. https://doi.org/10.2337/dc16-1246 25. Martin TL, Selby JV, Zhang D. Physician and Patient Prevention Practices in NIDDM in a Large Urban Managed-Care Organization. Diabetes Care. 1995 Aug 1;18(8):1124–32. https://doi.org/10.2337/diacare.18.8.1124 26. Mbanya JC, Aschner P, Gagliardino JJ, İlkova H, Lavalle F, Ramachandran A, et al. Screening, prevalence, treatment and control of kidney disease in patients with type 1 and type 2 diabetes in low-to-middle-income countries (2005–2017): the International Diabetes Management Practices Study (IDMPS). Diabetologia. 2021 Jun 1;64(6):1246–55. https://doi.org/10.1007/s00125-021-05406-6 27. Naeem F, McKay G, Fisher M. Cardiovascular outcomes trials with statins in diabetes. Br J Diabetes. 2018 Mar 1;18(1):7–13. https://doi.org/10.15277/bjd.2018.161 28. Lebanon Sinking into One of the Most Severe Global Crises Episodes, amidst Deliberate Inaction [Internet]. World Bank; 2021 [cited 2022 Mar 13]. Available from: https://www.worldbank.org/en/news/press-release/2021/05/01/lebanon-sinking-into-one-of-the-most-severe-global-crises-episodes 29. Parikh PB, Yang J, Leigh S, Dorjee K, Parikh R, Sakellarios N, et al. The impact of financial barriers on access to care, quality of care and vascular morbidity among patients with diabetes and coronary heart disease. J Gen Intern Med. 2014 Jan;29(1):76–81. https://doi.org/10.1007/s11606-013-2635-6 30. Alam L, Kazmi SKH, Alam M, Faraid V. Amid COVID-19 pandemic, are non-COVID patients left in the lurch? Pak J Med Sci. 2021;37(2):576–81. https://doi.org/10.12669/pjms.37.2.3536 31. Park YS, Kim SY, Park EC, Jang SI. Screening for Diabetes Complications during the COVID-19 Outbreak in South Korea. Int J Environ Res Public Health. 2022;19(9):5436. https://doi.org/10.3390/ijerph19095436 32. Cherfane M, Boueri M, Issa E, Abdallah R, Hamam A, Sbeity K, et al. Unveiling the unseen toll: exploring the impact of the Lebanese economic crisis on the health-seeking behaviors in a sample of patients with diabetes and hypertension. BMC Public Health. 2024 Feb 27;24(1):628. https://doi.org/10.1186/s12889-024-18116-6 33. Aoun N, Tajvar M. Healthcare delivery in Lebanon: a critical scoping review of strengths, weaknesses, opportunities, and threats. BMC Health Serv Res. 2024 Sep 27;24(1):1122. https://doi.org/10.1186/s12913-024-11593-w 34. Azhari T, Bassam L, Saad M. Lebanon’s healthcare on brink of collapse amid crisis, says minister. [Internet]. Reuters. 2022 [cited 2024 Jun 9]. Available from: https://www.reuters.com/world/middle-east/lebanons-healthcare-brink-collapse-amid-crisis-says-minister-2022-01-20/ 35. Bello AK, Levin A, Tonelli M, Okpechi IG, Feehally J, Harris D, et al. Assessment of Global Kidney Health Care Status. JAMA. 2017 May 9;317(18):1864–81. https://doi.org/10.1001/jama.2017.4046 36. Gregg EW, Li Y, Wang J, Burrows NR, Ali MK, Rolka D, et al. Changes in diabetes-related complications in the United States, 1990-2010. N Engl J Med. 2014 Apr 17;370(16):1514–23. https://doi.org/10.1056/nejmoa1310799 37. Chan JC, So WY, Yeung CY, Ko GT, Lau IT, Tsang MW, et al. Effects of structured versus usual care on renal endpoint in type 2 diabetes: the SURE study: a randomized multicenter translational study. Diabetes care. 2009;32(6):977–82. https://doi.org/10.2337/dc08-1908 38. King P, Peacock I, Donnelly R. The UK prospective diabetes study (UKPDS): clinical and therapeutic implications for type 2 diabetes. Br J Clin Pharmacol. 1999;48(5):643–8. https://doi.org/10.1046/j.1365-2125.1999.00092.x 39. Hughes-Carter DL, Hoebeke RE. Screening for diabetic kidney disease in primary care for the underinsured: a quality improvement initiative. Appl Nurs Res. 2016;30:148–53. https://doi.org/10.1016/j.apnr.2015.11.008 40. Tabaja M, Naccahe M, Kapuria B, Mazloum F, El Corm J, ElKhoury C, et al. (2024) Bridging the Gap in Primary Healthcare: Identifying Gaps and Recommendations to Enhancing the Utilization of PHC Services in Lebanon: A Qualitative Study. J Community Med Public Health. 2024;8:427. https://doi.org/10.29011/2577-2228.100427
Spinal Rosai-Dorfman Disease with Isolated Severe Neuropathic Pain: A Case Report
Introduction: Rosia-Dorfman disease is a rare histiocytic disorder that presents as generalized lymphadenopathy. Rarely, patients experience atypical extra-nodal manifestations which can mimic other diseases. Case Presentation: We report a challenging diagnosis of Rosai-Dorfman disease in a 52-year-old female presenting with isolated symptomatic neuropathic pain. After excluding common diseases, a challenging diagnosis was made based on imaging, CSF studies and clinical progression that showed thoracic spine involvement and emperipolesis confirming RDD diagnosis and with a great clinical response to corticosteroids. Discussion: Clinical, laboratory and radiologic manifestations of the disease can vary a lot depending on the areas involved and patient progression. This can lead to challenges in establishing the diagnosis and deciding on treatment. Then unusual, first reported manifestations in our patient made the diagnosis exceptionally challenging, highlighting the importance of this report. Conclusion: This disease can have an atypical presentation that should be detected early to avoid any delay in diagnosis or treatment. Unusual cases must be reported to aid in such a difficult diagnosis in future similar cases. Introduction Rosai-Dorfman disease (RDD) is a rare non-neoplastic histiocytic disorder, also known as sinus histiocytosis with massive lymphadenopathy. Histopathologically, RDD emperipolesis is seen as the phagocytosis of erythrocytes and lymphocytes without their destruction.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"ngf2xvTk","properties":{"formattedCitation":"\\super 1\\nosupersub{}","plainCitation":"1","noteIndex":0},"citationItems":[{"id":2597,"uris":["http://zotero.org/users/11334842/items/W5NWWSQL"],"itemData":{"id":2597,"type":"article-journal","container-title":"Pediatric Radiology","note":"publisher-place: Washington","page":"425–432","title":"Sinus Histiocytosis with Massive Lymphadenopathy (Rosai-Dorfman Disease)","volume":"20","author":[{"family":"McAlister","given":"W. H."},{"family":"Yousefi","given":"T. H."}],"issued":{"date-parts":[["1990"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->1<!-- [if supportFields]><![endif]--> Usually, this disease presents as painless lymphadenopathy affecting cervical nodes. However, extra-nodal involvement is seen in more than 40% of the cases. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1C5JFhX2","properties":{"formattedCitation":"\\super 2\\nosupersub{}","plainCitation":"2","noteIndex":0},"citationItems":[{"id":2590,"uris":["http://zotero.org/users/11334842/items/54W8YZIB"],"itemData":{"id":2590,"type":"article-journal","container-title":"Case Reports in Medicine","note":"publisher-place: Antananarivo, Madagascar\npublisher: Hindawi Publishing Corporation","title":"Rosai-Dorfman Disease Involving Multiple Organs: An Unusual Case with Poor Prognosis","author":[{"family":"Sendrasoa","given":"Fandresena Arilala"},{"family":"Ramarozatovo","given":"I. M."}],"issued":{"date-parts":[["2016"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->2<!-- [if supportFields]><![endif]--> Such presentations are challenging to diagnose because they have a plethora of symptoms and mimic many multisystemic illnesses and malignancies such as lymphomas, tuberculosis and other granulomatous diseases.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"r3LucQDJ","properties":{"formattedCitation":"\\super 3\\nosupersub{}","plainCitation":"3","noteIndex":0},"citationItems":[{"id":2724,"uris":["http://zotero.org/users/11334842/items/FRGYGMUK"],"itemData":{"id":2724,"type":"article-journal","abstract":"Rosai-Dorfman disease (RDD) is a rare medical condition with bilateral painless lymphadenopathy. We present the case of a young man diagnosed with a very unique presentation of Rosai-Dorfman disease., A 40-year-old African-American man presented with a firm, non-tender, progressive chest and neck mass appeared three months ago. Imaging of the neck demonstrated an 8.6-cm anterior neck subcutaneous soft tissue mass extending into the anterior mediastinum through the sternum with erosive changes in the sternum and the lesion is abutting the right common carotid artery and innominate vein and surrounds the medial aspect of the clavicles bilaterally. Ultrasound (US)-guided biopsy showed marked polytypic-appearing plasma cell proliferation associated with relatively prominent histiocytes with hemophagocytosis/emperipolesis and focal neutrophils. There were S100+ histiocytes; however, findings were not typical for RDD. As that biopsy was not diagnostic, incisional biopsy with adequate sampling was performed. Surgical pathology demonstrated a very abnormal infiltrate with prominent histiocytes including areas with the features of extranodal RDD. BRAF V600E immunohistochemistry (IHC) was negative. Modified radical neck dissection, proximal sternal resection and superior mediastinal nodal dissection surgery was recommended. However, the patient refused the procedure., Typical manifestations are lymphadenopathy with fever that our patient did not experience. Bone involvement happens in 5-10% of cases. There is not enough data about blood vessel invasion which make our case unique. Treatment plan is still controversial. Clinical monitoring is recommended if the symptoms are tolerable as regression has been reported in many cases (20-50%). Surgery is reserved for patients with vital organ involvement or extra-nodal disease.","container-title":"Cureus","DOI":"10.7759/cureus.7328","ISSN":"2168-8184","issue":"3","journalAbbreviation":"Cureus","note":"PMID: 32313769\nPMCID: PMC7164721","page":"e7328","source":"PubMed Central","title":"Rosai-Dorfman Disease and Unusual Local Invasive Presentation","volume":"12","author":[{"family":"Mohammadi","given":"Oranus"},{"family":"Zylberglait Lisigurski","given":"Miriam"},{"family":"Mehra","given":"Divy"},{"family":"Pishdad","given":"Reza"},{"family":"Gulec","given":"Seza"}]}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->3<!-- [if supportFields]><![endif]--> In addition, multi-site involvement is a common manifestation, affecting up to 73% of cases in some studies.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"IJpxOMLk","properties":{"formattedCitation":"\\super 4\\nosupersub{}","plainCitation":"4","noteIndex":0},"citationItems":[{"id":2727,"uris":["http://zotero.org/users/11334842/items/7RGJS23I"],"itemData":{"id":2727,"type":"article-journal","abstract":"Rosai-Dorfman disease is a rare subtype of non-Langerhans cell histiocytosis. With the last major report published in 1990, there is a paucity of contemporary data on this disease. Our objective was to report the clinicopathological features, treatments and outcomes of patients seen at a tertiary referral center. Sixty-four patients with histopathological diagnosis of Rosai-Dorfman disease were identified from 1994 to 2017 (median age 50 years; range, 2-79). The median duration from symptom onset to diagnosis was seven months (range, 0-128), which was also reflected in the number of biopsies required to establish the diagnosis (median 2; range, 1-6). The most common presentation was subcutaneous masses (40%). Of the 64 patients, 8% had classical (nodal only) and 92% had extra-nodal disease (67% extra-nodal only). The most common organs involved were skin and subcutaneous tissue (52%), followed by lymph nodes (33%). Three patients had an overlap with Erdheim-Chester disease, which had not been described before. Two of these were found to have MAP2K1 mutations. Commonly utilized first line treatments were surgical excision (38%) and systemic corticosteroids (27%). Corticosteroids led to a response in 56% of the cases. Of those treated initially, 15 (30%) patients developed recurrent disease. The most commonly used systemic agent was cladribine (n=6), with 67% overall response rate. Our study demonstrates that Rosai-Dorfman disease has diverse clinical manifestations and outcomes. While this disease has been historically considered a benign entity, a subset of patients endures an aggressive course necessitating the use of systemic therapies.","container-title":"Haematologica","DOI":"10.3324/haematol.2019.219626","ISSN":"1592-8721","issue":"2","language":"en","license":"Copyright (c)","note":"number: 2","page":"348-357","source":"haematologica.org","title":"Clinicopathological features, treatment approaches, and outcomes in Rosai-Dorfman disease","volume":"105","author":[{"family":"Goyal","given":"Gaurav"},{"family":"Ravindran","given":"Aishwarya"},{"family":"Young","given":"Jason R."},{"family":"Shah","given":"Mithun V."},{"family":"Bennani","given":"N. Nora"},{"family":"Patnaik","given":"Mrinal M."},{"family":"Nowakowski","given":"Grzegorz S."},{"family":"Thanarajasingam","given":"Gita"},{"family":"Habermann","given":"Thomas M."},{"family":"Vassallo","given":"Robert"},{"family":"Sher","given":"Taimur"},{"family":"Parikh","given":"Sameer A."},{"family":"Rech","given":"Karen L."},{"family":"Go","given":"Ronald S."}],"issued":{"date-parts":[["2020",2,1]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->4<!-- [if supportFields]><![endif]--> Involvement of the central nervous system (CNS) is rare with only 210 reported cases.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"ZFfqKh0f","properties":{"formattedCitation":"\\super 5\\nosupersub{}","plainCitation":"5","noteIndex":0},"citationItems":[{"id":2592,"uris":["http://zotero.org/users/11334842/items/5LDXFASD"],"itemData":{"id":2592,"type":"article-journal","container-title":"Neurological Research","note":"publisher-place: Jerusalem","title":"Diagnosis and Management of Rosai-Dorfman Disease Involving the Central Nervous System","author":[{"family":"Adeleye","given":"Amos O."},{"family":"Osunronbi","given":"G. A."}],"issued":{"date-parts":[["2010"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->5<!-- [if supportFields]><![endif]--> Due to this lack of literature, and in the absence of a consensus diagnostic and treatment approach, management of such patients is difficult.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"fnrCgrdk","properties":{"formattedCitation":"\\super 4\\nosupersub{}","plainCitation":"4","noteIndex":0},"citationItems":[{"id":2727,"uris":["http://zotero.org/users/11334842/items/7RGJS23I"],"itemData":{"id":2727,"type":"article-journal","abstract":"Rosai-Dorfman disease is a rare subtype of non-Langerhans cell histiocytosis. With the last major report published in 1990, there is a paucity of contemporary data on this disease. Our objective was to report the clinicopathological features, treatments and outcomes of patients seen at a tertiary referral center. Sixty-four patients with histopathological diagnosis of Rosai-Dorfman disease were identified from 1994 to 2017 (median age 50 years; range, 2-79). The median duration from symptom onset to diagnosis was seven months (range, 0-128), which was also reflected in the number of biopsies required to establish the diagnosis (median 2; range, 1-6). The most common presentation was subcutaneous masses (40%). Of the 64 patients, 8% had classical (nodal only) and 92% had extra-nodal disease (67% extra-nodal only). The most common organs involved were skin and subcutaneous tissue (52%), followed by lymph nodes (33%). Three patients had an overlap with Erdheim-Chester disease, which had not been described before. Two of these were found to have MAP2K1 mutations. Commonly utilized first line treatments were surgical excision (38%) and systemic corticosteroids (27%). Corticosteroids led to a response in 56% of the cases. Of those treated initially, 15 (30%) patients developed recurrent disease. The most commonly used systemic agent was cladribine (n=6), with 67% overall response rate. Our study demonstrates that Rosai-Dorfman disease has diverse clinical manifestations and outcomes. While this disease has been historically considered a benign entity, a subset of patients endures an aggressive course necessitating the use of systemic therapies.","container-title":"Haematologica","DOI":"10.3324/haematol.2019.219626","ISSN":"1592-8721","issue":"2","language":"en","license":"Copyright (c)","note":"number: 2","page":"348-357","source":"haematologica.org","title":"Clinicopathological features, treatment approaches, and outcomes in Rosai-Dorfman disease","volume":"105","author":[{"family":"Goyal","given":"Gaurav"},{"family":"Ravindran","given":"Aishwarya"},{"family":"Young","given":"Jason R."},{"family":"Shah","given":"Mithun V."},{"family":"Bennani","given":"N. Nora"},{"family":"Patnaik","given":"Mrinal M."},{"family":"Nowakowski","given":"Grzegorz S."},{"family":"Thanarajasingam","given":"Gita"},{"family":"Habermann","given":"Thomas M."},{"family":"Vassallo","given":"Robert"},{"family":"Sher","given":"Taimur"},{"family":"Parikh","given":"Sameer A."},{"family":"Rech","given":"Karen L."},{"family":"Go","given":"Ronald S."}],"issued":{"date-parts":[["2020",2,1]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->4<!-- [if supportFields]><![endif]--> Here, we present a patient with a progressive lymphadenopathy with thoracic spinal cord involvement, which is, to our knowledge, among the first reported cases of RDD with such a presentation. Case Report We describe a case of Mrs. X, a 52-year-old female who presented to us on the 30th of January, of 2023 for lower back pain radiating to the thighs bilaterally. Two months ago, she received a lumbar spine corticosteroid injection for radiculopathy. Four weeks later she started having headaches and low-grade fevers of 38.5C. She presented to another institution where a head scan revealed chronic sinusitis, and she was then discharged on antibiotics. The symptoms continued, and on 13th of January 2023 she was admitted in another institution, and a repeat head scan was also normal and a urinalysis, troponin, Brucella serology, Borrelia serology, gamma-glutamyl transferase, alkaline phosphatase, bilirubin, Aspartate transaminase, and Alkaline Transaminase were insignificant. She was discharged on symptomatic treatment. Two weeks later she started having progressively worsening abdominal pain with back tenderness radiating to the thighs, where she was readmitted, and a plain brain and spine Magnetic Resonance Imaging (MRI) showed mild degenerative spondylosis. An electromyogram (EMG) which was normal, and she was diagnosed with fibromyalgia. The symptoms persisted until the patient presented to our institution on January 30th, 2023. She is a non-smoker, occasional alcohol drinker without drug use history. She does not have previous medical or surgical history. She has no known allergies. There is no recent travel and no animal exposure. She lives in central Lebanon. Family history is significant for psoriasis, sarcoidosis, and breast cancer. Upon admission, physical exam was only significant for lower back, lower abdominal, and anterior and posterior thigh tenderness. Neurological exam was normal. Laboratory workup was unrevealing, provided in table 1. X-ray of the lumbosacral spine showed mild disc narrowing L5-S1. Enhanced brain and spine MRI showed a linear leptomeningeal enhancement of the mid-thoracic vertebra with intramedullary cord edema and patchy intramedullary and diffuse circumferential intradural extramedullary enhancement at the conus medullaris at L5-S1. This was suggestive of infection or inflammation. Lymphoma was ruled out by enhanced whole body Computed Tomography (CT). Blood flow cytometry excluded leukemia. Positron Emission Topography (PET) CT scan was negative for any nodal involvement or uptake. Upon further history, she mentioned that she had contact with refugees residing in Lebanon. This exposure, with the Lumbar Puncture (LP) and imaging results, raised the possibility of tuberculosis (TB) and she was started empirically on isoniazid, rifampin, pyranzimide, ethambutol with dexamethasone. The symptoms completely resolved after the first dose of dexamethasone. Cerebrospinal fluid (CSF) examination (table 2) showed monocytic cells and basophilic monocytoid cells with a high nucleus-to-cytoplasm ratio, occasional plasma cells, and images of emperipolesis, a proliferation of histiocytic cells with phagocytosed lymphoid cells that are not fragmented, with a collection of lymphocytic cells around them (figure 1). CSF cytology showed reactive neutrophils and macrophages without malignant cells. CSF cultures showed no growth and negative brucella antibodies. Acid-fast stain, and PCR for Tuberculosis were also negative. Peripheral blood smear showed no morphological abnormalities and a complete rheumatological workup was normal. TB treatment was stopped as the emperipolesis and histiocytosis were suggestive of Rosai-Dorfman Disease. The slides then underwent S-100 staining, which was strongly positive, further confirming the diagnosis. The patient was kept on dexamethasone, and her condition improved. She was discharged on prednisone 80 mg once daily. After 2 weeks, another LP showed decreasing protein concentration and leukocyte count (table 2). Follow up MRI showed findings consistent with ongoing epiduritis and resolving myelitis. The patient remained on prednisone, with no recurrence. Follow-up MRI showed improving T2 signal involving the central aspect of the spinal cord, decrease in intradural enhancement and loss of enhancement in the conus medullaris. On August 23, 2023, she was successfully tapered off steroids with no recurrence of symptoms. She is still symptom free today and has not had recurrence of symptoms. Follow-up has stopped and she was instructed to return to the clinic in case she has any new findings. Discussion This case illustrates an unusual presentation of RDD manifesting as cervical lymphadenopathy. The diagnosis could not be easily established due to the rarity of this disease and the unusual manifestations. Since first described in 1969, around 210 cases of RDD were reported, out of which 174 cases had CNS involvement.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"h1Ipa33a","properties":{"formattedCitation":"\\super 6\\nosupersub{}","plainCitation":"6","noteIndex":0},"citationItems":[{"id":2593,"uris":["http://zotero.org/users/11334842/items/U3365AMH"],"itemData":{"id":2593,"type":"article-journal","container-title":"Medicine","issue":"3","note":"publisher-place: Florida\npublisher: Lippincott Williams & Wilkins","title":"Rosai-Dorfman Disease of the Central Nervous System Report of 6 Cases and Review of the Literature","volume":"93","author":[{"family":"Sandoval-Sus","given":"Jose D."},{"family":"Hidalgo","given":"M. A.-L.-V."},{"family":"Montes","given":"J. J."}],"issued":{"date-parts":[["2014"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->6<!-- [if supportFields]><![endif]--> The pathogenesis of RDD is not well understood, believed to be a reactive non-neoplastic histiocytic disorder that lacks clonality. Several mutations are linked to RDD including ARAF, MAP2K1, NRAS, KRAS, and CSF1R as well as multiple gene alterations in intracellular trafficking, transcription, cell cycle regulation, Deoxyribonucleic acid (DNA) mismatch, and ubiquitin-proteasome pathway.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"3MiHLWas","properties":{"formattedCitation":"\\super 7\\nosupersub{}","plainCitation":"7","noteIndex":0},"citationItems":[{"id":2594,"uris":["http://zotero.org/users/11334842/items/ZYCY4ANQ"],"itemData":{"id":2594,"type":"article-journal","container-title":"Journal of Clinical Pathology","note":"publisher-place: Cape Town","title":"Rosai-Dorfman Disease: An Overview","author":[{"family":"Bruce-Brand","given":"Cassandra"},{"family":"Richardson","given":"J. O. M."}],"issued":{"date-parts":[["2020"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->7<!-- [if supportFields]><![endif]--> However, some presentations are linked to infectious etiologies such as EBV, CMV, HIV, and Herpes virus-6.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"ARVn52Ys","properties":{"formattedCitation":"\\super 2\\nosupersub{}","plainCitation":"2","noteIndex":0},"citationItems":[{"id":2590,"uris":["http://zotero.org/users/11334842/items/54W8YZIB"],"itemData":{"id":2590,"type":"article-journal","container-title":"Case Reports in Medicine","note":"publisher-place: Antananarivo, Madagascar\npublisher: Hindawi Publishing Corporation","title":"Rosai-Dorfman Disease Involving Multiple Organs: An Unusual Case with Poor Prognosis","author":[{"family":"Sendrasoa","given":"Fandresena Arilala"},{"family":"Ramarozatovo","given":"I. M."}],"issued":{"date-parts":[["2016"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->2<!-- [if supportFields]><![endif]--> The prevalence of RDD is about 1:200 000, most common in young adult males of African descent.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"54eHUbfu","properties":{"formattedCitation":"\\super 8\\nosupersub{}","plainCitation":"8","noteIndex":0},"citationItems":[{"id":"XtxpTS9d/Xf43s2Gt","uris":["http://zotero.org/users/11334842/items/CRDEBJVZ"],"itemData":{"id":2595,"type":"article-journal","container-title":"Blood","issue":"26","note":"publisher-place: Toronto","page":"2877–2890","title":"Consensus Recommendations for the Diagnosis and Clinical Management of Rosai-Dorfman-Destombes Disease","volume":"131","author":[{"family":"Abla","given":"Oussama"},{"family":"Weitzman","given":"E. J."},{"family":"Allen","given":"J."}],"issued":{"date-parts":[["2018",6]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->8<!-- [if supportFields]><![endif]--> RDD is classified as sporadic, cutaneous, and familial. The sporadic form classically presents as painless bilateral cervical lymphadenopathy mostly in the head and neck. It can also present as an extra-nodal disease in 40% of cases.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"OHTOpAVU","properties":{"formattedCitation":"\\super 8\\nosupersub{}","plainCitation":"8","noteIndex":0},"citationItems":[{"id":"XtxpTS9d/Xf43s2Gt","uris":["http://zotero.org/users/11334842/items/CRDEBJVZ"],"itemData":{"id":2595,"type":"article-journal","container-title":"Blood","issue":"26","note":"publisher-place: Toronto","page":"2877–2890","title":"Consensus Recommendations for the Diagnosis and Clinical Management of Rosai-Dorfman-Destombes Disease","volume":"131","author":[{"family":"Abla","given":"Oussama"},{"family":"Weitzman","given":"E. J."},{"family":"Allen","given":"J."}],"issued":{"date-parts":[["2018",6]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->8<!-- [if supportFields]><![endif]--> The median age is 50 years and it seems to have a slight female predominance of 1.5:1.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"pqQybywD","properties":{"formattedCitation":"\\super 4\\nosupersub{}","plainCitation":"4","noteIndex":0},"citationItems":[{"id":2727,"uris":["http://zotero.org/users/11334842/items/7RGJS23I"],"itemData":{"id":2727,"type":"article-journal","abstract":"Rosai-Dorfman disease is a rare subtype of non-Langerhans cell histiocytosis. With the last major report published in 1990, there is a paucity of contemporary data on this disease. Our objective was to report the clinicopathological features, treatments and outcomes of patients seen at a tertiary referral center. Sixty-four patients with histopathological diagnosis of Rosai-Dorfman disease were identified from 1994 to 2017 (median age 50 years; range, 2-79). The median duration from symptom onset to diagnosis was seven months (range, 0-128), which was also reflected in the number of biopsies required to establish the diagnosis (median 2; range, 1-6). The most common presentation was subcutaneous masses (40%). Of the 64 patients, 8% had classical (nodal only) and 92% had extra-nodal disease (67% extra-nodal only). The most common organs involved were skin and subcutaneous tissue (52%), followed by lymph nodes (33%). Three patients had an overlap with Erdheim-Chester disease, which had not been described before. Two of these were found to have MAP2K1 mutations. Commonly utilized first line treatments were surgical excision (38%) and systemic corticosteroids (27%). Corticosteroids led to a response in 56% of the cases. Of those treated initially, 15 (30%) patients developed recurrent disease. The most commonly used systemic agent was cladribine (n=6), with 67% overall response rate. Our study demonstrates that Rosai-Dorfman disease has diverse clinical manifestations and outcomes. While this disease has been historically considered a benign entity, a subset of patients endures an aggressive course necessitating the use of systemic therapies.","container-title":"Haematologica","DOI":"10.3324/haematol.2019.219626","ISSN":"1592-8721","issue":"2","language":"en","license":"Copyright (c)","note":"number: 2","page":"348-357","source":"haematologica.org","title":"Clinicopathological features, treatment approaches, and outcomes in Rosai-Dorfman disease","volume":"105","author":[{"family":"Goyal","given":"Gaurav"},{"family":"Ravindran","given":"Aishwarya"},{"family":"Young","given":"Jason R."},{"family":"Shah","given":"Mithun V."},{"family":"Bennani","given":"N. Nora"},{"family":"Patnaik","given":"Mrinal M."},{"family":"Nowakowski","given":"Grzegorz S."},{"family":"Thanarajasingam","given":"Gita"},{"family":"Habermann","given":"Thomas M."},{"family":"Vassallo","given":"Robert"},{"family":"Sher","given":"Taimur"},{"family":"Parikh","given":"Sameer A."},{"family":"Rech","given":"Karen L."},{"family":"Go","given":"Ronald S."}],"issued":{"date-parts":[["2020",2,1]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->4<!-- [if supportFields]><![endif]--> The gender and age distribution go with our patient demographics but she did not seem to have a family history of such a presentation. Skin involvement is seen in 10% of extra-nodal RDD cases, but isolated cutaneous manifestations are rare. Usually, this presents as skin-painless nodules, papules, or plaques affecting the head, neck, and upper trunk areas. These lesions can vary in size, shape, and color. The main diagnostic method is a histopathological picture of large histiocytes with abundant cytoplasm and emperipolesis showing phagocytosis of intact lymphocytic cells.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"WWkNfLvu","properties":{"formattedCitation":"\\super 9\\nosupersub{}","plainCitation":"9","noteIndex":0},"citationItems":[{"id":2596,"uris":["http://zotero.org/users/11334842/items/QDWRBMUP"],"itemData":{"id":2596,"type":"article-journal","container-title":"Dermatology and Therapy","issue":"4","note":"publisher-place: Warsaw","page":"1443–1448","title":"Cutaneous Rosai-Dorfman Disease: A Treatment Challenge","volume":"11","author":[{"family":"Gawdzik","given":"Anna"},{"family":"Król","given":"B. W.-K."}],"issued":{"date-parts":[["2021",8]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->9<!-- [if supportFields]><![endif]--> Intrathoracic involvement is not common, only seen in 2% of patients with RDD. The symptoms can mimic other diseases presenting as cough or even respiratory failure, it can appear as lung nodules, intrathoracic lymphadenopathy, pleural effusions, or interstitial lung disease. Cardiac involvement is extremely rare, described in less than 0.2% of patients.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"7nYiCzVi","properties":{"formattedCitation":"\\super 8\\nosupersub{}","plainCitation":"8","noteIndex":0},"citationItems":[{"id":"XtxpTS9d/Xf43s2Gt","uris":["http://zotero.org/users/11334842/items/CRDEBJVZ"],"itemData":{"id":2595,"type":"article-journal","container-title":"Blood","issue":"26","note":"publisher-place: Toronto","page":"2877–2890","title":"Consensus Recommendations for the Diagnosis and Clinical Management of Rosai-Dorfman-Destombes Disease","volume":"131","author":[{"family":"Abla","given":"Oussama"},{"family":"Weitzman","given":"E. J."},{"family":"Allen","given":"J."}],"issued":{"date-parts":[["2018",6]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->8<!-- [if supportFields]><![endif]--> Renal involvement is usually associated with poor prognosis. Symptoms can vary from flank pan and hematuria to severe renal failure which makes the diagnosis much more complicated.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"TBeXc7bi","properties":{"formattedCitation":"\\super 1\\nosupersub{}","plainCitation":"1","noteIndex":0},"citationItems":[{"id":2597,"uris":["http://zotero.org/users/11334842/items/W5NWWSQL"],"itemData":{"id":2597,"type":"article-journal","container-title":"Pediatric Radiology","note":"publisher-place: Washington","page":"425–432","title":"Sinus Histiocytosis with Massive Lymphadenopathy (Rosai-Dorfman Disease)","volume":"20","author":[{"family":"McAlister","given":"W. H."},{"family":"Yousefi","given":"T. H."}],"issued":{"date-parts":[["1990"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->1<!-- [if supportFields]><![endif]--> Testicular involvement in men, bone, gastric and hematological manifestations of RDD have been described in the literature.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"tRe3Ewga","properties":{"formattedCitation":"\\super 10\\nosupersub{}","plainCitation":"10","noteIndex":0},"citationItems":[{"id":2730,"uris":["http://zotero.org/users/11334842/items/X9IGNXFS"],"itemData":{"id":2730,"type":"article-journal","abstract":"A 47 year old Chinese man with diabetes mellitus and previously treated pulmonary tuberculosis presented with painless right testicular enlargement of 1 month's duration. He underwent an orchidectomy for presumed testicular neoplasm corroborated clinicoradiologically. Histological examination of the testicular mass revealed an inflammatory lesion comprising lymphocytes, plasma cells and sheets of pale staining histiocytes, some containing lymphocytes within their ample cytoplasm, suggestive of emperipolesis. S100 immunohistochemistry stained the histiocytes, while ultrastructural examination confirmed emperipolesis. A diagnosis of Rosai‐Dorfman disease was made, an exceedingly rare testicular lesion. Clinicoradiological findings mimicked a neoplasm, while the inflammatory histological appearances with occasionally discerned multinucleated cells raised the possibility of xanthogranulomatous orchitis. Tuberculous orchitis was excluded through negative Ziehl‐Neelsen stains and PCR for mycobacterium, while seminoma, which sometimes features a predominant inflammatory component obscuring neoplastic cells, was excluded by absent immunostaining for placental alkaline phosphatase and CD117.","container-title":"Journal of Clinical Pathology","DOI":"10.1136/jcp.2005.028423","ISSN":"0021-9746","issue":"3","journalAbbreviation":"J Clin Pathol","note":"PMID: 16505287\nPMCID: PMC1860335","page":"325-327","source":"PubMed Central","title":"Rosai‐Dorfman disease of the testis: an unusual entity that mimics testicular malignancy","title-short":"Rosai‐Dorfman disease of the testis","volume":"59","author":[{"family":"Fernandopulle","given":"S M"},{"family":"Hwang","given":"J S G"},{"family":"Kuick","given":"C H"},{"family":"Lui","given":"J"},{"family":"Tan","given":"P H"},{"family":"Siow","given":"W‐Y"},{"family":"Wong","given":"M"}],"issued":{"date-parts":[["2006",3]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->10<!-- [if supportFields]><![endif]--> However, our case had isolated CNS affection which made the diagnosis rather challenging. She had none of these described systemic findings. The lack of such systemic symptoms in our patient made the diagnosis more challenging. Involvement of the CNS is described in about 5 % of cases.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"54uYCzvv","properties":{"formattedCitation":"\\super 6\\nosupersub{}","plainCitation":"6","noteIndex":0},"citationItems":[{"id":2593,"uris":["http://zotero.org/users/11334842/items/U3365AMH"],"itemData":{"id":2593,"type":"article-journal","container-title":"Medicine","issue":"3","note":"publisher-place: Florida\npublisher: Lippincott Williams & Wilkins","title":"Rosai-Dorfman Disease of the Central Nervous System Report of 6 Cases and Review of the Literature","volume":"93","author":[{"family":"Sandoval-Sus","given":"Jose D."},{"family":"Hidalgo","given":"M. A.-L.-V."},{"family":"Montes","given":"J. J."}],"issued":{"date-parts":[["2014"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->6<!-- [if supportFields]><![endif]--> Moreover, Only 25% of the lesions reported are spinal, where it is mostly a manifestation of systemic disease.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"cc5exjSa","properties":{"formattedCitation":"\\super 6\\nosupersub{}","plainCitation":"6","noteIndex":0},"citationItems":[{"id":2593,"uris":["http://zotero.org/users/11334842/items/U3365AMH"],"itemData":{"id":2593,"type":"article-journal","container-title":"Medicine","issue":"3","note":"publisher-place: Florida\npublisher: Lippincott Williams & Wilkins","title":"Rosai-Dorfman Disease of the Central Nervous System Report of 6 Cases and Review of the Literature","volume":"93","author":[{"family":"Sandoval-Sus","given":"Jose D."},{"family":"Hidalgo","given":"M. A.-L.-V."},{"family":"Montes","given":"J. J."}],"issued":{"date-parts":[["2014"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->6<!-- [if supportFields]><![endif]--> In contrast to systemic RDD, isolated CNS manifestations lack constitutional symptoms and are usually unilateral. Symptoms may vary from headaches to seizures, motor and sensory abnormalities, and focal deficits.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"39aMllLn","properties":{"formattedCitation":"\\super 6\\nosupersub{}","plainCitation":"6","noteIndex":0},"citationItems":[{"id":2593,"uris":["http://zotero.org/users/11334842/items/U3365AMH"],"itemData":{"id":2593,"type":"article-journal","container-title":"Medicine","issue":"3","note":"publisher-place: Florida\npublisher: Lippincott Williams & Wilkins","title":"Rosai-Dorfman Disease of the Central Nervous System Report of 6 Cases and Review of the Literature","volume":"93","author":[{"family":"Sandoval-Sus","given":"Jose D."},{"family":"Hidalgo","given":"M. A.-L.-V."},{"family":"Montes","given":"J. J."}],"issued":{"date-parts":[["2014"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->6<!-- [if supportFields]><![endif]--> Our patient's symptoms included lower back pain, non-specific abdominal pain, and thigh pain, which was unusual as per the literature. In a similar case reported by Huang et al., the patient experienced sciatica-like symptoms caused by RDD of the sacral bone, which is a very rare presentation seen with our patient. Ophthalmic manifestations are described in 10% of CNS cases, where sinus and ophthalmic involvement is seen due to the close anatomical area. This can lead to vision impairment, with nasal obstruction, epistaxis and facial deformity.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"04Ni5lWN","properties":{"formattedCitation":"\\super 1\\nosupersub{}","plainCitation":"1","noteIndex":0},"citationItems":[{"id":2597,"uris":["http://zotero.org/users/11334842/items/W5NWWSQL"],"itemData":{"id":2597,"type":"article-journal","container-title":"Pediatric Radiology","note":"publisher-place: Washington","page":"425–432","title":"Sinus Histiocytosis with Massive Lymphadenopathy (Rosai-Dorfman Disease)","volume":"20","author":[{"family":"McAlister","given":"W. H."},{"family":"Yousefi","given":"T. H."}],"issued":{"date-parts":[["1990"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->1<!-- [if supportFields]><![endif]--> Our patient did not have any ophthalmic symptoms. Goyal et al. reported 60 cases of RDD followed-up from 1994 to 2017. They found that only 8% had nodal disease and above 90% had extra-nodal manifestations. 52% had skin and subcutaneous masses, 21% had bone or muscle involvement and 4 cases (6.2%) had CNS frontal lesions. Interestingly, the median time from initial presentation to diagnosis was around 7 months, which highlights how challenging the diagnosis of RDD is. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"4bcDc3B5","properties":{"formattedCitation":"\\super 4\\nosupersub{}","plainCitation":"4","noteIndex":0},"citationItems":[{"id":2727,"uris":["http://zotero.org/users/11334842/items/7RGJS23I"],"itemData":{"id":2727,"type":"article-journal","abstract":"Rosai-Dorfman disease is a rare subtype of non-Langerhans cell histiocytosis. With the last major report published in 1990, there is a paucity of contemporary data on this disease. Our objective was to report the clinicopathological features, treatments and outcomes of patients seen at a tertiary referral center. Sixty-four patients with histopathological diagnosis of Rosai-Dorfman disease were identified from 1994 to 2017 (median age 50 years; range, 2-79). The median duration from symptom onset to diagnosis was seven months (range, 0-128), which was also reflected in the number of biopsies required to establish the diagnosis (median 2; range, 1-6). The most common presentation was subcutaneous masses (40%). Of the 64 patients, 8% had classical (nodal only) and 92% had extra-nodal disease (67% extra-nodal only). The most common organs involved were skin and subcutaneous tissue (52%), followed by lymph nodes (33%). Three patients had an overlap with Erdheim-Chester disease, which had not been described before. Two of these were found to have MAP2K1 mutations. Commonly utilized first line treatments were surgical excision (38%) and systemic corticosteroids (27%). Corticosteroids led to a response in 56% of the cases. Of those treated initially, 15 (30%) patients developed recurrent disease. The most commonly used systemic agent was cladribine (n=6), with 67% overall response rate. Our study demonstrates that Rosai-Dorfman disease has diverse clinical manifestations and outcomes. While this disease has been historically considered a benign entity, a subset of patients endures an aggressive course necessitating the use of systemic therapies.","container-title":"Haematologica","DOI":"10.3324/haematol.2019.219626","ISSN":"1592-8721","issue":"2","language":"en","license":"Copyright (c)","note":"number: 2","page":"348-357","source":"haematologica.org","title":"Clinicopathological features, treatment approaches, and outcomes in Rosai-Dorfman disease","volume":"105","author":[{"family":"Goyal","given":"Gaurav"},{"family":"Ravindran","given":"Aishwarya"},{"family":"Young","given":"Jason R."},{"family":"Shah","given":"Mithun V."},{"family":"Bennani","given":"N. Nora"},{"family":"Patnaik","given":"Mrinal M."},{"family":"Nowakowski","given":"Grzegorz S."},{"family":"Thanarajasingam","given":"Gita"},{"family":"Habermann","given":"Thomas M."},{"family":"Vassallo","given":"Robert"},{"family":"Sher","given":"Taimur"},{"family":"Parikh","given":"Sameer A."},{"family":"Rech","given":"Karen L."},{"family":"Go","given":"Ronald S."}],"issued":{"date-parts":[["2020",2,1]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->4<!-- [if supportFields]><![endif]--> This was one of the largest studies of RDD reported. While a lot of the mentioned presentations were not seen with our patient, the article highlights the long median periods to establish the diagnosis in the presence of some suggestive findings. In our case, and with the lack of the already rare disease manifestations, the diagnosis remained challenging to establish. In another case series, 3 middle-aged patients with multiple subcutaneous and intra-abdominal masses were found to have RDD after excisional biopsy.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"XRbPe9ru","properties":{"formattedCitation":"\\super 11\\nosupersub{}","plainCitation":"11","noteIndex":0},"citationItems":[{"id":2733,"uris":["http://zotero.org/users/11334842/items/JX4N2UZ5"],"itemData":{"id":2733,"type":"article-journal","abstract":"Rosai-Dorfman Disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy, is an uncommon histiocytic condition characterized by massive histopathological aggregation of CD1-a negative, CD68-positive, and S100-positive histiocytes. It was initially described by Destombes in 1965 under the term “adenitis with lipid excess.” However, it is named after Rosai and Dorfman who reported further histopathological features of the disease in 1969. The diagnosis of this non-Langerhans cell histiocytosis can be challenging and requires high clinical suspicion. The diagnostic process usually involves imaging, tissue biopsies, and genetic testing as needed. In this case series, we are presenting three cases of rare disease. Case 2 had both nodal and extranodal forms, which makes this case rarer than cases 1 and 3, which present with extranodal lesions.","container-title":"Cureus","DOI":"10.7759/cureus.35193","ISSN":"2168-8184","issue":"2","journalAbbreviation":"Cureus","note":"PMID: 36960255\nPMCID: PMC10030647","page":"e35193","source":"PubMed Central","title":"Rosai-Dorfman Disease: Case Series and Literature Review","title-short":"Rosai-Dorfman Disease","volume":"15","author":[{"family":"Magableh","given":"Hamzah M"},{"family":"Jaber","given":"Hamzh D"},{"family":"Magableh","given":"Ahmad M"},{"family":"Alrabiah","given":"Mohammed A"},{"family":"Dahhan","given":"Abdulaziz F"},{"family":"Azzam","given":"Ayman Z"},{"family":"Amin","given":"Tarek"}]}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->11<!-- [if supportFields]><![endif]--> According to the authors, extra-nodal disease can mimic malignancy and other viral illnesses, and that in most cases immunohistochemistry (IHC) is the main tool for diagnosis, especially that it excludes other diseases.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"qnl4jxhH","properties":{"formattedCitation":"\\super 11\\nosupersub{}","plainCitation":"11","noteIndex":0},"citationItems":[{"id":2733,"uris":["http://zotero.org/users/11334842/items/JX4N2UZ5"],"itemData":{"id":2733,"type":"article-journal","abstract":"Rosai-Dorfman Disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy, is an uncommon histiocytic condition characterized by massive histopathological aggregation of CD1-a negative, CD68-positive, and S100-positive histiocytes. It was initially described by Destombes in 1965 under the term “adenitis with lipid excess.” However, it is named after Rosai and Dorfman who reported further histopathological features of the disease in 1969. The diagnosis of this non-Langerhans cell histiocytosis can be challenging and requires high clinical suspicion. The diagnostic process usually involves imaging, tissue biopsies, and genetic testing as needed. In this case series, we are presenting three cases of rare disease. Case 2 had both nodal and extranodal forms, which makes this case rarer than cases 1 and 3, which present with extranodal lesions.","container-title":"Cureus","DOI":"10.7759/cureus.35193","ISSN":"2168-8184","issue":"2","journalAbbreviation":"Cureus","note":"PMID: 36960255\nPMCID: PMC10030647","page":"e35193","source":"PubMed Central","title":"Rosai-Dorfman Disease: Case Series and Literature Review","title-short":"Rosai-Dorfman Disease","volume":"15","author":[{"family":"Magableh","given":"Hamzah M"},{"family":"Jaber","given":"Hamzh D"},{"family":"Magableh","given":"Ahmad M"},{"family":"Alrabiah","given":"Mohammed A"},{"family":"Dahhan","given":"Abdulaziz F"},{"family":"Azzam","given":"Ayman Z"},{"family":"Amin","given":"Tarek"}]}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->11<!-- [if supportFields]><![endif]--> In our case, IHC and pathologic examination of the CSF is what helped most in establishing the diagnosis, which goes with what this case series concludes. According to Mar et al, computed tomography (CT), MRI, and Positron Emission Tomography (PET) are important tools to suspect RDD.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"21vAOK6j","properties":{"formattedCitation":"\\super 12\\nosupersub{}","plainCitation":"12","noteIndex":0},"citationItems":[{"id":2736,"uris":["http://zotero.org/users/11334842/items/JC354BVG"],"itemData":{"id":2736,"type":"article-journal","abstract":"OBJECTIVE. Rosai-Dorfman disease (RDD) is an uncommon benign histiocytic disorder. Extranodal involvement occurs in 43% and most commonly involves the head and neck, skin, and bones. We review less common imaging findings outside the head and neck.CONCLUSION. The imaging manifestations of RDD overlap with a variety of neoplastic and nonneoplastic conditions. Confirmation of an RDD diagnosis is based on specific histologic features. Radiologic assessment is used to rule out multifocality on initial workup and to evaluate treatment response.","container-title":"American Journal of Roentgenology","DOI":"10.2214/AJR.15.15504","ISSN":"0361-803X","issue":"4","note":"publisher: American Roentgen Ray Society","page":"721-732","source":"ajronline.org (Atypon)","title":"Rosai-Dorfman Disease: Manifestations Outside of the Head and Neck","title-short":"Rosai-Dorfman Disease","volume":"208","author":[{"family":"Mar","given":"Winnie A."},{"family":"Yu","given":"Jonathan H."},{"family":"Knuttinen","given":"Martha Gracia"},{"family":"Horowitz","given":"Jeanne M."},{"family":"David","given":"Odile"},{"family":"Wilbur","given":"Andrew"},{"family":"Menias","given":"Christine O."}],"issued":{"date-parts":[["2017",4]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->12<!-- [if supportFields]><![endif]--> However, the diagnosis can overlap with other conditions like lymphoma, infection, and granulomatous disease. There are a variety of appearances on radiology for different RDD involvements.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"smkATHb2","properties":{"formattedCitation":"\\super 12\\nosupersub{}","plainCitation":"12","noteIndex":0},"citationItems":[{"id":2736,"uris":["http://zotero.org/users/11334842/items/JC354BVG"],"itemData":{"id":2736,"type":"article-journal","abstract":"OBJECTIVE. Rosai-Dorfman disease (RDD) is an uncommon benign histiocytic disorder. Extranodal involvement occurs in 43% and most commonly involves the head and neck, skin, and bones. We review less common imaging findings outside the head and neck.CONCLUSION. The imaging manifestations of RDD overlap with a variety of neoplastic and nonneoplastic conditions. Confirmation of an RDD diagnosis is based on specific histologic features. Radiologic assessment is used to rule out multifocality on initial workup and to evaluate treatment response.","container-title":"American Journal of Roentgenology","DOI":"10.2214/AJR.15.15504","ISSN":"0361-803X","issue":"4","note":"publisher: American Roentgen Ray Society","page":"721-732","source":"ajronline.org (Atypon)","title":"Rosai-Dorfman Disease: Manifestations Outside of the Head and Neck","title-short":"Rosai-Dorfman Disease","volume":"208","author":[{"family":"Mar","given":"Winnie A."},{"family":"Yu","given":"Jonathan H."},{"family":"Knuttinen","given":"Martha Gracia"},{"family":"Horowitz","given":"Jeanne M."},{"family":"David","given":"Odile"},{"family":"Wilbur","given":"Andrew"},{"family":"Menias","given":"Christine O."}],"issued":{"date-parts":[["2017",4]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->12<!-- [if supportFields]><![endif]--> For instance, cardiothoracic involvement can manifest as lymphadenopathy, tracheobronchial or lung nodules, pleural effusions, or cardiac masses.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"n47akb1Q","properties":{"formattedCitation":"\\super 12\\nosupersub{}","plainCitation":"12","noteIndex":0},"citationItems":[{"id":2736,"uris":["http://zotero.org/users/11334842/items/JC354BVG"],"itemData":{"id":2736,"type":"article-journal","abstract":"OBJECTIVE. Rosai-Dorfman disease (RDD) is an uncommon benign histiocytic disorder. Extranodal involvement occurs in 43% and most commonly involves the head and neck, skin, and bones. We review less common imaging findings outside the head and neck.CONCLUSION. The imaging manifestations of RDD overlap with a variety of neoplastic and nonneoplastic conditions. Confirmation of an RDD diagnosis is based on specific histologic features. Radiologic assessment is used to rule out multifocality on initial workup and to evaluate treatment response.","container-title":"American Journal of Roentgenology","DOI":"10.2214/AJR.15.15504","ISSN":"0361-803X","issue":"4","note":"publisher: American Roentgen Ray Society","page":"721-732","source":"ajronline.org (Atypon)","title":"Rosai-Dorfman Disease: Manifestations Outside of the Head and Neck","title-short":"Rosai-Dorfman Disease","volume":"208","author":[{"family":"Mar","given":"Winnie A."},{"family":"Yu","given":"Jonathan H."},{"family":"Knuttinen","given":"Martha Gracia"},{"family":"Horowitz","given":"Jeanne M."},{"family":"David","given":"Odile"},{"family":"Wilbur","given":"Andrew"},{"family":"Menias","given":"Christine O."}],"issued":{"date-parts":[["2017",4]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->12<!-- [if supportFields]><![endif]--> Abdominal involvement can affect any organ system, often presenting as masses or lymphadenopathy. Pelvic involvement can involve pelvic lymph nodes, and reproductive systems, and musculoskeletal involvement can manifest as subcutaneous masses or lytic bone lesions. Nevertheless, definitive diagnosis requires a multidisciplinary approach. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"8uFzFhdb","properties":{"formattedCitation":"\\super 12\\nosupersub{}","plainCitation":"12","noteIndex":0},"citationItems":[{"id":2736,"uris":["http://zotero.org/users/11334842/items/JC354BVG"],"itemData":{"id":2736,"type":"article-journal","abstract":"OBJECTIVE. Rosai-Dorfman disease (RDD) is an uncommon benign histiocytic disorder. Extranodal involvement occurs in 43% and most commonly involves the head and neck, skin, and bones. We review less common imaging findings outside the head and neck.CONCLUSION. The imaging manifestations of RDD overlap with a variety of neoplastic and nonneoplastic conditions. Confirmation of an RDD diagnosis is based on specific histologic features. Radiologic assessment is used to rule out multifocality on initial workup and to evaluate treatment response.","container-title":"American Journal of Roentgenology","DOI":"10.2214/AJR.15.15504","ISSN":"0361-803X","issue":"4","note":"publisher: American Roentgen Ray Society","page":"721-732","source":"ajronline.org (Atypon)","title":"Rosai-Dorfman Disease: Manifestations Outside of the Head and Neck","title-short":"Rosai-Dorfman Disease","volume":"208","author":[{"family":"Mar","given":"Winnie A."},{"family":"Yu","given":"Jonathan H."},{"family":"Knuttinen","given":"Martha Gracia"},{"family":"Horowitz","given":"Jeanne M."},{"family":"David","given":"Odile"},{"family":"Wilbur","given":"Andrew"},{"family":"Menias","given":"Christine O."}],"issued":{"date-parts":[["2017",4]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->12<!-- [if supportFields]><![endif]--> Rosai Dorfman Disease involving the CNS has a wide array of radiological findings. While intracranial lesions mostly consist of extra-axial masses mimicking a meningioma or diffuse pachymeningitis, spinal or epidural lesions are most common in the cervical and thoracic areas which are usually enhancing on MRI T2.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"pCXvAuci","properties":{"formattedCitation":"\\super 8\\nosupersub{}","plainCitation":"8","noteIndex":0},"citationItems":[{"id":"XtxpTS9d/Xf43s2Gt","uris":["http://zotero.org/users/11334842/items/CRDEBJVZ"],"itemData":{"id":2595,"type":"article-journal","container-title":"Blood","issue":"26","note":"publisher-place: Toronto","page":"2877–2890","title":"Consensus Recommendations for the Diagnosis and Clinical Management of Rosai-Dorfman-Destombes Disease","volume":"131","author":[{"family":"Abla","given":"Oussama"},{"family":"Weitzman","given":"E. J."},{"family":"Allen","given":"J."}],"issued":{"date-parts":[["2018",6]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->8<!-- [if supportFields]><![endif]--> A case report in 2019 describes significant edema on T1 and T2 and thickened meninges.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"KFL6V7wU","properties":{"formattedCitation":"\\super 13\\nosupersub{}","plainCitation":"13","noteIndex":0},"citationItems":[{"id":"XtxpTS9d/qihMpze6","uris":["http://zotero.org/users/11334842/items/RVXR9ZA9"],"itemData":{"id":2604,"type":"article-journal","abstract":"Rosai–Dorfman disease (RDD) with isolated central nervous system (CNS) involvement is an extremely rare disease. Most RDD of the CNS present as dural-based mass mimicking meningioma and other common lesions, which makes preoperative accurate diagnosis of great difficulty. We searched the pathology database in our hospital and 3 cases of RDD with isolated CNS involvement were finally included in our study. Radiological and clinical findings of these three cases were retrospectively analyzed. The lesions of 2 cases were dura-based against the cerebral convexity, presenting as a sheet-shaped thickened dura mater, another case was located just across the cerebral falx, the dural display in the center was intact. The 3 cases showed low signal intensity on T2-weighted image, obviously enhanced, significantly surrounding edema and finger-like protuberance but no invasion of the brain parenchyma or no sign of hyperplasia or sclerosis of the surrounding cranial bones. In conclusion, when we come across a disease that mimicking meningioma, especially when it manifests as the above radiological features, we should considered it might be a kind of proliferative disease of the meninges, such as RDD.","container-title":"Medicine","DOI":"10.1097/MD.0000000000015365","ISSN":"0025-7974","issue":"19","journalAbbreviation":"Medicine (Baltimore)","note":"PMID: 31083164\nPMCID: PMC6531066","page":"e15365","source":"PubMed Central","title":"Radiological and clinical findings of isolated meningeal Rosai–Dorfman disease of the central nervous system","volume":"98","author":[{"family":"Wen","given":"Jia-Hua"},{"family":"Wang","given":"Chao"},{"family":"Jin","given":"Yun-Yun"},{"family":"Xu","given":"Duo"},{"family":"Jiang","given":"Biao"},{"family":"He","given":"Xiao-Juan"},{"family":"Min","given":"Jie"}],"issued":{"date-parts":[["2019",5,13]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->13<!-- [if supportFields]><![endif]--> Another one describes a large enhancing soft-tissue mass at L5-S1, with histopathological findings of Rosai-Dorfman disease and complete resolution on steroids.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"pIc2iHKx","properties":{"formattedCitation":"\\super 14\\nosupersub{}","plainCitation":"14","noteIndex":0},"citationItems":[{"id":"XtxpTS9d/XsalHeoo","uris":["http://zotero.org/users/11334842/items/9JYWK9M6"],"itemData":{"id":2600,"type":"article-journal","container-title":"Cureus","issue":"6","note":"publisher-place: Doha","page":"e26317","title":"Rosai-Dorfman Disease of the Spine: A Case Report of a Rare Disease and Review of the Literature","volume":"14","author":[{"family":"Bahauddin","given":"R."},{"family":"Al-Taie","given":"A."},{"family":"Al-Khafaji","given":"F."},{"family":"Barah","given":"A."}],"issued":{"date-parts":[["2022"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->14<!-- [if supportFields]><![endif]--> Furthermore, a case series of 11 patients with isolated CNS RDD reported the possible involvement of the spinal canal, skull dura and different cerebral lobes.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"hqUluGmA","properties":{"formattedCitation":"\\super 15\\nosupersub{}","plainCitation":"15","noteIndex":0},"citationItems":[{"id":2601,"uris":["http://zotero.org/users/11334842/items/FFPYNRBU"],"itemData":{"id":2601,"type":"article-journal","container-title":"Modern Pathology","DOI":"10.1038/modpathol.3880278","issue":"3","page":"172–178","title":"Rosai-Dorfman Disease Isolated to the Central Nervous System: A Report of 11 Cases","volume":"14","author":[{"family":"Andriko","given":"J.-A. W."},{"family":"Morrison","given":"A."},{"family":"Colegial","given":"C. H."},{"family":"Davis","given":"B. J."},{"family":"Jones","given":"R. V."}],"issued":{"date-parts":[["2001"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->15<!-- [if supportFields]><![endif]--> Isolated thoracic spine findings were, to our knowledge, never described before, which presented a radiological picture that is not very familiar, which posed further difficulty in reaching a diagnosis with our patient. CSF and histopathological studies usually offer the definitive diagnosis. They show elevated proteins, low glucose, leukocytosis with lymphocytic predominance and emperipolesis as seen in our case. The histiocytes involved are usually positive for S100+, CD68+, and CD1a− (CD: Cluster of Differentiation).<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"4VUHrmIh","properties":{"formattedCitation":"\\super 8\\nosupersub{}","plainCitation":"8","noteIndex":0},"citationItems":[{"id":"XtxpTS9d/Xf43s2Gt","uris":["http://zotero.org/users/11334842/items/CRDEBJVZ"],"itemData":{"id":2595,"type":"article-journal","container-title":"Blood","issue":"26","note":"publisher-place: Toronto","page":"2877–2890","title":"Consensus Recommendations for the Diagnosis and Clinical Management of Rosai-Dorfman-Destombes Disease","volume":"131","author":[{"family":"Abla","given":"Oussama"},{"family":"Weitzman","given":"E. J."},{"family":"Allen","given":"J."}],"issued":{"date-parts":[["2018",6]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->8<!-- [if supportFields]><![endif]--> In our case they were positive for S100. On cytology, we hypercellularity with predominance of lymphocytes and histiocytes with emperipolesis is what is usually seen.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"k2Uox7vN","properties":{"formattedCitation":"\\super 16\\nosupersub{}","plainCitation":"16","noteIndex":0},"citationItems":[{"id":2607,"uris":["http://zotero.org/users/11334842/items/2DYZ2A4X"],"itemData":{"id":2607,"type":"article-journal","abstract":"Context:\nRosai–Dorfman disease, also known as Sinus histiocytosis with massive lymphadenopathy, is a benign proliferative disorder of histiocytes. It typically affects lymph nodes; however, extranodal disease is being increasingly reported. The latter entity poses exceptional diagnostic challenge clinico-radiologically by forming mass lesions. Fine needle aspiration cytology (FNAC) is the investigation of choice to avoid unnecessary surgery as the majority are self-limiting.\n\nAims:\nThe objective is to assess the utility of FNAC in the diagnosis of Rosai–Dorfman disease and to highlight the diagnostic difficulties.\n\nMaterial and Methods:\nThe cytology features of 12 cases of Rosai–Dorfman disease were analyzed and correlated with histopathology and immunohistochemistry.\n\nResults:\nThe present study included six nodal and six extranodal Rosai–Dorfman disease. The cytology smears showed a variable number of large histiocytes exhibiting characteristic emperipolesis. Ten cases diagnosed as Rosai–Dorfman disease on cytology were confirmed on histopathology. The presence of granulomas, atypical histiocytes, insignificant emperipolesis, and eosinophil infiltration were the challenges we faced.\n\nConclusions:\nFNAC, a simple and cost-effective method with its unique cytology features is the first line of investigation in the diagnosis of Rosai–Dorfman disease.","container-title":"Journal of Cytology","DOI":"10.4103/JOC.JOC_4_19","ISSN":"0970-9371","issue":"1","journalAbbreviation":"J Cytol","note":"PMID: 31942098\nPMCID: PMC6947738","page":"46-52","source":"PubMed Central","title":"Cytological Diagnosis of Rosai–Dorfman Disease: A Study of Twelve Cases with Emphasis on Diagnostic Challenges","title-short":"Cytological Diagnosis of Rosai–Dorfman Disease","volume":"37","author":[{"family":"Rajyalakshmi","given":"Rallapalli"},{"family":"Akhtar","given":"Mohammad"},{"family":"Swathi","given":"Yarlagadda"},{"family":"Chakravarthi","given":"Ranjani"},{"family":"Bhaskara Reddy","given":"Jeeru"},{"family":"Beulah Priscilla","given":"Maddirala"}],"issued":{"date-parts":[["2020"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->16<!-- [if supportFields]><![endif]-->These findings were seen on CSF examination and IHC with our patient, and they were what confirmed our diagnosis. Although there are no clear guidelines for the treatment of Rosai Dorfman disease, a consensus management was established by Abla et. Al. Although observation might be suitable for patients with uncomplicated lymphadenopathy, cutaneous RDD, or post-operatively for unifocal disease, treatment with prednisone (40-70 mg per day) or dexamethasone (8-20 mg per day) is recommended.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"7bW4xZCu","properties":{"formattedCitation":"\\super 8\\nosupersub{}","plainCitation":"8","noteIndex":0},"citationItems":[{"id":"XtxpTS9d/Xf43s2Gt","uris":["http://zotero.org/users/11334842/items/CRDEBJVZ"],"itemData":{"id":2595,"type":"article-journal","container-title":"Blood","issue":"26","note":"publisher-place: Toronto","page":"2877–2890","title":"Consensus Recommendations for the Diagnosis and Clinical Management of Rosai-Dorfman-Destombes Disease","volume":"131","author":[{"family":"Abla","given":"Oussama"},{"family":"Weitzman","given":"E. J."},{"family":"Allen","given":"J."}],"issued":{"date-parts":[["2018",6]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->8<!-- [if supportFields]><![endif]--> Surgical resection can also be an option for unifocal extra-nodal disease, or symptomatic cranial, spinal, sinus or airway disease. Neurosurgical evaluation in our patient deemed the lesions unresectable for no discrete masses could be found and due to the diffuse spread of enhancement involving different parts of the spinal cord and vertebrae. Sometimes, cladribine or methotrexate can be considered for in refractive diseases, however the exact duration of the therapy is unknown. Our patient was not offered any treatment other than steroids. Clofarabine is currently under study for CNS involvement but the myelosuppressive effects and the high cost of this medication are of concern.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"ylzhoROZ","properties":{"formattedCitation":"\\super 8\\nosupersub{}","plainCitation":"8","noteIndex":0},"citationItems":[{"id":"XtxpTS9d/Xf43s2Gt","uris":["http://zotero.org/users/11334842/items/CRDEBJVZ"],"itemData":{"id":2595,"type":"article-journal","container-title":"Blood","issue":"26","note":"publisher-place: Toronto","page":"2877–2890","title":"Consensus Recommendations for the Diagnosis and Clinical Management of Rosai-Dorfman-Destombes Disease","volume":"131","author":[{"family":"Abla","given":"Oussama"},{"family":"Weitzman","given":"E. J."},{"family":"Allen","given":"J."}],"issued":{"date-parts":[["2018",6]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->8<!-- [if supportFields]><![endif]--> In our case, the patient had an excellent response to prednisone and entered long-term remission, without any relapses even after steroids were tapered and stopped. She enjoys a healthy life with no residual symptoms. Other treatments are also available, such as cladribine, methotrexate, vincristine and mercaptopurine.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"9Maaxu1V","properties":{"formattedCitation":"\\super 8\\nosupersub{}","plainCitation":"8","noteIndex":0},"citationItems":[{"id":"XtxpTS9d/Xf43s2Gt","uris":["http://zotero.org/users/11334842/items/CRDEBJVZ"],"itemData":{"id":"XtxpTS9d/Xf43s2Gt","type":"article-journal","container-title":"Blood","issue":"26","note":"publisher-place: Toronto","page":"2877–2890","title":"Consensus Recommendations for the Diagnosis and Clinical Management of Rosai-Dorfman-Destombes Disease","volume":"131","author":[{"family":"Abla","given":"Oussama"},{"family":"Weitzman","given":"E. J."},{"family":"Allen","given":"J."}],"issued":{"date-parts":[["2018",6]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->8<!-- [if supportFields]><![endif]--> However, such treatments have undesirable side effects such as immunosuppression, and the data regarding their effect on RDD is less conclusive. Up until this time, they are considered in cases refractory to corticosteroids or when corticosteroids are contraindicated.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"wVWeU12M","properties":{"formattedCitation":"\\super 8\\nosupersub{}","plainCitation":"8","noteIndex":0},"citationItems":[{"id":"XtxpTS9d/Xf43s2Gt","uris":["http://zotero.org/users/11334842/items/CRDEBJVZ"],"itemData":{"id":"XtxpTS9d/Xf43s2Gt","type":"article-journal","container-title":"Blood","issue":"26","note":"publisher-place: Toronto","page":"2877–2890","title":"Consensus Recommendations for the Diagnosis and Clinical Management of Rosai-Dorfman-Destombes Disease","volume":"131","author":[{"family":"Abla","given":"Oussama"},{"family":"Weitzman","given":"E. J."},{"family":"Allen","given":"J."}],"issued":{"date-parts":[["2018",6]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->8<!-- [if supportFields]><![endif]--> Some case reports also consider sirolimus, but its use in this context is very limited, described more in the pediatric population. Besides, sirolimus availability and price can be limitations to its usage.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"t5Y7up2d","properties":{"formattedCitation":"\\super 8\\nosupersub{}","plainCitation":"8","noteIndex":0},"citationItems":[{"id":"XtxpTS9d/Xf43s2Gt","uris":["http://zotero.org/users/11334842/items/CRDEBJVZ"],"itemData":{"id":"XtxpTS9d/Xf43s2Gt","type":"article-journal","container-title":"Blood","issue":"26","note":"publisher-place: Toronto","page":"2877–2890","title":"Consensus Recommendations for the Diagnosis and Clinical Management of Rosai-Dorfman-Destombes Disease","volume":"131","author":[{"family":"Abla","given":"Oussama"},{"family":"Weitzman","given":"E. J."},{"family":"Allen","given":"J."}],"issued":{"date-parts":[["2018",6]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->8<!-- [if supportFields]><![endif]--> With regards to our patient, the initial non-specific symptoms of lower back pain and systemic symptoms of fever and headaches led to multiple inconclusive investigations. Initial differential diagnosis included infectious and rheumatologic causes, including degenerative disc diseases and discitis and ankylosing spondylitis. Upon imaging, MRI findings suggested inflammatory or infectious origins of the pain, excluding solid malignancies and discitis but keeping inflammatory and infectious etiology. Moreover, conditions such as sarcoidosis or granulomatous disease could be excluded by MRI. among the differentials. CSF analysis with emperipolesis is what shifted the diagnosis to RDD, confirmed by S-100 staining, which is very sensitive but not specific for RDD. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Q5UEN2uv","properties":{"formattedCitation":"\\super 12\\nosupersub{}","plainCitation":"12","noteIndex":0},"citationItems":[{"id":2736,"uris":["http://zotero.org/users/11334842/items/JC354BVG"],"itemData":{"id":2736,"type":"article-journal","abstract":"OBJECTIVE. Rosai-Dorfman disease (RDD) is an uncommon benign histiocytic disorder. Extranodal involvement occurs in 43% and most commonly involves the head and neck, skin, and bones. We review less common imaging findings outside the head and neck.CONCLUSION. The imaging manifestations of RDD overlap with a variety of neoplastic and nonneoplastic conditions. Confirmation of an RDD diagnosis is based on specific histologic features. Radiologic assessment is used to rule out multifocality on initial workup and to evaluate treatment response.","container-title":"American Journal of Roentgenology","DOI":"10.2214/AJR.15.15504","ISSN":"0361-803X","issue":"4","note":"publisher: American Roentgen Ray Society","page":"721-732","source":"ajronline.org (Atypon)","title":"Rosai-Dorfman Disease: Manifestations Outside of the Head and Neck","title-short":"Rosai-Dorfman Disease","volume":"208","author":[{"family":"Mar","given":"Winnie A."},{"family":"Yu","given":"Jonathan H."},{"family":"Knuttinen","given":"Martha Gracia"},{"family":"Horowitz","given":"Jeanne M."},{"family":"David","given":"Odile"},{"family":"Wilbur","given":"Andrew"},{"family":"Menias","given":"Christine O."}],"issued":{"date-parts":[["2017",4]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->12<!-- [if supportFields]><![endif]--> Emperipolesis and S100 staining together is what establishes the diagnosis. This case is a very good example of the diagnostic journey it takes to detect RDD, which involves a multi-disciplinary approach of neurology, rheumatology, infectious diseases, radiology and pathology. Conclusion RDD is a benign disease of histiocytes manifesting as a resistant refractory generalized lymphadenopathy sometimes with systemic manifestations that can be quite variant. Due to the wide array of reported sites of involvement, the clinical presentation as well as laboratory and radiologic findings can be diverse, posing a diagnostic challenge. While there are many cases describing RDD with CNS involvement, none has mentioned thoracic meningeal inflammation. To date, only CSF histopathological studies and microscopic evaluation aid in a definitive diagnosis. This is why reporting all new presentations of this disease is important, as they can aid in establishing an identifiable plethora of findings that help in establishing a timely diagnosis and a more cost-effective approach to this already rare disease. References 1. McAlister WH, Herman T, Dehner LP. Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease). Pediatr Radiol. 1990 Jul 1;20(6):425–32. https://doi.org/10.1007/BF02075199 2. Sendrasoa FA, Ranaivo IM, Raharolahy O, Andrianarison M, Razanakoto NH, Ramarozatovo LS, et al. Rosai-Dorfman disease involving multiple organs: An unusual case with poor prognosis. Case Rep Med. 2016 Oct 31;2016:3920516. https://doi.org/10.1155/2016/3920516 3. Mohammadi O, Zylberglait Lisigurski M, Mehra D, Pishdad R, Gulec S. Rosai-Dorfman Disease and Unusual Local Invasive Presentation. Cureus. 2020 Mar 19;12(3):e7328. https://doi.org/10.7759/cureus.7328 4. Goyal G, Ravindran A, Young JR, Shah MV, Bennani NN, Patnaik MM, et al. Clinicopathological features, treatment approaches, and outcomes in Rosai-Dorfman disease. Haematologica. 2020 Jan 31;105(2):348–57. https://doi.org/10.3324/haematol.2019.219626 5. Adeleye AO, Amir G, Fraifeld S, Shoshan Y, Umansky F, Spektor S. Diagnosis and management of Rosai–Dorfman disease involving the central nervous system. Neurol Res. 2010 Jul 1;32(6):572–8. https://doi.org/10.1179/016164109X12608733393836 6. Sandoval-Sus JD, Sandoval-Leon AC, Chapman JR, Velazquez-Vega J, Borja MJ, Rosenberg S, et al. Rosai-Dorfman Disease of the Central Nervous System: Report of 6 Cases and Review of the Literature. Medicine. 2014;93(3). https://doi.org/10.1097/MD.0000000000000030 7. Bruce-Brand C, Schneider JW, Schubert P. Rosai-Dorfman disease: an overview. J Clin Pathol. 2020 Nov 1;73(11):697. https://doi.org/10.1136/jclinpath-2020-206733 8. Abla O, Jacobsen E, Picarsic J, Krenova Z, Jaffe R, Emile JF, et al. Consensus recommendations for the diagnosis and clinical management of Rosai-Dorfman-Destombes disease. Blood. 2018 Jun 28;131(26):2877–90. https://doi.org/10.1182/blood-2018-03-839753 9. Gawdzik A, Ziarkiewicz-Wróblewska B, Chlebicka I, Jankowska-Konsur A, Szepietowski JC, Maj J. Cutaneous Rosai-Dorfman Disease: A Treatment Challenge. Dermatol Ther (Heidelb). 2021 Aug 1;11(4):1443–8. https://doi.org/10.1007/s13555-021-00557-1 10. Fernandopulle SM, Hwang JSG, Kuick CH, Lui J, Tan PH, Siow WY, et al. Rosai-Dorfman disease of the testis: an unusual entity that mimics testicular malignancy. J Clin Pathol. 2006 Mar 1;59(3):325–327. https://doi.org/10.1136/jcp.2005.028423 11. Magableh HM, Jaber HD, Magableh AM, Alrabiah MA, Dahhan AF, Azzam AZ, et al. Rosai-Dorfman Disease: Case Series and Literature Review. Cureus. 2023 Feb 19;15(2):e35193. https://doi.org/10.7759/cureus.35193 12. Mar WA, Yu JH, Knuttinen MG, Horowitz JM, David O, Wilbur A, et al. Rosai-Dorfman Disease: Manifestations Outside of the Head and Neck. Am J Roentgenol. 2017 Apr 1;208(4):721–32. https://doi.org/10.2214/AJR.15.15504 13. Wen JH, Wang C, Jin YY, Xu D, Jiang B, He XJ, et al. Radiological and clinical findings of isolated meningeal Rosai–Dorfman disease of the central nervous system. Medicine. 2019;98(19):e15365. https://doi.org/10.1097/MD.0000000000015365 14. Bahauddin R, Al-Taie A, Al-Khafaji F, Barah A. Rosai-Dorfman Disease of the Spine: A Case Report of a Rare Disease and Review of the Literature. Cureus. 2022 Jun 25;14(6):e26317. https://doi.org/10.7759/cureus.26317 15. Andriko JAW, Morrison A, Colegial CH, Davis BJ, Jones RV. Rosai-Dorfman Disease Isolated to the Central Nervous System: A Report of 11 Cases. Mod Pathol. 2001 Mar 1;14(3):172–8. https://doi.org/10.1038/modpathol.3880278 16. Rajyalakshmi R, Akhtar M, Swathi Y, Chakravarthi R, Reddy JB, Maddirala BP. Cytological Diagnosis of Rosai–Dorfman Disease: A Study of Twelve Cases with Emphasis on Diagnostic Challenges. J Cytol. 2020;37(1). https://doi.org/10.4103/JOC.JOC_4_19
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Post-COVID-19 Kawasaki-Like Vasculitis and Endocarditis: A Case Report
Background: Coronavirus Disease of 2019 (COVID-19) can cause mild to severe infection, but with a combination of inflammatory complications that target virtually anywhere in the body. Cardiac complications remain of utmost importance as they have the highest association with mortality. Case presentation: A 32-year-old male presents with a fever of unknown origin for a period of 3 months post SARS-CoV-2 infection. He was found to have endocarditis and underwent an aortic valve replacement that was complicated by an aortic aneurysm, needing another surgery. The fever and aneurysm remitted after a new COVID-19 infection and the patient underwent a Bentall procedure with reimplantation of the coronary arteries. Discussion: Cardiac complications of COVID-19 can range from small to large arteritis, valvopathy and aortic aneurysms, which can have significant morbidity and mortality, leading to the need of surgery and prolonged treatment. The scarcity of such cases makes reporting imperative so that clearer guidelines of management can be established. Conclusion: Cardiovascular complications of COVID-19 remain the scariest and the least reported, which necessitates the presence of more evidence of their management, which can be lifesaving. Introduction COVID-19 usually presents as upper respiratory infections and pneumonias triggering an inflammatory cascade that can be prolonged, in what is known as long COVID. This can manifest as autoimmune diseases, neurologic illness, cardiovascular disorders and others.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Iega9OAF","properties":{"formattedCitation":"[1, 2]","plainCitation":"[1, 2]","noteIndex":0},"citationItems":[{"id":535,"uris":["http://zotero.org/users/11334842/items/DX7JF2ZQ"],"itemData":{"id":535,"type":"article-journal","abstract":"Coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 virus, may result in multi-system pathology associated with the failure of multiple organ systems. The disease primarily manifests as a mild respiratory illness, however a minority of patients may progress to severe disease, with pneumonia, respiratory failure, and hyperinflammatory syndromes increasing mortality. This article explores the pathophysiology of SARS-CoV-2 infection and presents the management of severe COVID-19 pneumonia. Along with acute illness, the chapter looks at post-COVID sequelae, considers recovery from illness, and offers consideration for the disease into the future.","container-title":"Encyclopedia of Respiratory Medicine","DOI":"10.1016/B978-0-08-102723-3.00187-6","journalAbbreviation":"Encyclopedia of Respiratory Medicine","note":"PMID: null\nPMCID: PMC8101988","page":"342-349","source":"PubMed Central","title":"Management of Coronavirus Disease 2019 (COVID-19) Pneumonia","author":[{"family":"Thirkell","given":"Philip"},{"family":"Griffiths","given":"Mark"},{"family":"Waller","given":"Michael D."}],"issued":{"date-parts":[["2022"]]}}},{"id":534,"uris":["http://zotero.org/users/11334842/items/JYJAWN5J"],"itemData":{"id":534,"type":"article-journal","abstract":"The novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic threatening global public health. In the current paper, we describe our successful treatment of three COVID-19 pneumonia patients cases including severe cases and cases with mortality risk factors. One 32-year-old male COVID-19 patient was diagnosed with severe COVID-19 pneumonia and moderate ARDS. The second COVID-19 pneumonia patient had a history of diabetes and chronic bronchitis. The third case of COVID-19 pneumonia was an 82-year old female patient. All three cases had severe COVID pneumonia and therefore were aggressively managed with a multidisciplinary and personalized therapeutic approach that included nutritional support, antiviral pharmacotherapy, active control of comorbidities, prevention of complication development and psychological intervention. Our experience highlights the importance of the use of a multidisciplinary therapeutic approach that tailors to the specific condition of the patient in achieving a favorable clinical outcome.","container-title":"Journal of the Formosan Medical Association","DOI":"10.1016/j.jfma.2020.04.008","ISSN":"0929-6646","issue":"11","journalAbbreviation":"Journal of the Formosan Medical Association","language":"en","page":"1702-1709","source":"ScienceDirect","title":"Clinical features and multidisciplinary treatment outcome of COVID-19 pneumonia: A report of three cases","title-short":"Clinical features and multidisciplinary treatment outcome of COVID-19 pneumonia","volume":"119","author":[{"family":"Liu","given":"Chun"},{"family":"Wu","given":"Changhui"},{"family":"Zheng","given":"Xiangde"},{"family":"Zeng","given":"Fanwei"},{"family":"Liu","given":"Jinping"},{"family":"Wang","given":"Pingxi"},{"family":"Zeng","given":"Fanxin"},{"family":"Yuan","given":"Lin"},{"family":"Zhu","given":"Fangcheng"},{"family":"Gan","given":"Xuemei"},{"family":"Huang","given":"Yucheng"}],"issued":{"date-parts":[["2020",11,1]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[1, 2]<!-- [if supportFields]><![endif]--> The surplus of complications this viral infection can cause is unique, but its vascular complications are the most mortal, causing acute endothelial dysfunction driven by inflammation, leading to tissue ischemia.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"qnkPqtKa","properties":{"formattedCitation":"[3]","plainCitation":"[3]","noteIndex":0},"citationItems":[{"id":537,"uris":["http://zotero.org/users/11334842/items/7P3L5UDZ"],"itemData":{"id":537,"type":"article-journal","abstract":"Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a severe pandemic of the current century. The vicious tentacles of the disease have been disseminated worldwide with unknown complications and repercussions. Advanced COVID-19 syndrome is characterized by the uncontrolled and elevated release of pro-inflammatory cytokines and suppressed immunity, leading to the cytokine storm. The uncontrolled and dysregulated secretion of inflammatory and pro-inflammatory cytokines is positively associated with the severity of the viral infection and mortality rate. The secretion of various pro-inflammatory cytokines such as TNF-α, IL-1, and IL-6 leads to a hyperinflammatory response by recruiting macrophages, T and B cells in the lung alveolar cells. Moreover, it has been hypothesized that immune cells such as macrophages recruit inflammatory monocytes in the alveolar cells and allow the production of large amounts of cytokines in the alveoli, leading to a hyperinflammatory response in severely ill patients with COVID-19. This cascade of events may lead to multiple organ failure, acute respiratory distress, or pneumonia. Although the disease has a higher survival rate than other chronic diseases, the incidence of complications in the geriatric population are considerably high, with more systemic complications. This review sheds light on the pivotal roles played by various inflammatory markers in COVID-19-related complications. Different molecular pathways, such as the activation of JAK and JAK/STAT signaling are crucial in the progression of cytokine storm; hence, various mechanisms, immunological pathways, and functions of cytokines and other inflammatory markers have been discussed. A thorough understanding of cytokines’ molecular pathways and their activation procedures will add more insight into understanding immunopathology and designing appropriate drugs, therapies, and control measures to counter COVID-19. Recently, anti-inflammatory drugs and several antiviral drugs have been reported as effective therapeutic drug candidates to control hypercytokinemia or cytokine storm. Hence, the present review also discussed prospective anti-inflammatory and relevant immunomodulatory drugs currently in various trial phases and their possible implications.","container-title":"Vaccines","DOI":"10.3390/vaccines9050436","ISSN":"2076-393X","issue":"5","journalAbbreviation":"Vaccines (Basel)","note":"PMID: 33946736\nPMCID: PMC8145892","page":"436","source":"PubMed Central","title":"Role of Inflammatory Cytokines in COVID-19 Patients: A Review on Molecular Mechanisms, Immune Functions, Immunopathology and Immunomodulatory Drugs to Counter Cytokine Storm","title-short":"Role of Inflammatory Cytokines in COVID-19 Patients","volume":"9","author":[{"family":"Rabaan","given":"Ali A."},{"family":"Al-Ahmed","given":"Shamsah H."},{"family":"Muhammad","given":"Javed"},{"family":"Khan","given":"Amjad"},{"family":"Sule","given":"Anupam A"},{"family":"Tirupathi","given":"Raghavendra"},{"family":"Mutair","given":"Abbas Al"},{"family":"Alhumaid","given":"Saad"},{"family":"Al-Omari","given":"Awad"},{"family":"Dhawan","given":"Manish"},{"family":"Tiwari","given":"Ruchi"},{"family":"Sharun","given":"Khan"},{"family":"Mohapatra","given":"Ranjan K."},{"family":"Mitra","given":"Saikat"},{"family":"Bilal","given":"Muhammad"},{"family":"Alyami","given":"Salem A."},{"family":"Emran","given":"Talha Bin"},{"family":"Moni","given":"Mohammad Ali"},{"family":"Dhama","given":"Kuldeep"}],"issued":{"date-parts":[["2021",4,29]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[3]<!-- [if supportFields]><![endif]--> Nevertheless, very few data with weak evidence exist on managing such conditions. These complications can range from small to medium vasculitis all the way to aortitis, aortic valvopathy and aortic aneurysms causing acute myocardial ischemia and severe congestive heart failure (CHF).<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"xv2ax5Rj","properties":{"formattedCitation":"[4]","plainCitation":"[4]","noteIndex":0},"citationItems":[{"id":541,"uris":["http://zotero.org/users/11334842/items/Q85FKY3T"],"itemData":{"id":541,"type":"webpage","abstract":"Your access to the latest cardiovascular news, science, tools and resources.","note":"issue: 1\nvolume: 21","title":"COVID-19 and the heart","URL":"https://www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-21/covid-19-and-the-heart, https://www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-21/covid-19-and-the-heart","author":[{"family":"Rajan'","given":"'Rajesh"},{"family":"Jayakumar'","given":"'Rohini B."},{"family":"Al-Jarallah'","given":"'Mohammed"},{"family":"Dashti'","given":"'Raja"},{"family":"Kobalava'","given":"'Zhanna D."},{"family":"Brady'","given":"'Peter A."}],"accessed":{"date-parts":[["2023",7,27]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[4]<!-- [if supportFields]><![endif]--> They can be self-limiting over a few weeks, or life-threatening, requiring emergent intervention that can range from anticoagulation and control of the inflammatory storm, to intra-vascular or surgical intervention.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"f3j8BoCU","properties":{"formattedCitation":"[5]","plainCitation":"[5]","noteIndex":0},"citationItems":[{"id":547,"uris":["http://zotero.org/users/11334842/items/MLFUI6QP"],"itemData":{"id":547,"type":"article-journal","abstract":"Aortitis is a rare complication of the coronavirus disease 2019 (COVID-19) and is often treated empirically with steroids. We present a case of spontaneous resolution of aortitis without treatment. A 65-year-old man was admitted to our intensive care unit for severe COVID-19 pneumonia and underwent rehabilitation in the general ward. On day 12, he developed fever, and on day 13, he developed right cervical pain and increased inflammatory markers. On day 16, a cervical echocardiogram showed vasculitis in the right common carotid artery, and on day 17, computed tomography (CT) of the neck showed thickening of the arterial wall of the right common to the internal carotid arteries. A retrospective assessment of the CT scan on day 12 showed wall thickening from the thoracic aorta to the abdominal aorta, and a diagnosis of aortitis was made. Autoantibody analysis, culture, and magnetic resonance imaging (MRI) of the head and neck showed no abnormalities. During the investigation of the cause of aortitis, the fever and inflammatory reaction spontaneously resolved and the right cervical pain gradually improved. Therefore, the patient was diagnosed with transient COVID-19-related aortitis. To our knowledge, this is the first report describing the spontaneous resolution of COVID-19-related aortitis.","container-title":"Medicina","DOI":"10.3390/medicina59050816","ISSN":"1648-9144","issue":"5","language":"en","license":"http://creativecommons.org/licenses/by/3.0/","note":"number: 5\npublisher: Multidisciplinary Digital Publishing Institute","page":"816","source":"www.mdpi.com","title":"Spontaneous Improvement of Aortitis Associated with Severe COVID-19 Infection—A Case Report","volume":"59","author":[{"family":"Shimada","given":"Takashi"},{"family":"Itagaki","given":"Hideya"},{"family":"Shirota","given":"Yuko"},{"family":"Endo","given":"Tomoyuki"}],"issued":{"date-parts":[["2023",5]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[5]<!-- [if supportFields]><![endif]--> In this case report, we present a 32-yer-old male who had a Kawasaki-like vasculitis after his COVID-19 infection, that was complicated with aortitis, aortic valve inflammation and thoracic aortic aneurysm that required three surgeries and a long treatment duration. To our knowledge, such a case has never been described, which proves the importance of reporting. Case Presentation First admission: On 24/03/22, Mr. FK, a 32-year-old patient presented to our clinic for fever without focus. 3 months ago, he had COVID-19 infection, after which the fever never resolved, with fatigue, weight loss, and lower extremity weakness. He is previously healthy with no significant medical, surgical or travel history. He has a no significant family history of chronic disease. He was admitted for workup at another institution 1 month prior where he took 2 courses of Augmentin and Levofloxacin without improvement. The workup included negative blood cultures, and negative tests forHIV, syphilis, hepatitis B and C, brucella and tuberculosis, with negative anti-nuclear antibodies (ANA). FK has received the Pfizer mRNA COVID vaccine twice, 2 weeks apart a few months back with no complications. Upon initial physical examination, he was febrile (38°C) and tachycardic (110 BPM). Cardiac auscultation showed a holosystolic murmur in the aortic area. Lower extremities showed mild atrophy. The patient trans-thoracic echocardiography (TTE) showed a vegetation of the aortic valve with severe regurgitation (Figure 1), hence he was admitted for infectious endocarditis. Blood cultures were taken, and he was started on penicillin and gentamycin. Blood cultures and brucella, salmonella and coxiella serologies were negative. A complete autoimmune workup was also negative except for beta-2 glycoprotein. On 27/3/22, he complained of dyspnea and a chest x-ray showed mild congestion, managed by furosemide and oxygen. Shortly after, he had sudden dyspnea with hypotension, desaturation and rapidly progressing cardiogenic shock. Repeat TTE showed acute decompensated right heart failure and pulmonary congestion. He underwent emergency bioprosthetic aortic valve replacement. Intraoperatively, multiple coronary artery aneurysms were seen. The aortic valve was almost non-existent, extensively eroded without vegetations. It was replaced by a bovine valve. Coronary artery bypass grafting (CABG) could not be performed due to high mortality risk. Valve cultures were negative, and pathology showed neutrophilic infiltration. The diagnosis of non-infectious endocarditis and Kawasaki-like vasculitis was made based on the gross vascular findings and pathologic evaluation, and he was discharged on Prednisone1 mg/kg/day taper and followed up in an out-patient setting. Second admission: Three months later, the patient presented to the ED for severe chest pain. Four days prior, he was having flu-like symptoms for which COVID-19 PCR tested positive. He was found to have an anterior ST elevation myocardial infarction. A TTE showed septo-apical dyskinesia with severe dilatation of the aortic root. He received a loading dose of heparin and coronary angiography was performed (Figure 1). It showed a LAD stenosis and total occlusion of the diagonal artery. CT-Angio scan of the chest (Figure 2) showed an ascending aortic aneurysm of 7.3 cm diameter. TTE showed a severe dilatation of the sinus of Valsalva. Cardiothoracic surgery were consulted, and an aortic root replacement was recommended. He was started on methylprednisolone pulse therapy followed by dexamethasone 6 mg daily. He also received 6mg/kg IV tocilizumab (600 mg) and IV immunoglobulins (IVIG) 3g/kg once to halt the inflammatory reaction. For fever in immunosuppression, he was covered with remdesivir, meropenem and vancomycin. On 28/7/22, the patient underwent aortic aneurism repair. CABG was not performed because of high risk of rupture. Cultures of the ascending aorta were negative again, and pathology showed neutrophilic infiltration. The patient was discharged on prednisone, mycophenolate mofetil and a prophylactic dose of trimethoprim/sulfamethoxazole. Third admission: The patient re-presented on 16/11/22 for chest discomfort with high grade fever, cough, and hemoptysis. He was found to be hypotensive to 80/60 mmHg and with elevated inflammatory markers. Due to his immunosuppressed status, hypotension and fever, he received meropenem, vancomycin and voriconazole to cover for a possible sepsis. Besides, due to his known history of on-going vasculitis affecting the coronary vessels and aortic root, he was started on tocilizumab and IVIG. His diagnosis was a demand myocardial ischemia with cardiogenic shock, the reasons behind this to be investigated, with highest suspicion of recurrence of the vasculitis. On 19/11/22, his condition deteriorated again and TTE that showed severe mitral regurgitation and EF of 30%, with an aortic root aneurysm and prosthetic valve dehiscence with regurgitation. He underwent an emergent Bentall procedure and reimplantation of coronary arteries, replacing the bioprosthetic valve (Figure 3) with a metallic one. He recovered well and was placed on Prednisone taper again with daily baricitinib and clinical follow-up. Afterwards he was doing well and returned to supervised physical activity. On September 15th, 2023, the patient passed away of sudden onset ventricular fibrillation while at home. Discussion The case provides a rare depiction of a serious complication of COVID-19 infection, systemic vasculitis. At the time of the diagnosis, no clear management guidelines existed, therefore we extrapolated from what was known previously. COVID-19 infection overdrives the immune system, triggering a wide array of inflammation such as vasculitis.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"zSNL7v8Y","properties":{"formattedCitation":"[6]","plainCitation":"[6]","noteIndex":0},"citationItems":[{"id":107,"uris":["http://zotero.org/users/11334842/items/U24ZWAAW"],"itemData":{"id":107,"type":"article-journal","abstract":"The SARS-coronavirus-2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19), has spread worldwide and caused a global health emergency. SARS-CoV-2 is a coronaviridae virus that infects target cells by interacting with the plasma membrane-expressed angiotensin-converting enzyme 2 (ACE2) via the S1 component of the S protein. Effective host immune response to SARS-CoV-2 infection, which includes both innate and adaptive immunity, is critical for virus management and elimination. The intensity and outcome of COVID-19 may be related to an overabundance of pro-inflammatory cytokines, which results in a “cytokine storm” and acute respiratory distress syndrome. After SARS-CoV-2 infection, the immune system's hyperactivity and production of autoantibodies may result in autoimmune diseases such as autoimmune hemolytic anemia, autoimmune thrombocytopenia, Guillain-Barré syndrome, vasculitis, multiple sclerosis, pro-thrombotic state, and diffuse coagulopathy, as well as certain autoinflammatory conditions such as Kawasaki disease in children. We have reviewed the association between COVID-19 and autoimmune disorders in this article.","container-title":"Cell Biology International","DOI":"10.1002/cbin.11997","ISSN":"1095-8355","issue":"5","language":"en","license":"© 2023 International Federation for Cell Biology.","note":"_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1002/cbin.11997","page":"848-858","source":"Wiley Online Library","title":"COVID-19: A trigger of autoimmune diseases","title-short":"COVID-19","volume":"47","author":[{"family":"Zebardast","given":"Arghavan"},{"family":"Hasanzadeh","given":"Ali"},{"family":"Ebrahimian Shiadeh","given":"Seyedeh Arefeh"},{"family":"Tourani","given":"Mehdi"},{"family":"Yahyapour","given":"Yousef"}],"issued":{"date-parts":[["2023"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[6]<!-- [if supportFields]><![endif]--> It can trigger B and T lymphocytes, leading to cytokine release and vascular injury.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"XqnBYUmB","properties":{"formattedCitation":"[7]","plainCitation":"[7]","noteIndex":0},"citationItems":[{"id":106,"uris":["http://zotero.org/users/11334842/items/WLHJ8M6D"],"itemData":{"id":106,"type":"article-journal","abstract":"In the last two years, our world experienced one of the most devastating and fast-exploding pandemic, due to the wide spread of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The scientific community managed to develop effective vaccines, the main weapons to shield the immune system and protect people. Nevertheless, both SARS-CoV-2 infection and the vaccination against it have been associated with the stimulation of inflammatory cells such as T and B lymphocytes that results in a cytokine storm, endothelial inflammation and vascular injury, which can lead to different types of vasculitis. We present the first case of de novo MPO-ANCA-associated vasculitis, which developed shortly after SARS-CoV-2 vaccination, adequately responded to treatment, and subsequently relapsed after COVID-19 infection. With this case, we indicate an etiological connection between viral infection and disease development, as well as the possibility of a common immune mechanism between SARS-CoV-2 infection and vaccination, that can stimulate vascular events and lead to vasculitis. There have been several case reports of de novo vasculitis, affecting large, medium, or small vessels, following either infection or vaccination against COVID-19, during the pandemic outbreak. We summarize previous reports and also analyze proposed pathogenic mechanisms between SARS-CoV-2 and vasculitis.","container-title":"Life","DOI":"10.3390/life12071072","ISSN":"2075-1729","issue":"7","language":"en","license":"http://creativecommons.org/licenses/by/3.0/","note":"number: 7\npublisher: Multidisciplinary Digital Publishing Institute","page":"1072","source":"www.mdpi.com","title":"ANCA-Associated Vasculitis May Result as a Complication to Both SARS-CoV-2 Infection and Vaccination","volume":"12","author":[{"family":"Christodoulou","given":"Michalis"},{"family":"Iatridi","given":"Fotini"},{"family":"Chalkidis","given":"George"},{"family":"Lioulios","given":"Georgios"},{"family":"Nikolaidou","given":"Christina"},{"family":"Badis","given":"Kostas"},{"family":"Fylaktou","given":"Asimina"},{"family":"Papagianni","given":"Aikaterini"},{"family":"Stangou","given":"Maria"}],"issued":{"date-parts":[["2022",7]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[7]<!-- [if supportFields]><![endif]--> Kawasaki vasculitis affects medium-sized arteries in children and is linked to viral infections. Since the emergence of COVID-19, Multisystem Inflammatory Syndrome in Children (MISC) emerged, which had a similar presentation.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"3N6ihNnV","properties":{"formattedCitation":"[8]","plainCitation":"[8]","noteIndex":0},"citationItems":[{"id":105,"uris":["http://zotero.org/users/11334842/items/MASXQ7TG"],"itemData":{"id":105,"type":"article-journal","container-title":"Clinical and Experimental Pediatrics","DOI":"10.3345/cep.2022.00696","ISSN":"2713-4148","issue":"11","journalAbbreviation":"Clin Exp Pediatr","note":"PMID: 35879868\nPMCID: PMC9650356","page":"538-539","source":"PubMed Central","title":"Recent research trends in Kawasaki disease-related infection","volume":"65","author":[{"family":"Woo","given":"Hyang-Ok"}],"issued":{"date-parts":[["2022",7,22]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[8]<!-- [if supportFields]><![endif]--> MISC can present with cardiac manifestations, muco-cutaneous involvement and refractory fever.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Zra3zTMT","properties":{"formattedCitation":"[9]","plainCitation":"[9]","noteIndex":0},"citationItems":[{"id":102,"uris":["http://zotero.org/users/11334842/items/TFBJWVBY"],"itemData":{"id":102,"type":"article-journal","abstract":"Recent studies have noted an increasing number of Kawasaki-like cases in the pediatric population following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In the literature, the condition is described as multiple inflammatory syndrome in children (MIS-C) or pediatric inflammatory syndrome (PIMS). A similar clinical course of Kawasaki disease (KD) and MIS-C causes difficulties in distinguishing between both conditions. However, the differential diagnosis is crucial since patients with MIS-C can present severe symptoms (myocardial dysfunction, fever, mucocutaneous symptoms) and require more extensive monitoring during treatment than children diagnosed with KD. Along with assessing epidemiological and genetic factors, it is imperative to estimate the risk of developing MIS-C in KD patients with confirmed SARS-CoV-2 infection. Genetic predispositions, such as the ITPKC gene polymorphism in KD, ACE deletion (D) polymorphism in SARS-CoV-2, and inborn errors of immunity (IEIs) in MIS-C affect the regulation of immune system complex clearances and cellular adaptations. The virus has a tropism for both vascular and respiratory cells, which further causes additional symptoms necessitating standard therapy with antithrombotic treatment. The diagnostic criteria for KD, MIS-C, and SARS-CoV-2 help differentiate each condition and optimize treatment strategies. Unfortunately, long-term outcomes in KD patients who develop MIS-C due to SARS-CoV-2 infection have been inadequately documented due to the timing of the pandemic, further displaying the need for longitudinal studies in these patients. This review underlines the differences in diagnosis and treatment of KD and MIS-C. Overall, children with KD may develop MIS-C in the setting of SARS-CoV-2 infection, but further research is needed to outline specific etiologies, prognostic factors, and diagnoses.","container-title":"Medical Microbiology and Immunology","DOI":"10.1007/s00430-022-00756-3","ISSN":"1432-1831","issue":"1","journalAbbreviation":"Med Microbiol Immunol","language":"en","page":"3-12","source":"Springer Link","title":"SARS-CoV-2 infection in the context of Kawasaki disease and multisystem inflammatory syndrome in children","volume":"212","author":[{"family":"Folga","given":"Barbara Anna"},{"family":"Karpenko","given":"Corrinna Jade"},{"family":"Grygiel-Górniak","given":"Bogna"}],"issued":{"date-parts":[["2023",2,1]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[9]<!-- [if supportFields]><![endif]--> Many systemic reviews and case series then started studying vasculitis post COVID-19 infection, but in almost all, Kawasaki-like disease was only described in children. These findings, caused by COVID-19 usually present as a remitting fever with rashes, lymphadenopathy and mucosal lesions, diagnosed by biopsy. The prognosis in children is usually good with steroids and/or IVIG <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Ol1J4wHQ","properties":{"formattedCitation":"[10]","plainCitation":"[10]","noteIndex":0},"citationItems":[{"id":460,"uris":["http://zotero.org/users/11334842/items/TCILLHZS"],"itemData":{"id":460,"type":"article-journal","abstract":"Vasculitis is one of the complications of COVID-19. We conducted a systematic review analysing the association of COVID-19 with vasculitis. We searched Google Scholar and PubMed from December 1, 2019, to October 11, 2021. The review included 8 studies (7 case reports and 1 case series) reporting 9 cases of vasculitis secondary to COVID-19. The mean age was 29.17 ± 28.2 years, ranging from 6 months to 83 years. The male to female ratio was 4:5. Maculopapular, violaceous, papular and erythematous rash were common. Heparin(n = 2), corticosteroids (n = 6) (methylprednisolone) and intravenous immunoglobulin (n = 4) were prescribed in these patients. Significant clinical improvement was observed in 8 out of 9 patients. One person died during treatment. Our study discusses vasculitis as one of the complications of COVID-19. Furthermore, the pathophysiology, clinical presentation, and management of COVID-19 associated vasculitis is discussed., \n \n \n •\n This is a systematic review of all published cases of vasculitis secondary to COVID-19 from the start of COVID-19 outbreak to date.\n \n \n •\n Most common forms of vasculitis reported were Kawasaki disease Vasculitis, IgA vasculitis and Leucocytoclastic Vasculitis with symptoms being predominantly skin limited.\n \n \n •\n Steroids, LMWH and IVIG were the most common line of treatment.\n \n \n •\n An good overall prognosis was seen following treatment.","container-title":"Annals of Medicine and Surgery","DOI":"10.1016/j.amsu.2022.103249","ISSN":"2049-0801","journalAbbreviation":"Ann Med Surg (Lond)","note":"PMID: 35039779\nPMCID: PMC8754903","page":"103249","source":"PubMed Central","title":"COVID-19 associated vasculitis: A systematic review of case reports and case series","title-short":"COVID-19 associated vasculitis","volume":"74","author":[{"family":"Wong","given":"Kalai"},{"family":"Farooq Alam Shah","given":"Mir Umer"},{"family":"Khurshid","given":"Maman"},{"family":"Ullah","given":"Irfan"},{"family":"Tahir","given":"Muhammad Junaid"},{"family":"Yousaf","given":"Zohaib"}],"issued":{"date-parts":[["2022",1,13]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[10]<!-- [if supportFields]><![endif]--> Such a condition was never described in adults before. A systemic review published in France in 2020 state that it can be seen in African-French descent and is associated with self-limiting multi-system inflammation.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Fkrk6lkd","properties":{"formattedCitation":"[11]","plainCitation":"[11]","noteIndex":0},"citationItems":[{"id":551,"uris":["http://zotero.org/users/11334842/items/QTG9QVES"],"itemData":{"id":551,"type":"article-journal","abstract":"Objectives To describe the characteristics of children and adolescents affected by an outbreak of Kawasaki-like multisystem inflammatory syndrome and to evaluate a potential temporal association with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.\nDesign Prospective observational study.\nSetting General paediatric department of a university hospital in Paris, France.\nParticipants 21 children and adolescents (aged ≤18 years) with features of Kawasaki disease who were admitted to hospital between 27 April and 11 May 2020 and followed up until discharge by 15 May 2020.\nMain outcome measures The primary outcomes were clinical and biological data, imaging and echocardiographic findings, treatment, and outcomes. Nasopharyngeal swabs were prospectively tested for SARS-CoV-2 using reverse transcription-polymerase chain reaction (RT-PCR) and blood samples were tested for IgG antibodies to the virus.\nResults 21 children and adolescents (median age 7.9 (range 3.7-16.6) years) were admitted with features of Kawasaki disease over a 15 day period, with 12 (57%) of African ancestry. 12 (57%) presented with Kawasaki disease shock syndrome and 16 (76%) with myocarditis. 17 (81%) required intensive care support. All 21 patients had noticeable gastrointestinal symptoms during the early stage of illness and high levels of inflammatory markers. 19 (90%) had evidence of recent SARS-CoV-2 infection (positive RT-PCR result in 8/21, positive IgG antibody detection in 19/21). All 21 patients received intravenous immunoglobulin and 10 (48%) also received corticosteroids. The clinical outcome was favourable in all patients. Moderate coronary artery dilations were detected in 5 (24%) of the patients during hospital stay. By 15 May 2020, after 8 (5-17) days of hospital stay, all patients were discharged home.\nConclusions The ongoing outbreak of Kawasaki-like multisystem inflammatory syndrome among children and adolescents in the Paris area might be related to SARS-CoV-2. In this study an unusually high proportion of the affected children and adolescents had gastrointestinal symptoms, Kawasaki disease shock syndrome, and were of African ancestry.","container-title":"BMJ","DOI":"10.1136/bmj.m2094","ISSN":"1756-1833","journalAbbreviation":"BMJ","language":"en","license":"© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.. http://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.","note":"publisher: British Medical Journal Publishing Group\nsection: Research\nPMID: 32493739","page":"m2094","source":"www.bmj.com","title":"Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in Paris, France: prospective observational study","title-short":"Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in Paris, France","volume":"369","author":[{"family":"Toubiana","given":"Julie"},{"family":"Poirault","given":"Clément"},{"family":"Corsia","given":"Alice"},{"family":"Bajolle","given":"Fanny"},{"family":"Fourgeaud","given":"Jacques"},{"family":"Angoulvant","given":"François"},{"family":"Debray","given":"Agathe"},{"family":"Basmaci","given":"Romain"},{"family":"Salvador","given":"Elodie"},{"family":"Biscardi","given":"Sandra"},{"family":"Frange","given":"Pierre"},{"family":"Chalumeau","given":"Martin"},{"family":"Casanova","given":"Jean-Laurent"},{"family":"Cohen","given":"Jérémie F."},{"family":"Allali","given":"Slimane"}],"issued":{"date-parts":[["2020",6,3]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[11]<!-- [if supportFields]><![endif]--> In January 2022, Elouardi et al described a very similar presentation in a 28 year-old female who succumbed due to severe myocardial damage due to inflammation and coronary artery disease and aneurysms due to a Kawasaki-like vasculitis after infection with COVID-19.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"ixH82w2B","properties":{"formattedCitation":"[12]","plainCitation":"[12]","noteIndex":0},"citationItems":[{"id":554,"uris":["http://zotero.org/users/11334842/items/WHQCYQTI"],"itemData":{"id":554,"type":"article-journal","abstract":"Recently, few reports have described a serious condition linked to SARS-CoV-2 that mimics Kawasaki disease called multisystem inflammatory syndrome, especially in children (MIS-C) and young adults. In this work, we report on a severe form of MIS in a young female adult previously infected by SARS-CoV-2. She was treated by plasmapheresis with albumin and steroids, however outcome was fatal. We discuss the pathogenesis of this rare and life threatening entity and suggest some therapeutic regimen. This syndrome should not be misdiagnosed with an infectious or a drug induced cutaneous rash in the current context of COVID-19 pandemic.","container-title":"Revista Espanola De Anestesiologia Y Reanimacion","DOI":"10.1016/j.redare.2020.11.009","ISSN":"2341-1929","issue":"1","journalAbbreviation":"Rev Esp Anestesiol Reanim (Engl Ed)","note":"PMID: 35031265\nPMCID: PMC8739010","page":"43-47","source":"PubMed Central","title":"COVID-19 associated Kawasaki-like multisystem inflammatory syndrome in an adult","volume":"69","author":[{"family":"Elouardi","given":"Y."},{"family":"Rebahi","given":"H."},{"family":"Zarrouki","given":"Y."},{"family":"Ziadi","given":"A."},{"family":"Younous","given":"S."},{"family":"Samkaoui","given":"M.A."}],"issued":{"date-parts":[["2022",1]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[12]<!-- [if supportFields]><![endif]--> The involvement of large arteries has been rarely described. By February 2022, only 4 case reports were published about it.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"H9leBEmB","properties":{"formattedCitation":"[13]","plainCitation":"[13]","noteIndex":0},"citationItems":[{"id":549,"uris":["http://zotero.org/users/11334842/items/SI9NBDR9"],"itemData":{"id":549,"type":"article-journal","abstract":"Coronavirus disease 2019 (COVID-19) has a myriad of different presentations and various complications. Aortitis is one of the less explored pathologies associated with COVID-19 infections. In this review, we searched PubMed/Medline, Web of Science, Google Scholar, and Scopus for case series and case reports involving adults patients who presented with aortitis and COVID-19. We found and reviewed four published case reports of aortitis in a setting of COVID-19 infection. The mean age of the four adult patients was 69 ± 1.732 years (range = 63-71 years), and all patients were males. Most of the patients (75%) did not have any preexisting comorbidities. All patients were treated conservatively and recovered with excellent outcomes.","container-title":"Cureus","DOI":"10.7759/cureus.22226","ISSN":"2168-8184","issue":"2","journalAbbreviation":"Cureus","note":"PMID: 35340464\nPMCID: PMC8928452","page":"e22226","source":"PubMed Central","title":"COVID-19 Aortitis: A Review of Published Cases","title-short":"COVID-19 Aortitis","volume":"14","author":[{"family":"Abu Hassan","given":"Falah"},{"family":"Abu Alhalawa","given":"Minas"},{"family":"Majdoubeh","given":"Yacoub"},{"family":"Nepal","given":"Ashish"},{"family":"Sufan","given":"Sareen S"}]}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[13]<!-- [if supportFields]><![endif]--> Aortitis can also be caused in the early viremic phase, where the viruses attack the endothelium, causing vasa vasorum intramural thrombosis.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"GQ7r1O17","properties":{"formattedCitation":"[14]","plainCitation":"[14]","noteIndex":0},"citationItems":[{"id":546,"uris":["http://zotero.org/users/11334842/items/HH8LJA8S"],"itemData":{"id":546,"type":"article-journal","container-title":"Journal of Vascular Surgery","DOI":"10.1016/j.jvs.2020.08.029","ISSN":"07415214","issue":"1","journalAbbreviation":"Journal of Vascular Surgery","language":"en","page":"347-348","source":"DOI.org (Crossref)","title":"Vasculitis and aortitis: COVID-19 challenging complications","title-short":"Vasculitis and aortitis","volume":"73","author":[{"family":"Manenti","given":"Antonio"},{"family":"Farinetti","given":"Alberto"},{"family":"Manco","given":"Gianrocco"},{"family":"Mattioli","given":"Annavittoria"}],"issued":{"date-parts":[["2021",1]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[14]<!-- [if supportFields]><![endif]--> This can progress to myocarditis or to CHF, such as in our patient.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"YoqJFpSJ","properties":{"formattedCitation":"[4]","plainCitation":"[4]","noteIndex":0},"citationItems":[{"id":541,"uris":["http://zotero.org/users/11334842/items/Q85FKY3T"],"itemData":{"id":541,"type":"webpage","abstract":"Your access to the latest cardiovascular news, science, tools and resources.","note":"issue: 1\nvolume: 21","title":"COVID-19 and the heart","URL":"https://www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-21/covid-19-and-the-heart, https://www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-21/covid-19-and-the-heart","author":[{"family":"Rajan'","given":"'Rajesh"},{"family":"Jayakumar'","given":"'Rohini B."},{"family":"Al-Jarallah'","given":"'Mohammed"},{"family":"Dashti'","given":"'Raja"},{"family":"Kobalava'","given":"'Zhanna D."},{"family":"Brady'","given":"'Peter A."}],"accessed":{"date-parts":[["2023",7,27]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[4]<!-- [if supportFields]><![endif]--> No treatment guidelines for this condition exist. Data is mostly provided through case reports. A course of steroid taper has been suggested, in combination with other immunomodulatory agents, JAK inhibitors and IVIG.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"PYE8lcPX","properties":{"formattedCitation":"[6, 25]","plainCitation":"[6, 25]","dontUpdate":true,"noteIndex":0},"citationItems":[{"id":460,"uris":["http://zotero.org/users/11334842/items/TCILLHZS"],"itemData":{"id":460,"type":"article-journal","abstract":"Vasculitis is one of the complications of COVID-19. We conducted a systematic review analysing the association of COVID-19 with vasculitis. We searched Google Scholar and PubMed from December 1, 2019, to October 11, 2021. The review included 8 studies (7 case reports and 1 case series) reporting 9 cases of vasculitis secondary to COVID-19. The mean age was 29.17 ± 28.2 years, ranging from 6 months to 83 years. The male to female ratio was 4:5. Maculopapular, violaceous, papular and erythematous rash were common. Heparin(n = 2), corticosteroids (n = 6) (methylprednisolone) and intravenous immunoglobulin (n = 4) were prescribed in these patients. Significant clinical improvement was observed in 8 out of 9 patients. One person died during treatment. Our study discusses vasculitis as one of the complications of COVID-19. Furthermore, the pathophysiology, clinical presentation, and management of COVID-19 associated vasculitis is discussed., \n \n \n •\n This is a systematic review of all published cases of vasculitis secondary to COVID-19 from the start of COVID-19 outbreak to date.\n \n \n •\n Most common forms of vasculitis reported were Kawasaki disease Vasculitis, IgA vasculitis and Leucocytoclastic Vasculitis with symptoms being predominantly skin limited.\n \n \n •\n Steroids, LMWH and IVIG were the most common line of treatment.\n \n \n •\n An good overall prognosis was seen following treatment.","container-title":"Annals of Medicine and Surgery","DOI":"10.1016/j.amsu.2022.103249","ISSN":"2049-0801","journalAbbreviation":"Ann Med Surg (Lond)","note":"PMID: 35039779\nPMCID: PMC8754903","page":"103249","source":"PubMed Central","title":"COVID-19 associated vasculitis: A systematic review of case reports and case series","title-short":"COVID-19 associated vasculitis","volume":"74","author":[{"family":"Wong","given":"Kalai"},{"family":"Farooq Alam Shah","given":"Mir Umer"},{"family":"Khurshid","given":"Maman"},{"family":"Ullah","given":"Irfan"},{"family":"Tahir","given":"Muhammad Junaid"},{"family":"Yousaf","given":"Zohaib"}],"issued":{"date-parts":[["2022",1,13]]}}},{"id":540,"uris":["http://zotero.org/users/11334842/items/ZPKIMQUP"],"itemData":{"id":540,"type":"article-journal","abstract":"COVID-19 has been related to several autoimmune diseases, triggering the appearance of autoantibodies and endothelial dysfunction. Current evidence has drawn attention to vasculitis-like phenomena and leukocytoclastic vasculitis in some COVID-19 patients. Moreover, it has been hypothesized that COVID-19 could induce flares of preexisting autoimmune disorders. Here, we present two patients with previously controlled IgA vasculitis who developed a renal and cutaneous flare of vasculitis after mild COVID-19, one of them with new-onset ANCA vasculitis. These patients were treated with glucocorticoids and immunosuppressants achieving successful response. We also provide a focused literature review and conclude that COVID-19 may be associated with triggering of vasculitis and could induce flares of previous autoimmune diseases.","container-title":"Rheumatology International","DOI":"10.1007/s00296-022-05153-w","ISSN":"0172-8172","issue":"9","journalAbbreviation":"Rheumatol Int","note":"PMID: 35691980\nPMCID: PMC9188920","page":"1643-1652","source":"PubMed Central","title":"Vasculitis flare after COVID-19: report of two cases in patients with preexistent controlled IgA vasculitis and review of the literature","title-short":"Vasculitis flare after COVID-19","volume":"42","author":[{"family":"Valero","given":"Cristina"},{"family":"Baldivieso-Achá","given":"Juan Pablo"},{"family":"Uriarte","given":"Miren"},{"family":"Vicente-Rabaneda","given":"Esther F."},{"family":"Castañeda","given":"Santos"},{"family":"García-Vicuña","given":"Rosario"}],"issued":{"date-parts":[["2022"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[6]<!-- [if supportFields]><![endif]--> It is worth mentioning that there are reported cases of prolonged fever after COVID-19 vaccination itself, which presents as a chronic dysautonomia and fatigue. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"CgnePfFk","properties":{"formattedCitation":"[16]","plainCitation":"[16]","noteIndex":0},"citationItems":[{"id":2615,"uris":["http://zotero.org/users/11334842/items/D8PF8Z5G"],"itemData":{"id":2615,"type":"article-journal","abstract":"SARS-CoV-2 mRNA vaccination can entail chronic fatigue/dysautonomia tentatively termed post-acute COVID-19 vaccination syndrome (PACVS). We explored receptor autoantibodies and interleukin-6 (IL-6) as somatic correlates of PACVS. Blood markers determined ...","container-title":"Vaccines","DOI":"10.3390/vaccines11111642","issue":"11","language":"en","note":"publisher: Multidisciplinary Digital Publishing Institute (MDPI)\nPMID: 38005974","source":"www.ncbi.nlm.nih.gov","title":"Chronic Fatigue and Dysautonomia following COVID-19 Vaccination Is Distinguished from Normal Vaccination Response by Altered Blood Markers","URL":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10674626/","volume":"11","author":[{"family":"Semmler","given":"Amelie"},{"family":"Mundorf","given":"Anna Katharina"},{"family":"Kuechler","given":"Anna Sabrina"},{"family":"Schulze-Bosse","given":"Karin"},{"family":"Heidecke","given":"Harald"},{"family":"Schulze-Forster","given":"Kai"},{"family":"Schott","given":"Matthias"},{"family":"Uhrberg","given":"Markus"},{"family":"Weinhold","given":"Sandra"},{"family":"Lackner","given":"Karl J."},{"family":"Pawlitzki","given":"Marc"},{"family":"Meuth","given":"Sven Guenther"},{"family":"Boege","given":"Fritz"},{"family":"Ruhrländer","given":"Jana"}],"accessed":{"date-parts":[["2024",6,24]]},"issued":{"date-parts":[["2023",11]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[16]<!-- [if supportFields]><![endif]-->. There are also cases of multi-system inflammation following the vaccine, which are a very rare entity. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"sokR4CPq","properties":{"formattedCitation":"[17]","plainCitation":"[17]","noteIndex":0},"citationItems":[{"id":"2609","uris":["http://zotero.org/users/11334842/items/WWNM8UFR"],"itemData":{"id":2609,"type":"article-journal","abstract":"Of the various adverse reactions to COVID-19 vaccines, fever is a common systemic symptom that often resolves spontaneously without treatment. However, rare vaccine-induced conditions that present with fever and systemic inflammation have been reported. In this case, a 65-year-old man with BNT162b2 mRNA COVID-19 vaccination underwent 18F-FDG PET/CT to evaluate prolonged fever and elevated serum C-reactive protein. PET/CT showed hypermetabolic infiltration in the pericardium and peritoneum suggesting immune-mediated pericarditis and peritonitis. After administration of high-dose corticosteroids, the patient's symptom resolved. This case suggests that multisystem inflammatory syndrome and polyserositis can be induced by the COVID-19 vaccine.","container-title":"Clinical Nuclear Medicine","DOI":"10.1097/RLU.0000000000004094","ISSN":"0363-9762","issue":"5","language":"en-US","page":"e397","source":"journals.lww.com","title":"COVID-19 Vaccine–Induced Multisystem Inflammatory Syndrome With Polyserositis Detected by FDG PET/CT","volume":"47","author":[{"family":"Lee","given":"Soo Jin"},{"family":"Park","given":"Dong Won"},{"family":"Sohn","given":"Jang Won"},{"family":"Yoon","given":"Ho Joo"},{"family":"Kim","given":"Sang-Heon"}],"issued":{"date-parts":[["2022",5]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->[17]<!-- [if supportFields]><![endif]--> However, such an augmented inflammatory response is mostly reported post-COVID infection rather than vaccination, and in the case of our patient, the symptoms started after an infection. In addition, the exacerbation of his symptoms in the second admission were directly after a re-infection. He did not have any complications after he took his vaccines. Our patient presentation remains a unique one. He had a plethora of complications that were never described together. His presentation is a MISC-like reaction in an adult male, refractory to treatment. He had relapsed arteritis and valvopathy with every new infection. Reporting this case can shed light on the complications and treatment options for post-viral vasculitis considering scarce data with the subject. Conclusion COVID-19 has a variety of complications which can affect almost any organ in the body. Cardiovascular complications remain the rarest, yet the deadliest. Our patient had coronary vasculitis, aortitis and inflammatory aortic valve infiltration which were recurrent with every new COVID-19 infection he had, leading to 3 distinct open-heart surgeries. This is why reporting every case with such complications is crucial, to raise the possibility of clustering them into larger studies, that would provide more robust evidence-based data on managing such conditions. References 1. Thirkell P, Griffiths M, Waller MD. Management of Coronavirus Disease 2019 (COVID-19) Pneumonia. In: Janes SM, editor. Encyclopedia of Respiratory Medicine (Second Edition) [Internet]. Oxford: Academic Press; 2022. p. 342–9. https://doi.org/10.1016/B978-0-08-102723-3.00187-6. 2. Liu C, Wu C, Zheng X, Zeng F, Liu J, Wang P, et al. Clinical features and multidisciplinary treatment outcome of COVID-19 pneumonia: A report of three cases. J Formos Med Assoc. 2020 Nov 1;119(11):1702–9. https://doi.org/10.1016/j.jfma.2020.04.008. 3. Rabaan AA, Al-Ahmed SH, Muhammad J, Khan A, Sule AA, Tirupathi R, et al. Role of Inflammatory Cytokines in COVID-19 Patients: A Review on Molecular Mechanisms, Immune Functions, Immunopathology and Immunomodulatory Drugs to Counter Cytokine Storm. Vaccines (Basel). 2021;9(5):436. https://doi.org/10.3390/vaccines9050436. 4. Rajan R, Jayakumar RB, Al-Jarallah M, Dashti R, Kobablava ZD, Brady PA. Escardio. ESC; 2021 [cited 2023 Jul 27]. COVID-19 and the heart. Available from: https://www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-21/covid-19-and-the-heart 5. Shimada T, Itagaki H, Shirota Y, Endo T. Spontaneous Improvement of Aortitis Associated with Severe COVID-19 Infection—A Case Report. Medicina [Internet]. 2023;59(5). https://doi.org/10.3390/medicina59050816. 6. Zebardast A, Hasanzadeh A, Ebrahimian Shiadeh SA, Tourani M, Yahyapour Y. COVID-19: A trigger of autoimmune diseases. Cell Biol Int. 2023 May 1;47(5):848–58. https://doi.org/10.1002/cbin.11997. 7. Christodoulou M, Iatridi F, Chalkidis G, Lioulios G, Nikolaidou C, Badis K, et al. ANCA-Associated Vasculitis May Result as a Complication to Both SARS-CoV-2 Infection and Vaccination. Life. 2022;12(7):1072. https://doi.org/10.3390/life12071072. 8. Woo HO. Recent research trends in Kawasaki disease-related infection. Clin Exp Pediatr. 2022 Jul 22;65(11):538–9. https://doi.org/10.3345/cep.2022.00696. 9. Folga BA, Karpenko CJ, Grygiel-Górniak B. SARS-CoV-2 infection in the context of Kawasaki disease and multisystem inflammatory syndrome in children. Med Microbiol Immunol. 2023 Feb 1;212(1):3–12. https://doi.org/10.1007/s00430-022-00756-3. 10. Wong K, Farooq Alam Shah MU, Khurshid M, Ullah I, Tahir MJ, Yousaf Z. COVID-19 associated vasculitis: A systematic review of case reports and case series. Ann Med Surg (Lond). 2022;74:103249. https://doi.org/10.1016/j.amsu.2022.103249. 11. Toubiana J, Poirault C, Corsia A, Bajolle F, Fourgeaud J, Angoulvant F, et al. Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in Paris, France: prospective observational study. BMJ. 2020 Jun 3;369:m2094. https://doi.org/10.1136/bmj.m2094. 12. Elouardi Y, Rebahi H, Zarrouki Y, Ziadi A, Younous S, Samkaoui MA. COVID-19 associated Kawasaki-like multisystem inflammatory syndrome in an adult. Rev Esp Anestesiol Reanim (Engl Ed). 2022 Jan 1;69(1):43–7. https://doi.org/10.1016/j.redare.2020.11.009. 13. Abu Hassan F, Abu Alhalawa M, Majdoubeh Y, Nepal A, Sufan SS. COVID-19 Aortitis: A Review of Published Cases. Cureus. 2022 Feb 15;14(2):e22226. https://doi.org/10.7759/cureus.22226. 14. Manenti A, Farinetti A, Manco G, Mattioli A. Vasculitis and aortitis: COVID-19 challenging complications. J Vasc Surg. 2021 Jan 1;73(1):347–8. https://doi.org/10.1016/j.jvs.2020.08.029. 15. Semmler A, Mundorf AK, Kuechler AS, Schulze-Bosse K, Heidecke H, Schulze-Forster K, et al. Chronic Fatigue and Dysautonomia following COVID-19 Vaccination Is Distinguished from Normal Vaccination Response by Altered Blood Markers. Vaccines. 2023;11(11):1642. https://doi.org/10.3390/vaccines11111642. 16. Lee SJ, Park DW, Sohn JW, Yoon HJ, Kim SH. COVID-19 Vaccine–Induced Multisystem Inflammatory Syndrome With Polyserositis Detected by FDG PET/CT. Clin Nucl Med. 2022;47(5). https://doi.org/10.1097/RLU.0000000000004094.
Hippocampus infarct following a posterior cerebral artery occlusion
A 64-year-old gentleman, presented for subacute onset of short-term memory problem, preceded by headache, right arm numbness and visual disturbances. On neurological exam, he had anterograde amnesia, decreased pinprick sensation on his right arm and right homonymous hemianopsia. Brain Magnetic Resonance imaging (MRI) and Magnetic Resonance Angiography (MRA) showed subacute ischemic lesions in the left occipital lobe, hippocampus and thalamus, caused by a distal occlusion of the left Posterior Cerebral Artery (PCA). A distal occlusion of the PCA led to multiple infarcts in different anatomical structures, causing a constellation of variant neurological signs. Our case demonstrates an anterior hippocampus predominantly irrigated by the PCA. Background The Hippocampus is mainly supplied by the PCA and to a lesser degree from the anterior choroidal artery.[2] Visual analysis with Diffusion-Weighted MRI (DWI) have identified 4 patterns of lesions affecting the hippocampus: complete, lateral, dorsal and circumscribed lesions in the lateral hippocampus.[3] The PCA strokes are associated with headaches, visual symptoms, sensory-motor symptoms and neuropsychological symptoms[5] headaches being the initial and most frequently seen manifestation of infarcts in the posterior rather than the anterior circulation.[6] Other associated symptoms of posterior strokes include dizziness, confusion, nausea and vomiting.[5] When the involved region is limited to the hippocampal area, amnesia and memory processing are mainly affected.[3] This amnesia is usually temporarily, not lasting more than 24 hours, and it is called Transient Global Amnesia (TGA).[7] The prevalence of an isolated acute stroke of the hippocampus is 0.03% in a case series of 6800 patients.[8] Ischemic lesions are well identified on DWI due to strong contrast between affected and unaffected tissues, which offers more details in stroke syndromes.[4] The isolated involvement of the hippocampal structures enlighten its important role for memory processing.[9] Transient Global Amnesia TGA is characterized by a transient anterograde or retrograde amnesia without decrease level of consciousness or any other cognitive disturbances.[7] The patient usually shows a stereotyped behavior like repetitive questioning, due to short term memory impairment.[10] Transient Global Amnesia TGA rarely present post an ischemic stroke, and it is reported with lesions on the unilateral or bilateral hippocampus.[10,11] In the case discussed below, we present a patient with multiple comorbidities, presenting to the emergency with solely confusion and retrograde amnesia, that later on turned to be caused by stroke in the posterior cerebral artery; a very rare case presentation that needs to be addressed so emergency physicians and other care givers don’t miss out this diagnosis. Case Presentation A 64-year-old male patient presented to the Emergency Department (ED) for altered general status mainly manifested by confusion, distress, and a high blood pressure. The patient is known to have hypertension, diabetes, dyslipidemia, with reported compliance to medical treatment, along with coronary artery disease, status post stent insertion in 2011. In the Emergency Room, patient had severe headache, and a tingling sensation in his right arm involving the fingers; he denied any chest pain, dyspnea, orthopnea, fever or chills; he also denied any blurry vision or dipoplia, loss of consciousness, vertigo or dizziness. However, the patient’ family reported difficulty in arousing the patient from sleep during the morning of that same day with a retrograde amnesia of 30 minutes duration. Vital signs were as follow: heart rate: 78 BPM, blood pressure: of 190/100 mmHg, temperature: 36.7oC and oxygen saturation: 98% on room air. On review of system patient had no recent complaints or any signs of infection. On physical exam, the patient was oriented to people and place but not to time, and he was not able to recall the events of the day prior to his presentation. Systolic ejection murmur radiating to the right carotids was heard on heart auscultation. Neurologic exam showed intact Cranial Nerves (CN) III to XII, normal motricity in all limbs, positive pupillary light reflex, +2 DTR deep tendon reflexes and an equivocal Babinski on the right. There was decreased pinprick sensation on his right arm. On eye exam, the patient had a right homonymous hemianopsia. The rest of the bed side exam was normal. Stroke protocol was initiated, and brain MRI and MRA showed multiple areas of cortical ischemic lesions in the left occipital lobe, left hippocampus and left thalamus, which corresponds to subacute ischemic lesions in the territory of the left PCA (Figure 1). The patient was immediately started on dual antiplatelet and anticoagulation and admitted to regular floor. During his stay, his home medications were continued and he was being followed by neurologic exam daily until discharge. Marked improvement was noticed at 1 month follow up in outpatient clinic with return to baseline in cognition. Discussion A 64-year-old gentleman, with uncontrolled hypertension and diabetes mellitus, presented for subacute onset of short-term memory problem, preceded by right arm numbness and visual disturbances. On neurological exam, he had anterograde amnesia reported by family that lasted less than 1 hour, decreased pinprick sensation on his right arm and right homonymous hemianopsia. Two thirds of the hippocampus are vascularized by the P2 segment of the PCA and the rostral third is generally irrigated by segments of the anterior choroidal arteries [3]. A stroke to the PCA will therefore affect cognitive and memory function; the majority will show verbal long term memory deficit [12], and the duration of amnesia is usually at least 10 hours to few months [13]. However, the patient in this case discussion, had short term memory impairment, no verbal deficit, and the duration was very short. Also, in the literature, the TGA related to hippocampal infarcts was also associated with infarcts in other vasculature territories such as middle cerebral artery and internal carotid artery [14], and hence no direct causation between TGA and PCA strokes solely can be made. TGA as a symptom, can be caused by several triggers such as sexual intercourse, anxiety, head trauma, emotional distress…but no vascular triggers identified in the literature, symptoms last for an average of 6 hours [15]. In this case, brain MRI and MRA, showed subacute ischemic lesions in the left occipital lobe, hippocampus and thalamus (Figure1), caused by a distal occlusion of the left PCA (Figure 2). A distal occlusion of the PCA led to multiple infarcts in different anatomical structures, causing a constellation of variant neurological signs. It is highly important to recognize, diagnose, and rapidly intervene in similar cases, as data reported long term hippocampal atrophy and long term cognitive and memory impairment when injuries to hippocampus blood supply are left untreated [16]. Our case demonstrates an anterior hippocampus predominantly irrigated by the PCA and it highlights that a damage to the hippocampus can impair memory processes, and due to its vascularization by the PCA, the hippocampus is involved in large territorial strokes from adjacent structures and when affected, clinical symptoms and signs such as amnesia should draw urgent attention. Conclusion Symptoms like visual field defects, confusion, weakness and general status alteration are always associated with stroke to PCA. Due to false negative and radiological delay on early CT scans, brain MRI/MRA done in emergency is essential to ensure a rapid diagnosis and identification of the ischemic area. When there is an isolated hippocampal stroke, TGA is the most apparent symptom of presentation. Usually, the amnesia is transient and resolve within 24 hours after medical therapy. Declarations Authorship statement All authors contributed equally and validated the final version of record. Conflicts Of Interest The Author(s) declare(s) that there is no conflict of interest. Funding statement This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Registration No registration applicable. Data availability statement The data that support the findings of this study are available from the corresponding author upon reasonable request. Ethical approval A written and verbal consent was taken from the patient. References 1. Stephens RB, Stilwell DL. Arteries and Veins of the Human Brain. Thomas; 1969. (Thomas books). 2. Szabo K, Förster A, Jäger T, Kern R, Griebe M, Hennerici MG, et al. Hippocampal Lesion Patterns in Acute Posterior Cerebral Artery Stroke. Stroke. 2009 Jun 1;40(6):2042–5. https://doi.org/10.1161/STROKEAHA.108.536144. 3. Gass A, Ay H, Szabo K, Koroshetz WJ. Diffusion-weighted MRI for the “small stuff”: the details of acute cerebral ischaemia. Lancet Neurol. 2004;3(1):39–45. https://doi.org/10.1016/s1474-4422(03)006215. 4. Brandt T, Steinke W, Thie A, Pessin MS, Caplan LR. Posterior cerebral artery territory infarcts: clinical features, infarct topography, causes and outcome. Multicenter results and a review of the literature. Cerebrovasc Dis. 2000;10(3):170–182. https://doi.org/10.1159/000016053. 5. Koudstaal PJ, van Gijn J, Kappelle LJ. Headache in transient or permanent cerebral ischemia. Dutch TIA Study Group. Stroke. 1991 Jun 1;22(6):754–9. https://doi.org/10.1161/01.STR.22.6.754. 6. Arena JE, Rabinstein AA. Transient global amnesia. Mayo Clin Proc. 2015;90(2):264–272. https://doi.org/10.1016/j.mayocp.2014.12.001. 7. Kumral E, Deveci EE, Erdoğan C, Enüstün C. Isolated hippocampal infarcts: Vascular and neuropsychological findings. J Neurol Sci. 2015;356(12):83–89. https://doi.org/10.1016/j.jns.2015.06.01. 8. Naldi F, Baiardi S, Guarino M, Spinardi L, Cirignotta F, Stracciari A. Posterior hippocampal stroke presenting with transient global amnesia. Neurocase. 2017 Jan 2;23(1):22–5. https://doi.org/10.1080/13554794.2016.1270329. 9. Bhai S, Biffi A, Bakhadirov K, Prasad S. Complete Anterograde Amnesia From Simultaneous Bilateral Hippocampal Infarction. The Neurohospitalist. 2014 Jul 1;4(3):165–6. https://doi.org/10.1177/1941874414524795. 10. Cipolotti L, Bird CM. Amnesia and the hippocampus. Current Opinion in Neurology. 2006;19(6):593–8. https://doi.org/10.1097/01.wco.0000247608.42320.f9. 11. Sparaco M, Ciolli L, Zini A. Posterior circulation ischaemic stroke—a review part I: anatomy, aetiology and clinical presentations. Neurol Sci. 2019 Oct 1;40(10):1995–2006. https://doi.org/10.1007/s10072-019-03977-2. 12. Arboix A, Arbe G, García-Eroles L, Oliveres M, Parra O, Massons J. Infarctions in the vascular territory of the posterior cerebral artery: clinical features in 232 patients. BMC Res Notes. 2011 Sep 7;4(1):329. https://doi.org/10.1186/1756-0500-4-329. 13. Munk AH, Starup EB, Lambon Ralph MA, Leff AP, Starrfelt R, Robotham RJ. Colour perception deficits after posterior stroke: Not so rare after all? Cortex. 2023 Feb 1;159:118–30. https://doi.org/10.1016/j.cortex.2022.12.001. 14. Hoyer C, Szabo K. Pitfalls in the Diagnosis of Posterior Circulation Stroke in the Emergency Setting. Front Neurol. 2021;12:682827. https://doi.org/10.3389/fneur.2021.682827. 15. Salerno A, Strambo D, Nannoni S, Dunet V, Michel P. Patterns of ischemic posterior circulation strokes: A clinical, anatomical, and radiological review. Int J Stroke. 2022 Aug 1;17(7):714–22. https://doi.org/10.1177/17474930211046758. 16. Caplan LR. UpToDate. 2023. Patient education: Ischemic stroke treatment (Beyond the Basics). Available from: https://www.uptodate.com/contents/ischemic-stroke-treatment-beyond-the-basics#H7298680 17. Coutts SB, Ankolekar S, Appireddy R, Arenillas JF, Assis Z, Bailey P, et al. Tenecteplase versus standard of care for minor ischaemic stroke with proven occlusion (TEMPO-2): a randomised, open label, phase 3 superiority trial. Lancet. 2024 Jun 15;403(10444):2597–605. https://doi.org/10.1016/S0140-6736(24)00921-8. 18. Nguyen TQ, Tran MH, Phung HN, Nguyen KV, Tran HTM, Walter S, et al. Endovascular treatment for acute ischemic stroke beyond the 24-h time window: Selection by target mismatch profile. Int J Stroke. 2024 Mar 1;19(3):305–13. https://doi.org/10.1177/17474930231208817.
Subarachnoid hemorrhage associated with ecstasy abuse in a young adult: a case report
3,4-Methyl​enedioxy​methamphetamine (MDMA), is a synthetic amphetamine derivative. Its usage can be complicated by intracerebral or subarachnoid hemorrhage. Drug-related intracranial hemorrhage (ICH) is a relatively uncommon occurrence, often associated with an underlying vascular anomaly, We report the case of a 28-year-old male with a history of Ecstasy abuse prior to the onset of a sever holocranial headache. Cerebral computed tomography angiography revealed a right sided sub-arachnoid hemorrhage and blood within all four ventricles, as well as a right sided pontine hematoma and an arteriovenous malformation. As the drug epidemic continues to worsen, it is important to take a full drug history in patients presenting with a severe headache, and to not overlook ICH as a potential complication of recreational drug abuse. Key Messages - MDMA abuse complicated with an intracerebral accident is a well-recognized entity, but intracerebral hemorrhage remains relatively uncommon. - We report the first case of ecstasy abuse complicated with intracerebral hemorrhage, to our knowledge, occurring in a in a young adult in Tunisia. - Patients presenting with severe headache and a history of drug abuse might be at risk of developing intracerebral hemorrhage. Introduction 3,4-Methylenedioxymethamphetamine (MDMA), is a synthetic amphetamine derivative.(1) It was first developed in 1912 and was popularized in the 1980s as a recreational street drug due to its strong empathogen as well as its stimulant and minor psychedelic properties.(1) It is usually taken orally in its tablet form (“Ecstasy”) or crystal form (“Molly” or “Mandy”). MDMA abuse is associated with multiple potentially life threatening complications.(1) Intracranial hemorrhage (ICH), including intracerebral and subarachnoid hemorrhage, is a well-known yet relatively uncommon complication. Subsequent brain imaging often reveals an underlying vascular anomaly.(2–7) After a literature review using MeSH and keywords (MDMA, arteriovenous malformation, intracerebral hemorrhage) in PubMed. We report the first case of ecstasy abuse complicated with intracerebral hemorrhage, to our knowledge, occurring in a in a young adult in Tunisia. Case presentation 28-year-old male with a past history of infrequent MDMA abuse spanning years presented to the emergency department for an acute onset of a severe headache. At first medical contact he was afebrile and his vital signs were normal. On further history and physical exam, four and half hours prior to his presentation, he had ingested a half of tablet of “Ecstasy”. Following this ingestion, he presented with a headache, vomiting, dizziness and dysarthria. There had been no history of hypertension or headache and the patient reported no recent head trauma or loss of consciousness. The patient denied any history of other substance abuse. During his stay at the ED his symptoms progressed and he became sleepy but conscious and orientated. Verbal and motor response, as well as eye opening, were all normal. Pupils were symmetrical and not dilated. Neurologic examination found a nuchal rigidity but Kernig and Brudzinski’s signs were both negative. There was no focal deficit and no signs of head trauma. Laboratory tests showed a white blood cell count of 16800 cells per microliter (normal range (NR) : 4.5 to 11.0 × 109/L), hyperlactatemia of 4.5 mmol/L (NR : 0.5-2.2) and hyperglycemia at glucose 11 mmol/L (NR : 4 - 7 mmol/L ). The other tests including hemostasis and electrolytes were within NR. Urine sample analysis revealed the presence of MDMA. Tests for other psychoactive substances such as cocaine, heroin and benzodiazepine as well as blood alcohol were all negative. A computed tomography (CT)- head scan was obtained and showed a right-sided sulcal sub-arachnoid hemorrhage and blood within all four ventricles, as well as a right-sided pontine hematoma (figure 1 A and B). Within the latter, contrast-enhanced CT showed an arteriovenous malformation (figure 2). The patient was admitted to a neurosurgery unit. The AVM was classified as 4 according to the Spetzler Martin scoring system, thus a conservative treatment was adopted and endovascular embolization of the AVM was scheduled but refused by the patient. He remained stable with resolution of his headaches and no neurological deterioration. He was discharged home on day 7 of admission with a spontaneous regression of the hematoma, thus a ventricular shunt was not performed, on follow up, the patient remained asymptomatic and no complications were reported. Discussion MDMA is a synthetic amphetamine derivative.(1) It is taken orally to induce pleasurable feelings such as loss of inhibition, euphoria and empathy and is commonly associated with raves, concerts and dance parties .(1) It has a myriad of adverse effects, such as tachycardia, arterial hypertension, nausea, bruxism, headache, blurred vision, insomnia, anxiety and agitation , as well as more serious complications such as rhabdomyolysis, hyperpyrexia, cardiac arrythmia, hepatic necrosis and disseminated intravascular coagulation.(1) Among its complications, ICH is a well-recognized entity, (2–7) but remains relatively uncommon. To the best of the authors’ knowledge, this represents the first reported case of ICH following ecstasy abuse in Tunisia. Previously reported cases of drug induced ICH have most often revealed an underlying vascular anomaly, mainly cerebral arteriovenous malformations and aneurysms. (2,3,5). However, it is possible that the latter may form either acutely in response to the drug itself, or progressively from repeated abuse(2,5). Furthermore, some case reports of ICH following MDMA abuse have shown no unusual findings in the angiogram,(6) suggesting that a preexisting vascular anomaly is neither necessary nor sufficient to induce it. A summary of cases reported in literature are is provided in table 1. To this date, MDMA’s exact role in precipitating an intracranial hemorrhage is still unclear. Two main mechanisms of action have been postulated in literature: Cerebral vasculitis and transient elevated blood pressure. (2,5) The proposition of cerebral vasculitis as a possible mechanism stems from MDMA's resemblance to amphetamine,(5) supported by substantial evidence linking the latter to at least some level of cerebral angiitis. Citron et al.(8) reported 14 cases of necrotizing angiitis in drug abusers, twelve of which had previously used methamphetamine intravenously, and one of which admitted to using it exclusively. Moreover, cerebral angiitis has been experimentally produced in rhesus monkeys following a two week intravenous administration of amphetamine, with the angiographic findings showing an arterial “beading” immediately after its administration.(9) In the case of MDMA itself, some case reports of MDMA induced ICH reported arterial “beading”.(7) However, to the finest of the authors’ knowledge, there is no direct evidence linking it with cerebral vasculitis. Transient surge in blood pressure has also been proposed as a causal mechanism.(2) Hypertension is a well-documented adverse effect of MDMA and is related to its sympathomimetic effect.(1) It has been the traditional explanation for drug-induced ICH in the context of a preexisting cerebrovascular anomaly, especially AVMs.(5) This is clearly likely to be the case in our patient. Another potential mechanism has been suggested through an experimental study on mice,(10) which showed that exposure to methamphetamine elicited an initial five-minute increase of cerebral blood flow, followed by a prolonged decrease over 30 minutes. This study also showed a sustained vasoconstriction of the pial arterioles following the exposure. However, more studies are needed in order to elucidate how much of a role this mechanism plays. We recognize some limitations in our report. The CT angiography has a lower sensitivity in the detection rate of cerebrovascular anomalies than the gold standard, catheter angiography. With the latter not being performed, it is possible that some vascular anomalies, such as small aneurysms, and especially vasculitis, have evaded detection. Concerning management, according to Expert Consensus on the Management of Brain Arteriovenous Malformations in 2019, brain arteriovenous malformations (bAVMs) can be treated by one or a combination of the following treatment modalities, namely embolization, radiosurgery, or microsurgical resection. The committee made recommendations based on age, eloquence of adjacent cortex, feeders’ example superficial versus deep. These items were gathered to create the Spetzler Martin scoring system, which is an easy and successful scoring tool. In fact, Grade 4 and 5 arteriovenous malformations (AVMs), conservative management may be the best option, which is the case in our patient. (11) Conclusion We describe a case of ICH complicating MDMA abuse in a young adult. Cerebral accidents are a well-recognized entity in these patients, but ICH remains relatively uncommon. Patients with MDMA abuse are at risk for intracerebral accidents including intracerebral hemorrhage. A full medical history including illicit drug abuse must be taken in patients presenting with the onset of a severe headache. Declarations Authorship statement All authors contributed equally and validated the final version of record. Conflicts Of Interest The Author(s) declare(s) that there is no conflict of interest. Funding statement This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Registration No registration applicable. Data availability statement The data that support the findings of this study are available from the corresponding author upon reasonable request. Ethical approval Ethical approval for this study was not required. References 1. Kalant H. The pharmacology and toxicology of “ecstasy” (MDMA) and related drugs. CMAJ. 2001 Oct 2;165(7):917–28. 2. Gledhill JA, Moore DF, Bell D, Henry JA. Subarachnoid haemorrhage associated with MDMA abuse. J Neurol Neurosurg Psychiatry. 1993 Sep 1;56(9):1036–7. https://doi.org/10.1136/jnnp.56.9.1036. 3. Auer J, Berent R, Weber T, Lassnig E, Eber B. Subarachnoid haemorrhage with “Ecstasy” abuse in a young adult. Neurol Sci. 2002 Oct 1;23(4):199–201. https://doi.org/10.1007/s100720200062. 4. Harries DP, De Silva R. ‘Ecstasy’ and Intracerebral Haemorrhage. Scott Med J. 1992 Oct 1;37(5):150–2. https://doi.org/10.1177/003693309203700508. 5. Mcevoy AW, Kitchen ND, Thomas DGT. Intracerebral haemorrhage and drug abuse in young adults. Br J Neurosurg. 2000 Jan 1;14(5):449–54. https://doi.org/10.1080/02688690050175247. 6. Kahn DE, Ferraro N, Benveniste RJ. 3 cases of primary intracranial hemorrhage associated with “Molly”, a purified form of 3,4-methylenedioxymethamphetamine (MDMA). J Neurol Sci. 2012 Dec 15;323(1):257–60. https://doi.org/10.1016/j.jns.2012.08.031. 7. Lee GYF, Gong GWK, Vrodos N, Brophy BP. ‘Ecstasy’-induced subarachnoid haemorrhage: an under-reported neurological complication? J Clin Neurosci. 2003 Nov 1;10(6):705–7. https://doi.org/10.1016/S0967-5868(03)00151-6. 8. Citron BP, Halpern M, McCarron M, Lundberg GD, McCormick R, Pincus IJ, et al. Necrotizing Angiitis Associated with Drug Abuse. N Engl J Med. 1970 Nov 5;283(19):1003–11. https://doi.org/10.1056/NEJM197011052831901. 9. Rumbaugh CL, Bergeron RT, Scanlan RL, Teal JS, Segall HD, Fang HCH, et al. Cerebral Vascular Changes Secondary to Amphetamine Abuse in the Experimental Animal. Radiology. 1971 Nov 1;101(2):345–51. https://doi.org/10.1148/101.2.345. 10. Polesskaya O, Silva J, Sanfilippo C, Desrosiers T, Sun A, Shen J, et al. Methamphetamine causes sustained depression in cerebral blood flow. Brain Res. 2011 Feb 10;1373:91–100. https://doi.org/10.1016/j.brainres.2010.12.017. 11. Samaniego EA, Dabus G, Meyers PM, Kan PT, Frösen J, Lanzino G, et al. Most Promising Approaches to Improve Brain AVM Management: ARISE I Consensus Recommendations. Stroke. 2024 May 1;55(5):1449–63. https://doi.org/10.1161/STROKEAHA.124.046725.
Mpox, formerly Monkeypox, is a viral illness caused by the Monkeypox virus. It was first discovered in 1958, and the first human infection was recorded in 1970.1 After that it caused several outbreaks, namely in 2003, 2021 and 2022.2There are 2 types of this virus, Clade I, the more severe form, and Clade II, the milder form.1 The 2022-2023 outbreak was caused by Clade II, but the 2024 outbreak is caused by Clade I, which has a case-fatality rate of around 10%.1,3 On Wednesday, August 14, 2024, the World Health Organization (WHO) declared the spread of Clade1 to be a public health emergency of international concern (PHEIC).4 This review will focus on what the clinician needs to know about mpox, and how to identify, manage and prevent it. Mpox, formerly Monkeypox, is a viral illness caused by the Monkeypox virus. This virus is a member of the Poxviridae family, which makes it closely related to the ancient extinct virus, Smallpox (variola).<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"FGAdQUza","properties":{"formattedCitation":"\\super 1\\nosupersub{}","plainCitation":"1","noteIndex":0},"citationItems":[{"id":2890,"uris":["http://zotero.org/users/11334842/items/NCSJQG9H"],"itemData":{"id":2890,"type":"article-journal","abstract":"First described in 1958, the human monkeypox virus (hMPXV) is a neglected zoonotic pathogen closely associated with the smallpox virus. The virus usually spreads via close contact with the infected animal or human and has been endemic mostly in ...","container-title":"Virus Research","DOI":"10.1016/j.virusres.2022.198932","language":"en","note":"PMID: 36165924","page":"198932","source":"pmc.ncbi.nlm.nih.gov","title":"The virology of human monkeypox virus (hMPXV): A brief overview","title-short":"The virology of human monkeypox virus (hMPXV)","volume":"322","author":[{"family":"Lansiaux","given":"Edouard"},{"family":"Jain","given":"Nityanand"},{"family":"Laivacuma","given":"Sniedze"},{"family":"Reinis","given":"Aigars"}],"issued":{"date-parts":[["2022",9,19]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->1<!-- [if supportFields]><![endif]--> Mpox It was first discovered in 1958, and the first human infection was recorded in 1970.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"77B6uMDk","properties":{"formattedCitation":"\\super 2\\nosupersub{}","plainCitation":"2","noteIndex":0},"citationItems":[{"id":2849,"uris":["http://zotero.org/users/11334842/items/ETRHQ9LR"],"itemData":{"id":2849,"type":"webpage","abstract":"Mpox (monkeypox) is a viral disease that occurs mostly in central and western Africa. It was first identified in laboratory monkeys. However, it is much more common among animals such as rats, mice, rabbits, and the African Squirrel.","language":"en-us","title":"About Mpox | Mpox | Poxvirus | CDC","URL":"https://www.cdc.gov/poxvirus/mpox/about/index.html","accessed":{"date-parts":[["2024",8,23]]},"issued":{"date-parts":[["2024",4,18]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->2<!-- [if supportFields]><![endif]--> After that it caused several outbreaks, namely in 2003, 2021 and 2022.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"NACGfViA","properties":{"formattedCitation":"\\super 3\\nosupersub{}","plainCitation":"3","noteIndex":0},"citationItems":[{"id":2851,"uris":["http://zotero.org/users/11334842/items/P6UJPA4M"],"itemData":{"id":2851,"type":"webpage","abstract":"Mpox is a viral disease that occurs mostly in central and western Africa. It is called mpox because it was first identified in laboratory monkeys. However, it is much more common among animals such as rats, mice, rabbits, and the African Squirrel","language":"en-us","title":"Past U.S. Cases and Outbreaks | Mpox | Poxvirus | CDC","URL":"https://www.cdc.gov/poxvirus/mpox/outbreak/us-outbreaks.html","accessed":{"date-parts":[["2024",8,23]]},"issued":{"date-parts":[["2024",2,29]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->3<!-- [if supportFields]><![endif]--> There are 2 types of this virus, Clade I, the more severe form, and Clade II, the milder form.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2TO3Qdqx","properties":{"formattedCitation":"\\super 2\\nosupersub{}","plainCitation":"2","noteIndex":0},"citationItems":[{"id":2849,"uris":["http://zotero.org/users/11334842/items/ETRHQ9LR"],"itemData":{"id":2849,"type":"webpage","abstract":"Mpox (monkeypox) is a viral disease that occurs mostly in central and western Africa. It was first identified in laboratory monkeys. However, it is much more common among animals such as rats, mice, rabbits, and the African Squirrel.","language":"en-us","title":"About Mpox | Mpox | Poxvirus | CDC","URL":"https://www.cdc.gov/poxvirus/mpox/about/index.html","accessed":{"date-parts":[["2024",8,23]]},"issued":{"date-parts":[["2024",4,18]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->2<!-- [if supportFields]><![endif]--> The 2022-2023 outbreak was caused by Clade II, but the 2024 outbreak is caused by Clade I, which has a case-fatality rate of around 10%.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"UZlps033","properties":{"formattedCitation":"\\super 2,4\\nosupersub{}","plainCitation":"2,4","noteIndex":0},"citationItems":[{"id":2849,"uris":["http://zotero.org/users/11334842/items/ETRHQ9LR"],"itemData":{"id":2849,"type":"webpage","abstract":"Mpox (monkeypox) is a viral disease that occurs mostly in central and western Africa. It was first identified in laboratory monkeys. However, it is much more common among animals such as rats, mice, rabbits, and the African Squirrel.","language":"en-us","title":"About Mpox | Mpox | Poxvirus | CDC","URL":"https://www.cdc.gov/poxvirus/mpox/about/index.html","accessed":{"date-parts":[["2024",8,23]]},"issued":{"date-parts":[["2024",4,18]]}}},{"id":2857,"uris":["http://zotero.org/users/11334842/items/DHJALV9N"],"itemData":{"id":2857,"type":"webpage","language":"en","title":"Mpox","URL":"https://www.idsociety.org/public-health/Mpox/","accessed":{"date-parts":[["2024",8,23]]},"issued":{"date-parts":[["2024",8,16]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->2,4<!-- [if supportFields]><![endif]--> On Wednesday, August 14, 2024, the World Health Organization (WHO) declared the spread of Clade1 to be a public health emergency of international concern (PHEIC).<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"eVK4LKvv","properties":{"formattedCitation":"\\super 5\\nosupersub{}","plainCitation":"5","noteIndex":0},"citationItems":[{"id":2859,"uris":["http://zotero.org/users/11334842/items/BDXHCVQL"],"itemData":{"id":2859,"type":"webpage","abstract":"WHO Director-General Dr Tedros Adhanom Ghebreyesus has determined that the upsurge of mpox in the Democratic Republic of the Congo (DRC) and a growing number of countries in Africa constitutes a public health emergency of international concern (PHEIC) under the International Health Regulations (2005) (IHR).","language":"en","title":"WHO Director-General declares mpox outbreak a public health emergency of international concern","URL":"https://www.who.int/news/item/14-08-2024-who-director-general-declares-mpox-outbreak-a-public-health-emergency-of-international-concern","accessed":{"date-parts":[["2024",8,23]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->5<!-- [if supportFields]><![endif]--> This review will focus on what the clinician needs to know about mpox, and how to identify, manage and prevent it. Away from all stereotypes, anyone can catch mpox. It can spread directly from animals through hunting, skinning or cooking, and it can spread from human to human, by close contact (talking), kissing , by sexual contact or vertical transmission.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"GLQ74uEQ","properties":{"formattedCitation":"\\super 6\\nosupersub{}","plainCitation":"6","noteIndex":0},"citationItems":[{"id":2853,"uris":["http://zotero.org/users/11334842/items/4WS3G8HJ"],"itemData":{"id":2853,"type":"webpage","abstract":"WHO fact sheet on monkeypox: includes key facts, definition, outbreaks, transmission, symptoms, diagnosis, treatment, prevention, WHO response.","language":"en","title":"Mpox (monkeypox)","URL":"https://www.who.int/news-room/fact-sheets/detail/monkeypox","accessed":{"date-parts":[["2024",8,23]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->6<!-- [if supportFields]><![endif]--> The virus is able to infect a host by penetrating injured skin or mucosal membranes. That being said, it is possible for mpox to spread by fomites and linens.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"wUd5wzzP","properties":{"formattedCitation":"\\super 6\\nosupersub{}","plainCitation":"6","noteIndex":0},"citationItems":[{"id":2853,"uris":["http://zotero.org/users/11334842/items/4WS3G8HJ"],"itemData":{"id":2853,"type":"webpage","abstract":"WHO fact sheet on monkeypox: includes key facts, definition, outbreaks, transmission, symptoms, diagnosis, treatment, prevention, WHO response.","language":"en","title":"Mpox (monkeypox)","URL":"https://www.who.int/news-room/fact-sheets/detail/monkeypox","accessed":{"date-parts":[["2024",8,23]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->6<!-- [if supportFields]><![endif]--> When the outbreak started in 2022, it was mainly among the men who have sex with men (MSM) population, but it was later revealed that the primary mode of transmission was through skin contact that is prolonged during sexual encounters.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"NwB3QQLw","properties":{"formattedCitation":"\\super 7\\nosupersub{}","plainCitation":"7","noteIndex":0},"citationItems":[{"id":2893,"uris":["http://zotero.org/users/11334842/items/4P6PBEIW"],"itemData":{"id":2893,"type":"webpage","title":"Smallpox & Other Orthopoxvirus-Associated Infections | CDC Yellow Book 2024","URL":"https://wwwnc.cdc.gov/travel/yellowbook/2024/infections-diseases/smallpox-other-orthopoxvirus-associated-infections","accessed":{"date-parts":[["2024",11,7]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->7<!-- [if supportFields]><![endif]--> That being said, risk of transmission is not the same among all modes, as will be discussed later in this review. Signs and symptoms of mpox can start as early as 1 day or as long as 3 weeks after exposure.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"9orfzmvt","properties":{"formattedCitation":"\\super 6\\nosupersub{}","plainCitation":"6","noteIndex":0},"citationItems":[{"id":2853,"uris":["http://zotero.org/users/11334842/items/4WS3G8HJ"],"itemData":{"id":2853,"type":"webpage","abstract":"WHO fact sheet on monkeypox: includes key facts, definition, outbreaks, transmission, symptoms, diagnosis, treatment, prevention, WHO response.","language":"en","title":"Mpox (monkeypox)","URL":"https://www.who.int/news-room/fact-sheets/detail/monkeypox","accessed":{"date-parts":[["2024",8,23]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->6<!-- [if supportFields]><![endif]--> This period is not usually contagious, unless prodromal symptoms are present.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Sl23Ijoj","properties":{"formattedCitation":"\\super 8\\nosupersub{}","plainCitation":"8","noteIndex":0},"citationItems":[{"id":2869,"uris":["http://zotero.org/users/11334842/items/XPSDJPJM"],"itemData":{"id":2869,"type":"webpage","abstract":"Clinical Recognition. Mpox (monkeypox) is a viral disease that occurs mostly in central and western Africa. It was first identified in laboratory monkeys. However, it is much more common among animals such as rats, mice, rabbits, and the African Squirrel.","language":"en-us","title":"Clinical Recognition | Mpox | Poxvirus | CDC","URL":"https://www.cdc.gov/poxvirus/mpox/clinicians/clinical-recognition.html","accessed":{"date-parts":[["2024",8,27]]},"issued":{"date-parts":[["2023",9,21]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->8<!-- [if supportFields]><![endif]--> The infection lasts anywhere between 2 and 4 weeks.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"PSlOJrVU","properties":{"formattedCitation":"\\super 6\\nosupersub{}","plainCitation":"6","noteIndex":0},"citationItems":[{"id":2853,"uris":["http://zotero.org/users/11334842/items/4WS3G8HJ"],"itemData":{"id":2853,"type":"webpage","abstract":"WHO fact sheet on monkeypox: includes key facts, definition, outbreaks, transmission, symptoms, diagnosis, treatment, prevention, WHO response.","language":"en","title":"Mpox (monkeypox)","URL":"https://www.who.int/news-room/fact-sheets/detail/monkeypox","accessed":{"date-parts":[["2024",8,23]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->6<!-- [if supportFields]><![endif]--> The most common symptom is rash, but this can vary from fever, sore throat, headache, myalgias, fatigue to lymphadenopathy.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"iOeZyITH","properties":{"formattedCitation":"\\super 6\\nosupersub{}","plainCitation":"6","noteIndex":0},"citationItems":[{"id":2853,"uris":["http://zotero.org/users/11334842/items/4WS3G8HJ"],"itemData":{"id":2853,"type":"webpage","abstract":"WHO fact sheet on monkeypox: includes key facts, definition, outbreaks, transmission, symptoms, diagnosis, treatment, prevention, WHO response.","language":"en","title":"Mpox (monkeypox)","URL":"https://www.who.int/news-room/fact-sheets/detail/monkeypox","accessed":{"date-parts":[["2024",8,23]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->6<!-- [if supportFields]><![endif]--> Some rarer symptoms can be proctitis, tonsillitis and conjunctivitis that can progress.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"sQogofCF","properties":{"formattedCitation":"\\super 9,10\\nosupersub{}","plainCitation":"9,10","noteIndex":0},"citationItems":[{"id":2897,"uris":["http://zotero.org/users/11334842/items/MWLGFYLQ"],"itemData":{"id":2897,"type":"article-journal","abstract":"WHO has declared human mpox (formerly known as monkeypox) a global public health emergency since July, 2022. When case numbers were increasing, so did clinicians' exposures to new elements of the disease. Additionally, the burden of mpox is particularly apparent in immunocompromised patients, who can have more variable and severe manifestations of disease across organ systems. In this Grand Round, we report novel and severe oculocutaneous manifestations of mpox in this population, which are both sight and life threatening. Specifically, we highlight two patients with mpox and AIDS who had refractory skin necrosis that progressed to either ocular compromise or panfacial gangrene, or both. Both patients ultimately died due to systemic complications of their infections. Through clinical analogies, we show how past experiences with related orthopoxviruses, such as variola virus (smallpox) and vaccinia virus, can add useful context for understanding and treating these new disease states. We suspect that in patients who are immunocompromised, monkeypox virus can clinically evolve not only via viraemia but also through direct intradermal spread. We propose that intradermal spread occurs by a process clinically and immunologically analogous to progressive vaccinia, a complication previously seen after conventional smallpox vaccination. We share evidence in support of this theory and implications regarding early management and post-exposure prophylaxis for at-risk populations. Content note: this Grand Round contains graphic images of mpox lesions of the eyes and face.","container-title":"The Lancet. Infectious Diseases","DOI":"10.1016/S1473-3099(22)00869-6","ISSN":"1474-4457","issue":"5","journalAbbreviation":"Lancet Infect Dis","language":"eng","note":"PMID: 36702137\nPMCID: PMC9870321","page":"e190-e197","source":"PubMed","title":"Novel severe oculocutaneous manifestations of human monkeypox virus infection and their historical analogues","volume":"23","author":[{"family":"Carrubba","given":"Steven"},{"family":"Geevarghese","given":"Alexi"},{"family":"Solli","given":"Elena"},{"family":"Guttha","given":"Samyuktha"},{"family":"Sims","given":"Jeffrey"},{"family":"Sperber","given":"Laurence"},{"family":"Meehan","given":"Shane"},{"family":"Ostrovsky","given":"Ann"}],"issued":{"date-parts":[["2023",5]]}}},{"id":2895,"uris":["http://zotero.org/users/11334842/items/C5UCLAI6"],"itemData":{"id":2895,"type":"article-journal","abstract":"OBJECTIVE: To characterise the clinical features of monkeypox infection in humans.\nDESIGN: Descriptive case series.\nSETTING: A regional high consequences infectious disease centre with associated primary and secondary care referrals, and affiliated sexual health centres in south London between May and July 2022.\nPARTICIPANTS: 197 patients with polymerase chain reaction confirmed monkeypox infection.\nRESULTS: The median age of participants was 38 years. All 197 participants were men, and 196 identified as gay, bisexual, or other men who have sex with men. All presented with mucocutaneous lesions, most commonly on the genitals (n=111 participants, 56.3%) or in the perianal area (n=82, 41.6%). 170 (86.3%) participants reported systemic illness. The most common systemic symptoms were fever (n=122, 61.9%), lymphadenopathy (114, 57.9%), and myalgia (n=62, 31.5%). 102/166 (61.5%) developed systemic features before the onset of mucocutaneous manifestations and 64 (38.5%) after (n=4 unknown). 27 (13.7%) presented exclusively with mucocutaneous manifestations without systemic features. 71 (36.0%) reported rectal pain, 33 (16.8%) sore throat, and 31 (15.7%) penile oedema. 27 (13.7%) had oral lesions and 9 (4.6%) had tonsillar signs. 70/195 (35.9%) participants had concomitant HIV infection. 56 (31.5%) of those screened for sexually transmitted infections had a concomitant sexually transmitted infection. Overall, 20 (10.2%) participants were admitted to hospital for the management of symptoms, most commonly rectal pain and penile swelling.\nCONCLUSIONS: These findings confirm the ongoing unprecedented community transmission of monkeypox virus among gay, bisexual, and other men who have sex with men seen in the UK and many other non-endemic countries. A variable temporal association was observed between mucocutaneous and systemic features, suggesting a new clinical course to the disease. New clinical presentations of monkeypox infection were identified, including rectal pain and penile oedema. These presentations should be included in public health messaging to aid early diagnosis and reduce onward transmission.","container-title":"BMJ (Clinical research ed.)","DOI":"10.1136/bmj-2022-072410","ISSN":"1756-1833","journalAbbreviation":"BMJ","language":"eng","note":"PMID: 35902115\nPMCID: PMC9331915","page":"e072410","source":"PubMed","title":"Clinical features and novel presentations of human monkeypox in a central London centre during the 2022 outbreak: descriptive case series","title-short":"Clinical features and novel presentations of human monkeypox in a central London centre during the 2022 outbreak","volume":"378","author":[{"family":"Patel","given":"Aatish"},{"family":"Bilinska","given":"Julia"},{"family":"Tam","given":"Jerry C. H."},{"family":"Da Silva Fontoura","given":"Dayana"},{"family":"Mason","given":"Claire Y."},{"family":"Daunt","given":"Anna"},{"family":"Snell","given":"Luke B."},{"family":"Murphy","given":"Jamie"},{"family":"Potter","given":"Jack"},{"family":"Tuudah","given":"Cecilia"},{"family":"Sundramoorthi","given":"Rohan"},{"family":"Abeywickrema","given":"Movin"},{"family":"Pley","given":"Caitlin"},{"family":"Naidu","given":"Vasanth"},{"family":"Nebbia","given":"Gaia"},{"family":"Aarons","given":"Emma"},{"family":"Botgros","given":"Alina"},{"family":"Douthwaite","given":"Sam T."},{"family":"Nispen Tot Pannerden","given":"Claire","non-dropping-particle":"van"},{"family":"Winslow","given":"Helen"},{"family":"Brown","given":"Aisling"},{"family":"Chilton","given":"Daniella"},{"family":"Nori","given":"Achyuta"}],"issued":{"date-parts":[["2022",7,28]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->9,10<!-- [if supportFields]><![endif]--> The rash is a flat papule that becomes vesicular, which is itchy and sometimes painful.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Cowm0eq7","properties":{"formattedCitation":"\\super 6\\nosupersub{}","plainCitation":"6","noteIndex":0},"citationItems":[{"id":2853,"uris":["http://zotero.org/users/11334842/items/4WS3G8HJ"],"itemData":{"id":2853,"type":"webpage","abstract":"WHO fact sheet on monkeypox: includes key facts, definition, outbreaks, transmission, symptoms, diagnosis, treatment, prevention, WHO response.","language":"en","title":"Mpox (monkeypox)","URL":"https://www.who.int/news-room/fact-sheets/detail/monkeypox","accessed":{"date-parts":[["2024",8,23]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->6<!-- [if supportFields]><![endif]--> The rash usually umbilicates and develops into a pustule then followed by a dark scab.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"BVDxQl8X","properties":{"formattedCitation":"\\super 8\\nosupersub{}","plainCitation":"8","noteIndex":0},"citationItems":[{"id":2869,"uris":["http://zotero.org/users/11334842/items/XPSDJPJM"],"itemData":{"id":2869,"type":"webpage","abstract":"Clinical Recognition. Mpox (monkeypox) is a viral disease that occurs mostly in central and western Africa. It was first identified in laboratory monkeys. However, it is much more common among animals such as rats, mice, rabbits, and the African Squirrel.","language":"en-us","title":"Clinical Recognition | Mpox | Poxvirus | CDC","URL":"https://www.cdc.gov/poxvirus/mpox/clinicians/clinical-recognition.html","accessed":{"date-parts":[["2024",8,27]]},"issued":{"date-parts":[["2023",9,21]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->8<!-- [if supportFields]><![endif]--> As they dry-up, they crust then fall-off.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"0Sc7UKaP","properties":{"formattedCitation":"\\super 6\\nosupersub{}","plainCitation":"6","noteIndex":0},"citationItems":[{"id":2853,"uris":["http://zotero.org/users/11334842/items/4WS3G8HJ"],"itemData":{"id":2853,"type":"webpage","abstract":"WHO fact sheet on monkeypox: includes key facts, definition, outbreaks, transmission, symptoms, diagnosis, treatment, prevention, WHO response.","language":"en","title":"Mpox (monkeypox)","URL":"https://www.who.int/news-room/fact-sheets/detail/monkeypox","accessed":{"date-parts":[["2024",8,23]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->6<!-- [if supportFields]><![endif]--> Mpox rash can occur anywhere on the body, including palms, soles, eyes, genital and anal areas.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"QD8OSSJ6","properties":{"formattedCitation":"\\super 6\\nosupersub{}","plainCitation":"6","noteIndex":0},"citationItems":[{"id":2853,"uris":["http://zotero.org/users/11334842/items/4WS3G8HJ"],"itemData":{"id":2853,"type":"webpage","abstract":"WHO fact sheet on monkeypox: includes key facts, definition, outbreaks, transmission, symptoms, diagnosis, treatment, prevention, WHO response.","language":"en","title":"Mpox (monkeypox)","URL":"https://www.who.int/news-room/fact-sheets/detail/monkeypox","accessed":{"date-parts":[["2024",8,23]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->6<!-- [if supportFields]><![endif]--> When it occurs on the anogenital areas, patients might complain of dysuria or painful defecation.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"jUD8yBtm","properties":{"formattedCitation":"\\super 6\\nosupersub{}","plainCitation":"6","noteIndex":0},"citationItems":[{"id":2853,"uris":["http://zotero.org/users/11334842/items/4WS3G8HJ"],"itemData":{"id":2853,"type":"webpage","abstract":"WHO fact sheet on monkeypox: includes key facts, definition, outbreaks, transmission, symptoms, diagnosis, treatment, prevention, WHO response.","language":"en","title":"Mpox (monkeypox)","URL":"https://www.who.int/news-room/fact-sheets/detail/monkeypox","accessed":{"date-parts":[["2024",8,23]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->6<!-- [if supportFields]><![endif]--> The mpox rash remains infective until the whole scab falls off and new intact skin is formed.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"48klNRff","properties":{"formattedCitation":"\\super 6\\nosupersub{}","plainCitation":"6","noteIndex":0},"citationItems":[{"id":2853,"uris":["http://zotero.org/users/11334842/items/4WS3G8HJ"],"itemData":{"id":2853,"type":"webpage","abstract":"WHO fact sheet on monkeypox: includes key facts, definition, outbreaks, transmission, symptoms, diagnosis, treatment, prevention, WHO response.","language":"en","title":"Mpox (monkeypox)","URL":"https://www.who.int/news-room/fact-sheets/detail/monkeypox","accessed":{"date-parts":[["2024",8,23]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->6<!-- [if supportFields]><![endif]--> Mpox can cause multiple complications, such as blindness, dysphagia causing malnutrition and dehydration, encephalitis, myocarditis, proctitis, urethritis, bacterial superinfection causing sepsis, blindness or death.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"vXejS6M9","properties":{"formattedCitation":"\\super 6\\nosupersub{}","plainCitation":"6","noteIndex":0},"citationItems":[{"id":2853,"uris":["http://zotero.org/users/11334842/items/4WS3G8HJ"],"itemData":{"id":2853,"type":"webpage","abstract":"WHO fact sheet on monkeypox: includes key facts, definition, outbreaks, transmission, symptoms, diagnosis, treatment, prevention, WHO response.","language":"en","title":"Mpox (monkeypox)","URL":"https://www.who.int/news-room/fact-sheets/detail/monkeypox","accessed":{"date-parts":[["2024",8,23]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->6<!-- [if supportFields]><![endif]--> Immunosuppression, including uncontrolled HIV are risk factors for a more severe mpox infection.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"xrBQerZB","properties":{"formattedCitation":"\\super 6\\nosupersub{}","plainCitation":"6","noteIndex":0},"citationItems":[{"id":2853,"uris":["http://zotero.org/users/11334842/items/4WS3G8HJ"],"itemData":{"id":2853,"type":"webpage","abstract":"WHO fact sheet on monkeypox: includes key facts, definition, outbreaks, transmission, symptoms, diagnosis, treatment, prevention, WHO response.","language":"en","title":"Mpox (monkeypox)","URL":"https://www.who.int/news-room/fact-sheets/detail/monkeypox","accessed":{"date-parts":[["2024",8,23]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->6<!-- [if supportFields]><![endif]--> Therefore, the differential diagnosis of Mpox can be wide and tricky, including but not limited to chickenpox, smallpox, other rash-causing infectious and non-infectious complications and autoimmune diseases. The main differentiation before testing is through exposure history and the shape of the rash.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"hahUSLfh","properties":{"formattedCitation":"\\super 11\\nosupersub{}","plainCitation":"11","noteIndex":0},"citationItems":[{"id":2901,"uris":["http://zotero.org/users/11334842/items/VY9B39WS"],"itemData":{"id":2901,"type":"article-journal","abstract":"The current 2022 mpox (monkeypox) outbreak has been officially recognized as a public health emergency. The mpox clinical symptoms include high fever, fatigue, chills, headache, swollen lymph nodes, muscle aches, and a disseminated painful rash. However, recent cases of mpox have shown a shift in clinical symptoms, with anogenital skin lesions emerging as the predominant feature. Due to the predominant skin manifestations of mpox, dermatologists could be crucial in detecting new mpox cases and educating frontline healthcare professionals about mpox. The mpox virus is continuously evolving and has several variants. Genome sequencing has revealed that the Clade IIb variant is responsible for the 2022 mpox outbreak. Mpox spread may occur through animal-to-human and human-to-human transmission; however, unlike coronavirus disease 2019 (COVID-19), long-range airborne transmission has not been reported. Healthcare professionals are at higher risk of becoming infected since they are usually in close contact with both the patients and potentially contaminated fomites (e.g., examination table, gowns, gloves). Both public and healthcare professionals should take preventive and avoidance measures to limit the spread. Mpox is usually self-limiting and may require only symptomatic treatment; however, it may cause severe complications in special populations such as immunocompromised individuals. For severe infection, clinicians may consider antiviral drugs (off-label), tecovirimat and brincidofovir, originally approved for smallpox treatment. Two smallpox vaccines, ACAM2000® and JYNNEOSTM, can be used as pre-exposure prophylaxis against mpox. JYNNEOSTM, which carries approval for mpox use, has less adverse effect potential than ACAM2000®, and may also be used as post-exposure prophylaxis, preferably within 4 days of exposure.","container-title":"American Journal of Clinical Dermatology","DOI":"10.1007/s40257-023-00778-4","ISSN":"1179-1888","issue":"4","journalAbbreviation":"Am J Clin Dermatol","language":"en","page":"541-556","source":"Springer Link","title":"Differential Diagnosis, Prevention, and Treatment of mpox (Monkeypox): A Review for Dermatologists","title-short":"Differential Diagnosis, Prevention, and Treatment of mpox (Monkeypox)","volume":"24","author":[{"family":"Gupta","given":"Aditya K."},{"family":"Talukder","given":"Mesbah"},{"family":"Rosen","given":"Ted"},{"family":"Piguet","given":"Vincent"}],"issued":{"date-parts":[["2023",7,1]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->11<!-- [if supportFields]><![endif]--> Since a lot of infections and non-infectious conditions cause rashes that is similar to the mpox rash, diagnosis can be challenging.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"UwMUnmy3","properties":{"formattedCitation":"\\super 6\\nosupersub{}","plainCitation":"6","noteIndex":0},"citationItems":[{"id":2853,"uris":["http://zotero.org/users/11334842/items/4WS3G8HJ"],"itemData":{"id":2853,"type":"webpage","abstract":"WHO fact sheet on monkeypox: includes key facts, definition, outbreaks, transmission, symptoms, diagnosis, treatment, prevention, WHO response.","language":"en","title":"Mpox (monkeypox)","URL":"https://www.who.int/news-room/fact-sheets/detail/monkeypox","accessed":{"date-parts":[["2024",8,23]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->6<!-- [if supportFields]><![endif]--> The best diagnostic method is polymerase chain reaction (PCR) of samples collected by swabbing fluid directly from the lesion, extracting dried-up skin or crust by vigorous swabbing or scraping or oropharyngeal swabs. Blood PCR or serology is not recommended and has a low yield.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"UmrAl36V","properties":{"formattedCitation":"\\super 6\\nosupersub{}","plainCitation":"6","noteIndex":0},"citationItems":[{"id":2853,"uris":["http://zotero.org/users/11334842/items/4WS3G8HJ"],"itemData":{"id":2853,"type":"webpage","abstract":"WHO fact sheet on monkeypox: includes key facts, definition, outbreaks, transmission, symptoms, diagnosis, treatment, prevention, WHO response.","language":"en","title":"Mpox (monkeypox)","URL":"https://www.who.int/news-room/fact-sheets/detail/monkeypox","accessed":{"date-parts":[["2024",8,23]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->6<!-- [if supportFields]><![endif]--> There is only 1 vaccine that is Food and Drug Administration (FDA)-approved for mpox (and smallpox).<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"z4wNA7Gr","properties":{"formattedCitation":"\\super 12\\nosupersub{}","plainCitation":"12","noteIndex":0},"citationItems":[{"id":2855,"uris":["http://zotero.org/users/11334842/items/FM94V3JQ"],"itemData":{"id":2855,"type":"article-journal","abstract":"FDA plays a critical role in protecting the United States from chemical, biological, radiological, nuclear, and emerging infectious disease threats. This page covers FDA's role in mpox preparedness and response, and information about mpox (formerly called monkeypox).","container-title":"FDA","language":"en","note":"publisher: FDA","source":"www.fda.gov","title":"FDA Mpox Response","URL":"https://www.fda.gov/emergency-preparedness-and-response/mcm-issues/fda-mpox-response","author":[{"family":"Commissioner","given":"Office","dropping-particle":"of the"}],"accessed":{"date-parts":[["2024",8,23]]},"issued":{"date-parts":[["2024",8,19]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->12<!-- [if supportFields]><![endif]--> There are a few antivirals available for mpox treatment, but these are last resort and not FDA-approved.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"ntpGNiyv","properties":{"formattedCitation":"\\super 12\\nosupersub{}","plainCitation":"12","noteIndex":0},"citationItems":[{"id":2855,"uris":["http://zotero.org/users/11334842/items/FM94V3JQ"],"itemData":{"id":2855,"type":"article-journal","abstract":"FDA plays a critical role in protecting the United States from chemical, biological, radiological, nuclear, and emerging infectious disease threats. This page covers FDA's role in mpox preparedness and response, and information about mpox (formerly called monkeypox).","container-title":"FDA","language":"en","note":"publisher: FDA","source":"www.fda.gov","title":"FDA Mpox Response","URL":"https://www.fda.gov/emergency-preparedness-and-response/mcm-issues/fda-mpox-response","author":[{"family":"Commissioner","given":"Office","dropping-particle":"of the"}],"accessed":{"date-parts":[["2024",8,23]]},"issued":{"date-parts":[["2024",8,19]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->12<!-- [if supportFields]><![endif]--> Currently, the treatment of mpox is supportive management and isolation to prevent transmission.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"tYZ6erXi","properties":{"formattedCitation":"\\super 6\\nosupersub{}","plainCitation":"6","noteIndex":0},"citationItems":[{"id":2853,"uris":["http://zotero.org/users/11334842/items/4WS3G8HJ"],"itemData":{"id":2853,"type":"webpage","abstract":"WHO fact sheet on monkeypox: includes key facts, definition, outbreaks, transmission, symptoms, diagnosis, treatment, prevention, WHO response.","language":"en","title":"Mpox (monkeypox)","URL":"https://www.who.int/news-room/fact-sheets/detail/monkeypox","accessed":{"date-parts":[["2024",8,23]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->6<!-- [if supportFields]><![endif]--> Mpox screening requires stratifying cases to suspected, probable and confirmed. A suspected case in when there is a rash with clinical suspicion after being exposed. A probable case is defined by having a PCR-confirmed presence of Orthopoxvirus nucleic acid on a specimen, or after immunohistochemistry.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"4eNsK5Tk","properties":{"formattedCitation":"\\super 13\\nosupersub{}","plainCitation":"13","noteIndex":0},"citationItems":[{"id":2862,"uris":["http://zotero.org/users/11334842/items/7LPH7YPX"],"itemData":{"id":2862,"type":"document","title":"Mpox_Playbook_August_14_2024.docx","URL":"https://apic.org/wp-content/uploads/2024/08/Mpox_Playbook_August_14_2024.docx","accessed":{"date-parts":[["2024",8,27]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->13<!-- [if supportFields]><![endif]--> It can also be defined by the presence of anti-Orthopoxvirus IgM within 4-56 days of the rash, but this method of screening is not advised. A confirmed case is present when there is mpox-specific PCR positivity.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"s6Tyz7av","properties":{"formattedCitation":"\\super 13\\nosupersub{}","plainCitation":"13","noteIndex":0},"citationItems":[{"id":2862,"uris":["http://zotero.org/users/11334842/items/7LPH7YPX"],"itemData":{"id":2862,"type":"document","title":"Mpox_Playbook_August_14_2024.docx","URL":"https://apic.org/wp-content/uploads/2024/08/Mpox_Playbook_August_14_2024.docx","accessed":{"date-parts":[["2024",8,27]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->13<!-- [if supportFields]><![endif]--> If the rash does not develop within 5 days after onset of illness, or if a high quality specimen yields negative mpox PCR, this can exclude mpox.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"mEO05nwf","properties":{"formattedCitation":"\\super 13\\nosupersub{}","plainCitation":"13","noteIndex":0},"citationItems":[{"id":2862,"uris":["http://zotero.org/users/11334842/items/7LPH7YPX"],"itemData":{"id":2862,"type":"document","title":"Mpox_Playbook_August_14_2024.docx","URL":"https://apic.org/wp-content/uploads/2024/08/Mpox_Playbook_August_14_2024.docx","accessed":{"date-parts":[["2024",8,27]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->13<!-- [if supportFields]><![endif]--> Exposure is defined by the CDC as minimal, intermediate and high. Low exposure is contact with a person infected with mpox with completely covered lesions without contact with any lesions, crusts or fluids (even if dried up) directly.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"cRq83xU4","properties":{"formattedCitation":"\\super 14\\nosupersub{}","plainCitation":"14","noteIndex":0},"citationItems":[{"id":2863,"uris":["http://zotero.org/users/11334842/items/U8L3BBY6"],"itemData":{"id":2863,"type":"webpage","abstract":"Infection Control: Hospital. Mpox (monkeypox) is a viral disease that occurs mostly in central and western Africa. It was first identified in laboratory monkeys. However, it is much more common among animals such as rats, mice, rabbits, and the African Squirrel.","language":"en-us","title":"Infection Control: Healthcare Settings | Mpox | Poxvirus | CDC","title-short":"Infection Control","URL":"https://www.cdc.gov/poxvirus/mpox/clinicians/infection-control-healthcare.html","accessed":{"date-parts":[["2024",8,27]]},"issued":{"date-parts":[["2024",8,5]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->14<!-- [if supportFields]><![endif]--> Intermediate exposure is contact of exposed intact skin with lesions, crusts or fluids from a person with mpox or exposure to dried lesion fluids. Entering the room of a person with mpox or examining their mouth without personal protective equipment is also intermediate risk.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"WPdQSePZ","properties":{"formattedCitation":"\\super 14\\nosupersub{}","plainCitation":"14","noteIndex":0},"citationItems":[{"id":2863,"uris":["http://zotero.org/users/11334842/items/U8L3BBY6"],"itemData":{"id":2863,"type":"webpage","abstract":"Infection Control: Hospital. Mpox (monkeypox) is a viral disease that occurs mostly in central and western Africa. It was first identified in laboratory monkeys. However, it is much more common among animals such as rats, mice, rabbits, and the African Squirrel.","language":"en-us","title":"Infection Control: Healthcare Settings | Mpox | Poxvirus | CDC","title-short":"Infection Control","URL":"https://www.cdc.gov/poxvirus/mpox/clinicians/infection-control-healthcare.html","accessed":{"date-parts":[["2024",8,27]]},"issued":{"date-parts":[["2024",8,5]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->14<!-- [if supportFields]><![endif]--> High risk is defined as contact of broken skin/membranes with lesions or fluids from an individual with mpox. It can also be defined as exchange of body fluids, using soiled linen or sharps injury with material used by an infected individual.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"OXaPJ46M","properties":{"formattedCitation":"\\super 14\\nosupersub{}","plainCitation":"14","noteIndex":0},"citationItems":[{"id":2863,"uris":["http://zotero.org/users/11334842/items/U8L3BBY6"],"itemData":{"id":2863,"type":"webpage","abstract":"Infection Control: Hospital. Mpox (monkeypox) is a viral disease that occurs mostly in central and western Africa. It was first identified in laboratory monkeys. However, it is much more common among animals such as rats, mice, rabbits, and the African Squirrel.","language":"en-us","title":"Infection Control: Healthcare Settings | Mpox | Poxvirus | CDC","title-short":"Infection Control","URL":"https://www.cdc.gov/poxvirus/mpox/clinicians/infection-control-healthcare.html","accessed":{"date-parts":[["2024",8,27]]},"issued":{"date-parts":[["2024",8,5]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->14<!-- [if supportFields]><![endif]--> For minimal risk, people would be monitored, while for high-risk they would be monitored and receive PEP. For intermediate risk, PEP decision is case by case. Exposed people should be monitored for 21 days but not isolated. If any rash develops, in-patients should be put on airborne and contact isolation.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"5sdqr9q9","properties":{"formattedCitation":"\\super 14\\nosupersub{}","plainCitation":"14","noteIndex":0},"citationItems":[{"id":2863,"uris":["http://zotero.org/users/11334842/items/U8L3BBY6"],"itemData":{"id":2863,"type":"webpage","abstract":"Infection Control: Hospital. Mpox (monkeypox) is a viral disease that occurs mostly in central and western Africa. It was first identified in laboratory monkeys. However, it is much more common among animals such as rats, mice, rabbits, and the African Squirrel.","language":"en-us","title":"Infection Control: Healthcare Settings | Mpox | Poxvirus | CDC","title-short":"Infection Control","URL":"https://www.cdc.gov/poxvirus/mpox/clinicians/infection-control-healthcare.html","accessed":{"date-parts":[["2024",8,27]]},"issued":{"date-parts":[["2024",8,5]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->14<!-- [if supportFields]><![endif]--> Other individuals should be home isolated without access to pets. Isolation is stopped when mpox is ruled out by testing.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"6NUeREuL","properties":{"formattedCitation":"\\super 14\\nosupersub{}","plainCitation":"14","noteIndex":0},"citationItems":[{"id":2863,"uris":["http://zotero.org/users/11334842/items/U8L3BBY6"],"itemData":{"id":2863,"type":"webpage","abstract":"Infection Control: Hospital. Mpox (monkeypox) is a viral disease that occurs mostly in central and western Africa. It was first identified in laboratory monkeys. However, it is much more common among animals such as rats, mice, rabbits, and the African Squirrel.","language":"en-us","title":"Infection Control: Healthcare Settings | Mpox | Poxvirus | CDC","title-short":"Infection Control","URL":"https://www.cdc.gov/poxvirus/mpox/clinicians/infection-control-healthcare.html","accessed":{"date-parts":[["2024",8,27]]},"issued":{"date-parts":[["2024",8,5]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->14<!-- [if supportFields]><![endif]--> If any symptom other than rash develops, patients should be isolated for 5 days until any new symptom or rash develops, even if this extends beyond 21 days. If 5 days pass without any new rash or symptoms, isolation can be removed.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"0ntwD9N2","properties":{"formattedCitation":"\\super 14\\nosupersub{}","plainCitation":"14","noteIndex":0},"citationItems":[{"id":2863,"uris":["http://zotero.org/users/11334842/items/U8L3BBY6"],"itemData":{"id":2863,"type":"webpage","abstract":"Infection Control: Hospital. Mpox (monkeypox) is a viral disease that occurs mostly in central and western Africa. It was first identified in laboratory monkeys. However, it is much more common among animals such as rats, mice, rabbits, and the African Squirrel.","language":"en-us","title":"Infection Control: Healthcare Settings | Mpox | Poxvirus | CDC","title-short":"Infection Control","URL":"https://www.cdc.gov/poxvirus/mpox/clinicians/infection-control-healthcare.html","accessed":{"date-parts":[["2024",8,27]]},"issued":{"date-parts":[["2024",8,5]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->14<!-- [if supportFields]><![endif]--> Two vaccines are available for mpox: JYNNEOS, which is a 2-dose vaccine, and ACAM2000, which is not commercially available.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"bCKPimKL","properties":{"formattedCitation":"\\super 15\\nosupersub{}","plainCitation":"15","noteIndex":0},"citationItems":[{"id":2865,"uris":["http://zotero.org/users/11334842/items/3UT3H7A5"],"itemData":{"id":2865,"type":"webpage","abstract":"Mpox (monkeypox) is a viral disease that occurs mostly in central and western Africa. It was first identified in laboratory monkeys. However, it is much more common among animals such as rats, mice, rabbits, and the African Squirrel.","language":"en-us","title":"Vaccination | Mpox | Poxvirus | CDC","URL":"https://www.cdc.gov/poxvirus/mpox/interim-considerations/overview.html","accessed":{"date-parts":[["2024",8,27]]},"issued":{"date-parts":[["2024",8,27]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->15<!-- [if supportFields]><![endif]--> Vaccination provides long-lasting immunity for more than 5 years and no booster is needed. Previously infected people do not need to be re-vaccinated.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"DLmu9eoc","properties":{"formattedCitation":"\\super 15\\nosupersub{}","plainCitation":"15","noteIndex":0},"citationItems":[{"id":2865,"uris":["http://zotero.org/users/11334842/items/3UT3H7A5"],"itemData":{"id":2865,"type":"webpage","abstract":"Mpox (monkeypox) is a viral disease that occurs mostly in central and western Africa. It was first identified in laboratory monkeys. However, it is much more common among animals such as rats, mice, rabbits, and the African Squirrel.","language":"en-us","title":"Vaccination | Mpox | Poxvirus | CDC","URL":"https://www.cdc.gov/poxvirus/mpox/interim-considerations/overview.html","accessed":{"date-parts":[["2024",8,27]]},"issued":{"date-parts":[["2024",8,27]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->15<!-- [if supportFields]><![endif]--> The current guidelines for vaccination includes people with occupational exposure, men who have sex with men (MSM), non-binary and transgender people who have multiple sexual partners, commercial sex workers, sex in large public events where an active outbreak is happening, sex partners of infected individuals or any person who asks for it.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"KIVpf5oQ","properties":{"formattedCitation":"\\super 15\\nosupersub{}","plainCitation":"15","noteIndex":0},"citationItems":[{"id":2865,"uris":["http://zotero.org/users/11334842/items/3UT3H7A5"],"itemData":{"id":2865,"type":"webpage","abstract":"Mpox (monkeypox) is a viral disease that occurs mostly in central and western Africa. It was first identified in laboratory monkeys. However, it is much more common among animals such as rats, mice, rabbits, and the African Squirrel.","language":"en-us","title":"Vaccination | Mpox | Poxvirus | CDC","URL":"https://www.cdc.gov/poxvirus/mpox/interim-considerations/overview.html","accessed":{"date-parts":[["2024",8,27]]},"issued":{"date-parts":[["2024",8,27]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->15<!-- [if supportFields]><![endif]--> Of course, having taken the vaccine for Mpox or smallpox is a protective factor against infection. PEP should be given as soon as possible, within 14 days after exposure, in the form of the JYNNEOS vaccine.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"970SGVI7","properties":{"formattedCitation":"\\super 15\\nosupersub{}","plainCitation":"15","noteIndex":0},"citationItems":[{"id":2865,"uris":["http://zotero.org/users/11334842/items/3UT3H7A5"],"itemData":{"id":2865,"type":"webpage","abstract":"Mpox (monkeypox) is a viral disease that occurs mostly in central and western Africa. It was first identified in laboratory monkeys. However, it is much more common among animals such as rats, mice, rabbits, and the African Squirrel.","language":"en-us","title":"Vaccination | Mpox | Poxvirus | CDC","URL":"https://www.cdc.gov/poxvirus/mpox/interim-considerations/overview.html","accessed":{"date-parts":[["2024",8,27]]},"issued":{"date-parts":[["2024",8,27]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->15<!-- [if supportFields]><![endif]--> JYENNOS is a live attenuated virus that does not replicate, therefore it is safe in immunocompromised individuals.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"OrQxx2KT","properties":{"formattedCitation":"\\super 15\\nosupersub{}","plainCitation":"15","noteIndex":0},"citationItems":[{"id":2865,"uris":["http://zotero.org/users/11334842/items/3UT3H7A5"],"itemData":{"id":2865,"type":"webpage","abstract":"Mpox (monkeypox) is a viral disease that occurs mostly in central and western Africa. It was first identified in laboratory monkeys. However, it is much more common among animals such as rats, mice, rabbits, and the African Squirrel.","language":"en-us","title":"Vaccination | Mpox | Poxvirus | CDC","URL":"https://www.cdc.gov/poxvirus/mpox/interim-considerations/overview.html","accessed":{"date-parts":[["2024",8,27]]},"issued":{"date-parts":[["2024",8,27]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->15<!-- [if supportFields]><![endif]--> Currently giving it in pregnancy, breastfeeding and in people under 18 years of age is not a guideline.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"qqp178gn","properties":{"formattedCitation":"\\super 15\\nosupersub{}","plainCitation":"15","noteIndex":0},"citationItems":[{"id":2865,"uris":["http://zotero.org/users/11334842/items/3UT3H7A5"],"itemData":{"id":2865,"type":"webpage","abstract":"Mpox (monkeypox) is a viral disease that occurs mostly in central and western Africa. It was first identified in laboratory monkeys. However, it is much more common among animals such as rats, mice, rabbits, and the African Squirrel.","language":"en-us","title":"Vaccination | Mpox | Poxvirus | CDC","URL":"https://www.cdc.gov/poxvirus/mpox/interim-considerations/overview.html","accessed":{"date-parts":[["2024",8,27]]},"issued":{"date-parts":[["2024",8,27]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->15<!-- [if supportFields]><![endif]--> The only antiviral available to treat mpox is tecovirimat, but it is only authorized under “exceptional circumstances” in the United States and Europe, as studies have shown its effectiveness in decreasing mortality but safety has not been established.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"PA8R8HDF","properties":{"formattedCitation":"\\super 16\\nosupersub{}","plainCitation":"16","noteIndex":0},"citationItems":[{"id":2867,"uris":["http://zotero.org/users/11334842/items/SP5TIE3C"],"itemData":{"id":2867,"type":"webpage","language":"en","title":"Tecovirimat SIGA | European Medicines Agency (EMA)","URL":"https://www.ema.europa.eu/en/medicines/human/EPAR/tecovirimat-siga","accessed":{"date-parts":[["2024",8,27]]},"issued":{"date-parts":[["2022",1,28]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->16<!-- [if supportFields]><![endif]--> Tecovirimat should be given for 14 days. However, its efficacy and safety is not yet established and a lot of trials are on-going to determine this, making it less available for use.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Gmola5v9","properties":{"formattedCitation":"\\super 17\\nosupersub{}","plainCitation":"17","noteIndex":0},"citationItems":[{"id":2905,"uris":["http://zotero.org/users/11334842/items/PCBK4RRS"],"itemData":{"id":2905,"type":"webpage","abstract":"Information for healthcare professionals on the use of Tecovirimat (TPOXX) for treatment of mpox","container-title":"Mpox","language":"en-us","title":"Tecovirimat (TPOXX) for Treatment of Mpox","URL":"https://www.cdc.gov/mpox/hcp/clinical-care/tecovirimat.html","author":[{"family":"CDC","given":""}],"accessed":{"date-parts":[["2024",11,7]]},"issued":{"date-parts":[["2024",9,26]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->17<!-- [if supportFields]><![endif]--> Currently, taskforce is centered around acceptance and public health measures such as spreading prevention and awareness to stop the outbreak.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"uhfKKL7a","properties":{"formattedCitation":"\\super 18\\nosupersub{}","plainCitation":"18","noteIndex":0},"citationItems":[{"id":2907,"uris":["http://zotero.org/users/11334842/items/EUVYM4QJ"],"itemData":{"id":2907,"type":"article-journal","container-title":"The Lancet","DOI":"10.1016/S0140-6736(24)01751-3","ISSN":"0140-6736, 1474-547X","issue":"10454","journalAbbreviation":"The Lancet","language":"English","note":"publisher: Elsevier\nPMID: 39182498","page":"e1-e2","source":"www.thelancet.com","title":"Mpox declared a public health emergency","volume":"404","author":[{"family":"Adepoju","given":"Paul"}],"issued":{"date-parts":[["2024",8,24]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->18<!-- [if supportFields]><![endif]--> There are other options, such as Brincidofovir, which is a smallpox treatment, cidofovir and intravenous immunoglobulin (IVIG), but all of these are not part of the guidelines and are still under study for Mpox, though they offer promise of future treatments.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2hjblUKj","properties":{"formattedCitation":"\\super 19\\nosupersub{}","plainCitation":"19","noteIndex":0},"citationItems":[{"id":2903,"uris":["http://zotero.org/users/11334842/items/9W9FDJFW"],"itemData":{"id":2903,"type":"webpage","abstract":"Clinical guidance for available mpox biologics and treatment options","container-title":"Mpox","language":"en-us","title":"Clinical Treatment of Mpox","URL":"https://www.cdc.gov/mpox/hcp/clinical-care/index.html","author":[{"family":"CDC","given":""}],"accessed":{"date-parts":[["2024",11,7]]},"issued":{"date-parts":[["2024",9,26]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->19<!-- [if supportFields]><![endif]--> The algorithm (figure 1) provided below provides a walkthrough of how to manage a person exposed to mpox. Declarations Author contributions All authors contributed equally and validated the final version of record. Conflicts Of Interest The Author(s) declare(s) that there is no conflict of interest. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Registration No registration applicable Data availability statement The data that support the findings of this study are available from the corresponding author upon reasonable request. Ethical approval Ethical approval for this study was not required. References 1. Lansiaux E, Jain N, Laivacuma S, Reinis A. The virology of human monkeypox virus (hMPXV): A brief overview. Virus Research. 2022;322:198932 https://doi.org/10.1016/j.virusres.2022.198932 2. About Mpox [Internet]. CDC; 2024 [cited 2024 Aug 23]. Available from: https://www.cdc.gov/poxvirus/mpox/about/index.html 3. Past U.S. Cases and Outbreaks [Internet]. CDC; 2024 [cited 2024 Aug 23]. Available from: https://www.cdc.gov/poxvirus/mpox/outbreak/us-outbreaks.html 4. Mpox [Internet]. IDSA; [cited 2024 Aug 23]. Available from: https://www.idsociety.org/ID-topics/infectious-disease/mpox 5. WHO Director-General declares mpox outbreak a public health emergency of international concern [Internet]. World Health Organization; 2024 [cited 2024 Aug 23]. Available from: https://www.who.int/news/item/14-08-2024-who-director-general-declares-mpox-outbreak-a-public-health-emergency-of-international-concern 6. Mpox (monkeypox) [Internet]. World Health Organization; 2024 [cited 2024 Aug 23]. Available from: https://www.who.int/news-room/fact-sheets/detail/monkeypox 7. CDC Yellow Book 2024 [Internet]. CDC; [cited 2024 Nov 7]. Smallpox & Other Orthopoxvirus-Associated Infections. Available from: https://wwwnc.cdc.gov/travel/yellowbook/2024/infections-diseases/smallpox-other-orthopoxvirus-associated-infections 8. Clinical Recognition | Mpox | Poxvirus [Internet]. CDC; 2023 [cited 2024 Aug 27]. Available from: https://www.cdc.gov/poxvirus/mpox/clinicians/clinical-recognition.html 9. Carrubba S, Geevarghese A, Solli E, Guttha S, Sims J, Sperber L, et al. Novel severe oculocutaneous manifestations of human monkeypox virus infection and their historical analogues. Lancet Infect Dis. 2023;23(5):e190–e197. https://doi.org/10.1016/S1473-3099(22)00869-6 10. Patel A, Bilinska J, Tam JCH, Da Silva Fontoura D, Mason CY, Daunt A, et al. Clinical features and novel presentations of human monkeypox in a central London centre during the 2022 outbreak: descriptive case series. BMJ. 2022;378:e072410. https://doi.org/10.1136/bmj-2022-072410 11. Gupta AK, Talukder M, Rosen T, Piguet V. Differential Diagnosis, Prevention, and Treatment of mpox (Monkeypox): A Review for Dermatologists. Am J Clin Dermatol. 2023;24(4):541–556. https://doi.org/10.1007/s40257-023-00778-4 12. FDA Mpox Response [Internet]. FDA; 2024 [cited 2024 Aug 23]. Available from: https://www.fda.gov/emergency-preparedness-and-response/mcm-issues/fda-mpox-response 13. APIC Emerging Infectious Diseases Task Force. Playbook: Mpox [Internet]. APIC; 2024 [cited 2024 Aug 27]. Available from: https://apic.org/wp-content/uploads/2024/08/Mpox_Playbook_August_14_2024.docx 14. Infection Control: Healthcare Settings [Internet]. CDC; 2024 [cited 2024 Aug 27]. Available from: https://www.cdc.gov/poxvirus/mpox/clinicians/infection-control-healthcare.html 15. Vaccination | Mpox | Poxvirus [Internet]. CDC; 2024 [cited 2024 Aug 27]. Available from: https://www.cdc.gov/poxvirus/mpox/interim-considerations/overview.html 16. Tecovirimat SIGA [Internet]. European Medicines Agency (EMA); 2022 [cited 2024 Aug 27]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/tecovirimat-siga 17. Tecovirimat (TPOXX) for Treatment of Mpox [Internet]. CDC; 2024 [cited 2024 Nov 7]. Available from: https://www.cdc.gov/mpox/hcp/clinical-care/tecovirimat.html 18. Adepoju P. Mpox declared a public health emergency. The Lancet. 2024;404(10454):e1–e2. https://doi.org/10.1016/S0140-6736(24)01751-3 19. Clinical Treatment of Mpox [Internet]. CDC; 2024 [cited 2024 Nov 7]. Available from: https://www.cdc.gov/mpox/hcp/clinical-care/index.html
The Epidemiology of Syphilis and Co-infection with HIV in a Tertiary Care Center in Lebanon: A Retrospective Review
Introduction: Syphilis is an ancient STI causing a new worldwide outbreak in general and in Lebanon specifically. Methods: We conducted a retrospective chart review to assess the rate of syphilis increase in an infectious diseases clinic in Lebanon from 2006 to 2023. We studied the epidemiology of these cases, stage and treatment response and their association to HIV infection and its control. Results: There was an 862% increase in syphilis cases from 2006 to 2019.Most of our cases were middle aged men living with HIV. Most of them had well-controlled HIV infection with good CD4 counts. Most of the diagnosed cases of syphilis were primary and secondary, responding to penicillin G. Discussion: Our data mostly parallels international data, except for gender distribution. Despite successful treatment of most cases in our clinic, the alarming rise of new cases highlights the urgent need for public health measures to mitigate this epidemic. Conclusion: Inclusive awareness is needed to stop syphilis spread in Lebanon, and more screening is key in identifying new cases early for a successful eradication. Introduction Syphilis is a bacterial sexually transmitted disease. The disease starts as a painless sore on the genitalia, rectum, or mouth. Although the treatment of syphilis is simple, the co-infection of syphilis and the Human Immunodeficiency Virus (HIV) can have significant morbidity and sometimes mortality. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"6BQJQDzg","properties":{"formattedCitation":"\\super 1\\nosupersub{}","plainCitation":"1","noteIndex":0},"citationItems":[{"id":"ZDWdnF8m/SbUDOUCP","uris":["http://zotero.org/groups/5033608/items/JB6RXICK"],"itemData":{"id":306,"type":"article-journal","abstract":"OBJECTIVES: Co-infection of syphilis and HIV remains hard to manage and its morbidity shows a rising tendency. Syphilis has been associated with increased risk of HIV acquisition in high-risk groups, especially in men who have sex with men (MSM). This systematic review and meta-analysis estimates the effect of syphilis infection on subsequent HIV acquisition, and assesses its difference between MSM and other high-risk populations.\nMETHODS: Five electronic databases were searched for literature published to 21 September 2019 without language restrictions. Longitudinal studies that enrolled key populations to compare the incidence of HIV with and without syphilis exposure were included. We used a random-effects model to estimate the effect of syphilis infection on HIV acquisition among high-risk populations, which include MSM, sex workers, serodiscordant couples, people who inject drugs and attendees of STD clinics.\nRESULTS: A total of 17 cohorts and 5 case-control studies involving 65 232 participants were included. HIV incidence showed a two-time increase after syphilis exposure, compared with a control group (relative risk (RR) 2.67 (95% CI 2.05 to 3.47); p<0.05 for prevalence; RR 3.21 (95% CI 2.26 to 4.57); p=0.419 for incidence). No significant differences were observed between MSM and other high-risk groups in syphilis infection prevalence (RR 2.60 (95% CI 1.78 to 3.80); p<0.05 vs RR, 2.98 (95% CI 2.15 to 4.14); p<0.05; ratio of relative risk 0.76 (95% CI 0.49 to 1.17)).\nCONCLUSIONS: Syphilis infection increases the risk of HIV acquisition in high-risk populations. There is no evidence to suggest MSM are at greater risk than other high-risk populations. Prompt diagnosis, timely treatment, preventive interventions against syphilis infection would be a worthwhile investment for reducing HIV incidence. Strategies to combat stigma and discrimination targeted at MSM are pragmatically needed.","container-title":"Sexually Transmitted Infections","DOI":"10.1136/sextrans-2020-054706","ISSN":"1472-3263","issue":"7","journalAbbreviation":"Sex Transm Infect","language":"eng","note":"PMID: 33219164\nPMCID: PMC8543214","page":"525-533","source":"PubMed","title":"Effect of syphilis infection on HIV acquisition: a systematic review and meta-analysis","title-short":"Effect of syphilis infection on HIV acquisition","volume":"97","author":[{"family":"Wu","given":"Meng Yin"},{"family":"Gong","given":"Hui Zi"},{"family":"Hu","given":"Kui Ru"},{"family":"Zheng","given":"He-Yi"},{"family":"Wan","given":"Xia"},{"family":"Li","given":"Jun"}],"issued":{"date-parts":[["2021",11]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->1<!-- [if supportFields]><![endif]--> With advances in the treatment of HIV, it became easy to slow down viral replication shortly after anti-retroviral therapy is initiated. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"xiXh1oYT","properties":{"formattedCitation":"\\super 2\\nosupersub{}","plainCitation":"2","noteIndex":0},"citationItems":[{"id":"ZDWdnF8m/Qn7vftbQ","uris":["http://zotero.org/groups/5033608/items/GGY8AX6C"],"itemData":{"id":310,"type":"chapter","abstract":"Highly active antiretroviral therapy (HAART) is a medication regimen used to manage and treat human immunodeficiency virus type 1 (HIV-1). It is composed of several drugs in the antiretroviral classes of medications. This activity outlines the indications, mechanism of action, and contraindications for various HAART medications in the management of HIV. This activity will highlight the mechanism of action, adverse event profile, and other key factors pertinent to the interprofessional healthcare team members in the care of patients with HIV-1 and related conditions.","call-number":"NBK554533","container-title":"StatPearls","event-place":"Treasure Island (FL)","language":"eng","license":"Copyright © 2023, StatPearls Publishing LLC.","note":"PMID: 32119420","publisher":"StatPearls Publishing","publisher-place":"Treasure Island (FL)","source":"PubMed","title":"Highly Active Antiretroviral Therapy (HAART)","URL":"http://www.ncbi.nlm.nih.gov/books/NBK554533/","author":[{"family":"Eggleton","given":"Julie S."},{"family":"Nagalli","given":"Shivaraj"}],"accessed":{"date-parts":[["2023",9,16]]},"issued":{"date-parts":[["2023"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->2<!-- [if supportFields]><![endif]--> This is seen as an “undetectable" result on blood quantitative Polymerase Chain Reaction (PCR) for HIV, translating to an un-transmissibility of the virus <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"xJede1lb","properties":{"formattedCitation":"\\super 2\\nosupersub{}","plainCitation":"2","noteIndex":0},"citationItems":[{"id":"ZDWdnF8m/Qn7vftbQ","uris":["http://zotero.org/groups/5033608/items/GGY8AX6C"],"itemData":{"id":310,"type":"chapter","abstract":"Highly active antiretroviral therapy (HAART) is a medication regimen used to manage and treat human immunodeficiency virus type 1 (HIV-1). It is composed of several drugs in the antiretroviral classes of medications. This activity outlines the indications, mechanism of action, and contraindications for various HAART medications in the management of HIV. This activity will highlight the mechanism of action, adverse event profile, and other key factors pertinent to the interprofessional healthcare team members in the care of patients with HIV-1 and related conditions.","call-number":"NBK554533","container-title":"StatPearls","event-place":"Treasure Island (FL)","language":"eng","license":"Copyright © 2023, StatPearls Publishing LLC.","note":"PMID: 32119420","publisher":"StatPearls Publishing","publisher-place":"Treasure Island (FL)","source":"PubMed","title":"Highly Active Antiretroviral Therapy (HAART)","URL":"http://www.ncbi.nlm.nih.gov/books/NBK554533/","author":[{"family":"Eggleton","given":"Julie S."},{"family":"Nagalli","given":"Shivaraj"}],"accessed":{"date-parts":[["2023",9,16]]},"issued":{"date-parts":[["2023"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->2<!-- [if supportFields]><![endif]-->. Hence, treatment of HIV is one of the best methods to limit its spread. In addition, the widespread use of the HIV pre-exposure prophylaxis (PreP), is another effective protective factor against acquiring HIV in healthy individuals before exposure. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"LiKRd2xE","properties":{"formattedCitation":"\\super 3\\nosupersub{}","plainCitation":"3","noteIndex":0},"citationItems":[{"id":"ZDWdnF8m/Ea2WPQ5c","uris":["http://zotero.org/groups/5033608/items/8JFERPIR"],"itemData":{"id":313,"type":"webpage","title":"Pre-Exposure Prophylaxis (PrEP) | HIV Risk and Prevention | HIV/AIDS | CDC","URL":"https://www.cdc.gov/hiv/risk/prep/index.html","accessed":{"date-parts":[["2023",9,16]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->3<!-- [if supportFields]><![endif]--> This does not come without a downside, as undetectable viral load status in people on treatment as well as the availability of PreP offered people a false sense of security, encouraging them further to engage in unprotected sex. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"OCCJyx2G","properties":{"formattedCitation":"\\super 4\\nosupersub{}","plainCitation":"4","noteIndex":0},"citationItems":[{"id":"ZDWdnF8m/Y3hfjcKl","uris":["http://zotero.org/groups/5033608/items/GTI39QII"],"itemData":{"id":315,"type":"article-journal","abstract":"Among men who have sex with men (MSM), acute alcohol consumption is associated with higher rates of condomless anal intercourse, which is linked with a greater likelihood of exposure to HIV and other sexually transmitted infections. While pre-exposure prophylaxis (PrEP) to prevent HIV infection has become more widespread in this population in recent years, so too have concerns that PrEP uptake may be associated with health risk behaviors. This study investigated differences in sexual behaviors and drug use habits between PrEP users and nonusers in a sample of moderate- and heavy-drinking MSM. Results indicated that PrEP use was associated with riskier sexual practices, weaker self-regulatory cognitions related to condom use, and more frequent illicit drug use. These findings suggest that moderate-and heavy-drinking MSM who use PrEP may comprise a unique risk group that could benefit from targeted counseling or other interventions to reduce their risk of negative health consequences.","container-title":"AIDS education and prevention: official publication of the International Society for AIDS Education","DOI":"10.1521/aeap.2019.31.5.452","ISSN":"1943-2755","issue":"5","journalAbbreviation":"AIDS Educ Prev","language":"eng","note":"PMID: 31550196","page":"452-462","source":"PubMed","title":"Pre-Exposure Prophylaxis (PrEP) Use is Associated With Health Risk Behaviors Among Moderate- and Heavy-Drinking MSM","volume":"31","author":[{"family":"Luehring-Jones","given":"Peter"},{"family":"Palfai","given":"Tibor P."},{"family":"Tahaney","given":"Kelli D."},{"family":"Maisto","given":"Stephen A."},{"family":"Simons","given":"Jeffrey"}],"issued":{"date-parts":[["2019",10]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->4<!-- [if supportFields]><![endif]--> This increases the risk of acquiring other sexually transmitted infections (STIs). A perfect example is syphilis, which is acquired through unprotected intercourse, and whose screening can serve as a marker for risky sexual behavior. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"6UvFfS5k","properties":{"formattedCitation":"\\super 5\\nosupersub{}","plainCitation":"5","noteIndex":0},"citationItems":[{"id":"ZDWdnF8m/y0Y9f4eb","uris":["http://zotero.org/groups/5033608/items/PJQJQ5LM"],"itemData":{"id":317,"type":"article-journal","abstract":"This review summarizes the epidemiology, clinical presentation, diagnosis, treatment, and monitoring of syphilis in HIV-infected patients, and suggests that these cycles are better predicted by the natural dynamics ofSyphilis infection than by external, behavioral factors. Syphilis has been a subject of intrigue and controversy since it was first recognized in the 15th century. Coined “the great imitator,” it can manifest in a variety of ways depending on the host and stage of infection, thus making diagnosis and management difficult. HIV infection creates an additional layer of complexity: Both pathogens are sexually transmitted, and the presence of one may facilitate infection with the other. In addition, the presentation, diagnosis, and management of syphilis differ in subtle ways between HIV-infected and HIV-uninfected patients. In this review, we summarize the epidemiology, clinical presentation, diagnosis, treatment, and monitoring of syphilis in HIV-infected patients.\n\nSyphilis is a global public health problem, resulting in an estimated 12 million new infections per year.1 In the U.S., the incidence of primary and secondary syphilis has been rising and falling in 10-year cycles since the 1940s, with the lowest recorded rates occurring in 2000, followed by a resurgence over the next 10 years. Some researchers have attributed these decade-long cycles to social and behavioral changes2 — and, indeed, several recent outbreak investigations have implicated high-risk behaviors, such as anonymous sex, sex under the influence of drugs, and unprotected sex, as the basis for the latest rise in syphilis incidence.3,4,5 However, mathematical modeling suggests that these cycles are better predicted by the natural dynamics of syphilis infection than by external, behavioral factors.6 At this point, the exact contribution of each factor remains uncertain.\n\nSimilar to the HIV epidemic, the current syphilis epidemic predominantly affects three groups: men who have sex with men (MSM), injection-drug users, and individuals who engage in sex for money or drugs. The CDC estimates that, in 2008, MSM accounted for more than 60% of all new diagnoses of primary and secondary syphilis in the U.S. …","container-title":"NEJM Journal Watch","language":"en","source":"www.semanticscholar.org","title":"Syphilis and HIV: The Intersection of Two Epidemics","title-short":"Syphilis and HIV","URL":"https://www.semanticscholar.org/paper/Syphilis-and-HIV%3A-The-Intersection-of-Two-Epidemics-Miller-Hicks/9f552bdda0e4b0c74b796a52d086b436ad7b6f08","author":[{"family":"Miller","given":"B."},{"family":"Hicks","given":"C."}],"accessed":{"date-parts":[["2023",9,16]]},"issued":{"date-parts":[["2010"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->5<!-- [if supportFields]><![endif]--> The real-life situation is a translation of that, with the rising incidence of syphilis worldwide as well as in Lebanon, especially among the population of People Living with HIV (PLH). According to CDC, there has been an increase syphilis cases in the United States, from 101590 new cases in 2017 to 171074 in 2021. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"6tXjsFzM","properties":{"formattedCitation":"\\super 6\\nosupersub{}","plainCitation":"6","noteIndex":0},"citationItems":[{"id":"ZDWdnF8m/CrhDzxcn","uris":["http://zotero.org/groups/5033608/items/X5BVLKWR"],"itemData":{"id":328,"type":"webpage","abstract":"STD Information from CDC. Facts, Statistics, Treatment, and Other Resources.","language":"en-us","title":"Sexually Transmitted Disease Surveillance, 2021","URL":"https://www.cdc.gov/std/statistics/2021/default.htm","accessed":{"date-parts":[["2023",9,16]]},"issued":{"date-parts":[["2023",4,11]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->6<!-- [if supportFields]><![endif]--> The rates of congenital syphilis have also increased from 941 in 2017 to 2677 in 2021. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"RmZuYg9l","properties":{"formattedCitation":"\\super 6\\nosupersub{}","plainCitation":"6","noteIndex":0},"citationItems":[{"id":"ZDWdnF8m/CrhDzxcn","uris":["http://zotero.org/groups/5033608/items/X5BVLKWR"],"itemData":{"id":328,"type":"webpage","abstract":"STD Information from CDC. Facts, Statistics, Treatment, and Other Resources.","language":"en-us","title":"Sexually Transmitted Disease Surveillance, 2021","URL":"https://www.cdc.gov/std/statistics/2021/default.htm","accessed":{"date-parts":[["2023",9,16]]},"issued":{"date-parts":[["2023",4,11]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->6<!-- [if supportFields]><![endif]--> As per the World Health Organization (WHO), syphilis is present in up to 12% of the population of men who have sex with men (MSM). <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"wgA41CLj","properties":{"formattedCitation":"\\super 7\\nosupersub{}","plainCitation":"7","noteIndex":0},"citationItems":[{"id":"ZDWdnF8m/onUpaPGj","uris":["http://zotero.org/groups/5033608/items/B8S56GLP"],"itemData":{"id":321,"type":"webpage","title":"New study highlights unacceptably high global prevalence of syphilis among men who have sex with men","URL":"https://www.who.int/news/item/09-07-2021-new-study-highlights-unacceptably-high-global-prevalence-of-syphilis-among-men-who-have-sex-with-men","accessed":{"date-parts":[["2023",9,16]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->7<!-- [if supportFields]><![endif]--> Besides, with the economic crisis smashing Lebanon since 2019 and subsequent shortage of and rising prices of drugs and condoms, there is a reduced usage of PrEP and condoms. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"FKWFidGO","properties":{"formattedCitation":"\\super 8\\nosupersub{}","plainCitation":"8","noteIndex":0},"citationItems":[{"id":"ZDWdnF8m/97P6vC7d","uris":["http://zotero.org/groups/5033608/items/US35CHAU"],"itemData":{"id":323,"type":"webpage","title":"Prevalence of HIV and other sexually transmitted infections and their association with sexual practices and substance use among 2238 MSM in Lebanon - PubMed","URL":"https://pubmed.ncbi.nlm.nih.gov/31641252/","accessed":{"date-parts":[["2023",9,16]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->8<!-- [if supportFields]><![endif]--> It has become certain that syphilis and HIV have a high rate of co-occurrence. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"uGsrk7Se","properties":{"formattedCitation":"\\super 9\\nosupersub{}","plainCitation":"9","noteIndex":0},"citationItems":[{"id":"ZDWdnF8m/iTBVPrYc","uris":["http://zotero.org/groups/5033608/items/ZG38PX96"],"itemData":{"id":308,"type":"article-journal","abstract":"PURPOSE OF REVIEW: To highlight recent trends in the epidemiology of HIV and syphilis, the impact of the COVID epidemic, our approach to care of co-infected patients, and our views on important next steps in advancing the field.\nRECENT FINDINGS: HIV and syphilis co-infection has been on the rise in recent years although since the COVID pandemic there is a decrease in new diagnoses-it remains unclear if this represents a true decline or inadequate testing or under-reporting. Standard HIV care should include regular syphilis serology .Treatment and serological follow-up of syphilis in HIV positive and negative patients can be conducted similarly. Challenges remain in the diagnosis and management of neurosyphilis. New models for testing and prevention will be crucial next steps in controlling co-infection. The intersection of HIV and syphilis infections continues to pose new and unique challenges in diagnosis, treatment, and prevention.","container-title":"Current HIV/AIDS reports","DOI":"10.1007/s11904-021-00564-z","ISSN":"1548-3576","issue":"4","journalAbbreviation":"Curr HIV/AIDS Rep","language":"eng","note":"PMID: 34091858\nPMCID: PMC8180186","page":"280-288","source":"PubMed","title":"The Intersection of HIV and Syphilis: Update on the Key Considerations in Testing and Management","title-short":"The Intersection of HIV and Syphilis","volume":"18","author":[{"family":"Ren","given":"Melody"},{"family":"Dashwood","given":"Thomas"},{"family":"Walmsley","given":"Sharon"}],"issued":{"date-parts":[["2021",8]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->9<!-- [if supportFields]><![endif]--> These two diseases share a synergistic relationship. Syphilis provides a favorable environment for HIV acquisition through the impairment of mucosal barrier and increased presence of white blood cells (WBCs) in the area. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"snZo98fC","properties":{"formattedCitation":"\\super 9\\nosupersub{}","plainCitation":"9","noteIndex":0},"citationItems":[{"id":"ZDWdnF8m/iTBVPrYc","uris":["http://zotero.org/groups/5033608/items/ZG38PX96"],"itemData":{"id":308,"type":"article-journal","abstract":"PURPOSE OF REVIEW: To highlight recent trends in the epidemiology of HIV and syphilis, the impact of the COVID epidemic, our approach to care of co-infected patients, and our views on important next steps in advancing the field.\nRECENT FINDINGS: HIV and syphilis co-infection has been on the rise in recent years although since the COVID pandemic there is a decrease in new diagnoses-it remains unclear if this represents a true decline or inadequate testing or under-reporting. Standard HIV care should include regular syphilis serology .Treatment and serological follow-up of syphilis in HIV positive and negative patients can be conducted similarly. Challenges remain in the diagnosis and management of neurosyphilis. New models for testing and prevention will be crucial next steps in controlling co-infection. The intersection of HIV and syphilis infections continues to pose new and unique challenges in diagnosis, treatment, and prevention.","container-title":"Current HIV/AIDS reports","DOI":"10.1007/s11904-021-00564-z","ISSN":"1548-3576","issue":"4","journalAbbreviation":"Curr HIV/AIDS Rep","language":"eng","note":"PMID: 34091858\nPMCID: PMC8180186","page":"280-288","source":"PubMed","title":"The Intersection of HIV and Syphilis: Update on the Key Considerations in Testing and Management","title-short":"The Intersection of HIV and Syphilis","volume":"18","author":[{"family":"Ren","given":"Melody"},{"family":"Dashwood","given":"Thomas"},{"family":"Walmsley","given":"Sharon"}],"issued":{"date-parts":[["2021",8]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->9<!-- [if supportFields]><![endif]--> Moreover, syphilis infection can result in decreased CD4 count and increased HIV viral load. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"5xIwG6Yq","properties":{"formattedCitation":"\\super 10\\nosupersub{}","plainCitation":"10","noteIndex":0},"citationItems":[{"id":"ZDWdnF8m/KBcjh1hU","uris":["http://zotero.org/groups/5033608/items/PEFI3EZB"],"itemData":{"id":330,"type":"article-journal","abstract":"Objectives: \n To assess the effect of human immunodeficiency virus (HIV)-1 and syphilis coinfection on HIV-ribonucleic acid (RNA) viral load, CD4 cell count, and the response in rapid plasmin reagin (RPR) to treatment of the syphilis infection.\n Study Design: \n Cases of syphilis diagnosed during 1 year in HIV-infected patients in Copenhagen were included. HIV-RNA, CD4 cell counts, and RPR-serology were measured before, during, and after syphilis.\n Results: \n Forty-one patients were included. CD4 cell count decreased significantly during infection in patients with primary and secondary stages of syphilis (mean 106 cells/mm3, P = 0.03). Treatment of syphilis was associated with an increase in the CD4 cell count and a decrease in HIV-RNA in the overall group (mean 66 cells/mm3 and −0.261 RNA log10 copies/ml, P = 0.02 and 0.04). The serological response rates for 15 patients treated with penicillin and 25 treated with doxycycline were the same.\n Conclusion: \n Syphilis was associated with a decrease in CD4 cell counts and an increase in HIV-RNA levels that both improved after treatment of syphilis.","container-title":"Sexually Transmitted Diseases","DOI":"10.1097/01.olq.0000187262.56820.c0","ISSN":"0148-5717","issue":"3","language":"en-US","page":"143","source":"journals.lww.com","title":"Syphilis and Human Immunodeficiency Virus (HIV)-1 Coinfection: Influence on CD4 T-Cell Count, HIV-1 Viral Load, and Treatment Response","title-short":"Syphilis and Human Immunodeficiency Virus (HIV)-1 Coinfection","volume":"33","author":[{"family":"Kofoed","given":"Kristian"},{"family":"Gerstoft","given":"Jan"},{"family":"Mathiesen","given":"Lars R."},{"family":"Benfield","given":"Thomas"}],"issued":{"date-parts":[["2006",3]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->10<!-- [if supportFields]><![endif]--> To our knowledge, no studies have previously assessed the relation of HIV CD4 count and viral load on the serologic response of syphilis to treatment. Therefore, this study provides scientific evidence about syphilis rates in people who live with HIV and in the general population by gathering data from 2006 till 2023, thus reflecting the outcome of the economic crisis during this period. Furthermore, this study discusses the effect of HIV on syphilis’ serology response to treatment. Material & Methods Study type: Retrospective observational study. Objectives: - To determine the prevalence of syphilis in our ID clinic from 2006 to 2023 - To determine the rate of co-infection with HIV among those diagnosed with syphilis. - To describe the demographics of people with syphilis and the reason they get tested. - To describe their response to treatment - To address the effect of HIV on the prognosis of syphilis Procedure: We included 11396 Lebanese adults since 2006 till 26 December 2023 and documented their syphilis and HIV status. The study included 2 phases: Phase I: Files from 12/2006 till 12/2023: We accessed the files of 11396 patients who presented to the infectious diseases (ID) clinics at the LAU Medical Center – Rizk Hospital in Beirut, Lebanon (LAUMCRH) who are at least 18 years old. We checked these patients’ syphilis and HIV status. This data helped to determine the changing rate of syphilis throughout the years in the population of patients presenting to infectious diseases clinics at our center. Phase II: We followed up the data of 91 patients who had syphilis from December 2016 till April 2023 and collected information about their age, gender, sexual orientation, reason for syphilis screening, syphilis serology response to treatment, and their HIV status. Those who were HIV positive were further assessed to determine their CD4 count, HIV viral load, and if both infections were concomitant at the time of diagnosis. Ethical Considerations This study was done in accordance with the Declaration of Helsenki and was approved by the by the Ethical Committee for Research at Lebanese American University (LAU­), Institutional Review Board. In order not to breach patient confidentiality, another sheet was made linking the patient names to numbers and this number is the one to be used in the data collection sheet. The former was destroyed. Results The percentage of syphilis positivity in patients presenting to ID clinics remained less than 1% from 2006 till 2013 but has increased to 3.37% in 2014 and 8.08% in 2015. After that, it plateaued until 2020 where new cases started increasing in frequency again up to 19.52% in 2023. The analysis of the 91 patients who admitted to the infectious disease clinic showed that 95.6% (88 patients) were males, 3.3% were females and 1% transgender women. Among those, 3% were heterosexual, 46% were homosexual and 48% did not have documentation of their sexual orientation. In terms of age distribution, most of these patients fell within the age range of 30-39 years (43 patients), followed by the age range of 40-49 years (20 patients). There were 13 patients aged between 18-29, 10 patients aged between 50-59, and 4 patients who were 60 years old or older. Among those with a diagnosis of syphilis, 81% (74/91) were HIV positive. 9% of those had concomitant acquisition of both infections, diagnosed with syphilis and HIV in the first visit and 91% were already known to be PLH at the time of diagnosis. 86% of these patients had a controlled HIV infection and 91% had a CD4 count above 200/mm3. Most diagnosed syphilis cases were primary and secondary syphilis (98%). All of them were treated with benzathine penicillin G, and only 2 patients were treated with doxycycline. 32% of the patients did not follow-up with a VDRL test after the injection, 24.7% showed decreasing serology, 31.8% showed stable serology after 6 months and 11% were re-infected at some point after this follow-up. Those reasons for syphilis screening varied between voluntary, suspected partner, pre-workup testing, and physician-initiated testing and counseling. For the reason of syphilis screening among PLH, 85% were referred by a physician for syphilis testing during a physical examination. The remaining patients had different reasons for admission: 5.8% sought voluntary testing, 4.6% were admitted due to suspected exposure from a sexual partner, and another 4.6% were admitted for pre-work up testing. Statistical analysis was performed using IBM SPSS 29.0. Descriptive statistics were reported using frequencies and percentages for the categorical variables, and median, mean, and standard deviation for the continuous variables. In our analysis, we utilized the chi square test to assess the relationship between categorical variables. We used Fischer’s exact test since the sample size and the expected frequencies are low. Based on the chi square tests that were performed to see association between CD4 counts and serological response to treatment, there was no statistically significant association found between CD4 levels, HIV status, HIV VL on diagnosis, patient age and the serologic response to treatment (respective p-values 0.2, 0.051, 0.129, 0.21) . No significant association was seen between concomitant acquisition of syphilis and HIV and serologic response to treatment (p=0.19). Discussion This study highlights the magnitude of the syphilis epidemic that is exploding in numbers all over the world. The WHO states that 7.1 million people were diagnosed with syphilis in 2020, with a global trend that is increasing exponentially. While a variety risk factors exist for syphilis, it shares many of them with other STIs, namely HIV, which is by itself considered a risk-factor for syphilis acquisition. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1uCZKU6I","properties":{"formattedCitation":"\\super 11\\nosupersub{}","plainCitation":"11","noteIndex":0},"citationItems":[{"id":"ZDWdnF8m/b5IbnOY5","uris":["http://zotero.org/users/11334842/items/JDYDZIMZ"],"itemData":{"id":2567,"type":"webpage","abstract":"WHO fact sheet on syphilis, including overview, symptoms, treatment, prevention and WHO response.","language":"en","title":"Syphilis","URL":"https://www.who.int/news-room/fact-sheets/detail/syphilis","accessed":{"date-parts":[["2024",6,18]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->11<!-- [if supportFields]><![endif]--> This is highlighted in our data, where the biggest bulk of syphilis cases were in PLH. However, in our population, these PLH have a well-controlled HIV infection, which reflects a close medical follow-up, which translates to increased STI screening, further showed by the high rates of physician referral cause for screening. Therefore, the high rates of syphilis in PLH in our clinic, while true, might be an over-estimation of the true connection between HIV and syphilis. The majority of cases were seen in the middle-aged people, which goes in accordance with the global trend <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"LBzABWAc","properties":{"formattedCitation":"\\super 12\\nosupersub{}","plainCitation":"12","noteIndex":0},"citationItems":[{"id":"ZDWdnF8m/ccb9VOYc","uris":["http://zotero.org/users/11334842/items/JHUGYGAK"],"itemData":{"id":1392,"type":"webpage","abstract":"STD Information from CDC. Facts, Statistics, Treatment, and Other Resources.","language":"en-us","title":"Table 16B. Primary and Secondary Syphilis — Rates of Reported Cases* by Race/Hispanic Ethnicity, Age Group, and Sex, United States, 2021","URL":"https://www.cdc.gov/std/statistics/2021/tables/16b.htm","accessed":{"date-parts":[["2024",1,24]]},"issued":{"date-parts":[["2023",4,11]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->12<!-- [if supportFields]><![endif]-->, where such ages are usually the most likely to engage in risky sexual behavior and IV drug use. Another notable finding in our data is the high prevalence of syphilis in the male population, where more than 95% of cases are seen in men. This is different than in other areas of the world, such as the United States (US), where two-thirds of the syphilis population is male, and the rest is mostly female. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"O2I8evVi","properties":{"formattedCitation":"\\super 12\\nosupersub{}","plainCitation":"12","noteIndex":0},"citationItems":[{"id":"ZDWdnF8m/ccb9VOYc","uris":["http://zotero.org/users/11334842/items/JHUGYGAK"],"itemData":{"id":1392,"type":"webpage","abstract":"STD Information from CDC. Facts, Statistics, Treatment, and Other Resources.","language":"en-us","title":"Table 16B. Primary and Secondary Syphilis — Rates of Reported Cases* by Race/Hispanic Ethnicity, Age Group, and Sex, United States, 2021","URL":"https://www.cdc.gov/std/statistics/2021/tables/16b.htm","accessed":{"date-parts":[["2024",1,24]]},"issued":{"date-parts":[["2023",4,11]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->12<!-- [if supportFields]><![endif]--> This would reflect that some of the risk factors associated with syphilis might be area specific, such as the much higher rate of unprotected intercourse, multiple sexual partners and IV drug use in the male population in Lebanon. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Rv1t1SXY","properties":{"formattedCitation":"\\super 13\\nosupersub{}","plainCitation":"13","noteIndex":0},"citationItems":[{"id":2569,"uris":["http://zotero.org/users/11334842/items/Y9N6YVHY"],"itemData":{"id":2569,"type":"article-journal","abstract":"Little is known about clinical presentation and cascade of care among patients living with HIV (PLWH) in Beirut, Lebanon. The study aims to examine the reasons for HIV testing and to evaluate the clinical characteristics of, predictors of advanced HIV stage at presentation in, and rates of ART initiation, retention in care, and viral load suppression among PLWH in Lebanon. We conducted a retrospective study of PLWH presenting to a tertiary-care centre-affiliated outpatient clinic from 2008 to 2016 with new HIV infection diagnoses. We identified a total of 423 patients: 89% were men, 55% were 30–50 years old, and 58% self-identified as men who have sex with men. About 35% of the patients had concurrent sexually transmitted diseases at the time of HIV diagnosis. Thirty percent of infection cases were identified by provider-initiated HIV testing, 36% of cases were identified by patient-initiated testing, and 34% of patients underwent testing for screening purposes. The proportion of individuals presenting with advanced HIV disease decreased from 40% in 2008–2009 to 24% in 2014–2015. Age older than 50 years and identification of HIV by a medical provider were independent predictors of advanced HIV infection at presentation. Among patients having indications for treatment (n = 253), 239 (94%) were prescribed antiretroviral therapy, and 147 (58%) had evidence of viral suppression at 1 year. Furthermore, 266 patients (63%) were retained in care. The care continuum for PLWH in Lebanon is comparable with those in high-income countries yet still far behind the Joint United Nations Programme on HIV/AIDS 90–90–90 set target.","container-title":"AIDS and Behavior","DOI":"10.1007/s10461-020-02788-3","ISSN":"1573-3254","issue":"8","journalAbbreviation":"AIDS Behav","language":"en","page":"2290-2298","source":"Springer Link","title":"HIV in Lebanon: Reasons for Testing, Engagement in Care, and Outcomes in Patients with Newly Diagnosed HIV Infections","title-short":"HIV in Lebanon","volume":"24","author":[{"family":"Wilson Dib","given":"Rita"},{"family":"Dandachi","given":"Dima"},{"family":"Matar","given":"Mireille"},{"family":"Shayya","given":"Annoir"},{"family":"Davila","given":"Jessica A."},{"family":"Giordano","given":"Thomas P."},{"family":"Mokhbat","given":"Jacques E."}],"issued":{"date-parts":[["2020",8,1]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->13<!-- [if supportFields]><![endif]--> Besides, there were no cases of congenital syphilis seen in our clinic throughout those years, which can be explained need to be married in couples who have children and the enforced premarital screening in the Lebanese population, despite STI screening not being part of the prenatal tests offered. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"s8zfC4oY","properties":{"formattedCitation":"\\super 14\\nosupersub{}","plainCitation":"14","noteIndex":0},"citationItems":[{"id":2571,"uris":["http://zotero.org/users/11334842/items/3YHUTXET"],"itemData":{"id":2571,"type":"article-journal","abstract":"Congenital syphilis remains a significant public health problem nowadays. We describe the presentation of an infant with a delayed diagnosis of congenital syphilis, with a negative initial non-treponemal test. Our aim is to shed light on the incidence of missed prevention, the importance of awareness, maternal screening, and early diagnosis.","container-title":"Frontiers in Pediatrics","DOI":"10.3389/fped.2020.499534","ISSN":"2296-2360","journalAbbreviation":"Front Pediatr","note":"PMID: 33553061\nPMCID: PMC7855964","page":"499534","source":"PubMed Central","title":"Case Report: A Delayed Diagnosis of Congenital Syphilis—Too Many Missed Opportunities","title-short":"Case Report","volume":"8","author":[{"family":"Khafaja","given":"Sarah"},{"family":"Youssef","given":"Yolla"},{"family":"Darjani","given":"Nidale"},{"family":"Youssef","given":"Nour"},{"family":"Fattah","given":"Captain Mohammad"},{"family":"Hanna-Wakim","given":"Rima"}],"issued":{"date-parts":[["2021",1,20]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->14<!-- [if supportFields]><![endif]--> Another explanation might be that such individuals might follow-up in the obstetrics clinics rather than ID clinics. While half of our population did not have documentation about their sexual orientation, we can see that the majority of those who did were MSM, which is in accordance with data in other countries such as the USA, <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"KvjWUvNI","properties":{"formattedCitation":"\\super 15\\nosupersub{}","plainCitation":"15","noteIndex":0},"citationItems":[{"id":"ZDWdnF8m/ydEs4TwV","uris":["http://zotero.org/users/11334842/items/FN95KF8Y"],"itemData":{"id":1678,"type":"article-journal","container-title":"PubMed Central","DOI":"10.15585/mmwr.mm6613a1","ISSN":"0149-2195","page":"349-354","title":"State-Specific Rates of Primary and Secondary Syphilis Among Men Who Have Sex with Men — United States, 2015","author":[{"family":"Voux","given":"Alex / Kidd","non-dropping-particle":"de"}],"issued":{"date-parts":[["2017",4,7]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->15<!-- [if supportFields]><![endif]--> and this can be explained by the high sexual activity of MSM compared with MSW and WSM. Besides, this population often faces stigma which leads to more secrecy around their sexual behavior and any STI symptoms they have. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"IDZC3GFn","properties":{"formattedCitation":"\\super 16\\nosupersub{}","plainCitation":"16","noteIndex":0},"citationItems":[{"id":2574,"uris":["http://zotero.org/users/11334842/items/Z22DB5GU"],"itemData":{"id":2574,"type":"article-journal","abstract":"This qualitative study sought to explore the sexual identity development of men who have sex with men (MSM) in Beirut, the stigma experienced by these men, and how their psychological well-being and social engagement are shaped by how they cope with this stigma. Semi-structured interviews were conducted with 31 MSM, and content analysis was used to identify emergent themes. While many men reported feeling very comfortable with their sexual orientation and had disclosed their sexual orientation to family, most men struggled at least somewhat with their sexuality, often because of perceived stigma from others and internal religious conflict about the immorality of homosexuality. Most participants described experiencing verbal harassment or ridicule, or being treated as different or lesser than in social relationships with friends or family. Mechanisms for coping with stigma included social avoidance (trying to pass as heterosexual; limiting interaction with MSM to the internet) or withdrawal from relationships in an attempt to limit exposure to stigma. Our findings suggest that effective coping with both internal and external sexual stigma is central to the psychological well-being and social engagement of MSM in Beirut, much like what has been found in Western gay communities.","container-title":"Culture, health & sexuality","DOI":"10.1080/13691058.2013.775345","ISSN":"1369-1058","issue":"5","journalAbbreviation":"Cult Health Sex","note":"PMID: 23730919\nPMCID: PMC3742541","page":"570-582","source":"PubMed Central","title":"Sexual Stigma, Psychological Well-Being and Social Engagement among Men Who Have Sex with Men in Beirut, Lebanon","volume":"15","author":[{"family":"Wagner","given":"Glenn J."},{"family":"Aunon","given":"Frances M."},{"family":"Kaplan","given":"Rachel L."},{"family":"Karam","given":"Rita"},{"family":"Khouri","given":"Danielle"},{"family":"Tohme","given":"Johnny"},{"family":"Mokhbat","given":"Jacques"}],"issued":{"date-parts":[["2013"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->16<!-- [if supportFields]><![endif]--> Since Lebanon is a country where the fight against gender inequality is on-going, women can have challenges regarding access proper sexual education or healthcare related to sexual health, especially if not married.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"xYTgquyA","properties":{"formattedCitation":"\\super 17\\nosupersub{}","plainCitation":"17","noteIndex":0},"citationItems":[{"id":2873,"uris":["http://zotero.org/users/11334842/items/8X8RUVKH"],"itemData":{"id":2873,"type":"article-journal","abstract":"The study explores women’s perception and experience of sexual difficulties. The need to address the subject was triggered by the scarcity of research that reflects on women’s subjective views on sexual difficulties. This is particularly crucial for middle-aged women who frequently experience hormonal and psychosocial changes that may affect their sexual life.","container-title":"BMC Women's Health","DOI":"10.1186/s12905-020-01132-0","ISSN":"1472-6874","issue":"1","journalAbbreviation":"BMC Women's Health","page":"203","source":"BioMed Central","title":"Middle-aged Lebanese women’s interpretation of sexual difficulties: a qualitative inquiry","title-short":"Middle-aged Lebanese women’s interpretation of sexual difficulties","volume":"21","author":[{"family":"Azar","given":"Mathilde"},{"family":"Bradbury-Jones","given":"Caroline"},{"family":"Kroll","given":"Thilo"}],"issued":{"date-parts":[["2021",5,17]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->17<!-- [if supportFields]><![endif]--> Besides, sex is highly stigmatized before marriage, possibly making unmarried women less sexually active then men.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"44D3RIEo","properties":{"formattedCitation":"\\super 18\\nosupersub{}","plainCitation":"18","noteIndex":0},"citationItems":[{"id":2871,"uris":["http://zotero.org/users/11334842/items/668CD4II"],"itemData":{"id":2871,"type":"webpage","abstract":"While the Lebanese government has adopted a law against sexual harassment, there is still a long journey ahead for women in their fight for gender equality in Lebanon.","container-title":"OHCHR","language":"en","title":"The fight for gender equality in Lebanon","URL":"https://www.ohchr.org/en/stories/2022/05/fight-gender-equality-lebanon","accessed":{"date-parts":[["2024",9,5]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->18<!-- [if supportFields]><![endif]--> However, even if they developed symptoms of syphilis, women may not be aware of their seriousness or the need to get tested or they might choose to hide them.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"RHC7taZJ","properties":{"formattedCitation":"\\super 19,20\\nosupersub{}","plainCitation":"19,20","noteIndex":0},"citationItems":[{"id":2876,"uris":["http://zotero.org/users/11334842/items/EDX5876B"],"itemData":{"id":2876,"type":"post-weblog","abstract":"The return of syphilis is a powerful indicator that U.S. approaches to health care delivery, public health, and equity have failed.","container-title":"STAT","language":"en-US","title":"Stigma and the return of syphilis","URL":"https://www.statnews.com/2024/05/30/syphilis-rates-climbing-stigma/","author":[{"family":"Brandt","given":"Jacob D. Moses","suffix":"Allan M."}],"accessed":{"date-parts":[["2024",9,5]]},"issued":{"date-parts":[["2024",5,30]]}}},{"id":2878,"uris":["http://zotero.org/users/11334842/items/7DZKGHDV"],"itemData":{"id":2878,"type":"article-journal","abstract":"Background We analyzed the prevalence of active infection with common curable sexually transmitted infections (STIs) including N. gonorrhea, C. trachomatis, T. vaginalis, and T. pallidum, as well as active infection with HPV, herpes simplex virus types I (HSV-1) and II (HSV-2), M. hominis, M. genitalium, C. albicans, and Ureaplasma in 351 Lebanese women. Methods A cross-sectional study, involving 351 sexually active women, 40 years or younger, who were recruited from outpatient Obstetrics and Gynecology clinic attendees between September 2016 and November 2017. Results The prevalence of active infection was low at 0.3% for N. gonorrhea, 0.6% for HSV-2, 2.8% for C. trachomatis, and 2.9% for any curable STIs. Prevalence of active HPV infection was high assessed at 15.7% for high-risk and 12.2% for low-risk genotypes. Furthermore, the prevalence was 2.0% for M. genitalium, 6.8% for ureaplasma, 13.7% for Candida albicans, and 20.5% for M. hominis. No active infections with T. vaginalis, T. pallidum, or HSV-1 were observed. Significant age differences were noted in the prevalence of high-risk and low-risk HPV genotypes, but no such differences were noted in the prevalence of other infections. No appreciable variations were identified in the prevalence of key STIs based on smoking, marital status, or the number of sexual partners. Conclusions The study documented active infection with substantial prevalence for multiple STIs among women attending outpatient gynecology and obstetrics clinics in Lebanon. These findings underscore the importance of strengthening STI surveillance, linkage to care, and prevention interventions in reducing STI incidence among women.","container-title":"PLOS ONE","DOI":"10.1371/journal.pone.0301231","ISSN":"1932-6203","issue":"4","journalAbbreviation":"PLOS ONE","language":"en","note":"publisher: Public Library of Science","page":"e0301231","source":"PLoS Journals","title":"Estimates of the incidence, prevalence, and factors associated with common sexually transmitted infections among Lebanese women","volume":"19","author":[{"family":"Chemaitelly","given":"Hiam"},{"family":"Finan","given":"Ramzi R."},{"family":"Racoubian","given":"Eddie"},{"family":"Aimagambetova","given":"Gulzhanat"},{"family":"Almawi","given":"Wassim Y."}],"issued":{"date-parts":[["2024",4,18]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->19,20<!-- [if supportFields]><![endif]--> All these would possibly lead to less syphilis diagnoses in women.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"rywy0wa5","properties":{"formattedCitation":"\\super 19\\nosupersub{}","plainCitation":"19","noteIndex":0},"citationItems":[{"id":2876,"uris":["http://zotero.org/users/11334842/items/EDX5876B"],"itemData":{"id":2876,"type":"post-weblog","abstract":"The return of syphilis is a powerful indicator that U.S. approaches to health care delivery, public health, and equity have failed.","container-title":"STAT","language":"en-US","title":"Stigma and the return of syphilis","URL":"https://www.statnews.com/2024/05/30/syphilis-rates-climbing-stigma/","author":[{"family":"Brandt","given":"Jacob D. Moses","suffix":"Allan M."}],"accessed":{"date-parts":[["2024",9,5]]},"issued":{"date-parts":[["2024",5,30]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->19<!-- [if supportFields]><![endif]--> Regarding men, MSM practices are also highly stigmatized in Lebanon, making the MSM population seek less sexual medical help or hide any symptoms that develop.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Aig7gJ0K","properties":{"formattedCitation":"\\super 21\\nosupersub{}","plainCitation":"21","noteIndex":0},"citationItems":[{"id":2880,"uris":["http://zotero.org/users/11334842/items/FQXUGXIL"],"itemData":{"id":2880,"type":"article-journal","abstract":"Background\nIn Lebanon, men who have sex with men (MSM) face high rates of stigma, discrimination, and violence. Minority stress, or the unique stressors related to anti-MSM stigma and discrimination, negatively impacts the mental health of MSM. These stressors are heightened for those with intersectional minority identities such as displaced Syrian MSM in Lebanon.\nMethods\nIn this qualitative study conducted in 2020–21, part of a larger study focused on the mental and sexual health risks among MSM, we collected qualitative data from Lebanese and displaced Syrian MSM living in Lebanon and analyzed reports of their experiences with stigma, mental health, and coping strategies. We conducted semi-structured, in-depth interviews with 12 displaced Syrian MSM and 13 Lebanese MSM.\nResults\nOur findings highlight how MSM in Lebanon navigate stigma and the mental health risks that result. Common stressors among Lebanese and displaced Syrian MSM were related to finances, sexual orientation discrimination, and social isolation. Comparing the two groups, we found that stressors specific to displaced Syrian MSM were related to adverse childhood experiences, recent exposure to the Syrian war, displacement, and discrimination in Lebanon based on their intersectional identities as MSM and Syrians. For Lebanese participants, the most common stigma coping strategies were avoidance, drinking alcohol, using drugs, or having sex. As for displaced Syrian MSM, the most common stigma coping strategy was seeking the freely available mental health services offered to them through non-governmental organizations.\nConclusion\nOur findings suggest that increased targeted mental health and social support interventions, informed by the unique experiences of Lebanese and displaced Syrian MSM, are highly needed to improve the coping and mental health resources of all MSM in Lebanon.","container-title":"Social Science & Medicine","DOI":"10.1016/j.socscimed.2023.116248","ISSN":"0277-9536","journalAbbreviation":"Social Science & Medicine","page":"116248","source":"ScienceDirect","title":"Experiences of stigma, mental health, and coping strategies in Lebanon among Lebanese and displaced Syrian men who have sex with men: A qualitative study","title-short":"Experiences of stigma, mental health, and coping strategies in Lebanon among Lebanese and displaced Syrian men who have sex with men","volume":"335","author":[{"family":"Abboud","given":"Sarah"},{"family":"Seal","given":"David W."},{"family":"Pachankis","given":"John E."},{"family":"Khoshnood","given":"Kaveh"},{"family":"Khouri","given":"Danielle"},{"family":"Fouad","given":"Fouad M."},{"family":"Heimer","given":"Robert"}],"issued":{"date-parts":[["2023",10,1]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->21<!-- [if supportFields]><![endif]--> This would lead to prolonged cases of latent syphilis and more transmission and might hint that the actual numbers of positive cases with syphilis is much higher than documented.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1Msvl276","properties":{"formattedCitation":"\\super 21\\nosupersub{}","plainCitation":"21","noteIndex":0},"citationItems":[{"id":2880,"uris":["http://zotero.org/users/11334842/items/FQXUGXIL"],"itemData":{"id":2880,"type":"article-journal","abstract":"Background\nIn Lebanon, men who have sex with men (MSM) face high rates of stigma, discrimination, and violence. Minority stress, or the unique stressors related to anti-MSM stigma and discrimination, negatively impacts the mental health of MSM. These stressors are heightened for those with intersectional minority identities such as displaced Syrian MSM in Lebanon.\nMethods\nIn this qualitative study conducted in 2020–21, part of a larger study focused on the mental and sexual health risks among MSM, we collected qualitative data from Lebanese and displaced Syrian MSM living in Lebanon and analyzed reports of their experiences with stigma, mental health, and coping strategies. We conducted semi-structured, in-depth interviews with 12 displaced Syrian MSM and 13 Lebanese MSM.\nResults\nOur findings highlight how MSM in Lebanon navigate stigma and the mental health risks that result. Common stressors among Lebanese and displaced Syrian MSM were related to finances, sexual orientation discrimination, and social isolation. Comparing the two groups, we found that stressors specific to displaced Syrian MSM were related to adverse childhood experiences, recent exposure to the Syrian war, displacement, and discrimination in Lebanon based on their intersectional identities as MSM and Syrians. For Lebanese participants, the most common stigma coping strategies were avoidance, drinking alcohol, using drugs, or having sex. As for displaced Syrian MSM, the most common stigma coping strategy was seeking the freely available mental health services offered to them through non-governmental organizations.\nConclusion\nOur findings suggest that increased targeted mental health and social support interventions, informed by the unique experiences of Lebanese and displaced Syrian MSM, are highly needed to improve the coping and mental health resources of all MSM in Lebanon.","container-title":"Social Science & Medicine","DOI":"10.1016/j.socscimed.2023.116248","ISSN":"0277-9536","journalAbbreviation":"Social Science & Medicine","page":"116248","source":"ScienceDirect","title":"Experiences of stigma, mental health, and coping strategies in Lebanon among Lebanese and displaced Syrian men who have sex with men: A qualitative study","title-short":"Experiences of stigma, mental health, and coping strategies in Lebanon among Lebanese and displaced Syrian men who have sex with men","volume":"335","author":[{"family":"Abboud","given":"Sarah"},{"family":"Seal","given":"David W."},{"family":"Pachankis","given":"John E."},{"family":"Khoshnood","given":"Kaveh"},{"family":"Khouri","given":"Danielle"},{"family":"Fouad","given":"Fouad M."},{"family":"Heimer","given":"Robert"}],"issued":{"date-parts":[["2023",10,1]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->21<!-- [if supportFields]><![endif]--> It is important to note the stagnation in cases during the coronavirus pandemic years, which is linked to decreased testing for STIs during that period and more social isolation, as stated by the CDC.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"o9wO7kmI","properties":{"formattedCitation":"\\super 22\\nosupersub{}","plainCitation":"22","noteIndex":0},"citationItems":[{"id":"ZDWdnF8m/42eAELdI","uris":["http://zotero.org/users/11334842/items/299D3BMR"],"itemData":{"id":1415,"type":"webpage","abstract":"STD Information from CDC. Facts, Statistics, Treatment, and Other Resources.","language":"en-us","title":"Impact of COVID-19 on STDs","URL":"https://www.cdc.gov/std/statistics/2021/impact.htm","accessed":{"date-parts":[["2024",1,24]]},"issued":{"date-parts":[["2023",4,11]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->22<!-- [if supportFields]><![endif]--> The cases re-emerge in numbers after the pandemic resolved, which can be explained by the increased encounters after isolation, the economic crisis and rising prices of effective protection means as well as resuming testing in a lot of individuals. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"k26pEi29","properties":{"formattedCitation":"\\super 23,24\\nosupersub{}","plainCitation":"23,24","noteIndex":0},"citationItems":[{"id":2578,"uris":["http://zotero.org/users/11334842/items/Q65ZKVRR"],"itemData":{"id":2578,"type":"article-journal","abstract":"Dear Editor,\n\nLebanon registered its first COVID-19 case on 21 February 2020, which was followed by a nationwide lockdown (15 March–8 June), resulting in strict curfews, the prohibition of public gatherings and the closure of the international airport in Beirut.1 The pandemic has had compounding effects on the political and economic crisis with severe economic and health consequences.2 \n\nThroughout the lockdown, one of the largest sexually transmitted infections (STIs) and HIV clinics in Beirut with linkages to major civil organisations in direct contact with sexual health beneficiaries has remained open for emergencies such as postexposure prophylaxis (PEP) for HIV and STI testing in people exposed to risk. Access to remote consultations has also been available. The clinic has noted a major reduction in …","container-title":"Sexually Transmitted Infections","DOI":"10.1136/sextrans-2020-054734","ISSN":"1368-4973, 1472-3263","issue":"4","journalAbbreviation":"Sex Transm Infect","language":"en","license":"© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.. This article is made freely available for use in accordance with BMJ’s website terms and conditions for the duration of the covid-19 pandemic or until otherwise determined by BMJ. You may use, download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained.https://bmj.com/coronavirus/usage","note":"publisher: BMJ Publishing Group Ltd\nsection: Miscellaneous\nPMID: 33028650","page":"318-318","source":"sti.bmj.com","title":"Emerging impact of the COVID-19 outbreak on sexual health in Lebanon","volume":"97","author":[{"family":"Maatouk","given":"Ismael"},{"family":"Assi","given":"Moubadda"},{"family":"Jaspal","given":"Rusi"}],"issued":{"date-parts":[["2021",6,1]]}}},{"id":2577,"uris":["http://zotero.org/users/11334842/items/ASUDVG2M"],"itemData":{"id":2577,"type":"webpage","title":"FEATURE-Safe sex: the latest casualty of Lebanon's economic meltdown | Reuters","URL":"https://www.reuters.com/article/idUSL8N2UW2GH/","accessed":{"date-parts":[["2024",6,18]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->23,24<!-- [if supportFields]><![endif]--> Besides, most of our population was treated with the gold-standard benzathine penicillin G, which would explain the low rates of treatment failure. Here it is worth mentioning that the majority of cases were diagnosed in the early PSS stages, which translates to easier disease eradication. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Mo51sqgv","properties":{"formattedCitation":"\\super 25\\nosupersub{}","plainCitation":"25","noteIndex":0},"citationItems":[{"id":2582,"uris":["http://zotero.org/users/11334842/items/FYJ5R2A7"],"itemData":{"id":2582,"type":"webpage","abstract":"Includes management of syphilis, recommended treatment options by syphilis stage, post treatment follow-up, reporting and partner notification.","genre":"education and awareness;guidance","language":"eng","note":"Last Modified: 2024-04-11","title":"Syphilis guide: Treatment and follow-up","title-short":"Syphilis guide","URL":"https://www.canada.ca/en/public-health/services/infectious-diseases/sexual-health-sexually-transmitted-infections/canadian-guidelines/syphilis/treatment-follow-up.html","author":[{"family":"Canada","given":"Public Health Agency","dropping-particle":"of"}],"accessed":{"date-parts":[["2024",6,18]]},"issued":{"date-parts":[["2021",10,19]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->25<!-- [if supportFields]><![endif]--> In addition, most of PLH had a controlled HIV infection, which would contribute to higher treatment success as well. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"UgMinzSo","properties":{"formattedCitation":"\\super 26\\nosupersub{}","plainCitation":"26","noteIndex":0},"citationItems":[{"id":2584,"uris":["http://zotero.org/users/11334842/items/2WZMXQGB"],"itemData":{"id":2584,"type":"article-journal","abstract":"Background\nSyphilis and human immunodeficiency virus (HIV) frequently coexist in patients, but the effects of immunosuppression on the course of syphilis are unknown. Our goal was to determine whether the degree of HIV-mediated immunosuppression and the use of highly active antiretroviral therapy impact syphilis serologic responses.\n\nMethods\nWe assessed all cases of syphilis with positive serologic test results from 1990 through 2006 in a prospective, observational clinical cohort of HIV-infected patients. We defined seroreversion as the loss of reactivity in a patient who previously had a serologic test result positive for syphilis. We defined serologic failure as the lack of a 4-fold decrease in rapid plasma reagin titers 270–365 days after therapy or a 4-fold increase in titers ⩾30 days after therapy. We used Cox proportional hazards models with statistical adjustments for multiple failure instances.\n\nResults\nOne hundred eighty subjects experienced 231 cases of syphilis. The median follow-up time was 5.3 years. A total of 71 episodes of serologic failure were documented. A CD4 cell count of <200 cells/mL at the time of syphilis diagnosis was associated with an increased risk of serologic failure (adjusted hazard ratio, 2.48; 95% confidence interval, 1.26–4.88). The receipt of highly active antiretroviral therapy was associated with a 60% reduction in the rate of serologic failure (adjusted hazard ratio, 0.40; 95% confidence interval, 0.21–0.75), independent of concomitant CD4 cell response. Rapid plasma reagin seroreversion was infrequent (16.1%) and inconsistent, and it was more likely to occur among patients who received macrolides.\n\nConclusion\nThe use of highly active antiretroviral therapy to reverse immunosuppression and the routine use of macrolides for the prevention of opportunistic infections may reduce syphilis serologic failure rates among HIV-infected patients who have syphilis.","container-title":"Clinical infectious diseases : an official publication of the Infectious Diseases Society of America","DOI":"10.1086/589295","ISSN":"1058-4838","issue":"2","journalAbbreviation":"Clin Infect Dis","note":"PMID: 18532887\nPMCID: PMC2562285","page":"258-265","source":"PubMed Central","title":"Antiretroviral Therapy Is Associated with Reduced Serologic Failure Rates for Syphilis among HIV-Infected Patients","volume":"47","author":[{"family":"Ghanem","given":"Khalil G."},{"family":"Moore","given":"Richard D."},{"family":"Rompalo","given":"Anne M."},{"family":"Erbelding","given":"Emily J."},{"family":"Zenilman","given":"Jonathan M."},{"family":"Gebo","given":"Kelly A."}],"issued":{"date-parts":[["2008",7,15]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->26<!-- [if supportFields]><![endif]--> Since most of our patients had controlled HIV infection and early syphilis detection, most were successful in successfully treating their infection, and this would explain why no statistically significant association was seen between HIV infection, viral load, CD4 count and syphilis treatment success. However, despite successfully treating most patients presenting to our clinic, syphilis is on the rise, and in dangerous rates. This would impact the national cost of medical care and can lead to a public health crisis, where congenital syphilis usually starts rising few years after the PSS surge. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"X9yYO44E","properties":{"formattedCitation":"\\super 27\\nosupersub{}","plainCitation":"27","noteIndex":0},"citationItems":[{"id":2380,"uris":["http://zotero.org/users/11334842/items/KI5SAWV3"],"itemData":{"id":2380,"type":"article-journal","abstract":"Background \n The purpose of this study was to estimate the cost of syphilis in the United States, in terms of the average lifetime direct medical cost per infection.\n Methods \n We used a decision tree model of the natural history of syphilis. The model allowed for numerous possible outcomes of infection, including treatment for syphilis at various stages, inadvertent treatment, and late syphilis outcomes in those who are alive and still infected 30 years after acquisition. Future costs were discounted at 3% annually. Model inputs, such as the cost and probability of each outcome, were based on published sources. The probabilities we applied yielded outcomes consistent with reported cases of syphilis by stage from national surveillance data and number of deaths due to late syphilis from national mortality data.\n Results \n The estimated, discounted lifetime cost per infection was $1190 under base case assumptions (2019 dollars). Treatment costs associated with late syphilis outcomes, such as cardiovascular syphilis, accounted for only $26 of the average lifetime cost per infection. Results were most sensitive to assumptions regarding the treatment cost per case of unknown duration or late syphilis. In the probabilistic sensitivity analyses, the 2.5th and 97.5th percentiles of the 10,000 simulations of the lifetime cost per infection were $729 and $1884, respectively.\n Conclusions \n Our estimate of the lifetime cost per infection is about 50% higher than in a previous study, a difference due in large part to our higher cost assumptions for benzathine penicillin G.","container-title":"Sexually Transmitted Diseases","DOI":"10.1097/OLQ.0000000000001353","ISSN":"0148-5717","issue":"4","language":"en-US","page":"253","source":"journals.lww.com","title":"The Estimated Lifetime Medical Cost of Syphilis in the United States","volume":"48","author":[{"family":"Chesson","given":"Harrell W."},{"family":"Peterman","given":"Thomas A."}],"issued":{"date-parts":[["2021",4]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->27<!-- [if supportFields]><![endif]--> This study highlights the urgent need for deployment of robust public health interventions to maximize prevention, sexual health, screening, and diagnosis to help impede this syphilis outbreak. Limitations This was a retrospective review, which limits our analysis to the data documented in the charts. This would make the data more prone to selection and information bias, making it more difficult to interpret temporal relationships and control bias. To mitigate that, we limited our analysis to the data that is most complete in our records and maintained a descriptive approach that would visualize the data with greatest transparency and limit over-interpretation. Perhaps larger scale prospective studies with more power are needed in the future for a more robust assessment of the current situation regarding syphilis in Lebanon. Besides, they would provide new statistics of the current situation, which is much needed to closely monitor a disease that is having a new outbreak. Conclusion As syphilis continues to be a national public health threat, its predominant association with HIV and MSM populations make it imperative to implement public health measures that are specific to these populations. These measures can be promoting awareness, sexual health, condoms and others. Indeed, there is also a need to maximize screening for early detection and successful treatment. Public health interventions such as educational campaigns to target the populations with the highest risk is crucial. Finally, in PLH, maintaining good immunity by viral suppression aids in successful treatment of syphilis. References 1. Wu MY, Gong HZ, Hu KR, Zheng HY, Wan X, Li J. Effect of syphilis infection on HIV acquisition: a systematic review and meta-analysis. Sex Transm Infect. 2021;97(7):525-533. https://doi.org/10.1136/sextrans-2020-054706. 2. Eggleton JS, Nagalli S. Highly active antiretroviral therapy (HAART). In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32119420. 3. Pre-Exposure Prophylaxis (PrEP) [Internet]. CDC; [cited 2023 Sep 16]. Available from: https://www.cdc.gov/hiv/risk/prep/index.html 4. Luehring-Jones P, Palfai TP, Tahaney KD, Maisto SA, Simons J. Pre-Exposure Prophylaxis (PrEP) Use is Associated With Health Risk Behaviors Among Moderate- and Heavy-Drinking MSM. AIDS Educ Prev. 2019;31(5):452-462. https://doi.org/10.1521/aeap.2019.31.5.452. 5. Miller BA, Hicks CB. Syphilis and HIV: The Intersection of Two Epidemics. NEJM Journal Watch. 2010 Jan 1. Available from: https://www.semanticscholar.org/paper/Syphilis-and-HIV%3A-The-Intersection-of-Two-Epidemics-Miller-Hicks/9f552bdda0e4b0c74b796a52d086b436ad7b6f08. 6. Sexually Transmitted Disease Surveillance [Internet]. CDC; [cited 2023 Sep 16]. Available from: https://www.cdc.gov/std/statistics/2021/default.htm 7. New study highlights unacceptably high global prevalence of syphilis among men who have sex with men [Internet]. World Health Organization; 2021 [cited 2023 Sep 16]. Available from: https://www.who.int/news/item/09-07-2021-new-study-highlights-unacceptably-high-global-prevalence-of-syphilis-among-men-who-have-sex-with-men 8. Assi A, Abu Zaki S, Ghosn J, Kinge N, Naous J, Ghanem A, et al. Prevalence of HIV and other sexually transmitted infections and their association with sexual practices and substance use among 2238 MSM in Lebanon. Sci Rep. 2019 Oct 22;9(1):15142. https://doi.org/10.1038/s41598-019-51688-7. 9. Ren M, Dashwood T, Walmsley S. The Intersection of HIV and Syphilis: Update on the Key Considerations in Testing and Management. Curr HIV/AIDS Rep. 2021;18(4):280–288. https://doi.org/10.1007/s11904-021-00564-z. 10. Kofoed K, Gerstoft J, Mathiesen LR, Benfield T. Syphilis and Human Immunodeficiency Virus (HIV)-1 Coinfection: Influence on CD4 T-Cell Count, HIV-1 Viral Load, and Treatment Response. Sex Transm Dis. 2006;33(3):143. https://doi.org/10.1097/01.olq.0000187262.56820.c0. 11. Syphilis [Internet]. World Health Organization; 2025 [cited 2024 June 18]. Available from: https://www.who.int/news-room/fact-sheets/detail/syphilis 12. Pre-Exposure Prophylaxis (PrEP) [Internet]. CDC; [cited 2023 Sep 16]. Available from: https://www.cdc.gov/hiv/risk/prep/index.html 13. Table 16B. Primary and Secondary Syphilis — Rates of Reported Cases* by Race/Hispanic Ethnicity, Age Group, and Sex, United States, 2021 [Internet]. CDC; 2023 [cited 2024 Jan 24]. Available from: https://www.cdc.gov/std/statistics/2021/tables/16b.htm 14. Wilson Dib R, Dandachi D, Matar M, Shayya A, Davila JA, Giordano TP, et al. HIV in Lebanon: Reasons for Testing, Engagement in Care, and Outcomes in Patients with Newly Diagnosed HIV Infections. AIDS Behav. 2020 Aug 1;24(8):2290–8. https://doi.org/10.1007/s10461-020-02788-3. 15. Khafaja S, Youssef Y, Darjani N, Youssef N, Fattah CM, Hanna-Wakim R. Case Report: A Delayed Diagnosis of Congenital Syphilis—Too Many Missed Opportunities. Front Pediatr. 2021;8:499534. https://doi.org/10.3389/fped.2020.499534. 16. de Voux A, Kidd S, Grey JA, Rosenberg ES, Gift TL, Weinstock H, et al. State-Specific Rates of Primary and Secondary Syphilis Among Men Who Have Sex with Men — United States, 2015. MMWR Morb Mortal Wkly Rep 2017;66:349–354. http://dx.doi.org/10.15585/mmwr.mm6613a1. 17. Wagner GJ, Aunon FM, Kaplan RL, Karam R, Khouri D, Tohme J, et al. Sexual stigma, psychological well-being and social engagement among men who have sex with men in Beirut, Lebanon. Cult Health Sex. 2013 May 1;15(5):570–82. https://doi.org/10.1080/13691058.2013.775345. 18. Azar M, Bradbury-Jones C, Kroll T. Middle-aged Lebanese women’s interpretation of sexual difficulties: a qualitative inquiry. BMC Women’s Health. 2021;21(1):203. https://doi.org/10.1186/s12905-020-01132-0. 19. The fight for gender equality in Lebanon [Internet]. OHCHR; 2022 [cited 2024 Sep 5]. Available from: https://www.ohchr.org/en/stories/2022/05/fight-gender-equality-lebanon 20. Moses JD, Brandt AM. Stigma and the return of syphilis. STAT [Internet]. 2024 May 30; Available from: https://www.statnews.com/2024/05/30/syphilis-rates-climbing-stigma/ 21. Chemaitelly H, Finan RR, Racoubian E, Aimagambetova G, Almawi WY. Estimates of the incidence, prevalence, and factors associated with common sexually transmitted infections among Lebanese women. PLOS ONE. 2024;19(4):e0301231. https://doi.org/10.1371/journal.pone.0301231. 22. Abboud S, Seal DW, Pachankis JE, Khoshnood K, Khouri D, Fouad FM, et al. Experiences of stigma, mental health, and coping strategies in Lebanon among Lebanese and displaced Syrian men who have sex with men: A qualitative study. Soc Sci Med. 2023 Oct 1;335:116248. https://doi.org/10.1016/j.socscimed.2023.116248. 23. Impact of COVID-19 on STDs [Internet]. CDC; 2023 [cited 2024 Jan 24]. Available from: https://www.cdc.gov/std/statistics/2021/impact.htm 24. Maatouk I, Assi M, Jaspal R. Emerging impact of the COVID-19 outbreak on sexual health in Lebanon. Sex Transm Infect. 2021;97(4):318-318. https://doi.org/10.1136/sextrans-2020-054734. 25. Ramadan T. FEATURE-Safe sex: the latest casualty of Lebanon’s economic meltdown [Internet]. Reuters; 2022 [cited 2024 Jun 18]. Available from: https://www.reuters.com/article/idUSL8N2UW2GH/ 26. Syphilis guide: Treatment and follow-up [Internet]. Government of Canada; 2021 [cited 2024 Jun 18]. Available from: https://www.canada.ca/en/public-health/services/infectious-diseases/sexual-health-sexually-transmitted-infections/canadian-guidelines/syphilis/treatment-follow-up.html 27. Ghanem KG, Moore RD, Rompalo AM, Erbelding EJ, Zenilman JM, Gebo KA. Antiretroviral Therapy Is Associated with Reduced Serologic Failure Rates for Syphilis among HIV-Infected Patients. Clin Infect Dis. 2008;47(2):258–265. https://doi.org/10.1086/589295. 28. Chesson HW, Peterman TA. The Estimated Lifetime Medical Cost of Syphilis in the United States. Sex Transm Dis. 2021;48(4):253. https://doi.org/10.1097/OLQ.0000000000001353.
Copyright (c) 2024 Hilal Abdessamad, Dalida El Khatib, Moussa Hojeij, Rana Asmar, Julien Maamari, Hicham Baba, Rabih Ghazi, Wael T Azzam, Rola Husni, Jacques E. Mokhbat (Author) https://creativecommons.org/licenses/by/4.0
Bacteriophage-Based Treatment in Infectious Diseases: What Do We Know So Far? A Narrative Review
Purpose: To summarize the literature on bacteriophage use in human infection Methods: Using the MeSH terms “Phage” “Therapy”, “Treatment” “Outcome”, a search was performed in ScienceDirect, Scopus and Pubmed databases, including narrative review, systematic reviews and clinical trials, dating from 2020 till June 2023. A total of 191 articles and 389 articles were retrieved respectively from each database, which after duplication removal, added up to 505. After the primary screen, 131 texts were collected. Following that, a secondary ended up with 56 articles included. Conclusion: With the constant increase in antibiotic resistance, there is a need for newer antimicrobial agents, which led to the revival of bacteriophages. Due to advances in molecular microbiology, phages became a possibility that has proven itself promising. More studies and funding are needed towards this field, that offers us a promising salvation from the antimicrobial resistance pandemic. Introduction: Bacteriophages, which are viruses that selectively infect bacterial cells, are ubiquitous in the environment and exhibit extensive morphological and genomic diversity <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"tdCTl7xh","properties":{"formattedCitation":"\\super 1\\nosupersub{}","plainCitation":"1","noteIndex":0},"citationItems":[{"id":1103,"uris":["http://zotero.org/users/11334842/items/UV9M5H9G"],"itemData":{"id":1103,"type":"article-journal","abstract":"INTRODUCTION: The quest to combat bacterial infections has dreaded humankind for centuries. Infections involving ESKAPE (Enterococcus spp., Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) impose therapeutic challenges due to the emergence of antimicrobial drug resistance. Recently, investigations with bacteriophages have led to the development of novel strategies against ESKAPE infections. Also, bacteriophages have been demonstrated to be instrumental in the dissemination of virulence markers in ESKAPE pathogens. AREAS COVERED: The review highlights the potential of bacteriophage in and against the pathogenicity of antibiotic-resistant ESKAPE pathogens. The review also emphasizes the challenges of employing bacteriophage in treating ESKAPE pathogens and the knowledge gap in the bacteriophage mediated antibiotic resistance and pathogenicity in ESKAPE infections. EXPERT OPINION: Bacteriophage infection can kill the host bacteria but in survivors can transfer genes that contribute toward the survival of the pathogens in the host and resistance toward multiple antimicrobials. The knowledge on the dual role of bacteriophages in the treatment and pathogenicity will assist in the prediction and development of novel therapeutics targeting antimicrobial-resistant ESKAPE. Therefore, extensive investigations on the efficacy of synthetic bacteriophage, bacteriophage cocktails, and bacteriophage in combination with antibiotics are needed to develop effective therapeutics against ESKAPE infections.","container-title":"Expert Review of Anti-Infective Therapy","DOI":"10.1080/14787210.2021.1858800","ISSN":"1744-8336","issue":"7","language":"eng","note":"section: 0","page":"845–865","title":"Bacteriophages for ESKAPE: role in pathogenicity and measures of control","volume":"19","author":[{"family":"Patil","given":"Amrita"},{"family":"Banerji","given":"Rajashri"},{"family":"Kanojiya","given":"Poonam"},{"family":"Koratkar","given":"Santosh"},{"family":"Saroj","given":"Sunil"}],"issued":{"date-parts":[["2021",7]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->1<!-- [if supportFields]><![endif]-->. They possess basal plates with tail fibers that facilitate their initial attachment to host cells and introduce their genetic material via the sheath region. Bacteriophages follow a lytic or lysogenic life cycle within host bacterial cells, with the former resulting in the lysis of the host cell and the latter leading to the persistence of the bacteriophage in a latent state. Environmental cues, such as pH, nutrients, temperature, or exposure to antibiotics, can trigger prophages to enter a lytic cycle and the lysis of the host cell <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1WvkhKOR","properties":{"formattedCitation":"\\super 1\\nosupersub{}","plainCitation":"1","noteIndex":0},"citationItems":[{"id":1103,"uris":["http://zotero.org/users/11334842/items/UV9M5H9G"],"itemData":{"id":1103,"type":"article-journal","abstract":"INTRODUCTION: The quest to combat bacterial infections has dreaded humankind for centuries. Infections involving ESKAPE (Enterococcus spp., Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) impose therapeutic challenges due to the emergence of antimicrobial drug resistance. Recently, investigations with bacteriophages have led to the development of novel strategies against ESKAPE infections. Also, bacteriophages have been demonstrated to be instrumental in the dissemination of virulence markers in ESKAPE pathogens. AREAS COVERED: The review highlights the potential of bacteriophage in and against the pathogenicity of antibiotic-resistant ESKAPE pathogens. The review also emphasizes the challenges of employing bacteriophage in treating ESKAPE pathogens and the knowledge gap in the bacteriophage mediated antibiotic resistance and pathogenicity in ESKAPE infections. EXPERT OPINION: Bacteriophage infection can kill the host bacteria but in survivors can transfer genes that contribute toward the survival of the pathogens in the host and resistance toward multiple antimicrobials. The knowledge on the dual role of bacteriophages in the treatment and pathogenicity will assist in the prediction and development of novel therapeutics targeting antimicrobial-resistant ESKAPE. Therefore, extensive investigations on the efficacy of synthetic bacteriophage, bacteriophage cocktails, and bacteriophage in combination with antibiotics are needed to develop effective therapeutics against ESKAPE infections.","container-title":"Expert Review of Anti-Infective Therapy","DOI":"10.1080/14787210.2021.1858800","ISSN":"1744-8336","issue":"7","language":"eng","note":"section: 0","page":"845–865","title":"Bacteriophages for ESKAPE: role in pathogenicity and measures of control","volume":"19","author":[{"family":"Patil","given":"Amrita"},{"family":"Banerji","given":"Rajashri"},{"family":"Kanojiya","given":"Poonam"},{"family":"Koratkar","given":"Santosh"},{"family":"Saroj","given":"Sunil"}],"issued":{"date-parts":[["2021",7]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->1<!-- [if supportFields]><![endif]-->. Lytic bacteriophages are gaining popularity as a treatment for antibiotic-resistant bacterial infections, particularly the challenging 'ESKAPE' (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"17NnexMo","properties":{"formattedCitation":"\\super 1\\nosupersub{}","plainCitation":"1","noteIndex":0},"citationItems":[{"id":1103,"uris":["http://zotero.org/users/11334842/items/UV9M5H9G"],"itemData":{"id":1103,"type":"article-journal","abstract":"INTRODUCTION: The quest to combat bacterial infections has dreaded humankind for centuries. Infections involving ESKAPE (Enterococcus spp., Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) impose therapeutic challenges due to the emergence of antimicrobial drug resistance. Recently, investigations with bacteriophages have led to the development of novel strategies against ESKAPE infections. Also, bacteriophages have been demonstrated to be instrumental in the dissemination of virulence markers in ESKAPE pathogens. AREAS COVERED: The review highlights the potential of bacteriophage in and against the pathogenicity of antibiotic-resistant ESKAPE pathogens. The review also emphasizes the challenges of employing bacteriophage in treating ESKAPE pathogens and the knowledge gap in the bacteriophage mediated antibiotic resistance and pathogenicity in ESKAPE infections. EXPERT OPINION: Bacteriophage infection can kill the host bacteria but in survivors can transfer genes that contribute toward the survival of the pathogens in the host and resistance toward multiple antimicrobials. The knowledge on the dual role of bacteriophages in the treatment and pathogenicity will assist in the prediction and development of novel therapeutics targeting antimicrobial-resistant ESKAPE. Therefore, extensive investigations on the efficacy of synthetic bacteriophage, bacteriophage cocktails, and bacteriophage in combination with antibiotics are needed to develop effective therapeutics against ESKAPE infections.","container-title":"Expert Review of Anti-Infective Therapy","DOI":"10.1080/14787210.2021.1858800","ISSN":"1744-8336","issue":"7","language":"eng","note":"section: 0","page":"845–865","title":"Bacteriophages for ESKAPE: role in pathogenicity and measures of control","volume":"19","author":[{"family":"Patil","given":"Amrita"},{"family":"Banerji","given":"Rajashri"},{"family":"Kanojiya","given":"Poonam"},{"family":"Koratkar","given":"Santosh"},{"family":"Saroj","given":"Sunil"}],"issued":{"date-parts":[["2021",7]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->1<!-- [if supportFields]><![endif]-->. The “ESKAPE” pathogens are both Gram negative and positive species that are significant contributors to hospital-acquired infections, some of which are fatal <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"hzZy4pPZ","properties":{"formattedCitation":"\\super 1\\nosupersub{}","plainCitation":"1","noteIndex":0},"citationItems":[{"id":1103,"uris":["http://zotero.org/users/11334842/items/UV9M5H9G"],"itemData":{"id":1103,"type":"article-journal","abstract":"INTRODUCTION: The quest to combat bacterial infections has dreaded humankind for centuries. Infections involving ESKAPE (Enterococcus spp., Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) impose therapeutic challenges due to the emergence of antimicrobial drug resistance. Recently, investigations with bacteriophages have led to the development of novel strategies against ESKAPE infections. Also, bacteriophages have been demonstrated to be instrumental in the dissemination of virulence markers in ESKAPE pathogens. AREAS COVERED: The review highlights the potential of bacteriophage in and against the pathogenicity of antibiotic-resistant ESKAPE pathogens. The review also emphasizes the challenges of employing bacteriophage in treating ESKAPE pathogens and the knowledge gap in the bacteriophage mediated antibiotic resistance and pathogenicity in ESKAPE infections. EXPERT OPINION: Bacteriophage infection can kill the host bacteria but in survivors can transfer genes that contribute toward the survival of the pathogens in the host and resistance toward multiple antimicrobials. The knowledge on the dual role of bacteriophages in the treatment and pathogenicity will assist in the prediction and development of novel therapeutics targeting antimicrobial-resistant ESKAPE. Therefore, extensive investigations on the efficacy of synthetic bacteriophage, bacteriophage cocktails, and bacteriophage in combination with antibiotics are needed to develop effective therapeutics against ESKAPE infections.","container-title":"Expert Review of Anti-Infective Therapy","DOI":"10.1080/14787210.2021.1858800","ISSN":"1744-8336","issue":"7","language":"eng","note":"section: 0","page":"845–865","title":"Bacteriophages for ESKAPE: role in pathogenicity and measures of control","volume":"19","author":[{"family":"Patil","given":"Amrita"},{"family":"Banerji","given":"Rajashri"},{"family":"Kanojiya","given":"Poonam"},{"family":"Koratkar","given":"Santosh"},{"family":"Saroj","given":"Sunil"}],"issued":{"date-parts":[["2021",7]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->1<!-- [if supportFields]><![endif]-->. A recent study done by the US center for Diseases Control and Prevention, showed that we have roughly 51,000 health care associated infections reported to be caused by P.aeruginosa every year, 13% of these infections are MDR causing about 400 deaths per year. P.aeruginosa is found to have an increasing number of strains that are MDR without any effective antibiotic to stop this bacterium <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"RoOBkf6e","properties":{"formattedCitation":"\\super 2\\nosupersub{}","plainCitation":"2","noteIndex":0},"citationItems":[{"id":1145,"uris":["http://zotero.org/users/11334842/items/XVQ9IE9G"],"itemData":{"id":1145,"type":"article-journal","abstract":"Multi-Drug Resistant (MDR) Pseudomonas aeruginosa is one of the most important bacterial pathogens that causes infection with a high mortality rate due to resistance to different antibiotics. This bacterium prompts extensive tissue damage with varying factors of virulence, and its biofilm production causes chronic and antibiotic-resistant infections. Therefore, due to the non-applicability of antibiotics for the destruction of P. aeruginosa biofilm, alternative approaches have been considered by researchers, and phage therapy is one of these new therapeutic solutions. Bacteriophages can be used to eradicate P. aeruginosa biofilm by destroying the extracellular matrix, increasing the permeability of antibiotics into the inner layer of biofilm, and inhibiting its formation by stopping the quorum-sensing activity. Furthermore, the combined use of bacteriophages and other compounds with anti-biofilm properties such as nanoparticles, enzymes, and natural products can be of more interest because they invade the biofilm by various mechanisms and can be more effective than the one used alone. On the other hand, the use of bacteriophages for biofilm destruction has some limitations such as limited host range, high-density biofilm, sub-populate phage resistance in biofilm, and inhibition of phage infection via quorum sensing in biofilm. Therefore, in this review, we specifically discuss the use of phage therapy for inhibition of P. aeruginosa biofilm in clinical and in vitro studies to identify different aspects of this treatment for broader use.","container-title":"Annals of Clinical Microbiology and Antimicrobials","DOI":"10.1186/s12941-020-00389-5","ISSN":"1476-0711","issue":"1","language":"eng","note":"section: 0","page":"45","title":"Bacteriophage therapy against Pseudomonas aeruginosa biofilms: a review","volume":"19","author":[{"family":"Chegini","given":"Zahra"},{"family":"Khoshbayan","given":"Amin"},{"family":"Taati Moghadam","given":"Majid"},{"family":"Farahani","given":"Iman"},{"family":"Jazireian","given":"Parham"},{"family":"Shariati","given":"Aref"}],"issued":{"date-parts":[["2020",9]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->2<!-- [if supportFields]><![endif]-->. The ESKAPE pathogen's capacity to evade the antibacterial effects of traditional antibiotic treatment renders the conventional therapy with antibiotics progressively less effective over time and raises the eminent need for alternative therapies, one of which is phage therapy <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"eBviphTt","properties":{"formattedCitation":"\\super 3\\nosupersub{}","plainCitation":"3","noteIndex":0},"citationItems":[{"id":1119,"uris":["http://zotero.org/users/11334842/items/V6FI3YDR"],"itemData":{"id":1119,"type":"article-journal","abstract":"Globally, the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) are the major cause of nosocomial infections. These pathogens are multidrug resistant, and their negative impacts have brought serious health challenges and economic burden on many countries worldwide. Thus, this narrative review exploits different emerging alternative therapeutic strategies including combination antibiotics, antimicrobial peptides ((AMPs), bacteriophage and photodynamic therapies used in the treatment of the ESKAPE pathogens, their merits, limitations, and future prospects. Our findings indicate that ESKAPE pathogens exhibit resistance to drug using different mechanisms including drug inactivation by irreversible enzyme cleavage, drug-binding site alteration, diminution in permeability of drug or drug efflux increment to reduce accumulation of drug as well as biofilms production. However, the scientific community has shown significant interest in using these novel strategies with numerous benefits although they have some limitations including but not limited to instability and toxicity of the therapeutic agents, or the host developing immune response against the therapeutic agents. Thus, comprehension of resistance mechanisms of these pathogens is necessary to further develop or modify these approaches in order to overcome these health challenges including the barriers of bacterial resistance.","container-title":"Microbial Pathogenesis","DOI":"10.1016/j.micpath.2022.105963","ISSN":"1096-1208","language":"eng","note":"section: 0","page":"105963","title":"Coping with the ESKAPE pathogens: Evolving strategies, challenges and future prospects","volume":"175","author":[{"family":"Aloke","given":"Chinyere"},{"family":"Achilonu","given":"Ikechukwu"}],"issued":{"date-parts":[["2023",2]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->3<!-- [if supportFields]><![endif]-->. One application of phage therapy aims to target bacterial biofilms, which are a significant contributor to the antibiotic resistance of ESKAPE pathogens. In a study of 15 A.baumannii isolates, lytic phage reduced bacteria by 87%, indicating potential for breaking down biofilms on medical devices <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"qytyZfqv","properties":{"formattedCitation":"\\super 4\\nosupersub{}","plainCitation":"4","noteIndex":0},"citationItems":[{"id":1205,"uris":["http://zotero.org/users/11334842/items/8SHEUGH9"],"itemData":{"id":1205,"type":"article-journal","abstract":"Introduction Acinetobacter baumannii is responsible for most nosocomial infections in hospitals. It can form biofilms and has a high degree of antibiotic resistance. Colistin is one of the last therapeutic options for the treatment of MDR infections. Recently, strains of this pathogen resistance to the colistin were reported increasingly. Therefore, alternative antibacterial methods, such as phage therapy, are being researched. This study aims to survey the efficacy of isolated Myoviridae bacteriophage against biofilm embedded colistin-resistant Acinetobacter baumannii. Method In this study, 15 isolates of bacteria were isolated, and their biofilm was measured using violet crystal staining, and their MIC was measured using the broth microdilution method. On the other hand, lytic phage was isolated and purified from wastewater. Finally, the effect of phage on bacteria was calculated using MTT staining method. Results From 15 MDR A. baumannii clinical isolates, 26.6% were resistant to colistin, 80% were able to produce strong biofilm, and 20% have weak biofilm. The isolated lytic phage (IsfAB78) was able to reduce the biofilm by up to 87%. Conclusions This study showed that the isolated lytic phage impacted the biofilm of MDR A. baumannii. Phage IsfAB78 is the right candidate for this purpose.","container-title":"Gene Reports","DOI":"10.1016/j.genrep.2020.100984","ISSN":"2452-0144","language":"en","note":"section: 0","page":"100984","title":"Efficacy of isolated bacteriophage against biofilm embedded colistin-resistant Acinetobacter baumannii","volume":"22","author":[{"family":"Ebrahimi","given":"Saeedeh"},{"family":"Sisakhtpour","given":"Behnam"},{"family":"Mirzaei","given":"Arezoo"},{"family":"Karbasizadeh","given":"Vajihe"},{"family":"Moghim","given":"Sharareh"}],"issued":{"date-parts":[["2021",3]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->4<!-- [if supportFields]><![endif]-->. However, phage treatment was not completely effective against all isolates, so combining multiple phages or phages with antibiotics may be necessary for optimal results <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"bhivj6yC","properties":{"formattedCitation":"\\super 4\\nosupersub{}","plainCitation":"4","noteIndex":0},"citationItems":[{"id":1205,"uris":["http://zotero.org/users/11334842/items/8SHEUGH9"],"itemData":{"id":1205,"type":"article-journal","abstract":"Introduction Acinetobacter baumannii is responsible for most nosocomial infections in hospitals. It can form biofilms and has a high degree of antibiotic resistance. Colistin is one of the last therapeutic options for the treatment of MDR infections. Recently, strains of this pathogen resistance to the colistin were reported increasingly. Therefore, alternative antibacterial methods, such as phage therapy, are being researched. This study aims to survey the efficacy of isolated Myoviridae bacteriophage against biofilm embedded colistin-resistant Acinetobacter baumannii. Method In this study, 15 isolates of bacteria were isolated, and their biofilm was measured using violet crystal staining, and their MIC was measured using the broth microdilution method. On the other hand, lytic phage was isolated and purified from wastewater. Finally, the effect of phage on bacteria was calculated using MTT staining method. Results From 15 MDR A. baumannii clinical isolates, 26.6% were resistant to colistin, 80% were able to produce strong biofilm, and 20% have weak biofilm. The isolated lytic phage (IsfAB78) was able to reduce the biofilm by up to 87%. Conclusions This study showed that the isolated lytic phage impacted the biofilm of MDR A. baumannii. Phage IsfAB78 is the right candidate for this purpose.","container-title":"Gene Reports","DOI":"10.1016/j.genrep.2020.100984","ISSN":"2452-0144","language":"en","note":"section: 0","page":"100984","title":"Efficacy of isolated bacteriophage against biofilm embedded colistin-resistant Acinetobacter baumannii","volume":"22","author":[{"family":"Ebrahimi","given":"Saeedeh"},{"family":"Sisakhtpour","given":"Behnam"},{"family":"Mirzaei","given":"Arezoo"},{"family":"Karbasizadeh","given":"Vajihe"},{"family":"Moghim","given":"Sharareh"}],"issued":{"date-parts":[["2021",3]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->4<!-- [if supportFields]><![endif]-->. The "seesaw effect" is another mechanism of action observed in phage therapy. Here, induction of phage resistance leads to regained antibiotic susceptibility, highlighting an interesting evolutionary genetic trade-off. This suggests that using a combination of antibiotics and phages may be a beneficial approach when dealing with these superbugs <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"9MbH6Lkh","properties":{"formattedCitation":"\\super 2\\nosupersub{}","plainCitation":"2","noteIndex":0},"citationItems":[{"id":1145,"uris":["http://zotero.org/users/11334842/items/XVQ9IE9G"],"itemData":{"id":1145,"type":"article-journal","abstract":"Multi-Drug Resistant (MDR) Pseudomonas aeruginosa is one of the most important bacterial pathogens that causes infection with a high mortality rate due to resistance to different antibiotics. This bacterium prompts extensive tissue damage with varying factors of virulence, and its biofilm production causes chronic and antibiotic-resistant infections. Therefore, due to the non-applicability of antibiotics for the destruction of P. aeruginosa biofilm, alternative approaches have been considered by researchers, and phage therapy is one of these new therapeutic solutions. Bacteriophages can be used to eradicate P. aeruginosa biofilm by destroying the extracellular matrix, increasing the permeability of antibiotics into the inner layer of biofilm, and inhibiting its formation by stopping the quorum-sensing activity. Furthermore, the combined use of bacteriophages and other compounds with anti-biofilm properties such as nanoparticles, enzymes, and natural products can be of more interest because they invade the biofilm by various mechanisms and can be more effective than the one used alone. On the other hand, the use of bacteriophages for biofilm destruction has some limitations such as limited host range, high-density biofilm, sub-populate phage resistance in biofilm, and inhibition of phage infection via quorum sensing in biofilm. Therefore, in this review, we specifically discuss the use of phage therapy for inhibition of P. aeruginosa biofilm in clinical and in vitro studies to identify different aspects of this treatment for broader use.","container-title":"Annals of Clinical Microbiology and Antimicrobials","DOI":"10.1186/s12941-020-00389-5","ISSN":"1476-0711","issue":"1","language":"eng","note":"section: 0","page":"45","title":"Bacteriophage therapy against Pseudomonas aeruginosa biofilms: a review","volume":"19","author":[{"family":"Chegini","given":"Zahra"},{"family":"Khoshbayan","given":"Amin"},{"family":"Taati Moghadam","given":"Majid"},{"family":"Farahani","given":"Iman"},{"family":"Jazireian","given":"Parham"},{"family":"Shariati","given":"Aref"}],"issued":{"date-parts":[["2020",9]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->2<!-- [if supportFields]><![endif]-->. Phage therapy aims to provide personalized clinical treatment for patients. Successful trials include a 68-year-old patient with diabetes and necrotizing pancreatitis, and 4 severely ill COVID-19 patients with A.baumannii infection. Both trials showed positive results with complete resolution of A.baumannii infection demonstrating the significant potential of phage therapy for personalized or commercial use <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"jTI7ocpY","properties":{"formattedCitation":"\\super 5,6\\nosupersub{}","plainCitation":"5,6","noteIndex":0},"citationItems":[{"id":1303,"uris":["http://zotero.org/users/11334842/items/IMCDGVZV"],"itemData":{"id":1303,"type":"article-journal","container-title":"Antimicrobial Agents and Chemotherapy","DOI":"10.1128/aac.00954-17","issue":"10","language":"en","page":"00954–17","title":"Development and Use of Personalized Bacteriophage-Based Therapeutic Cocktails To Treat a Patient with a Disseminated Resistant Acinetobacter baumannii Infection","volume":"61","author":[{"family":"Schooley","given":"R.T."},{"family":"Biswas","given":"B."},{"family":"Gill","given":"J.J."},{"family":"Hernandez-Morales","given":"A."},{"family":"Lancaster","given":"J."},{"family":"Lessor","given":"L."},{"family":"Barr","given":"J.J."},{"family":"Reed","given":"S.L."},{"family":"Rohwer","given":"F."},{"family":"Benler","given":"S."},{"family":"Segall","given":"A.M."},{"family":"Taplitz","given":"R."},{"family":"Smith","given":"D.M."},{"family":"Kerr","given":"K."},{"family":"Kumaraswamy","given":"M."},{"family":"Nizet","given":"V."},{"family":"Lin","given":"L."},{"family":"McCauley","given":"M.D."},{"family":"Strathdee","given":"S.A."},{"family":"Hamilton","given":"T."}],"issued":{"date-parts":[["2017"]]}}},{"id":1304,"uris":["http://zotero.org/users/11334842/items/CKGBCAFU"],"itemData":{"id":1304,"type":"article-journal","container-title":"Emerging microbes & infections","issue":"1","language":"en","page":"612–618","title":"Pre-optimized phage therapy on secondary Acinetobacter baumannii infection in four critical COVID-19 patients","volume":"10","author":[{"family":"Wu","given":"N."},{"family":"Dai","given":"J."},{"family":"Guo","given":"M."},{"family":"Li","given":"J."},{"family":"Zhou","given":"X."},{"family":"Li","given":"F."},{"family":"Zhu","given":"T."}],"issued":{"date-parts":[["2021"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->5,6<!-- [if supportFields]><![endif]-->. Similarly, case reports have shown the clearance of P.aeruginosa using phage therapy in several types of infections and has also been able to prove the safety of this therapy in a randomised, double blinded placebo-controlled clinical trial <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"DrxtxDEL","properties":{"formattedCitation":"\\super 7\\nosupersub{}","plainCitation":"7","noteIndex":0},"citationItems":[{"id":1245,"uris":["http://zotero.org/users/11334842/items/XSBXTJXR"],"itemData":{"id":1245,"type":"article-journal","abstract":"Pseudomonas aeruginosa is an important Gram-negative pathogen with intrinsic resistance to many clinically used antibiotics. It is particularly troublesome in nosocomial infections, immunocompromised patients, and individuals with cystic fibrosis. Antimicrobial resistance (AMR) is a huge threat to global health, with a predicted 10 million people dying from resistant infections by 2050. A promising therapy for combatting AMR infections is phage therapy. However, more research is required to investigate mechanisms that may influence the efficacy of phage therapy. An important overlooked aspect is the impact of membrane lipid remodelling on phage binding ability. P. aeruginosa undergoes changes in membrane lipids when it encounters phosphorus stress, an environmental perturbation that is likely to occur during infection. Lipid changes include the substitution of glycerophospholipids with surrogate glycolipids and the over-production of ornithine-containing aminolipids. Given that membrane lipids are known to influence the structure and function of membrane proteins, we propose that changes in the composition of membrane lipids during infection may alter phage binding and subsequent phage infection dynamics. Consideration of such effects needs to be urgently prioritised in order to develop the most effective phage therapy strategies for P. aeruginosa infections.","container-title":"Environmental Microbiology","DOI":"10.1111/1462-2920.16136","ISSN":"1462-2920","issue":"10","language":"eng","note":"section: 0","page":"4533–4546","title":"Membrane lipid renovation in Pseudomonas aeruginosa - implications for phage therapy?","volume":"24","author":[{"family":"Lyon","given":"Rhiannon"},{"family":"Jones","given":"Rebekah A."},{"family":"Shropshire","given":"Holly"},{"family":"Aberdeen","given":"Isabel"},{"family":"Scanlan","given":"David J."},{"family":"Millard","given":"Andrew"},{"family":"Chen","given":"Yin"}],"issued":{"date-parts":[["2022",10]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->7<!-- [if supportFields]><![endif]-->. Moreover, trials on bacteriophage therapy against acute and chronic S.aureus infections resulted in complete resolution of the diseases in 40% of patients after bacteriophage monotherapy, with better results (70%) after bacteriophage/antibiotic combination treatment <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"ON8yw43E","properties":{"formattedCitation":"\\super 8\\nosupersub{}","plainCitation":"8","noteIndex":0},"citationItems":[{"id":1221,"uris":["http://zotero.org/users/11334842/items/IUA99M77"],"itemData":{"id":1221,"type":"article-journal","abstract":"Bacteriophages, highly prevalent in all environments, have found their use in medicine as an alternative or complement to antibiotics. The therapeutic use of bacteriophages was particularly popular in the 1920s and 1930s, until the discovery and introduction of antibiotics. Due to the dynamic growth of antibiotic resistance among bacterial strains, numerous international institutions (such as the FDA) have declared the search for novel treatment modalities to be of the highest priority. To date, bacteriophage therapy has not been registered for general use in Western countries. The regulation of biological medicinal products (within medicinal product regulation) does not contain a specific documentation frame for bacteriophages (only for vaccines, blood derived products, etc.) which, as active substances, need to meet specific requirements. Recently, the FDA allowed bacteriophage therapy to be used in the United States, via the Emergency Investigational New Drug scheme; clinical trials to compare the safety and efficacy of bacteriophage therapy are also permitted. To date, several therapeutic products of this type have made it to phase I or II; some clinical programmes have also been completed. This article cites numerous animal model studies and registered clinical trials, showing the safety and effectiveness of bacteriophage therapy, including infections caused by bacterial strains resistant to antibiotic treatment.","container-title":"Journal of Applied Microbiology","DOI":"10.1111/jam.14535","ISSN":"1365-2672","issue":"4","language":"eng","note":"section: 0","page":"985–1002","title":"Therapeutic bacteriophages as a rescue treatment for drug-resistant infections - an in vivo studies overview","volume":"128","author":[{"family":"Kwiatek","given":"M."},{"family":"Parasion","given":"S."},{"family":"Nakonieczna","given":"A."}],"issued":{"date-parts":[["2020",4]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->8<!-- [if supportFields]><![endif]-->. The main obstacle in evaluating the effectiveness of phage therapy in clinical settings is the limited number of trials due to the lack of regulations and safety guidelines, which prevent physicians from using them <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"nTk2dZMN","properties":{"formattedCitation":"\\super 9\\nosupersub{}","plainCitation":"9","noteIndex":0},"citationItems":[{"id":1215,"uris":["http://zotero.org/users/11334842/items/KRHR9D2P"],"itemData":{"id":1215,"type":"article-journal","abstract":"Klebsiella spp. are commensals of the human microbiota, and a leading cause of opportunistic nosocomial infections. The incidence of multidrug resistant (MDR) strains of Klebsiella pneumoniae causing serious infections is increasing, and Klebsiella oxytoca is an emerging pathogen. Alternative strategies to tackle infections caused by these bacteria are required as strains become resistant to last-resort antibiotics such as colistin. Bacteriophages (phages) are viruses that can infect and kill bacteria. They and their gene products are now being considered as alternatives or adjuncts to antimicrobial therapies. Several in vitro and in vivo studies have shown the potential for lytic phages to combat MDR K. pneumoniae infections. Ready access to cheap sequencing technologies has led to a large increase in the number of genomes available for Klebsiella-infecting phages, with these phages being heterogeneous at the whole-genome level. This review summarizes our current knowledge on phages of Klebsiella spp. and highlights technological and biological issues relevant to the development of phage-based therapies targeting these bacteria.","container-title":"Journal of Medical Microbiology","DOI":"10.1099/jmm.0.001141","ISSN":"1473-5644","issue":"2","language":"eng","note":"section: 0","page":"176–194","title":"Bacteriophages of Klebsiella spp., their diversity and potential therapeutic uses","volume":"69","author":[{"family":"Herridge","given":"Warren P."},{"family":"Shibu","given":"Preetha"},{"family":"O'Shea","given":"Jessica"},{"family":"Brook","given":"Thomas C."},{"family":"Hoyles","given":"Lesley"}],"issued":{"date-parts":[["2020",2]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->9<!-- [if supportFields]><![endif]-->. Amongst the studies that were conducted, some notable limitations include a decreasing susceptibility to the phage over time, requiring multiple doses which was seen in the previously mentioned diabetic patient <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"crnjSViB","properties":{"formattedCitation":"\\super 5\\nosupersub{}","plainCitation":"5","noteIndex":0},"citationItems":[{"id":1303,"uris":["http://zotero.org/users/11334842/items/IMCDGVZV"],"itemData":{"id":1303,"type":"article-journal","container-title":"Antimicrobial Agents and Chemotherapy","DOI":"10.1128/aac.00954-17","issue":"10","language":"en","page":"00954–17","title":"Development and Use of Personalized Bacteriophage-Based Therapeutic Cocktails To Treat a Patient with a Disseminated Resistant Acinetobacter baumannii Infection","volume":"61","author":[{"family":"Schooley","given":"R.T."},{"family":"Biswas","given":"B."},{"family":"Gill","given":"J.J."},{"family":"Hernandez-Morales","given":"A."},{"family":"Lancaster","given":"J."},{"family":"Lessor","given":"L."},{"family":"Barr","given":"J.J."},{"family":"Reed","given":"S.L."},{"family":"Rohwer","given":"F."},{"family":"Benler","given":"S."},{"family":"Segall","given":"A.M."},{"family":"Taplitz","given":"R."},{"family":"Smith","given":"D.M."},{"family":"Kerr","given":"K."},{"family":"Kumaraswamy","given":"M."},{"family":"Nizet","given":"V."},{"family":"Lin","given":"L."},{"family":"McCauley","given":"M.D."},{"family":"Strathdee","given":"S.A."},{"family":"Hamilton","given":"T."}],"issued":{"date-parts":[["2017"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->5<!-- [if supportFields]><![endif]-->. Certain limitations are associated with the pathophysiology of specific pathogens, such as K.pneumoniae, which can reside inside cells within vacuoles, making it inaccessible to bacteriophages <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"7ZikLp1z","properties":{"formattedCitation":"\\super 10\\nosupersub{}","plainCitation":"10","noteIndex":0},"citationItems":[{"id":1308,"uris":["http://zotero.org/users/11334842/items/8DVKF8IE"],"itemData":{"id":1308,"type":"article-journal","container-title":"Cellular Microbiology","DOI":"10.1111/cmi.12466","issue":"11","language":"en","page":"1537–1560","title":"K lebsiella pneumoniae survives within macrophages by avoiding delivery to lysosomes","volume":"17","author":[{"family":"Cano","given":"V."},{"family":"March","given":"C."},{"family":"Insua","given":"J.L."},{"family":"Aguiló","given":"N."},{"family":"Llobet","given":"E."},{"family":"Moranta","given":"D."},{"family":"Regueiro","given":"V."},{"family":"Brennan","given":"G.P."},{"family":"Millán‐Lou","given":"M.I."},{"family":"Martín","given":"C."},{"family":"Garmendia","given":"J."},{"family":"Bengoechea","given":"J.A."}],"issued":{"date-parts":[["2015"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->10<!-- [if supportFields]><![endif]-->. Another is the development of anti-phage antibodies after oral phage therapy, which can reduce the efficacy of lytic phages. This was observed in patients with A.baumannii, K.pneumoniae, or P.aeruginosa infections after 2-3 weeks of phage therapy. Repeated phage treatment resulted in higher antibody levels, but its impact on phage therapy effectiveness requires further investigation <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"l00jDLvS","properties":{"formattedCitation":"\\super 11\\nosupersub{}","plainCitation":"11","noteIndex":0},"citationItems":[{"id":1309,"uris":["http://zotero.org/users/11334842/items/EP6UHW6W"],"itemData":{"id":1309,"type":"article-journal","container-title":"Viruses","DOI":"10.3390/v13010051.","issue":"1","language":"en","page":"51","title":"Bacteriophage Treatment: Critical Evaluation of Its Application on World Health Organization Priority Pathogens","volume":"13","author":[{"family":"Al-Ishak","given":"R."},{"family":"Skariah","given":"S."},{"family":"Busselberg","given":"D."}],"issued":{"date-parts":[["2020"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->11<!-- [if supportFields]><![endif]-->. Bacteriophage therapy is superior to antibiotics usage as they generally possess self- replicating properties, selective targeting of a host, and lower side effects.<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"oe8XIHug","properties":{"formattedCitation":"\\super 1\\nosupersub{}","plainCitation":"1","noteIndex":0},"citationItems":[{"id":1103,"uris":["http://zotero.org/users/11334842/items/UV9M5H9G"],"itemData":{"id":1103,"type":"article-journal","abstract":"INTRODUCTION: The quest to combat bacterial infections has dreaded humankind for centuries. Infections involving ESKAPE (Enterococcus spp., Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) impose therapeutic challenges due to the emergence of antimicrobial drug resistance. Recently, investigations with bacteriophages have led to the development of novel strategies against ESKAPE infections. Also, bacteriophages have been demonstrated to be instrumental in the dissemination of virulence markers in ESKAPE pathogens. AREAS COVERED: The review highlights the potential of bacteriophage in and against the pathogenicity of antibiotic-resistant ESKAPE pathogens. The review also emphasizes the challenges of employing bacteriophage in treating ESKAPE pathogens and the knowledge gap in the bacteriophage mediated antibiotic resistance and pathogenicity in ESKAPE infections. EXPERT OPINION: Bacteriophage infection can kill the host bacteria but in survivors can transfer genes that contribute toward the survival of the pathogens in the host and resistance toward multiple antimicrobials. The knowledge on the dual role of bacteriophages in the treatment and pathogenicity will assist in the prediction and development of novel therapeutics targeting antimicrobial-resistant ESKAPE. Therefore, extensive investigations on the efficacy of synthetic bacteriophage, bacteriophage cocktails, and bacteriophage in combination with antibiotics are needed to develop effective therapeutics against ESKAPE infections.","container-title":"Expert Review of Anti-Infective Therapy","DOI":"10.1080/14787210.2021.1858800","ISSN":"1744-8336","issue":"7","language":"eng","note":"section: 0","page":"845–865","title":"Bacteriophages for ESKAPE: role in pathogenicity and measures of control","volume":"19","author":[{"family":"Patil","given":"Amrita"},{"family":"Banerji","given":"Rajashri"},{"family":"Kanojiya","given":"Poonam"},{"family":"Koratkar","given":"Santosh"},{"family":"Saroj","given":"Sunil"}],"issued":{"date-parts":[["2021",7]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->1<!-- [if supportFields]><![endif]--> Phage therapy can be utilized alone or in conjunction with antibiotics, and has demonstrated both efficacy and safety in clinical trials. However, certain limitations regarding clinical use and research remain, all of which will be discussed in detail in our review. This review is expected to provide a better understanding of phage therapy against ESKAPE organisms in terms of its effectiveness, indications of use and its anticipated side effects, by critically analyzing the existing literature and providing a comprehensive overview of this topic, in addition to identifying the current gaps in literature and providing new insights for future research for bacteriophages as a promising alternative to antibiotics in the treatment of bacterial infections. Methods This study reviewed the current knowledge regarding phage therapy in ESKAPE organisms, with particular emphasis on clinical indications, as well as therapeutic outcomes and side effects. In order not to exclude any important clinical article, a search strategy using the following principal MeSH terms was created: Phage Therapy, Treatment Outcome. The search was limited to ScienceDirect, Scopus and Pubmed databases, including narrative review, systematic reviews and clinical trials, dating from January 2020 till June 2023. A total of 191 articles and 389 articles were retrieved respectively from each database, which after duplication removal, added up to 505. Articles found in Scopus were duplicates from pubmed so they were automatically excluded. A primary screen was done through the article abstracts and title, and a total of 131 texts were collected. Following that, a secondary screening through the entire text was conducted, with a total of 56 articles were eventually included in the review. Study design: Narrative review Inclusion criteria: ● Articles tackling MDR bacteriophage therapy for infections caused by ESKAPE microorganisms since the year 2020 Exclusion criteria: ● Articles in foreign language ● Phage therapy in the context of oncologic & inflammatory non-infectious conditions ● Studies dealing with non-human subjects ● Studies done in laboratory settings (in-vitro) Results: Part I: General Overview: Multidrug resistant bacteria are becoming a major problem that the healthcare system is facing. Bacterial infections are slowly switching from curable to deadly diseases due to resistance <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"7CsmvKtJ","properties":{"formattedCitation":"\\super 12\\nosupersub{}","plainCitation":"12","noteIndex":0},"citationItems":[{"id":1095,"uris":["http://zotero.org/users/11334842/items/34TH4T66"],"itemData":{"id":1095,"type":"article-journal","abstract":"Interest in the therapeutic use of bacteriophages (phages) has emerged in recent years, driven mainly by the antimicrobial resistance crisis. This review aimed to summarize some important studies addressing the use of phages as a therapeutic alternative for multiresistant bacterial infections. To this end, a literature search was conducted to address the efficacy and versatility of phage therapy, the advantages and disadvantages of its use, and potential limitations for the application of phage therapy that need to be overcome, especially in Western countries. Thus, this review highlights that phage therapy may be a promising route in the treatment of infections caused by multidrug-resistant pathogens and that a combined approach has the potential to prolong the life of the current available antimicrobials. In addition, standardized clinical trials using monoclonal or polyclonal phages, alone or in combination with antimicrobials, are crucial to determine the real potential of these treatments in clinical practice.","container-title":"Archives of Microbiology","DOI":"10.1007/s00203-020-02167-5","ISSN":"1432-072X","issue":"4","language":"eng","note":"section: 0","page":"1271–1279","title":"Phage therapy as strategy to face post-antibiotic era: a guide to beginners and experts","volume":"203","author":[{"family":"Royer","given":"Sabrina"},{"family":"Morais","given":"Aléxia Pinheiro"},{"family":"Fonseca Batistão","given":"Deivid William","non-dropping-particle":"da"}],"issued":{"date-parts":[["2021",5]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->12<!-- [if supportFields]><![endif]-->. ESKAPE organisms are known to have different virulence factors and resistance abilities that makes them difficult to treat. As these bacteria continue to develop resistance to almost all known antibiotics, shifting towards non-antibiotic interventions becomes a pressing need <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"V71PAp17","properties":{"formattedCitation":"\\super 13\\nosupersub{}","plainCitation":"13","noteIndex":0},"citationItems":[{"id":1091,"uris":["http://zotero.org/users/11334842/items/EGD6LNAS"],"itemData":{"id":1091,"type":"article-journal","abstract":"PURPOSE OF REVIEW: The current article summarizes the recent advances in the use of bacteriophages to treat pulmonary infections, particularly those caused by Gram-negative drug-resistant bacteria, including Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae and Burkholderia species. It provides an updated overview of the current available evidence, with a summary of published clinical cases, case series and clinical trials currently underway.Recent finding Personalized treatment with bacteriophages is still in its infancy in Europe and the USA, despite extensive experience in Eastern countries. However, more patients are expected to be treated with clinical trials in progress and others planned. SUMMARY: Despite very promising initial results and the confirmation of phage safety, there are still many ethical and practical implications to be considered, from the necessary regulatory approval to optimization of dose and route of administration, to developing strategies to tackle bacterial resistance. Patients with cystic fibrosis are a group where phage therapy, if successful, could have a major impact.","container-title":"Current Opinion in Pulmonary Medicine","DOI":"10.1097/MCP.0000000000000864","ISSN":"1531-6971","issue":"3","language":"eng","note":"section: 0","page":"225–231","title":"Advancing bacteriophages as a treatment of antibiotic-resistant bacterial pulmonary infections","volume":"28","author":[{"family":"Satta","given":"Giovanni"},{"family":"O'Callagharn","given":"Christopher"},{"family":"Clokie","given":"Martha R. J."},{"family":"Di Luca","given":"Mariagrazia"}],"issued":{"date-parts":[["2022",5]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->13<!-- [if supportFields]><![endif]-->. Bacteriophages are types of viruses that are known to infect bacteria <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"bfEORseu","properties":{"formattedCitation":"\\super 14\\nosupersub{}","plainCitation":"14","noteIndex":0},"citationItems":[{"id":1312,"uris":["http://zotero.org/users/11334842/items/WNIDIH7K"],"itemData":{"id":1312,"type":"article-journal","abstract":"Background\nThe host-unrestricted, non-typhoidal Salmonella enterica serovar Enteritidis (S. Enteritidis) and the serovar Typhimurium (S. Typhimurium) are major causative agents of food-borne gastroenteritis, and the host-restricted Salmonella enterica serovar Gallinarum (S. Gallinarum) is responsible for fowl typhoid. Increasing drug resistance in Salmonella contributes to the reduction of effective therapeutic and/or preventive options. Bacteriophages appear to be promising antibacterial tools, able to combat infectious diseases caused by a wide range of Salmonella strains belonging to both host-unrestricted and host-restricted Salmonella serovars.\n\nMethods\nIn this study, five novel lytic Salmonella phages, named UPWr_S1-5, were isolated and characterized, including host range determination by plaque formation, morphology visualization with transmission electron microscopy, and establishment of physiological parameters. Moreover, phage genomes were sequenced, annotated and analyzed, and their genomes were compared with reference Salmonella phages by use of average nucleotide identity, phylogeny, dot plot, single nucleotide variation and protein function analysis.\n\nResults\nIt was found that UPWr_S1-5 phages belong to the genus Jerseyvirus within the Siphoviridae family. All UPWr_S phages were found to efficiently infect various Salmonella serovars. Host range determination revealed differences in host infection profiles and exhibited ability to infect Salmonella enterica serovars such as Enteritidis, Gallinarum, Senftenberg, Stanley and Chester. The lytic life cycle of UPWr_S phages was confirmed using the mitomycin C test assay. Genomic analysis revealed that genomes of UPWr_S phages are composed of 51 core and 19 accessory genes, with 33 of all predicted genes having assigned functions. UPWr_S genome organization comparison revealed 3 kinds of genomes and mosaic structure. UPWr_S phages showed very high sequence similarity to each other, with more than 95% average nucleotide identity.\n\nConclusions\nFive novel UPWr_S1-5 bacteriophages were isolated and characterized. They exhibit host lysis range within 5 different serovars and are efficient in lysis of both host-unrestricted and host-restricted Salmonella serovars. Therefore, because of their ability to infect various Salmonella serovars and lytic life cycle, UPWr_S1-5 phages can be considered as useful tools in biological control of salmonellosis.\n\nSupplementary Information\nThe online version contains supplementary material available at 10.1186/s12985-021-01655-4.","container-title":"Virology Journal","DOI":"10.1186/s12985-021-01655-4","ISSN":"1743-422X","journalAbbreviation":"Virol J","note":"PMID: 34496915\nPMCID: PMC8425127","page":"183","source":"PubMed Central","title":"Genomic and functional characterization of five novel Salmonella-targeting bacteriophages","volume":"18","author":[{"family":"Kuźmińska-Bajor","given":"Marta"},{"family":"Śliwka","given":"Paulina"},{"family":"Ugorski","given":"Maciej"},{"family":"Korzeniowski","given":"Paweł"},{"family":"Skaradzińska","given":"Aneta"},{"family":"Kuczkowski","given":"Maciej"},{"family":"Narajaczyk","given":"Magdalena"},{"family":"Wieliczko","given":"Alina"},{"family":"Kolenda","given":"Rafał"}],"issued":{"date-parts":[["2021",9,8]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->14<!-- [if supportFields]><![endif]-->. In the 1900’s, bacteriophage-based therapies were discovered and did show positive results for treating bacterial infection <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"PrCwtCL3","properties":{"formattedCitation":"\\super 14\\nosupersub{}","plainCitation":"14","noteIndex":0},"citationItems":[{"id":1312,"uris":["http://zotero.org/users/11334842/items/WNIDIH7K"],"itemData":{"id":1312,"type":"article-journal","abstract":"Background\nThe host-unrestricted, non-typhoidal Salmonella enterica serovar Enteritidis (S. Enteritidis) and the serovar Typhimurium (S. Typhimurium) are major causative agents of food-borne gastroenteritis, and the host-restricted Salmonella enterica serovar Gallinarum (S. Gallinarum) is responsible for fowl typhoid. Increasing drug resistance in Salmonella contributes to the reduction of effective therapeutic and/or preventive options. Bacteriophages appear to be promising antibacterial tools, able to combat infectious diseases caused by a wide range of Salmonella strains belonging to both host-unrestricted and host-restricted Salmonella serovars.\n\nMethods\nIn this study, five novel lytic Salmonella phages, named UPWr_S1-5, were isolated and characterized, including host range determination by plaque formation, morphology visualization with transmission electron microscopy, and establishment of physiological parameters. Moreover, phage genomes were sequenced, annotated and analyzed, and their genomes were compared with reference Salmonella phages by use of average nucleotide identity, phylogeny, dot plot, single nucleotide variation and protein function analysis.\n\nResults\nIt was found that UPWr_S1-5 phages belong to the genus Jerseyvirus within the Siphoviridae family. All UPWr_S phages were found to efficiently infect various Salmonella serovars. Host range determination revealed differences in host infection profiles and exhibited ability to infect Salmonella enterica serovars such as Enteritidis, Gallinarum, Senftenberg, Stanley and Chester. The lytic life cycle of UPWr_S phages was confirmed using the mitomycin C test assay. Genomic analysis revealed that genomes of UPWr_S phages are composed of 51 core and 19 accessory genes, with 33 of all predicted genes having assigned functions. UPWr_S genome organization comparison revealed 3 kinds of genomes and mosaic structure. UPWr_S phages showed very high sequence similarity to each other, with more than 95% average nucleotide identity.\n\nConclusions\nFive novel UPWr_S1-5 bacteriophages were isolated and characterized. They exhibit host lysis range within 5 different serovars and are efficient in lysis of both host-unrestricted and host-restricted Salmonella serovars. Therefore, because of their ability to infect various Salmonella serovars and lytic life cycle, UPWr_S1-5 phages can be considered as useful tools in biological control of salmonellosis.\n\nSupplementary Information\nThe online version contains supplementary material available at 10.1186/s12985-021-01655-4.","container-title":"Virology Journal","DOI":"10.1186/s12985-021-01655-4","ISSN":"1743-422X","journalAbbreviation":"Virol J","note":"PMID: 34496915\nPMCID: PMC8425127","page":"183","source":"PubMed Central","title":"Genomic and functional characterization of five novel Salmonella-targeting bacteriophages","volume":"18","author":[{"family":"Kuźmińska-Bajor","given":"Marta"},{"family":"Śliwka","given":"Paulina"},{"family":"Ugorski","given":"Maciej"},{"family":"Korzeniowski","given":"Paweł"},{"family":"Skaradzińska","given":"Aneta"},{"family":"Kuczkowski","given":"Maciej"},{"family":"Narajaczyk","given":"Magdalena"},{"family":"Wieliczko","given":"Alina"},{"family":"Kolenda","given":"Rafał"}],"issued":{"date-parts":[["2021",9,8]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->14<!-- [if supportFields]><![endif]-->. D'Herelle's groundbreaking work in 1917, leading to the first application of phages as therapeutic agents in 1919 <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"5iGtzgcY","properties":{"formattedCitation":"\\super 15\\nosupersub{}","plainCitation":"15","noteIndex":0},"citationItems":[{"id":1109,"uris":["http://zotero.org/users/11334842/items/5ZKHMNHA"],"itemData":{"id":1109,"type":"article-journal","abstract":"The emerging resistivity of antibiotic resistance superbugs desire the need to resolve the global problem of antibiotic resistance. Among several other methods currently being adopted, one possible solution may be the development of supplemental therapies for antibiotics. The use of the normal and advanced bactericidal properties of bacteriophages (bacteriophage therapy) may be one of the viable infection control options. It is evident, however, that the safe and regulated application of phage treatment will need extensive knowledge of the characteristics and behaviour of certain phage-bacterium systems. This mini review offers an overview of the potential for phage therapy as well as the constraints and obstacles it faces in becoming a commonly accepted infection management strategy.","container-title":"Frontiers in Pharmacology","DOI":"10.3389/fphar.2023.1036051","ISSN":"1663-9812","language":"eng","note":"section: 0","page":"1036051","title":"Phages against killer superbugs: An enticing strategy against antibiotics-resistant pathogens","volume":"14","author":[{"family":"Baral","given":"Bikash"}],"issued":{"date-parts":[["2023"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->15<!-- [if supportFields]><![endif]-->. Back then, antibiotics were the most successful and safest agents available <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"t4p96R8X","properties":{"formattedCitation":"\\super 14\\nosupersub{}","plainCitation":"14","noteIndex":0},"citationItems":[{"id":1312,"uris":["http://zotero.org/users/11334842/items/WNIDIH7K"],"itemData":{"id":1312,"type":"article-journal","abstract":"Background\nThe host-unrestricted, non-typhoidal Salmonella enterica serovar Enteritidis (S. Enteritidis) and the serovar Typhimurium (S. Typhimurium) are major causative agents of food-borne gastroenteritis, and the host-restricted Salmonella enterica serovar Gallinarum (S. Gallinarum) is responsible for fowl typhoid. Increasing drug resistance in Salmonella contributes to the reduction of effective therapeutic and/or preventive options. Bacteriophages appear to be promising antibacterial tools, able to combat infectious diseases caused by a wide range of Salmonella strains belonging to both host-unrestricted and host-restricted Salmonella serovars.\n\nMethods\nIn this study, five novel lytic Salmonella phages, named UPWr_S1-5, were isolated and characterized, including host range determination by plaque formation, morphology visualization with transmission electron microscopy, and establishment of physiological parameters. Moreover, phage genomes were sequenced, annotated and analyzed, and their genomes were compared with reference Salmonella phages by use of average nucleotide identity, phylogeny, dot plot, single nucleotide variation and protein function analysis.\n\nResults\nIt was found that UPWr_S1-5 phages belong to the genus Jerseyvirus within the Siphoviridae family. All UPWr_S phages were found to efficiently infect various Salmonella serovars. Host range determination revealed differences in host infection profiles and exhibited ability to infect Salmonella enterica serovars such as Enteritidis, Gallinarum, Senftenberg, Stanley and Chester. The lytic life cycle of UPWr_S phages was confirmed using the mitomycin C test assay. Genomic analysis revealed that genomes of UPWr_S phages are composed of 51 core and 19 accessory genes, with 33 of all predicted genes having assigned functions. UPWr_S genome organization comparison revealed 3 kinds of genomes and mosaic structure. UPWr_S phages showed very high sequence similarity to each other, with more than 95% average nucleotide identity.\n\nConclusions\nFive novel UPWr_S1-5 bacteriophages were isolated and characterized. They exhibit host lysis range within 5 different serovars and are efficient in lysis of both host-unrestricted and host-restricted Salmonella serovars. Therefore, because of their ability to infect various Salmonella serovars and lytic life cycle, UPWr_S1-5 phages can be considered as useful tools in biological control of salmonellosis.\n\nSupplementary Information\nThe online version contains supplementary material available at 10.1186/s12985-021-01655-4.","container-title":"Virology Journal","DOI":"10.1186/s12985-021-01655-4","ISSN":"1743-422X","journalAbbreviation":"Virol J","note":"PMID: 34496915\nPMCID: PMC8425127","page":"183","source":"PubMed Central","title":"Genomic and functional characterization of five novel Salmonella-targeting bacteriophages","volume":"18","author":[{"family":"Kuźmińska-Bajor","given":"Marta"},{"family":"Śliwka","given":"Paulina"},{"family":"Ugorski","given":"Maciej"},{"family":"Korzeniowski","given":"Paweł"},{"family":"Skaradzińska","given":"Aneta"},{"family":"Kuczkowski","given":"Maciej"},{"family":"Narajaczyk","given":"Magdalena"},{"family":"Wieliczko","given":"Alina"},{"family":"Kolenda","given":"Rafał"}],"issued":{"date-parts":[["2021",9,8]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->14<!-- [if supportFields]><![endif]-->. The rise of antibiotics, providing a more convenient way to manage infectious diseases, overshadowed the phage therapy approach <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"vnM9D4tS","properties":{"formattedCitation":"\\super 15\\nosupersub{}","plainCitation":"15","noteIndex":0},"citationItems":[{"id":1109,"uris":["http://zotero.org/users/11334842/items/5ZKHMNHA"],"itemData":{"id":1109,"type":"article-journal","abstract":"The emerging resistivity of antibiotic resistance superbugs desire the need to resolve the global problem of antibiotic resistance. Among several other methods currently being adopted, one possible solution may be the development of supplemental therapies for antibiotics. The use of the normal and advanced bactericidal properties of bacteriophages (bacteriophage therapy) may be one of the viable infection control options. It is evident, however, that the safe and regulated application of phage treatment will need extensive knowledge of the characteristics and behaviour of certain phage-bacterium systems. This mini review offers an overview of the potential for phage therapy as well as the constraints and obstacles it faces in becoming a commonly accepted infection management strategy.","container-title":"Frontiers in Pharmacology","DOI":"10.3389/fphar.2023.1036051","ISSN":"1663-9812","language":"eng","note":"section: 0","page":"1036051","title":"Phages against killer superbugs: An enticing strategy against antibiotics-resistant pathogens","volume":"14","author":[{"family":"Baral","given":"Bikash"}],"issued":{"date-parts":[["2023"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->15<!-- [if supportFields]><![endif]-->. Consequently, phage therapy was largely abandoned globally, except in a few countries like Georgia, Poland, and Russia, where it continued to be an approved treatment for specific bacterial infections <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"YEwxeeyI","properties":{"formattedCitation":"\\super 15\\nosupersub{}","plainCitation":"15","noteIndex":0},"citationItems":[{"id":1109,"uris":["http://zotero.org/users/11334842/items/5ZKHMNHA"],"itemData":{"id":1109,"type":"article-journal","abstract":"The emerging resistivity of antibiotic resistance superbugs desire the need to resolve the global problem of antibiotic resistance. Among several other methods currently being adopted, one possible solution may be the development of supplemental therapies for antibiotics. The use of the normal and advanced bactericidal properties of bacteriophages (bacteriophage therapy) may be one of the viable infection control options. It is evident, however, that the safe and regulated application of phage treatment will need extensive knowledge of the characteristics and behaviour of certain phage-bacterium systems. This mini review offers an overview of the potential for phage therapy as well as the constraints and obstacles it faces in becoming a commonly accepted infection management strategy.","container-title":"Frontiers in Pharmacology","DOI":"10.3389/fphar.2023.1036051","ISSN":"1663-9812","language":"eng","note":"section: 0","page":"1036051","title":"Phages against killer superbugs: An enticing strategy against antibiotics-resistant pathogens","volume":"14","author":[{"family":"Baral","given":"Bikash"}],"issued":{"date-parts":[["2023"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->15<!-- [if supportFields]><![endif]-->. With the resurgence of interest in addressing bacterial infections, particularly due to multidrug resistance, there is a renewed focus on phage therapy as a potential solution <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"dMfJGDUO","properties":{"formattedCitation":"\\super 15\\nosupersub{}","plainCitation":"15","noteIndex":0},"citationItems":[{"id":1109,"uris":["http://zotero.org/users/11334842/items/5ZKHMNHA"],"itemData":{"id":1109,"type":"article-journal","abstract":"The emerging resistivity of antibiotic resistance superbugs desire the need to resolve the global problem of antibiotic resistance. Among several other methods currently being adopted, one possible solution may be the development of supplemental therapies for antibiotics. The use of the normal and advanced bactericidal properties of bacteriophages (bacteriophage therapy) may be one of the viable infection control options. It is evident, however, that the safe and regulated application of phage treatment will need extensive knowledge of the characteristics and behaviour of certain phage-bacterium systems. This mini review offers an overview of the potential for phage therapy as well as the constraints and obstacles it faces in becoming a commonly accepted infection management strategy.","container-title":"Frontiers in Pharmacology","DOI":"10.3389/fphar.2023.1036051","ISSN":"1663-9812","language":"eng","note":"section: 0","page":"1036051","title":"Phages against killer superbugs: An enticing strategy against antibiotics-resistant pathogens","volume":"14","author":[{"family":"Baral","given":"Bikash"}],"issued":{"date-parts":[["2023"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->15<!-- [if supportFields]><![endif]-->. Being easily accessible with an acceptable safety profile, people misused antibiotics, leading to widespread antibiotic resistance. As this issue continued, pan-drug resistant organisms emerged and resistance became a global public health concern, persuading research to go to non-antibiotic agents to treat them <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"cmgNpLIA","properties":{"formattedCitation":"\\super 12\\nosupersub{}","plainCitation":"12","noteIndex":0},"citationItems":[{"id":1095,"uris":["http://zotero.org/users/11334842/items/34TH4T66"],"itemData":{"id":1095,"type":"article-journal","abstract":"Interest in the therapeutic use of bacteriophages (phages) has emerged in recent years, driven mainly by the antimicrobial resistance crisis. This review aimed to summarize some important studies addressing the use of phages as a therapeutic alternative for multiresistant bacterial infections. To this end, a literature search was conducted to address the efficacy and versatility of phage therapy, the advantages and disadvantages of its use, and potential limitations for the application of phage therapy that need to be overcome, especially in Western countries. Thus, this review highlights that phage therapy may be a promising route in the treatment of infections caused by multidrug-resistant pathogens and that a combined approach has the potential to prolong the life of the current available antimicrobials. In addition, standardized clinical trials using monoclonal or polyclonal phages, alone or in combination with antimicrobials, are crucial to determine the real potential of these treatments in clinical practice.","container-title":"Archives of Microbiology","DOI":"10.1007/s00203-020-02167-5","ISSN":"1432-072X","issue":"4","language":"eng","note":"section: 0","page":"1271–1279","title":"Phage therapy as strategy to face post-antibiotic era: a guide to beginners and experts","volume":"203","author":[{"family":"Royer","given":"Sabrina"},{"family":"Morais","given":"Aléxia Pinheiro"},{"family":"Fonseca Batistão","given":"Deivid William","non-dropping-particle":"da"}],"issued":{"date-parts":[["2021",5]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->12<!-- [if supportFields]><![endif]-->. In fact, phages have been extremely effective against several types of infection, regardless of the pathogen itself. This is due to their ability to multiply specifically, which means that a lower therapeutic dose is needed to overcome the infection <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"ZuV8mWig","properties":{"formattedCitation":"\\super 16\\nosupersub{}","plainCitation":"16","noteIndex":0},"citationItems":[{"id":1337,"uris":["http://zotero.org/users/11334842/items/8UXJXXPR"],"itemData":{"id":1337,"type":"article-journal","abstract":"Phage therapy, which can be described as a phage-mediated biocontrol of bacteria (or, simply, biocontrol), is the application of bacterial viruses-also bacteriophages or phages-to reduce densities of nuisance or pathogenic bacteria. Predictive calculations for phage therapy dosing should be useful toward rational development of therapeutic as well as biocontrol products. Here, I consider the theoretical basis of a number of concepts relevant to phage dosing for phage therapy including minimum inhibitory concentration (but also \"inundation threshold\"), minimum bactericidal concentration (but also \"clearance threshold\"), decimal reduction time (D value), time until bacterial eradication, threshold bacterial density necessary to support phage population growth (\"proliferation threshold\"), and bacterial density supporting half-maximal phage population growth rates (K(B)). I also address the concepts of phage killing titers, multiplicity of infection, and phage peak densities. Though many of the presented ideas are not unique to this chapter, I nonetheless provide variations on derivations and resulting formulae, plus as appropriate discuss relative importance. The overriding goal is to present a variety of calculations that are useful toward phage therapy dosing so that they may be found in one location and presented in a manner that allows facile appreciation, comparison, and implementation. The importance of phage density as a key determinant of the phage potential to eradicate bacterial targets is stressed throughout the chapter.","container-title":"Advances in Applied Microbiology","DOI":"10.1016/B978-0-12-387044-5.00001-7","ISSN":"0065-2164","journalAbbreviation":"Adv Appl Microbiol","language":"eng","note":"PMID: 22050820","page":"1-40","source":"PubMed","title":"Phage therapy pharmacology: calculating phage dosing","title-short":"Phage therapy pharmacology","volume":"77","author":[{"family":"Abedon","given":"Stephen"}],"issued":{"date-parts":[["2011"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->16<!-- [if supportFields]><![endif]-->. In addition, resistance develops about ten times slower than antibiotic resistance <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"lqGsNfv6","properties":{"formattedCitation":"\\super 16\\nosupersub{}","plainCitation":"16","noteIndex":0},"citationItems":[{"id":1337,"uris":["http://zotero.org/users/11334842/items/8UXJXXPR"],"itemData":{"id":1337,"type":"article-journal","abstract":"Phage therapy, which can be described as a phage-mediated biocontrol of bacteria (or, simply, biocontrol), is the application of bacterial viruses-also bacteriophages or phages-to reduce densities of nuisance or pathogenic bacteria. Predictive calculations for phage therapy dosing should be useful toward rational development of therapeutic as well as biocontrol products. Here, I consider the theoretical basis of a number of concepts relevant to phage dosing for phage therapy including minimum inhibitory concentration (but also \"inundation threshold\"), minimum bactericidal concentration (but also \"clearance threshold\"), decimal reduction time (D value), time until bacterial eradication, threshold bacterial density necessary to support phage population growth (\"proliferation threshold\"), and bacterial density supporting half-maximal phage population growth rates (K(B)). I also address the concepts of phage killing titers, multiplicity of infection, and phage peak densities. Though many of the presented ideas are not unique to this chapter, I nonetheless provide variations on derivations and resulting formulae, plus as appropriate discuss relative importance. The overriding goal is to present a variety of calculations that are useful toward phage therapy dosing so that they may be found in one location and presented in a manner that allows facile appreciation, comparison, and implementation. The importance of phage density as a key determinant of the phage potential to eradicate bacterial targets is stressed throughout the chapter.","container-title":"Advances in Applied Microbiology","DOI":"10.1016/B978-0-12-387044-5.00001-7","ISSN":"0065-2164","journalAbbreviation":"Adv Appl Microbiol","language":"eng","note":"PMID: 22050820","page":"1-40","source":"PubMed","title":"Phage therapy pharmacology: calculating phage dosing","title-short":"Phage therapy pharmacology","volume":"77","author":[{"family":"Abedon","given":"Stephen"}],"issued":{"date-parts":[["2011"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->16<!-- [if supportFields]><![endif]-->. Our ability to genetically engineer viruses, provides us with a tool that can kill bacteria safely and effectively without many side effects that are seen with antibiotics <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"WHrV2q5E","properties":{"formattedCitation":"\\super 13\\nosupersub{}","plainCitation":"13","noteIndex":0},"citationItems":[{"id":1091,"uris":["http://zotero.org/users/11334842/items/EGD6LNAS"],"itemData":{"id":1091,"type":"article-journal","abstract":"PURPOSE OF REVIEW: The current article summarizes the recent advances in the use of bacteriophages to treat pulmonary infections, particularly those caused by Gram-negative drug-resistant bacteria, including Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae and Burkholderia species. It provides an updated overview of the current available evidence, with a summary of published clinical cases, case series and clinical trials currently underway.Recent finding Personalized treatment with bacteriophages is still in its infancy in Europe and the USA, despite extensive experience in Eastern countries. However, more patients are expected to be treated with clinical trials in progress and others planned. SUMMARY: Despite very promising initial results and the confirmation of phage safety, there are still many ethical and practical implications to be considered, from the necessary regulatory approval to optimization of dose and route of administration, to developing strategies to tackle bacterial resistance. Patients with cystic fibrosis are a group where phage therapy, if successful, could have a major impact.","container-title":"Current Opinion in Pulmonary Medicine","DOI":"10.1097/MCP.0000000000000864","ISSN":"1531-6971","issue":"3","language":"eng","note":"section: 0","page":"225–231","title":"Advancing bacteriophages as a treatment of antibiotic-resistant bacterial pulmonary infections","volume":"28","author":[{"family":"Satta","given":"Giovanni"},{"family":"O'Callagharn","given":"Christopher"},{"family":"Clokie","given":"Martha R. J."},{"family":"Di Luca","given":"Mariagrazia"}],"issued":{"date-parts":[["2022",5]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->13<!-- [if supportFields]><![endif]-->.This is especially important in respiratory infections for example, that are a leading cause of morbidity and mortality <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Zmz8vCjr","properties":{"formattedCitation":"\\super 17\\nosupersub{}","plainCitation":"17","noteIndex":0},"citationItems":[{"id":691,"uris":["http://zotero.org/users/11334842/items/JH9SSXSU"],"itemData":{"id":691,"type":"article-journal","container-title":"Transplant Infectious Disease","ISSN":"1398-2273","issue":"4","journalAbbreviation":"Transplant Infectious Disease","note":"publisher: Wiley Online Library","page":"e13599","title":"Clinical prediction tool for extended‐spectrum beta‐lactamase‐producing Enterobacterales as the etiology of a bloodstream infection in solid organ transplant recipients","volume":"23","author":[{"family":"Wang","given":"Rebecca"},{"family":"Han","given":"Jennifer H"},{"family":"Lautenbach","given":"Ebbing"},{"family":"Tamma","given":"Pranita D"},{"family":"Thom","given":"Kerri A"},{"family":"Alby","given":"Kevin"},{"family":"Blumberg","given":"Emily A"},{"family":"Bilker","given":"Warren B"},{"family":"Werzen","given":"Alissa"},{"family":"Omorogbe","given":"Jacqueline"}],"issued":{"date-parts":[["2021"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->17<!-- [if supportFields]><![endif]-->. Nowadays, we can find numerous formulations for bacteriophage therapies, such as isolated purified phages, phage lysates, phage cocktails consisting of multiple distinct, and nanoparticles encapsulating phages for controlled release, along with phage-derived enzymes <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"gHGh8NxB","properties":{"formattedCitation":"\\super 15\\nosupersub{}","plainCitation":"15","noteIndex":0},"citationItems":[{"id":1109,"uris":["http://zotero.org/users/11334842/items/5ZKHMNHA"],"itemData":{"id":1109,"type":"article-journal","abstract":"The emerging resistivity of antibiotic resistance superbugs desire the need to resolve the global problem of antibiotic resistance. Among several other methods currently being adopted, one possible solution may be the development of supplemental therapies for antibiotics. The use of the normal and advanced bactericidal properties of bacteriophages (bacteriophage therapy) may be one of the viable infection control options. It is evident, however, that the safe and regulated application of phage treatment will need extensive knowledge of the characteristics and behaviour of certain phage-bacterium systems. This mini review offers an overview of the potential for phage therapy as well as the constraints and obstacles it faces in becoming a commonly accepted infection management strategy.","container-title":"Frontiers in Pharmacology","DOI":"10.3389/fphar.2023.1036051","ISSN":"1663-9812","language":"eng","note":"section: 0","page":"1036051","title":"Phages against killer superbugs: An enticing strategy against antibiotics-resistant pathogens","volume":"14","author":[{"family":"Baral","given":"Bikash"}],"issued":{"date-parts":[["2023"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->15<!-- [if supportFields]><![endif]-->. The search for such alternative treatments gained traction from the 1980s to 1990s with antibiotic resistance, and phage isolation became a focal point for potential treatment options. However, challenges such as inadequate phage characterization, lack of controlled trials, and economic factors in assessment locations have hindered conclusive evidence of phage therapy's effectiveness <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"4WsEmjJh","properties":{"formattedCitation":"\\super 18\\nosupersub{}","plainCitation":"18","noteIndex":0},"citationItems":[{"id":1273,"uris":["http://zotero.org/users/11334842/items/YLKHYX2P"],"itemData":{"id":1273,"type":"article-journal","abstract":"Bacteriophages (phages) are viruses that infect prokaryotic cells. Phages exist in many shapes and sizes with the majority of them being less than 100 nm in size. Essentially, the majority of phages identified are double-stranded DNA virions with the remaining few being found as RNA or single-stranded DNA viruses. These biological entities are plentiful in different environments, especially in wet sources. Treatment of a bacterial disease using phage application has been documented in the pre-antibiotic era. Different studies have emerging to value the efficacy of phage use in in-vitro and in-vivo based systems against specific bacterial agents of humans, animals or plant diseases. The process represents a natural and nontoxic framework to avert infections due to pathogenic and antimicrobial-resistant bacteria. Most of the published researches on the usefulness of phages against disease-causing bacteria (including antimicrobial-resistant strains) of humans, animals or plants are emerging from the US and European countries with very few studies available from Africa. This review assesses published articles in the area of phage applications against pathogenic or antimicrobial-resistant bacteria from experimental, clinical and field settings. The knowledge and skill of isolating lytic phages against bacteria can be operational for its simpler procedures and economic benefit. Future studies in Africa and other emerging countries may consider in-house phage preparations for effective control and eradication of pathogenic and multidrug resistant bacteria of humans, animals and plants.","container-title":"Infection and Drug Resistance","DOI":"10.2147/IDR.S284331","ISSN":"1178-6973","language":"eng","note":"section: 0","page":"17–31","title":"Bacteriophages Against Pathogenic Bacteria and Possibilities for Future Application in Africa","volume":"14","author":[{"family":"Kassa","given":"Tesfaye"}],"issued":{"date-parts":[["2021"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->18<!-- [if supportFields]><![endif]-->. The cost of basic medical care is a significant concern in developing countries, exacerbated by the expense of acquiring effective antibiotics to combat antibacterial resistance <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"F0RXB4rp","properties":{"formattedCitation":"\\super 18\\nosupersub{}","plainCitation":"18","noteIndex":0},"citationItems":[{"id":1273,"uris":["http://zotero.org/users/11334842/items/YLKHYX2P"],"itemData":{"id":1273,"type":"article-journal","abstract":"Bacteriophages (phages) are viruses that infect prokaryotic cells. Phages exist in many shapes and sizes with the majority of them being less than 100 nm in size. Essentially, the majority of phages identified are double-stranded DNA virions with the remaining few being found as RNA or single-stranded DNA viruses. These biological entities are plentiful in different environments, especially in wet sources. Treatment of a bacterial disease using phage application has been documented in the pre-antibiotic era. Different studies have emerging to value the efficacy of phage use in in-vitro and in-vivo based systems against specific bacterial agents of humans, animals or plant diseases. The process represents a natural and nontoxic framework to avert infections due to pathogenic and antimicrobial-resistant bacteria. Most of the published researches on the usefulness of phages against disease-causing bacteria (including antimicrobial-resistant strains) of humans, animals or plants are emerging from the US and European countries with very few studies available from Africa. This review assesses published articles in the area of phage applications against pathogenic or antimicrobial-resistant bacteria from experimental, clinical and field settings. The knowledge and skill of isolating lytic phages against bacteria can be operational for its simpler procedures and economic benefit. Future studies in Africa and other emerging countries may consider in-house phage preparations for effective control and eradication of pathogenic and multidrug resistant bacteria of humans, animals and plants.","container-title":"Infection and Drug Resistance","DOI":"10.2147/IDR.S284331","ISSN":"1178-6973","language":"eng","note":"section: 0","page":"17–31","title":"Bacteriophages Against Pathogenic Bacteria and Possibilities for Future Application in Africa","volume":"14","author":[{"family":"Kassa","given":"Tesfaye"}],"issued":{"date-parts":[["2021"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->18<!-- [if supportFields]><![endif]-->. The potential of phage therapy in these areas is considerable, where infectious diseases cause millions of deaths annually. Phages could serve as a locally produced remedy, addressing antibiotic limitations and cost barriers <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"9THBClqg","properties":{"formattedCitation":"\\super 18\\nosupersub{}","plainCitation":"18","noteIndex":0},"citationItems":[{"id":1273,"uris":["http://zotero.org/users/11334842/items/YLKHYX2P"],"itemData":{"id":1273,"type":"article-journal","abstract":"Bacteriophages (phages) are viruses that infect prokaryotic cells. Phages exist in many shapes and sizes with the majority of them being less than 100 nm in size. Essentially, the majority of phages identified are double-stranded DNA virions with the remaining few being found as RNA or single-stranded DNA viruses. These biological entities are plentiful in different environments, especially in wet sources. Treatment of a bacterial disease using phage application has been documented in the pre-antibiotic era. Different studies have emerging to value the efficacy of phage use in in-vitro and in-vivo based systems against specific bacterial agents of humans, animals or plant diseases. The process represents a natural and nontoxic framework to avert infections due to pathogenic and antimicrobial-resistant bacteria. Most of the published researches on the usefulness of phages against disease-causing bacteria (including antimicrobial-resistant strains) of humans, animals or plants are emerging from the US and European countries with very few studies available from Africa. This review assesses published articles in the area of phage applications against pathogenic or antimicrobial-resistant bacteria from experimental, clinical and field settings. The knowledge and skill of isolating lytic phages against bacteria can be operational for its simpler procedures and economic benefit. Future studies in Africa and other emerging countries may consider in-house phage preparations for effective control and eradication of pathogenic and multidrug resistant bacteria of humans, animals and plants.","container-title":"Infection and Drug Resistance","DOI":"10.2147/IDR.S284331","ISSN":"1178-6973","language":"eng","note":"section: 0","page":"17–31","title":"Bacteriophages Against Pathogenic Bacteria and Possibilities for Future Application in Africa","volume":"14","author":[{"family":"Kassa","given":"Tesfaye"}],"issued":{"date-parts":[["2021"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->18<!-- [if supportFields]><![endif]-->. In recent years, the acceptance and application of phage therapy have increased in Western countries, paralleling Eastern countries where phages have been used clinically <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"poz910w4","properties":{"formattedCitation":"\\super 18\\nosupersub{}","plainCitation":"18","noteIndex":0},"citationItems":[{"id":1273,"uris":["http://zotero.org/users/11334842/items/YLKHYX2P"],"itemData":{"id":1273,"type":"article-journal","abstract":"Bacteriophages (phages) are viruses that infect prokaryotic cells. Phages exist in many shapes and sizes with the majority of them being less than 100 nm in size. Essentially, the majority of phages identified are double-stranded DNA virions with the remaining few being found as RNA or single-stranded DNA viruses. These biological entities are plentiful in different environments, especially in wet sources. Treatment of a bacterial disease using phage application has been documented in the pre-antibiotic era. Different studies have emerging to value the efficacy of phage use in in-vitro and in-vivo based systems against specific bacterial agents of humans, animals or plant diseases. The process represents a natural and nontoxic framework to avert infections due to pathogenic and antimicrobial-resistant bacteria. Most of the published researches on the usefulness of phages against disease-causing bacteria (including antimicrobial-resistant strains) of humans, animals or plants are emerging from the US and European countries with very few studies available from Africa. This review assesses published articles in the area of phage applications against pathogenic or antimicrobial-resistant bacteria from experimental, clinical and field settings. The knowledge and skill of isolating lytic phages against bacteria can be operational for its simpler procedures and economic benefit. Future studies in Africa and other emerging countries may consider in-house phage preparations for effective control and eradication of pathogenic and multidrug resistant bacteria of humans, animals and plants.","container-title":"Infection and Drug Resistance","DOI":"10.2147/IDR.S284331","ISSN":"1178-6973","language":"eng","note":"section: 0","page":"17–31","title":"Bacteriophages Against Pathogenic Bacteria and Possibilities for Future Application in Africa","volume":"14","author":[{"family":"Kassa","given":"Tesfaye"}],"issued":{"date-parts":[["2021"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->18<!-- [if supportFields]><![endif]-->. Successful cases include patients infected with multidrug-resistant Acinetobacter baumannii and Pseudomonas aeruginosa. However, challenges have emerged, such as phage resistance and technical complexities in phage preparation <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"39qBQXcO","properties":{"formattedCitation":"\\super 18\\nosupersub{}","plainCitation":"18","noteIndex":0},"citationItems":[{"id":1273,"uris":["http://zotero.org/users/11334842/items/YLKHYX2P"],"itemData":{"id":1273,"type":"article-journal","abstract":"Bacteriophages (phages) are viruses that infect prokaryotic cells. Phages exist in many shapes and sizes with the majority of them being less than 100 nm in size. Essentially, the majority of phages identified are double-stranded DNA virions with the remaining few being found as RNA or single-stranded DNA viruses. These biological entities are plentiful in different environments, especially in wet sources. Treatment of a bacterial disease using phage application has been documented in the pre-antibiotic era. Different studies have emerging to value the efficacy of phage use in in-vitro and in-vivo based systems against specific bacterial agents of humans, animals or plant diseases. The process represents a natural and nontoxic framework to avert infections due to pathogenic and antimicrobial-resistant bacteria. Most of the published researches on the usefulness of phages against disease-causing bacteria (including antimicrobial-resistant strains) of humans, animals or plants are emerging from the US and European countries with very few studies available from Africa. This review assesses published articles in the area of phage applications against pathogenic or antimicrobial-resistant bacteria from experimental, clinical and field settings. The knowledge and skill of isolating lytic phages against bacteria can be operational for its simpler procedures and economic benefit. Future studies in Africa and other emerging countries may consider in-house phage preparations for effective control and eradication of pathogenic and multidrug resistant bacteria of humans, animals and plants.","container-title":"Infection and Drug Resistance","DOI":"10.2147/IDR.S284331","ISSN":"1178-6973","language":"eng","note":"section: 0","page":"17–31","title":"Bacteriophages Against Pathogenic Bacteria and Possibilities for Future Application in Africa","volume":"14","author":[{"family":"Kassa","given":"Tesfaye"}],"issued":{"date-parts":[["2021"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->18<!-- [if supportFields]><![endif]-->. Part II: Advantages and Ease of Phage Utilization: Specificity There are several advantages of using therapeutic bacteriophages. For instance, phages exhibit a high degree of specificity, targeting only the harmful microorganisms while leaving beneficial microflora untouched <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"cYqZaNEK","properties":{"formattedCitation":"\\super 15\\nosupersub{}","plainCitation":"15","noteIndex":0},"citationItems":[{"id":1109,"uris":["http://zotero.org/users/11334842/items/5ZKHMNHA"],"itemData":{"id":1109,"type":"article-journal","abstract":"The emerging resistivity of antibiotic resistance superbugs desire the need to resolve the global problem of antibiotic resistance. Among several other methods currently being adopted, one possible solution may be the development of supplemental therapies for antibiotics. The use of the normal and advanced bactericidal properties of bacteriophages (bacteriophage therapy) may be one of the viable infection control options. It is evident, however, that the safe and regulated application of phage treatment will need extensive knowledge of the characteristics and behaviour of certain phage-bacterium systems. This mini review offers an overview of the potential for phage therapy as well as the constraints and obstacles it faces in becoming a commonly accepted infection management strategy.","container-title":"Frontiers in Pharmacology","DOI":"10.3389/fphar.2023.1036051","ISSN":"1663-9812","language":"eng","note":"section: 0","page":"1036051","title":"Phages against killer superbugs: An enticing strategy against antibiotics-resistant pathogens","volume":"14","author":[{"family":"Baral","given":"Bikash"}],"issued":{"date-parts":[["2023"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->15<!-- [if supportFields]><![endif]-->. They are highly specific to their target bacteria and don't harm mammalian cells <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"cmPTYqLX","properties":{"formattedCitation":"\\super 3\\nosupersub{}","plainCitation":"3","noteIndex":0},"citationItems":[{"id":1119,"uris":["http://zotero.org/users/11334842/items/V6FI3YDR"],"itemData":{"id":1119,"type":"article-journal","abstract":"Globally, the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) are the major cause of nosocomial infections. These pathogens are multidrug resistant, and their negative impacts have brought serious health challenges and economic burden on many countries worldwide. Thus, this narrative review exploits different emerging alternative therapeutic strategies including combination antibiotics, antimicrobial peptides ((AMPs), bacteriophage and photodynamic therapies used in the treatment of the ESKAPE pathogens, their merits, limitations, and future prospects. Our findings indicate that ESKAPE pathogens exhibit resistance to drug using different mechanisms including drug inactivation by irreversible enzyme cleavage, drug-binding site alteration, diminution in permeability of drug or drug efflux increment to reduce accumulation of drug as well as biofilms production. However, the scientific community has shown significant interest in using these novel strategies with numerous benefits although they have some limitations including but not limited to instability and toxicity of the therapeutic agents, or the host developing immune response against the therapeutic agents. Thus, comprehension of resistance mechanisms of these pathogens is necessary to further develop or modify these approaches in order to overcome these health challenges including the barriers of bacterial resistance.","container-title":"Microbial Pathogenesis","DOI":"10.1016/j.micpath.2022.105963","ISSN":"1096-1208","language":"eng","note":"section: 0","page":"105963","title":"Coping with the ESKAPE pathogens: Evolving strategies, challenges and future prospects","volume":"175","author":[{"family":"Aloke","given":"Chinyere"},{"family":"Achilonu","given":"Ikechukwu"}],"issued":{"date-parts":[["2023",2]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->3<!-- [if supportFields]><![endif]-->. They usually target specific bacterial hosts based on the presence of complementary receptors on the bacterial surface <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"bD6GHjeD","properties":{"formattedCitation":"\\super 19\\nosupersub{}","plainCitation":"19","noteIndex":0},"citationItems":[{"id":1143,"uris":["http://zotero.org/users/11334842/items/YD3LKXA9"],"itemData":{"id":1143,"type":"article-journal","abstract":"Bacteriophages (simply referred to as Phages) are a class of viruses with the ability to infect and kill prokaryotic cells (bacteria), but are unable to infect mammalian cells. This unique ability to achieve specific infectiousness by bacteriophages has been harnessed in antibacterial treatments dating back almost a decade before the antibiotic era began. Bacteriophages were used as therapeutic agents in treatment of dysentery caused by Shigella dysenteriae as far back as 1919 and in the experimental treatment of a wide variety of other bacterial infections caused by Vibrio cholerae, Staphylococcus sp., Pseudomonas sp. etc, with varying degrees of success. Phage therapy and its many prospects soon fell out of favour in western medicine after the Second World War, with the discovery of penicillin. The Soviet Union and other countries in Eastern Europe however mastered the craft of bacteriophage isolation, purification and cocktail preparation, with phage-based therapeutics becoming widely available over-the-counter. With the recent rise in cases of multi-drug resistant bacterial infections, the clamour for a return to phage therapy, as a potential solution to the anti-microbial resistance (AMR) crisis has grown louder. This review provides an extensive exposé on phage therapy, addressing its historical use, evidences of its safety and efficacy, its pros and cons when compared with antibiotics, cases of compassionate use for treating life-threatening antibiotic-resistant infections, the limitations to its acceptance and how these may be circumvented.","container-title":"AIMS microbiology","DOI":"10.3934/microbiol.2020014","ISSN":"2471-1888","issue":"3","language":"eng","note":"section: 0","page":"204–230","title":"An exegesis of bacteriophage therapy: An emerging player in the fight against anti-microbial resistance","volume":"6","author":[{"family":"Adesanya","given":"Oluwafolajimi"},{"family":"Oduselu","given":"Tolulope"},{"family":"Akin-Ajani","given":"Oluwawapelumi"},{"family":"Adewumi","given":"Olubusuyi M."},{"family":"Ademowo","given":"Olusegun G."}],"issued":{"date-parts":[["2020"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->19<!-- [if supportFields]><![endif]-->. This specificity is advantageous as it allows for a narrow spectrum of action, reducing the impact on beneficial gut microbes and the development of secondary infections and antibiotic resistance <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"tshaRTDd","properties":{"formattedCitation":"\\super 19\\nosupersub{}","plainCitation":"19","noteIndex":0},"citationItems":[{"id":1143,"uris":["http://zotero.org/users/11334842/items/YD3LKXA9"],"itemData":{"id":1143,"type":"article-journal","abstract":"Bacteriophages (simply referred to as Phages) are a class of viruses with the ability to infect and kill prokaryotic cells (bacteria), but are unable to infect mammalian cells. This unique ability to achieve specific infectiousness by bacteriophages has been harnessed in antibacterial treatments dating back almost a decade before the antibiotic era began. Bacteriophages were used as therapeutic agents in treatment of dysentery caused by Shigella dysenteriae as far back as 1919 and in the experimental treatment of a wide variety of other bacterial infections caused by Vibrio cholerae, Staphylococcus sp., Pseudomonas sp. etc, with varying degrees of success. Phage therapy and its many prospects soon fell out of favour in western medicine after the Second World War, with the discovery of penicillin. The Soviet Union and other countries in Eastern Europe however mastered the craft of bacteriophage isolation, purification and cocktail preparation, with phage-based therapeutics becoming widely available over-the-counter. With the recent rise in cases of multi-drug resistant bacterial infections, the clamour for a return to phage therapy, as a potential solution to the anti-microbial resistance (AMR) crisis has grown louder. This review provides an extensive exposé on phage therapy, addressing its historical use, evidences of its safety and efficacy, its pros and cons when compared with antibiotics, cases of compassionate use for treating life-threatening antibiotic-resistant infections, the limitations to its acceptance and how these may be circumvented.","container-title":"AIMS microbiology","DOI":"10.3934/microbiol.2020014","ISSN":"2471-1888","issue":"3","language":"eng","note":"section: 0","page":"204–230","title":"An exegesis of bacteriophage therapy: An emerging player in the fight against anti-microbial resistance","volume":"6","author":[{"family":"Adesanya","given":"Oluwafolajimi"},{"family":"Oduselu","given":"Tolulope"},{"family":"Akin-Ajani","given":"Oluwawapelumi"},{"family":"Adewumi","given":"Olubusuyi M."},{"family":"Ademowo","given":"Olusegun G."}],"issued":{"date-parts":[["2020"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->19<!-- [if supportFields]><![endif]-->. Studies have shown that phage therapy can be administered without disturbing the normal gut microbiome <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"7pQhw0cu","properties":{"formattedCitation":"\\super 19\\nosupersub{}","plainCitation":"19","noteIndex":0},"citationItems":[{"id":1143,"uris":["http://zotero.org/users/11334842/items/YD3LKXA9"],"itemData":{"id":1143,"type":"article-journal","abstract":"Bacteriophages (simply referred to as Phages) are a class of viruses with the ability to infect and kill prokaryotic cells (bacteria), but are unable to infect mammalian cells. This unique ability to achieve specific infectiousness by bacteriophages has been harnessed in antibacterial treatments dating back almost a decade before the antibiotic era began. Bacteriophages were used as therapeutic agents in treatment of dysentery caused by Shigella dysenteriae as far back as 1919 and in the experimental treatment of a wide variety of other bacterial infections caused by Vibrio cholerae, Staphylococcus sp., Pseudomonas sp. etc, with varying degrees of success. Phage therapy and its many prospects soon fell out of favour in western medicine after the Second World War, with the discovery of penicillin. The Soviet Union and other countries in Eastern Europe however mastered the craft of bacteriophage isolation, purification and cocktail preparation, with phage-based therapeutics becoming widely available over-the-counter. With the recent rise in cases of multi-drug resistant bacterial infections, the clamour for a return to phage therapy, as a potential solution to the anti-microbial resistance (AMR) crisis has grown louder. This review provides an extensive exposé on phage therapy, addressing its historical use, evidences of its safety and efficacy, its pros and cons when compared with antibiotics, cases of compassionate use for treating life-threatening antibiotic-resistant infections, the limitations to its acceptance and how these may be circumvented.","container-title":"AIMS microbiology","DOI":"10.3934/microbiol.2020014","ISSN":"2471-1888","issue":"3","language":"eng","note":"section: 0","page":"204–230","title":"An exegesis of bacteriophage therapy: An emerging player in the fight against anti-microbial resistance","volume":"6","author":[{"family":"Adesanya","given":"Oluwafolajimi"},{"family":"Oduselu","given":"Tolulope"},{"family":"Akin-Ajani","given":"Oluwawapelumi"},{"family":"Adewumi","given":"Olubusuyi M."},{"family":"Ademowo","given":"Olusegun G."}],"issued":{"date-parts":[["2020"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->19<!-- [if supportFields]><![endif]-->. This specificity contrasts with antibiotics that affect a broad range of bacteria, reducing the risk of complications like dysbacteriosis and secondary infections <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"3p3CbAyT","properties":{"formattedCitation":"\\super 15\\nosupersub{}","plainCitation":"15","noteIndex":0},"citationItems":[{"id":1109,"uris":["http://zotero.org/users/11334842/items/5ZKHMNHA"],"itemData":{"id":1109,"type":"article-journal","abstract":"The emerging resistivity of antibiotic resistance superbugs desire the need to resolve the global problem of antibiotic resistance. Among several other methods currently being adopted, one possible solution may be the development of supplemental therapies for antibiotics. The use of the normal and advanced bactericidal properties of bacteriophages (bacteriophage therapy) may be one of the viable infection control options. It is evident, however, that the safe and regulated application of phage treatment will need extensive knowledge of the characteristics and behaviour of certain phage-bacterium systems. This mini review offers an overview of the potential for phage therapy as well as the constraints and obstacles it faces in becoming a commonly accepted infection management strategy.","container-title":"Frontiers in Pharmacology","DOI":"10.3389/fphar.2023.1036051","ISSN":"1663-9812","language":"eng","note":"section: 0","page":"1036051","title":"Phages against killer superbugs: An enticing strategy against antibiotics-resistant pathogens","volume":"14","author":[{"family":"Baral","given":"Bikash"}],"issued":{"date-parts":[["2023"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->15<!-- [if supportFields]><![endif]-->. Self-Replication Bacteriophages have a unique mechanism of action that allows them to lyse host targets and produce more phage copies, eliminating the need for repeated dosing or administration to maintain therapeutic concentration <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Fms0dR4A","properties":{"formattedCitation":"\\super 19\\nosupersub{}","plainCitation":"19","noteIndex":0},"citationItems":[{"id":1143,"uris":["http://zotero.org/users/11334842/items/YD3LKXA9"],"itemData":{"id":1143,"type":"article-journal","abstract":"Bacteriophages (simply referred to as Phages) are a class of viruses with the ability to infect and kill prokaryotic cells (bacteria), but are unable to infect mammalian cells. This unique ability to achieve specific infectiousness by bacteriophages has been harnessed in antibacterial treatments dating back almost a decade before the antibiotic era began. Bacteriophages were used as therapeutic agents in treatment of dysentery caused by Shigella dysenteriae as far back as 1919 and in the experimental treatment of a wide variety of other bacterial infections caused by Vibrio cholerae, Staphylococcus sp., Pseudomonas sp. etc, with varying degrees of success. Phage therapy and its many prospects soon fell out of favour in western medicine after the Second World War, with the discovery of penicillin. The Soviet Union and other countries in Eastern Europe however mastered the craft of bacteriophage isolation, purification and cocktail preparation, with phage-based therapeutics becoming widely available over-the-counter. With the recent rise in cases of multi-drug resistant bacterial infections, the clamour for a return to phage therapy, as a potential solution to the anti-microbial resistance (AMR) crisis has grown louder. This review provides an extensive exposé on phage therapy, addressing its historical use, evidences of its safety and efficacy, its pros and cons when compared with antibiotics, cases of compassionate use for treating life-threatening antibiotic-resistant infections, the limitations to its acceptance and how these may be circumvented.","container-title":"AIMS microbiology","DOI":"10.3934/microbiol.2020014","ISSN":"2471-1888","issue":"3","language":"eng","note":"section: 0","page":"204–230","title":"An exegesis of bacteriophage therapy: An emerging player in the fight against anti-microbial resistance","volume":"6","author":[{"family":"Adesanya","given":"Oluwafolajimi"},{"family":"Oduselu","given":"Tolulope"},{"family":"Akin-Ajani","given":"Oluwawapelumi"},{"family":"Adewumi","given":"Olubusuyi M."},{"family":"Ademowo","given":"Olusegun G."}],"issued":{"date-parts":[["2020"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->19<!-- [if supportFields]><![endif]-->. This enhances their local antibacterial impact compared to antibiotics which require multiple dosing <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"GMA8krux","properties":{"formattedCitation":"\\super 15\\nosupersub{}","plainCitation":"15","noteIndex":0},"citationItems":[{"id":1109,"uris":["http://zotero.org/users/11334842/items/5ZKHMNHA"],"itemData":{"id":1109,"type":"article-journal","abstract":"The emerging resistivity of antibiotic resistance superbugs desire the need to resolve the global problem of antibiotic resistance. Among several other methods currently being adopted, one possible solution may be the development of supplemental therapies for antibiotics. The use of the normal and advanced bactericidal properties of bacteriophages (bacteriophage therapy) may be one of the viable infection control options. It is evident, however, that the safe and regulated application of phage treatment will need extensive knowledge of the characteristics and behaviour of certain phage-bacterium systems. This mini review offers an overview of the potential for phage therapy as well as the constraints and obstacles it faces in becoming a commonly accepted infection management strategy.","container-title":"Frontiers in Pharmacology","DOI":"10.3389/fphar.2023.1036051","ISSN":"1663-9812","language":"eng","note":"section: 0","page":"1036051","title":"Phages against killer superbugs: An enticing strategy against antibiotics-resistant pathogens","volume":"14","author":[{"family":"Baral","given":"Bikash"}],"issued":{"date-parts":[["2023"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->15<!-- [if supportFields]><![endif]--> <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1y177ssG","properties":{"formattedCitation":"\\super 19\\nosupersub{}","plainCitation":"19","noteIndex":0},"citationItems":[{"id":1143,"uris":["http://zotero.org/users/11334842/items/YD3LKXA9"],"itemData":{"id":1143,"type":"article-journal","abstract":"Bacteriophages (simply referred to as Phages) are a class of viruses with the ability to infect and kill prokaryotic cells (bacteria), but are unable to infect mammalian cells. This unique ability to achieve specific infectiousness by bacteriophages has been harnessed in antibacterial treatments dating back almost a decade before the antibiotic era began. Bacteriophages were used as therapeutic agents in treatment of dysentery caused by Shigella dysenteriae as far back as 1919 and in the experimental treatment of a wide variety of other bacterial infections caused by Vibrio cholerae, Staphylococcus sp., Pseudomonas sp. etc, with varying degrees of success. Phage therapy and its many prospects soon fell out of favour in western medicine after the Second World War, with the discovery of penicillin. The Soviet Union and other countries in Eastern Europe however mastered the craft of bacteriophage isolation, purification and cocktail preparation, with phage-based therapeutics becoming widely available over-the-counter. With the recent rise in cases of multi-drug resistant bacterial infections, the clamour for a return to phage therapy, as a potential solution to the anti-microbial resistance (AMR) crisis has grown louder. This review provides an extensive exposé on phage therapy, addressing its historical use, evidences of its safety and efficacy, its pros and cons when compared with antibiotics, cases of compassionate use for treating life-threatening antibiotic-resistant infections, the limitations to its acceptance and how these may be circumvented.","container-title":"AIMS microbiology","DOI":"10.3934/microbiol.2020014","ISSN":"2471-1888","issue":"3","language":"eng","note":"section: 0","page":"204–230","title":"An exegesis of bacteriophage therapy: An emerging player in the fight against anti-microbial resistance","volume":"6","author":[{"family":"Adesanya","given":"Oluwafolajimi"},{"family":"Oduselu","given":"Tolulope"},{"family":"Akin-Ajani","given":"Oluwawapelumi"},{"family":"Adewumi","given":"Olubusuyi M."},{"family":"Ademowo","given":"Olusegun G."}],"issued":{"date-parts":[["2020"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->19<!-- [if supportFields]><![endif]-->. Side Effect Profile Ad El Haddad et al. also demonstrated that administration of phages was generally well-tolerated, with no instances of adverse effects or toxicity reported <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"iE8yxPhg","properties":{"formattedCitation":"\\super 20\\nosupersub{}","plainCitation":"20","noteIndex":0},"citationItems":[{"id":1295,"uris":["http://zotero.org/users/11334842/items/3ZV2PTLG"],"itemData":{"id":1295,"type":"article-journal","abstract":"Bacteriophages (phages) may constitute a natural, safe, and effective strategy to prevent and control multidrug-resistant organisms (MDROs), and ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens in particular. Few clinical studies have assessed the safety and efficacy of phages in patients infected with MDROs. This systematic review summarizes and critically evaluates published studies of phages in clinical practice and presents the appropriate phage selection criteria, as well as recommendations for clinicians and scientists for a successful therapy. Articles were identified through a search of the PubMed, Ovid, EMBASE, and Cochrane Library databases. Among 1102 articles and abstracts, 30 studies were selected and evaluated using selective inclusion criteria, phage criteria, and study characteristics. Most studies showed efficacy (87%) and safety (67%) of the tested phages, but few studies examined phage resistance (35%). Clinical studies and regulatory changes are needed to determine the safety and efficacy of phages and to advance their use in patients with MDRO infections.","container-title":"Clinical Infectious Diseases","DOI":"10.1093/cid/ciy947","ISSN":"1058-4838","issue":"1","note":"section: 0","page":"167–178","title":"A Systematic and Critical Review of Bacteriophage Therapy Against Multidrug-resistant ESKAPE Organisms in Humans","volume":"69","author":[{"family":"El Haddad","given":"Lynn"},{"family":"Harb","given":"Cynthia P"},{"family":"Gebara","given":"Marc A"},{"family":"Stibich","given":"Mark A"},{"family":"Chemaly","given":"Roy F"}],"issued":{"date-parts":[["2019",6]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->20<!-- [if supportFields]><![endif]-->. This was supported by many clinical trials <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"L2eX0aGp","properties":{"formattedCitation":"\\super 19\\nosupersub{}","plainCitation":"19","noteIndex":0},"citationItems":[{"id":1143,"uris":["http://zotero.org/users/11334842/items/YD3LKXA9"],"itemData":{"id":1143,"type":"article-journal","abstract":"Bacteriophages (simply referred to as Phages) are a class of viruses with the ability to infect and kill prokaryotic cells (bacteria), but are unable to infect mammalian cells. This unique ability to achieve specific infectiousness by bacteriophages has been harnessed in antibacterial treatments dating back almost a decade before the antibiotic era began. Bacteriophages were used as therapeutic agents in treatment of dysentery caused by Shigella dysenteriae as far back as 1919 and in the experimental treatment of a wide variety of other bacterial infections caused by Vibrio cholerae, Staphylococcus sp., Pseudomonas sp. etc, with varying degrees of success. Phage therapy and its many prospects soon fell out of favour in western medicine after the Second World War, with the discovery of penicillin. The Soviet Union and other countries in Eastern Europe however mastered the craft of bacteriophage isolation, purification and cocktail preparation, with phage-based therapeutics becoming widely available over-the-counter. With the recent rise in cases of multi-drug resistant bacterial infections, the clamour for a return to phage therapy, as a potential solution to the anti-microbial resistance (AMR) crisis has grown louder. This review provides an extensive exposé on phage therapy, addressing its historical use, evidences of its safety and efficacy, its pros and cons when compared with antibiotics, cases of compassionate use for treating life-threatening antibiotic-resistant infections, the limitations to its acceptance and how these may be circumvented.","container-title":"AIMS microbiology","DOI":"10.3934/microbiol.2020014","ISSN":"2471-1888","issue":"3","language":"eng","note":"section: 0","page":"204–230","title":"An exegesis of bacteriophage therapy: An emerging player in the fight against anti-microbial resistance","volume":"6","author":[{"family":"Adesanya","given":"Oluwafolajimi"},{"family":"Oduselu","given":"Tolulope"},{"family":"Akin-Ajani","given":"Oluwawapelumi"},{"family":"Adewumi","given":"Olubusuyi M."},{"family":"Ademowo","given":"Olusegun G."}],"issued":{"date-parts":[["2020"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->19<!-- [if supportFields]><![endif]-->. In addition, Phages have immunomodulatory properties, inhibiting inflammatory cytokine production and maintaining immune tolerance <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"JaGrbAyo","properties":{"formattedCitation":"\\super 19\\nosupersub{}","plainCitation":"19","noteIndex":0},"citationItems":[{"id":1143,"uris":["http://zotero.org/users/11334842/items/YD3LKXA9"],"itemData":{"id":1143,"type":"article-journal","abstract":"Bacteriophages (simply referred to as Phages) are a class of viruses with the ability to infect and kill prokaryotic cells (bacteria), but are unable to infect mammalian cells. This unique ability to achieve specific infectiousness by bacteriophages has been harnessed in antibacterial treatments dating back almost a decade before the antibiotic era began. Bacteriophages were used as therapeutic agents in treatment of dysentery caused by Shigella dysenteriae as far back as 1919 and in the experimental treatment of a wide variety of other bacterial infections caused by Vibrio cholerae, Staphylococcus sp., Pseudomonas sp. etc, with varying degrees of success. Phage therapy and its many prospects soon fell out of favour in western medicine after the Second World War, with the discovery of penicillin. The Soviet Union and other countries in Eastern Europe however mastered the craft of bacteriophage isolation, purification and cocktail preparation, with phage-based therapeutics becoming widely available over-the-counter. With the recent rise in cases of multi-drug resistant bacterial infections, the clamour for a return to phage therapy, as a potential solution to the anti-microbial resistance (AMR) crisis has grown louder. This review provides an extensive exposé on phage therapy, addressing its historical use, evidences of its safety and efficacy, its pros and cons when compared with antibiotics, cases of compassionate use for treating life-threatening antibiotic-resistant infections, the limitations to its acceptance and how these may be circumvented.","container-title":"AIMS microbiology","DOI":"10.3934/microbiol.2020014","ISSN":"2471-1888","issue":"3","language":"eng","note":"section: 0","page":"204–230","title":"An exegesis of bacteriophage therapy: An emerging player in the fight against anti-microbial resistance","volume":"6","author":[{"family":"Adesanya","given":"Oluwafolajimi"},{"family":"Oduselu","given":"Tolulope"},{"family":"Akin-Ajani","given":"Oluwawapelumi"},{"family":"Adewumi","given":"Olubusuyi M."},{"family":"Ademowo","given":"Olusegun G."}],"issued":{"date-parts":[["2020"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->19<!-- [if supportFields]><![endif]-->. Phages are generally safe when manufactured under Good Manufacturing Practice (GMP) guidelines, removing endotoxins and debris <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"33FKtEZF","properties":{"formattedCitation":"\\super 21\\nosupersub{}","plainCitation":"21","noteIndex":0},"citationItems":[{"id":1121,"uris":["http://zotero.org/users/11334842/items/3UF62TYT"],"itemData":{"id":1121,"type":"article-journal","abstract":"Antibiotic therapy has become increasingly ineffective against bacterial infections due to the rise of resistance. In particular, ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) have caused life-threatening infections in humans and represent a major global health threat due to a high degree of antibiotic resistance. To respond to this urgent call, novel strategies are urgently needed, such as bacteriophages (or phages), phage-encoded enzymes, immunomodulators and monoclonal antibodies. This review critically analyses these promising antimicrobial therapies for the treatment of multidrug-resistant bacterial infections. Recent advances in these novel therapeutic strategies are discussed, focusing on preclinical and clinical investigations, as well as combinatorial approaches. In this 'Bad Bugs, No Drugs' era, novel therapeutic strategies can play a key role in treating deadly infections and help extend the lifetime of antibiotics.","container-title":"Advanced Drug Delivery Reviews","DOI":"10.1016/j.addr.2022.114378","ISSN":"1872-8294","language":"eng","note":"section: 0","page":"114378","title":"Novel antimicrobial agents for combating antibiotic-resistant bacteria","volume":"187","author":[{"family":"Chang","given":"Rachel Yoon Kyung"},{"family":"Nang","given":"Sue C."},{"family":"Chan","given":"Hak-Kim"},{"family":"Li","given":"Jian"}],"issued":{"date-parts":[["2022",8]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->21<!-- [if supportFields]><![endif]-->. Concerns arise from bacteriolysis events during phage administration, thus optimal dosing is crucial to prevent excessive cell wall fragmentation and cytokine increase <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"87cqTvvq","properties":{"formattedCitation":"\\super 21\\nosupersub{}","plainCitation":"21","noteIndex":0},"citationItems":[{"id":1121,"uris":["http://zotero.org/users/11334842/items/3UF62TYT"],"itemData":{"id":1121,"type":"article-journal","abstract":"Antibiotic therapy has become increasingly ineffective against bacterial infections due to the rise of resistance. In particular, ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) have caused life-threatening infections in humans and represent a major global health threat due to a high degree of antibiotic resistance. To respond to this urgent call, novel strategies are urgently needed, such as bacteriophages (or phages), phage-encoded enzymes, immunomodulators and monoclonal antibodies. This review critically analyses these promising antimicrobial therapies for the treatment of multidrug-resistant bacterial infections. Recent advances in these novel therapeutic strategies are discussed, focusing on preclinical and clinical investigations, as well as combinatorial approaches. In this 'Bad Bugs, No Drugs' era, novel therapeutic strategies can play a key role in treating deadly infections and help extend the lifetime of antibiotics.","container-title":"Advanced Drug Delivery Reviews","DOI":"10.1016/j.addr.2022.114378","ISSN":"1872-8294","language":"eng","note":"section: 0","page":"114378","title":"Novel antimicrobial agents for combating antibiotic-resistant bacteria","volume":"187","author":[{"family":"Chang","given":"Rachel Yoon Kyung"},{"family":"Nang","given":"Sue C."},{"family":"Chan","given":"Hak-Kim"},{"family":"Li","given":"Jian"}],"issued":{"date-parts":[["2022",8]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->21<!-- [if supportFields]><![endif]-->. Al-Ishaq et al. reviewed studies demonstrated that various phage cocktails or individual phages were highly effective against pathogens and were considered safe, with no reported side effects <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"OL3Ftw8a","properties":{"formattedCitation":"\\super 11\\nosupersub{}","plainCitation":"11","noteIndex":0},"citationItems":[{"id":1309,"uris":["http://zotero.org/users/11334842/items/EP6UHW6W"],"itemData":{"id":1309,"type":"article-journal","container-title":"Viruses","DOI":"10.3390/v13010051.","issue":"1","language":"en","page":"51","title":"Bacteriophage Treatment: Critical Evaluation of Its Application on World Health Organization Priority Pathogens","volume":"13","author":[{"family":"Al-Ishak","given":"R."},{"family":"Skariah","given":"S."},{"family":"Busselberg","given":"D."}],"issued":{"date-parts":[["2020"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->11<!-- [if supportFields]><![endif]-->. Resistance Resistance development, a major concern with antibiotics, is less problematic with phages due to their ability to coexist with bacteria and evolve to counter resistance <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"B9WnkpZj","properties":{"formattedCitation":"\\super 3\\nosupersub{}","plainCitation":"3","noteIndex":0},"citationItems":[{"id":1119,"uris":["http://zotero.org/users/11334842/items/V6FI3YDR"],"itemData":{"id":1119,"type":"article-journal","abstract":"Globally, the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) are the major cause of nosocomial infections. These pathogens are multidrug resistant, and their negative impacts have brought serious health challenges and economic burden on many countries worldwide. Thus, this narrative review exploits different emerging alternative therapeutic strategies including combination antibiotics, antimicrobial peptides ((AMPs), bacteriophage and photodynamic therapies used in the treatment of the ESKAPE pathogens, their merits, limitations, and future prospects. Our findings indicate that ESKAPE pathogens exhibit resistance to drug using different mechanisms including drug inactivation by irreversible enzyme cleavage, drug-binding site alteration, diminution in permeability of drug or drug efflux increment to reduce accumulation of drug as well as biofilms production. However, the scientific community has shown significant interest in using these novel strategies with numerous benefits although they have some limitations including but not limited to instability and toxicity of the therapeutic agents, or the host developing immune response against the therapeutic agents. Thus, comprehension of resistance mechanisms of these pathogens is necessary to further develop or modify these approaches in order to overcome these health challenges including the barriers of bacterial resistance.","container-title":"Microbial Pathogenesis","DOI":"10.1016/j.micpath.2022.105963","ISSN":"1096-1208","language":"eng","note":"section: 0","page":"105963","title":"Coping with the ESKAPE pathogens: Evolving strategies, challenges and future prospects","volume":"175","author":[{"family":"Aloke","given":"Chinyere"},{"family":"Achilonu","given":"Ikechukwu"}],"issued":{"date-parts":[["2023",2]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->3<!-- [if supportFields]><![endif]-->. Even phage-resistant bacteria remain susceptible to other phages, and the process of introducing new phages is faster and more cost-effective compared to developing new antimicrobials according to regulations <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"YEiCDd0p","properties":{"formattedCitation":"\\super 15\\nosupersub{}","plainCitation":"15","noteIndex":0},"citationItems":[{"id":1109,"uris":["http://zotero.org/users/11334842/items/5ZKHMNHA"],"itemData":{"id":1109,"type":"article-journal","abstract":"The emerging resistivity of antibiotic resistance superbugs desire the need to resolve the global problem of antibiotic resistance. Among several other methods currently being adopted, one possible solution may be the development of supplemental therapies for antibiotics. The use of the normal and advanced bactericidal properties of bacteriophages (bacteriophage therapy) may be one of the viable infection control options. It is evident, however, that the safe and regulated application of phage treatment will need extensive knowledge of the characteristics and behaviour of certain phage-bacterium systems. This mini review offers an overview of the potential for phage therapy as well as the constraints and obstacles it faces in becoming a commonly accepted infection management strategy.","container-title":"Frontiers in Pharmacology","DOI":"10.3389/fphar.2023.1036051","ISSN":"1663-9812","language":"eng","note":"section: 0","page":"1036051","title":"Phages against killer superbugs: An enticing strategy against antibiotics-resistant pathogens","volume":"14","author":[{"family":"Baral","given":"Bikash"}],"issued":{"date-parts":[["2023"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->15<!-- [if supportFields]><![endif]-->. Phages can reach infection sites effectively since they reproduce in the presence of their host bacteria and spread throughout the body when administered systemically <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"YGPfqZ67","properties":{"formattedCitation":"\\super 3\\nosupersub{}","plainCitation":"3","noteIndex":0},"citationItems":[{"id":1119,"uris":["http://zotero.org/users/11334842/items/V6FI3YDR"],"itemData":{"id":1119,"type":"article-journal","abstract":"Globally, the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) are the major cause of nosocomial infections. These pathogens are multidrug resistant, and their negative impacts have brought serious health challenges and economic burden on many countries worldwide. Thus, this narrative review exploits different emerging alternative therapeutic strategies including combination antibiotics, antimicrobial peptides ((AMPs), bacteriophage and photodynamic therapies used in the treatment of the ESKAPE pathogens, their merits, limitations, and future prospects. Our findings indicate that ESKAPE pathogens exhibit resistance to drug using different mechanisms including drug inactivation by irreversible enzyme cleavage, drug-binding site alteration, diminution in permeability of drug or drug efflux increment to reduce accumulation of drug as well as biofilms production. However, the scientific community has shown significant interest in using these novel strategies with numerous benefits although they have some limitations including but not limited to instability and toxicity of the therapeutic agents, or the host developing immune response against the therapeutic agents. Thus, comprehension of resistance mechanisms of these pathogens is necessary to further develop or modify these approaches in order to overcome these health challenges including the barriers of bacterial resistance.","container-title":"Microbial Pathogenesis","DOI":"10.1016/j.micpath.2022.105963","ISSN":"1096-1208","language":"eng","note":"section: 0","page":"105963","title":"Coping with the ESKAPE pathogens: Evolving strategies, challenges and future prospects","volume":"175","author":[{"family":"Aloke","given":"Chinyere"},{"family":"Achilonu","given":"Ikechukwu"}],"issued":{"date-parts":[["2023",2]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->3<!-- [if supportFields]><![endif]-->. They can even penetrate areas like the blood-brain barrier, which may be inaccessible to drugs. Some phages can also disrupt biofilms. This growth behavior might allow for less frequent and lower treatment doses compared to antibiotics <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"xEGkOGXL","properties":{"formattedCitation":"\\super 3\\nosupersub{}","plainCitation":"3","noteIndex":0},"citationItems":[{"id":1119,"uris":["http://zotero.org/users/11334842/items/V6FI3YDR"],"itemData":{"id":1119,"type":"article-journal","abstract":"Globally, the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) are the major cause of nosocomial infections. These pathogens are multidrug resistant, and their negative impacts have brought serious health challenges and economic burden on many countries worldwide. Thus, this narrative review exploits different emerging alternative therapeutic strategies including combination antibiotics, antimicrobial peptides ((AMPs), bacteriophage and photodynamic therapies used in the treatment of the ESKAPE pathogens, their merits, limitations, and future prospects. Our findings indicate that ESKAPE pathogens exhibit resistance to drug using different mechanisms including drug inactivation by irreversible enzyme cleavage, drug-binding site alteration, diminution in permeability of drug or drug efflux increment to reduce accumulation of drug as well as biofilms production. However, the scientific community has shown significant interest in using these novel strategies with numerous benefits although they have some limitations including but not limited to instability and toxicity of the therapeutic agents, or the host developing immune response against the therapeutic agents. Thus, comprehension of resistance mechanisms of these pathogens is necessary to further develop or modify these approaches in order to overcome these health challenges including the barriers of bacterial resistance.","container-title":"Microbial Pathogenesis","DOI":"10.1016/j.micpath.2022.105963","ISSN":"1096-1208","language":"eng","note":"section: 0","page":"105963","title":"Coping with the ESKAPE pathogens: Evolving strategies, challenges and future prospects","volume":"175","author":[{"family":"Aloke","given":"Chinyere"},{"family":"Achilonu","given":"Ikechukwu"}],"issued":{"date-parts":[["2023",2]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->3<!-- [if supportFields]><![endif]-->. Fighting Biofilms Some microbial agents produce biofilms, which makes them possess unique properties and resist conventional treatment methods <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"AwMOSjtu","properties":{"formattedCitation":"\\super 19\\nosupersub{}","plainCitation":"19","noteIndex":0},"citationItems":[{"id":1143,"uris":["http://zotero.org/users/11334842/items/YD3LKXA9"],"itemData":{"id":1143,"type":"article-journal","abstract":"Bacteriophages (simply referred to as Phages) are a class of viruses with the ability to infect and kill prokaryotic cells (bacteria), but are unable to infect mammalian cells. This unique ability to achieve specific infectiousness by bacteriophages has been harnessed in antibacterial treatments dating back almost a decade before the antibiotic era began. Bacteriophages were used as therapeutic agents in treatment of dysentery caused by Shigella dysenteriae as far back as 1919 and in the experimental treatment of a wide variety of other bacterial infections caused by Vibrio cholerae, Staphylococcus sp., Pseudomonas sp. etc, with varying degrees of success. Phage therapy and its many prospects soon fell out of favour in western medicine after the Second World War, with the discovery of penicillin. The Soviet Union and other countries in Eastern Europe however mastered the craft of bacteriophage isolation, purification and cocktail preparation, with phage-based therapeutics becoming widely available over-the-counter. With the recent rise in cases of multi-drug resistant bacterial infections, the clamour for a return to phage therapy, as a potential solution to the anti-microbial resistance (AMR) crisis has grown louder. This review provides an extensive exposé on phage therapy, addressing its historical use, evidences of its safety and efficacy, its pros and cons when compared with antibiotics, cases of compassionate use for treating life-threatening antibiotic-resistant infections, the limitations to its acceptance and how these may be circumvented.","container-title":"AIMS microbiology","DOI":"10.3934/microbiol.2020014","ISSN":"2471-1888","issue":"3","language":"eng","note":"section: 0","page":"204–230","title":"An exegesis of bacteriophage therapy: An emerging player in the fight against anti-microbial resistance","volume":"6","author":[{"family":"Adesanya","given":"Oluwafolajimi"},{"family":"Oduselu","given":"Tolulope"},{"family":"Akin-Ajani","given":"Oluwawapelumi"},{"family":"Adewumi","given":"Olubusuyi M."},{"family":"Ademowo","given":"Olusegun G."}],"issued":{"date-parts":[["2020"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->19<!-- [if supportFields]><![endif]-->. While antibiotics have limited effect against biofilm bacteria, bacteriophages have proven highly effective in eradicating them <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"sjgNzf7Y","properties":{"formattedCitation":"\\super 19\\nosupersub{}","plainCitation":"19","noteIndex":0},"citationItems":[{"id":1143,"uris":["http://zotero.org/users/11334842/items/YD3LKXA9"],"itemData":{"id":1143,"type":"article-journal","abstract":"Bacteriophages (simply referred to as Phages) are a class of viruses with the ability to infect and kill prokaryotic cells (bacteria), but are unable to infect mammalian cells. This unique ability to achieve specific infectiousness by bacteriophages has been harnessed in antibacterial treatments dating back almost a decade before the antibiotic era began. Bacteriophages were used as therapeutic agents in treatment of dysentery caused by Shigella dysenteriae as far back as 1919 and in the experimental treatment of a wide variety of other bacterial infections caused by Vibrio cholerae, Staphylococcus sp., Pseudomonas sp. etc, with varying degrees of success. Phage therapy and its many prospects soon fell out of favour in western medicine after the Second World War, with the discovery of penicillin. The Soviet Union and other countries in Eastern Europe however mastered the craft of bacteriophage isolation, purification and cocktail preparation, with phage-based therapeutics becoming widely available over-the-counter. With the recent rise in cases of multi-drug resistant bacterial infections, the clamour for a return to phage therapy, as a potential solution to the anti-microbial resistance (AMR) crisis has grown louder. This review provides an extensive exposé on phage therapy, addressing its historical use, evidences of its safety and efficacy, its pros and cons when compared with antibiotics, cases of compassionate use for treating life-threatening antibiotic-resistant infections, the limitations to its acceptance and how these may be circumvented.","container-title":"AIMS microbiology","DOI":"10.3934/microbiol.2020014","ISSN":"2471-1888","issue":"3","language":"eng","note":"section: 0","page":"204–230","title":"An exegesis of bacteriophage therapy: An emerging player in the fight against anti-microbial resistance","volume":"6","author":[{"family":"Adesanya","given":"Oluwafolajimi"},{"family":"Oduselu","given":"Tolulope"},{"family":"Akin-Ajani","given":"Oluwawapelumi"},{"family":"Adewumi","given":"Olubusuyi M."},{"family":"Ademowo","given":"Olusegun G."}],"issued":{"date-parts":[["2020"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->19<!-- [if supportFields]><![endif]-->. Bacteriophages can infect and lyse biofilm-forming bacteria, degrade the EPS matrix, and penetrate through water channels within the biofilm structure <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"ovFmSGaA","properties":{"formattedCitation":"\\super 19\\nosupersub{}","plainCitation":"19","noteIndex":0},"citationItems":[{"id":1143,"uris":["http://zotero.org/users/11334842/items/YD3LKXA9"],"itemData":{"id":1143,"type":"article-journal","abstract":"Bacteriophages (simply referred to as Phages) are a class of viruses with the ability to infect and kill prokaryotic cells (bacteria), but are unable to infect mammalian cells. This unique ability to achieve specific infectiousness by bacteriophages has been harnessed in antibacterial treatments dating back almost a decade before the antibiotic era began. Bacteriophages were used as therapeutic agents in treatment of dysentery caused by Shigella dysenteriae as far back as 1919 and in the experimental treatment of a wide variety of other bacterial infections caused by Vibrio cholerae, Staphylococcus sp., Pseudomonas sp. etc, with varying degrees of success. Phage therapy and its many prospects soon fell out of favour in western medicine after the Second World War, with the discovery of penicillin. The Soviet Union and other countries in Eastern Europe however mastered the craft of bacteriophage isolation, purification and cocktail preparation, with phage-based therapeutics becoming widely available over-the-counter. With the recent rise in cases of multi-drug resistant bacterial infections, the clamour for a return to phage therapy, as a potential solution to the anti-microbial resistance (AMR) crisis has grown louder. This review provides an extensive exposé on phage therapy, addressing its historical use, evidences of its safety and efficacy, its pros and cons when compared with antibiotics, cases of compassionate use for treating life-threatening antibiotic-resistant infections, the limitations to its acceptance and how these may be circumvented.","container-title":"AIMS microbiology","DOI":"10.3934/microbiol.2020014","ISSN":"2471-1888","issue":"3","language":"eng","note":"section: 0","page":"204–230","title":"An exegesis of bacteriophage therapy: An emerging player in the fight against anti-microbial resistance","volume":"6","author":[{"family":"Adesanya","given":"Oluwafolajimi"},{"family":"Oduselu","given":"Tolulope"},{"family":"Akin-Ajani","given":"Oluwawapelumi"},{"family":"Adewumi","given":"Olubusuyi M."},{"family":"Ademowo","given":"Olusegun G."}],"issued":{"date-parts":[["2020"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->19<!-- [if supportFields]><![endif]-->. This is why phage therapy shows promise in treating persistent infections caused by biofilm formation on implanted medical devices <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"ATEv2tl6","properties":{"formattedCitation":"\\super 19\\nosupersub{}","plainCitation":"19","noteIndex":0},"citationItems":[{"id":1143,"uris":["http://zotero.org/users/11334842/items/YD3LKXA9"],"itemData":{"id":1143,"type":"article-journal","abstract":"Bacteriophages (simply referred to as Phages) are a class of viruses with the ability to infect and kill prokaryotic cells (bacteria), but are unable to infect mammalian cells. This unique ability to achieve specific infectiousness by bacteriophages has been harnessed in antibacterial treatments dating back almost a decade before the antibiotic era began. Bacteriophages were used as therapeutic agents in treatment of dysentery caused by Shigella dysenteriae as far back as 1919 and in the experimental treatment of a wide variety of other bacterial infections caused by Vibrio cholerae, Staphylococcus sp., Pseudomonas sp. etc, with varying degrees of success. Phage therapy and its many prospects soon fell out of favour in western medicine after the Second World War, with the discovery of penicillin. The Soviet Union and other countries in Eastern Europe however mastered the craft of bacteriophage isolation, purification and cocktail preparation, with phage-based therapeutics becoming widely available over-the-counter. With the recent rise in cases of multi-drug resistant bacterial infections, the clamour for a return to phage therapy, as a potential solution to the anti-microbial resistance (AMR) crisis has grown louder. This review provides an extensive exposé on phage therapy, addressing its historical use, evidences of its safety and efficacy, its pros and cons when compared with antibiotics, cases of compassionate use for treating life-threatening antibiotic-resistant infections, the limitations to its acceptance and how these may be circumvented.","container-title":"AIMS microbiology","DOI":"10.3934/microbiol.2020014","ISSN":"2471-1888","issue":"3","language":"eng","note":"section: 0","page":"204–230","title":"An exegesis of bacteriophage therapy: An emerging player in the fight against anti-microbial resistance","volume":"6","author":[{"family":"Adesanya","given":"Oluwafolajimi"},{"family":"Oduselu","given":"Tolulope"},{"family":"Akin-Ajani","given":"Oluwawapelumi"},{"family":"Adewumi","given":"Olubusuyi M."},{"family":"Ademowo","given":"Olusegun G."}],"issued":{"date-parts":[["2020"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->19<!-- [if supportFields]><![endif]-->. The use of bacteriophages for biofilm degradation is limited by their high host specificity. A phage can only eliminate its target bacterial species within a biofilm community, which is often composed of multiple bacterial species <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"gEPCRo5s","properties":{"formattedCitation":"\\super 19\\nosupersub{}","plainCitation":"19","noteIndex":0},"citationItems":[{"id":1143,"uris":["http://zotero.org/users/11334842/items/YD3LKXA9"],"itemData":{"id":1143,"type":"article-journal","abstract":"Bacteriophages (simply referred to as Phages) are a class of viruses with the ability to infect and kill prokaryotic cells (bacteria), but are unable to infect mammalian cells. This unique ability to achieve specific infectiousness by bacteriophages has been harnessed in antibacterial treatments dating back almost a decade before the antibiotic era began. Bacteriophages were used as therapeutic agents in treatment of dysentery caused by Shigella dysenteriae as far back as 1919 and in the experimental treatment of a wide variety of other bacterial infections caused by Vibrio cholerae, Staphylococcus sp., Pseudomonas sp. etc, with varying degrees of success. Phage therapy and its many prospects soon fell out of favour in western medicine after the Second World War, with the discovery of penicillin. The Soviet Union and other countries in Eastern Europe however mastered the craft of bacteriophage isolation, purification and cocktail preparation, with phage-based therapeutics becoming widely available over-the-counter. With the recent rise in cases of multi-drug resistant bacterial infections, the clamour for a return to phage therapy, as a potential solution to the anti-microbial resistance (AMR) crisis has grown louder. This review provides an extensive exposé on phage therapy, addressing its historical use, evidences of its safety and efficacy, its pros and cons when compared with antibiotics, cases of compassionate use for treating life-threatening antibiotic-resistant infections, the limitations to its acceptance and how these may be circumvented.","container-title":"AIMS microbiology","DOI":"10.3934/microbiol.2020014","ISSN":"2471-1888","issue":"3","language":"eng","note":"section: 0","page":"204–230","title":"An exegesis of bacteriophage therapy: An emerging player in the fight against anti-microbial resistance","volume":"6","author":[{"family":"Adesanya","given":"Oluwafolajimi"},{"family":"Oduselu","given":"Tolulope"},{"family":"Akin-Ajani","given":"Oluwawapelumi"},{"family":"Adewumi","given":"Olubusuyi M."},{"family":"Ademowo","given":"Olusegun G."}],"issued":{"date-parts":[["2020"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->19<!-- [if supportFields]><![endif]-->. While a cocktail of bacteriophages could be a solution, an alternative approach is the use of polyvalent phages with broad or multiple host ranges <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"FukJjhQO","properties":{"formattedCitation":"\\super 19\\nosupersub{}","plainCitation":"19","noteIndex":0},"citationItems":[{"id":1143,"uris":["http://zotero.org/users/11334842/items/YD3LKXA9"],"itemData":{"id":1143,"type":"article-journal","abstract":"Bacteriophages (simply referred to as Phages) are a class of viruses with the ability to infect and kill prokaryotic cells (bacteria), but are unable to infect mammalian cells. This unique ability to achieve specific infectiousness by bacteriophages has been harnessed in antibacterial treatments dating back almost a decade before the antibiotic era began. Bacteriophages were used as therapeutic agents in treatment of dysentery caused by Shigella dysenteriae as far back as 1919 and in the experimental treatment of a wide variety of other bacterial infections caused by Vibrio cholerae, Staphylococcus sp., Pseudomonas sp. etc, with varying degrees of success. Phage therapy and its many prospects soon fell out of favour in western medicine after the Second World War, with the discovery of penicillin. The Soviet Union and other countries in Eastern Europe however mastered the craft of bacteriophage isolation, purification and cocktail preparation, with phage-based therapeutics becoming widely available over-the-counter. With the recent rise in cases of multi-drug resistant bacterial infections, the clamour for a return to phage therapy, as a potential solution to the anti-microbial resistance (AMR) crisis has grown louder. This review provides an extensive exposé on phage therapy, addressing its historical use, evidences of its safety and efficacy, its pros and cons when compared with antibiotics, cases of compassionate use for treating life-threatening antibiotic-resistant infections, the limitations to its acceptance and how these may be circumvented.","container-title":"AIMS microbiology","DOI":"10.3934/microbiol.2020014","ISSN":"2471-1888","issue":"3","language":"eng","note":"section: 0","page":"204–230","title":"An exegesis of bacteriophage therapy: An emerging player in the fight against anti-microbial resistance","volume":"6","author":[{"family":"Adesanya","given":"Oluwafolajimi"},{"family":"Oduselu","given":"Tolulope"},{"family":"Akin-Ajani","given":"Oluwawapelumi"},{"family":"Adewumi","given":"Olubusuyi M."},{"family":"Ademowo","given":"Olusegun G."}],"issued":{"date-parts":[["2020"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->19<!-- [if supportFields]><![endif]-->. Studies have shown the effectiveness of polyvalent phages in lysing mixed biofilms consisting of different bacterial species <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"o2qWrv1A","properties":{"formattedCitation":"\\super 19\\nosupersub{}","plainCitation":"19","noteIndex":0},"citationItems":[{"id":1143,"uris":["http://zotero.org/users/11334842/items/YD3LKXA9"],"itemData":{"id":1143,"type":"article-journal","abstract":"Bacteriophages (simply referred to as Phages) are a class of viruses with the ability to infect and kill prokaryotic cells (bacteria), but are unable to infect mammalian cells. This unique ability to achieve specific infectiousness by bacteriophages has been harnessed in antibacterial treatments dating back almost a decade before the antibiotic era began. Bacteriophages were used as therapeutic agents in treatment of dysentery caused by Shigella dysenteriae as far back as 1919 and in the experimental treatment of a wide variety of other bacterial infections caused by Vibrio cholerae, Staphylococcus sp., Pseudomonas sp. etc, with varying degrees of success. Phage therapy and its many prospects soon fell out of favour in western medicine after the Second World War, with the discovery of penicillin. The Soviet Union and other countries in Eastern Europe however mastered the craft of bacteriophage isolation, purification and cocktail preparation, with phage-based therapeutics becoming widely available over-the-counter. With the recent rise in cases of multi-drug resistant bacterial infections, the clamour for a return to phage therapy, as a potential solution to the anti-microbial resistance (AMR) crisis has grown louder. This review provides an extensive exposé on phage therapy, addressing its historical use, evidences of its safety and efficacy, its pros and cons when compared with antibiotics, cases of compassionate use for treating life-threatening antibiotic-resistant infections, the limitations to its acceptance and how these may be circumvented.","container-title":"AIMS microbiology","DOI":"10.3934/microbiol.2020014","ISSN":"2471-1888","issue":"3","language":"eng","note":"section: 0","page":"204–230","title":"An exegesis of bacteriophage therapy: An emerging player in the fight against anti-microbial resistance","volume":"6","author":[{"family":"Adesanya","given":"Oluwafolajimi"},{"family":"Oduselu","given":"Tolulope"},{"family":"Akin-Ajani","given":"Oluwawapelumi"},{"family":"Adewumi","given":"Olubusuyi M."},{"family":"Ademowo","given":"Olusegun G."}],"issued":{"date-parts":[["2020"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->19<!-- [if supportFields]><![endif]-->. This opens up opportunities for the expanded use of polyvalent phages in biofilm degradation, and there are numerous studies exploring their application in the literature <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"ZKgFAw5c","properties":{"formattedCitation":"\\super 19\\nosupersub{}","plainCitation":"19","noteIndex":0},"citationItems":[{"id":1143,"uris":["http://zotero.org/users/11334842/items/YD3LKXA9"],"itemData":{"id":1143,"type":"article-journal","abstract":"Bacteriophages (simply referred to as Phages) are a class of viruses with the ability to infect and kill prokaryotic cells (bacteria), but are unable to infect mammalian cells. This unique ability to achieve specific infectiousness by bacteriophages has been harnessed in antibacterial treatments dating back almost a decade before the antibiotic era began. Bacteriophages were used as therapeutic agents in treatment of dysentery caused by Shigella dysenteriae as far back as 1919 and in the experimental treatment of a wide variety of other bacterial infections caused by Vibrio cholerae, Staphylococcus sp., Pseudomonas sp. etc, with varying degrees of success. Phage therapy and its many prospects soon fell out of favour in western medicine after the Second World War, with the discovery of penicillin. The Soviet Union and other countries in Eastern Europe however mastered the craft of bacteriophage isolation, purification and cocktail preparation, with phage-based therapeutics becoming widely available over-the-counter. With the recent rise in cases of multi-drug resistant bacterial infections, the clamour for a return to phage therapy, as a potential solution to the anti-microbial resistance (AMR) crisis has grown louder. This review provides an extensive exposé on phage therapy, addressing its historical use, evidences of its safety and efficacy, its pros and cons when compared with antibiotics, cases of compassionate use for treating life-threatening antibiotic-resistant infections, the limitations to its acceptance and how these may be circumvented.","container-title":"AIMS microbiology","DOI":"10.3934/microbiol.2020014","ISSN":"2471-1888","issue":"3","language":"eng","note":"section: 0","page":"204–230","title":"An exegesis of bacteriophage therapy: An emerging player in the fight against anti-microbial resistance","volume":"6","author":[{"family":"Adesanya","given":"Oluwafolajimi"},{"family":"Oduselu","given":"Tolulope"},{"family":"Akin-Ajani","given":"Oluwawapelumi"},{"family":"Adewumi","given":"Olubusuyi M."},{"family":"Ademowo","given":"Olusegun G."}],"issued":{"date-parts":[["2020"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->19<!-- [if supportFields]><![endif]-->. Cost Effectiveness Miedzybrodski et al. conducted a study involving six patients with antibiotic-resistant infections and compared the economic benefits of phage therapy with antibiotic therapy. The patients received oral phage preparation for 6.5 weeks, and the total cost of treatment was approximately 524 EUR <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"5o1vZKad","properties":{"formattedCitation":"\\super 19\\nosupersub{}","plainCitation":"19","noteIndex":0},"citationItems":[{"id":1143,"uris":["http://zotero.org/users/11334842/items/YD3LKXA9"],"itemData":{"id":1143,"type":"article-journal","abstract":"Bacteriophages (simply referred to as Phages) are a class of viruses with the ability to infect and kill prokaryotic cells (bacteria), but are unable to infect mammalian cells. This unique ability to achieve specific infectiousness by bacteriophages has been harnessed in antibacterial treatments dating back almost a decade before the antibiotic era began. Bacteriophages were used as therapeutic agents in treatment of dysentery caused by Shigella dysenteriae as far back as 1919 and in the experimental treatment of a wide variety of other bacterial infections caused by Vibrio cholerae, Staphylococcus sp., Pseudomonas sp. etc, with varying degrees of success. Phage therapy and its many prospects soon fell out of favour in western medicine after the Second World War, with the discovery of penicillin. The Soviet Union and other countries in Eastern Europe however mastered the craft of bacteriophage isolation, purification and cocktail preparation, with phage-based therapeutics becoming widely available over-the-counter. With the recent rise in cases of multi-drug resistant bacterial infections, the clamour for a return to phage therapy, as a potential solution to the anti-microbial resistance (AMR) crisis has grown louder. This review provides an extensive exposé on phage therapy, addressing its historical use, evidences of its safety and efficacy, its pros and cons when compared with antibiotics, cases of compassionate use for treating life-threatening antibiotic-resistant infections, the limitations to its acceptance and how these may be circumvented.","container-title":"AIMS microbiology","DOI":"10.3934/microbiol.2020014","ISSN":"2471-1888","issue":"3","language":"eng","note":"section: 0","page":"204–230","title":"An exegesis of bacteriophage therapy: An emerging player in the fight against anti-microbial resistance","volume":"6","author":[{"family":"Adesanya","given":"Oluwafolajimi"},{"family":"Oduselu","given":"Tolulope"},{"family":"Akin-Ajani","given":"Oluwawapelumi"},{"family":"Adewumi","given":"Olubusuyi M."},{"family":"Ademowo","given":"Olusegun G."}],"issued":{"date-parts":[["2020"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->19<!-- [if supportFields]><![endif]-->. In comparison, the total cost of a ten-day course of vancomycin, linezolid, and teicoplanin ranged from 344 EUR to 2,620.85 EUR. Based on this analysis, the authors concluded that phage therapy was more cost-effective than antibiotic therapy for these infections <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"N7d0Mh2P","properties":{"formattedCitation":"\\super 19\\nosupersub{}","plainCitation":"19","noteIndex":0},"citationItems":[{"id":1143,"uris":["http://zotero.org/users/11334842/items/YD3LKXA9"],"itemData":{"id":1143,"type":"article-journal","abstract":"Bacteriophages (simply referred to as Phages) are a class of viruses with the ability to infect and kill prokaryotic cells (bacteria), but are unable to infect mammalian cells. This unique ability to achieve specific infectiousness by bacteriophages has been harnessed in antibacterial treatments dating back almost a decade before the antibiotic era began. Bacteriophages were used as therapeutic agents in treatment of dysentery caused by Shigella dysenteriae as far back as 1919 and in the experimental treatment of a wide variety of other bacterial infections caused by Vibrio cholerae, Staphylococcus sp., Pseudomonas sp. etc, with varying degrees of success. Phage therapy and its many prospects soon fell out of favour in western medicine after the Second World War, with the discovery of penicillin. The Soviet Union and other countries in Eastern Europe however mastered the craft of bacteriophage isolation, purification and cocktail preparation, with phage-based therapeutics becoming widely available over-the-counter. With the recent rise in cases of multi-drug resistant bacterial infections, the clamour for a return to phage therapy, as a potential solution to the anti-microbial resistance (AMR) crisis has grown louder. This review provides an extensive exposé on phage therapy, addressing its historical use, evidences of its safety and efficacy, its pros and cons when compared with antibiotics, cases of compassionate use for treating life-threatening antibiotic-resistant infections, the limitations to its acceptance and how these may be circumvented.","container-title":"AIMS microbiology","DOI":"10.3934/microbiol.2020014","ISSN":"2471-1888","issue":"3","language":"eng","note":"section: 0","page":"204–230","title":"An exegesis of bacteriophage therapy: An emerging player in the fight against anti-microbial resistance","volume":"6","author":[{"family":"Adesanya","given":"Oluwafolajimi"},{"family":"Oduselu","given":"Tolulope"},{"family":"Akin-Ajani","given":"Oluwawapelumi"},{"family":"Adewumi","given":"Olubusuyi M."},{"family":"Ademowo","given":"Olusegun G."}],"issued":{"date-parts":[["2020"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->19<!-- [if supportFields]><![endif]-->. Chances for synergistic effect Applying a magnetic field can disrupt the chemical agents that hold microbial biofilms together <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"kDgG4Ygj","properties":{"formattedCitation":"\\super 19\\nosupersub{}","plainCitation":"19","noteIndex":0},"citationItems":[{"id":1143,"uris":["http://zotero.org/users/11334842/items/YD3LKXA9"],"itemData":{"id":1143,"type":"article-journal","abstract":"Bacteriophages (simply referred to as Phages) are a class of viruses with the ability to infect and kill prokaryotic cells (bacteria), but are unable to infect mammalian cells. This unique ability to achieve specific infectiousness by bacteriophages has been harnessed in antibacterial treatments dating back almost a decade before the antibiotic era began. Bacteriophages were used as therapeutic agents in treatment of dysentery caused by Shigella dysenteriae as far back as 1919 and in the experimental treatment of a wide variety of other bacterial infections caused by Vibrio cholerae, Staphylococcus sp., Pseudomonas sp. etc, with varying degrees of success. Phage therapy and its many prospects soon fell out of favour in western medicine after the Second World War, with the discovery of penicillin. The Soviet Union and other countries in Eastern Europe however mastered the craft of bacteriophage isolation, purification and cocktail preparation, with phage-based therapeutics becoming widely available over-the-counter. With the recent rise in cases of multi-drug resistant bacterial infections, the clamour for a return to phage therapy, as a potential solution to the anti-microbial resistance (AMR) crisis has grown louder. This review provides an extensive exposé on phage therapy, addressing its historical use, evidences of its safety and efficacy, its pros and cons when compared with antibiotics, cases of compassionate use for treating life-threatening antibiotic-resistant infections, the limitations to its acceptance and how these may be circumvented.","container-title":"AIMS microbiology","DOI":"10.3934/microbiol.2020014","ISSN":"2471-1888","issue":"3","language":"eng","note":"section: 0","page":"204–230","title":"An exegesis of bacteriophage therapy: An emerging player in the fight against anti-microbial resistance","volume":"6","author":[{"family":"Adesanya","given":"Oluwafolajimi"},{"family":"Oduselu","given":"Tolulope"},{"family":"Akin-Ajani","given":"Oluwawapelumi"},{"family":"Adewumi","given":"Olubusuyi M."},{"family":"Ademowo","given":"Olusegun G."}],"issued":{"date-parts":[["2020"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->19<!-- [if supportFields]><![endif]-->. Studies have shown that antibiotics and magnetized bacteriophages can effectively penetrate and inhibit the growth of biofilms <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"nHoLckrp","properties":{"formattedCitation":"\\super 19\\nosupersub{}","plainCitation":"19","noteIndex":0},"citationItems":[{"id":1143,"uris":["http://zotero.org/users/11334842/items/YD3LKXA9"],"itemData":{"id":1143,"type":"article-journal","abstract":"Bacteriophages (simply referred to as Phages) are a class of viruses with the ability to infect and kill prokaryotic cells (bacteria), but are unable to infect mammalian cells. This unique ability to achieve specific infectiousness by bacteriophages has been harnessed in antibacterial treatments dating back almost a decade before the antibiotic era began. Bacteriophages were used as therapeutic agents in treatment of dysentery caused by Shigella dysenteriae as far back as 1919 and in the experimental treatment of a wide variety of other bacterial infections caused by Vibrio cholerae, Staphylococcus sp., Pseudomonas sp. etc, with varying degrees of success. Phage therapy and its many prospects soon fell out of favour in western medicine after the Second World War, with the discovery of penicillin. The Soviet Union and other countries in Eastern Europe however mastered the craft of bacteriophage isolation, purification and cocktail preparation, with phage-based therapeutics becoming widely available over-the-counter. With the recent rise in cases of multi-drug resistant bacterial infections, the clamour for a return to phage therapy, as a potential solution to the anti-microbial resistance (AMR) crisis has grown louder. This review provides an extensive exposé on phage therapy, addressing its historical use, evidences of its safety and efficacy, its pros and cons when compared with antibiotics, cases of compassionate use for treating life-threatening antibiotic-resistant infections, the limitations to its acceptance and how these may be circumvented.","container-title":"AIMS microbiology","DOI":"10.3934/microbiol.2020014","ISSN":"2471-1888","issue":"3","language":"eng","note":"section: 0","page":"204–230","title":"An exegesis of bacteriophage therapy: An emerging player in the fight against anti-microbial resistance","volume":"6","author":[{"family":"Adesanya","given":"Oluwafolajimi"},{"family":"Oduselu","given":"Tolulope"},{"family":"Akin-Ajani","given":"Oluwawapelumi"},{"family":"Adewumi","given":"Olubusuyi M."},{"family":"Ademowo","given":"Olusegun G."}],"issued":{"date-parts":[["2020"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->19<!-- [if supportFields]><![endif]-->. This opens up new possibilities for using magnetic fields as an adjunct to antibiotic therapy and for applying bacteriophage therapy to eradicate drug-resistant bacterial infections caused by biofilm accumulation <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"FQO1fE4E","properties":{"formattedCitation":"\\super 19\\nosupersub{}","plainCitation":"19","noteIndex":0},"citationItems":[{"id":1143,"uris":["http://zotero.org/users/11334842/items/YD3LKXA9"],"itemData":{"id":1143,"type":"article-journal","abstract":"Bacteriophages (simply referred to as Phages) are a class of viruses with the ability to infect and kill prokaryotic cells (bacteria), but are unable to infect mammalian cells. This unique ability to achieve specific infectiousness by bacteriophages has been harnessed in antibacterial treatments dating back almost a decade before the antibiotic era began. Bacteriophages were used as therapeutic agents in treatment of dysentery caused by Shigella dysenteriae as far back as 1919 and in the experimental treatment of a wide variety of other bacterial infections caused by Vibrio cholerae, Staphylococcus sp., Pseudomonas sp. etc, with varying degrees of success. Phage therapy and its many prospects soon fell out of favour in western medicine after the Second World War, with the discovery of penicillin. The Soviet Union and other countries in Eastern Europe however mastered the craft of bacteriophage isolation, purification and cocktail preparation, with phage-based therapeutics becoming widely available over-the-counter. With the recent rise in cases of multi-drug resistant bacterial infections, the clamour for a return to phage therapy, as a potential solution to the anti-microbial resistance (AMR) crisis has grown louder. This review provides an extensive exposé on phage therapy, addressing its historical use, evidences of its safety and efficacy, its pros and cons when compared with antibiotics, cases of compassionate use for treating life-threatening antibiotic-resistant infections, the limitations to its acceptance and how these may be circumvented.","container-title":"AIMS microbiology","DOI":"10.3934/microbiol.2020014","ISSN":"2471-1888","issue":"3","language":"eng","note":"section: 0","page":"204–230","title":"An exegesis of bacteriophage therapy: An emerging player in the fight against anti-microbial resistance","volume":"6","author":[{"family":"Adesanya","given":"Oluwafolajimi"},{"family":"Oduselu","given":"Tolulope"},{"family":"Akin-Ajani","given":"Oluwawapelumi"},{"family":"Adewumi","given":"Olubusuyi M."},{"family":"Ademowo","given":"Olusegun G."}],"issued":{"date-parts":[["2020"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->19<!-- [if supportFields]><![endif]-->. Effective on Multi-Drug Resistant (MDR) bacteria Importantly, many of the bacterial strains used in the studies were resistant to commonly used antibiotics, making phage therapy a valuable alternative <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"E2kDV3Ou","properties":{"formattedCitation":"\\super 11\\nosupersub{}","plainCitation":"11","noteIndex":0},"citationItems":[{"id":1309,"uris":["http://zotero.org/users/11334842/items/EP6UHW6W"],"itemData":{"id":1309,"type":"article-journal","container-title":"Viruses","DOI":"10.3390/v13010051.","issue":"1","language":"en","page":"51","title":"Bacteriophage Treatment: Critical Evaluation of Its Application on World Health Organization Priority Pathogens","volume":"13","author":[{"family":"Al-Ishak","given":"R."},{"family":"Skariah","given":"S."},{"family":"Busselberg","given":"D."}],"issued":{"date-parts":[["2020"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->11<!-- [if supportFields]><![endif]-->. In most cases, phages effectively reduced bacterial concentrations, improved outcomes, and provided protection against lethal infections or degraded biofilms <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"wf59X3Ql","properties":{"formattedCitation":"\\super 11\\nosupersub{}","plainCitation":"11","noteIndex":0},"citationItems":[{"id":1309,"uris":["http://zotero.org/users/11334842/items/EP6UHW6W"],"itemData":{"id":1309,"type":"article-journal","container-title":"Viruses","DOI":"10.3390/v13010051.","issue":"1","language":"en","page":"51","title":"Bacteriophage Treatment: Critical Evaluation of Its Application on World Health Organization Priority Pathogens","volume":"13","author":[{"family":"Al-Ishak","given":"R."},{"family":"Skariah","given":"S."},{"family":"Busselberg","given":"D."}],"issued":{"date-parts":[["2020"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->11<!-- [if supportFields]><![endif]-->. Antibiotic resistance can be decreased and improved antimicrobial effects are possible using phage-antibiotic therapy. According to studies, using phages in combination with antibiotics results in a lower antibiotic MIC, which helps remove biofilm <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"xoPwUDnq","properties":{"formattedCitation":"\\super 22\\nosupersub{}","plainCitation":"22","noteIndex":0},"citationItems":[{"id":1229,"uris":["http://zotero.org/users/11334842/items/S76547XD"],"itemData":{"id":1229,"type":"article-journal","abstract":"Increasing rates of infection by antibiotic resistant bacteria have led to a resurgence of interest in bacteriophage (phage) therapy. Several phage therapy studies in animals and humans have been completed over the last two decades. We conducted a systematic review of safety and toxicity data associated with phage therapy in both animals and humans reported in English language publications from 2008-2021. Overall, 69 publications met our eligibility criteria including 20 animal studies, 35 clinical case reports or case series, and 14 clinical trials. After summarizing safety and toxicity data from these publications, we discuss potential approaches to optimize safety and toxicity monitoring with the therapeutic use of phage moving forward. In our systematic review of the literature, we found some adverse events associated with phage therapy, but serious events were extremely rare. Comprehensive and standardized reporting of potential toxicities associated with phage therapy has generally been lacking in the published literature. Structured safety and tolerability endpoints are necessary when phages are administered as anti-infective therapeutics.","container-title":"Viruses","DOI":"10.3390/v13071268","ISSN":"1999-4915","issue":"7","language":"eng","note":"section: 0","page":"1268","title":"The Safety and Toxicity of Phage Therapy: A Review of Animal and Clinical Studies","volume":"13","author":[{"family":"Liu","given":"Dan"},{"family":"Van Belleghem","given":"Jonas D."},{"family":"Vries","given":"Christiaan R.","non-dropping-particle":"de"},{"family":"Burgener","given":"Elizabeth"},{"family":"Chen","given":"Qingquan"},{"family":"Manasherob","given":"Robert"},{"family":"Aronson","given":"Jenny R."},{"family":"Amanatullah","given":"Derek F."},{"family":"Tamma","given":"Pranita D."},{"family":"Suh","given":"Gina A."}],"issued":{"date-parts":[["2021",6]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->22<!-- [if supportFields]><![endif]-->. The best concentration of each antibiotic in a combination varies, though. Simultaneous administration produces synergism for aminoglycosides but not ciprofloxacin, demonstrating antibiotic class-specificity <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"zh4KJ6DN","properties":{"formattedCitation":"\\super 22\\nosupersub{}","plainCitation":"22","noteIndex":0},"citationItems":[{"id":1229,"uris":["http://zotero.org/users/11334842/items/S76547XD"],"itemData":{"id":1229,"type":"article-journal","abstract":"Increasing rates of infection by antibiotic resistant bacteria have led to a resurgence of interest in bacteriophage (phage) therapy. Several phage therapy studies in animals and humans have been completed over the last two decades. We conducted a systematic review of safety and toxicity data associated with phage therapy in both animals and humans reported in English language publications from 2008-2021. Overall, 69 publications met our eligibility criteria including 20 animal studies, 35 clinical case reports or case series, and 14 clinical trials. After summarizing safety and toxicity data from these publications, we discuss potential approaches to optimize safety and toxicity monitoring with the therapeutic use of phage moving forward. In our systematic review of the literature, we found some adverse events associated with phage therapy, but serious events were extremely rare. Comprehensive and standardized reporting of potential toxicities associated with phage therapy has generally been lacking in the published literature. Structured safety and tolerability endpoints are necessary when phages are administered as anti-infective therapeutics.","container-title":"Viruses","DOI":"10.3390/v13071268","ISSN":"1999-4915","issue":"7","language":"eng","note":"section: 0","page":"1268","title":"The Safety and Toxicity of Phage Therapy: A Review of Animal and Clinical Studies","volume":"13","author":[{"family":"Liu","given":"Dan"},{"family":"Van Belleghem","given":"Jonas D."},{"family":"Vries","given":"Christiaan R.","non-dropping-particle":"de"},{"family":"Burgener","given":"Elizabeth"},{"family":"Chen","given":"Qingquan"},{"family":"Manasherob","given":"Robert"},{"family":"Aronson","given":"Jenny R."},{"family":"Amanatullah","given":"Derek F."},{"family":"Tamma","given":"Pranita D."},{"family":"Suh","given":"Gina A."}],"issued":{"date-parts":[["2021",6]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->22<!-- [if supportFields]><![endif]-->. Sequential delivery, for example with aminoglycosides, improves phage multiplication and bacterial death. The features of the host strain affect treatment effectiveness; antibiotic administration time and sequence affect synergistic effects. Due to phage specificity and antibiotic pharmacokinetics in physiological conditions, phage-antibiotic interaction results differ <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"kwohOGkZ","properties":{"formattedCitation":"\\super 22\\nosupersub{}","plainCitation":"22","noteIndex":0},"citationItems":[{"id":1229,"uris":["http://zotero.org/users/11334842/items/S76547XD"],"itemData":{"id":1229,"type":"article-journal","abstract":"Increasing rates of infection by antibiotic resistant bacteria have led to a resurgence of interest in bacteriophage (phage) therapy. Several phage therapy studies in animals and humans have been completed over the last two decades. We conducted a systematic review of safety and toxicity data associated with phage therapy in both animals and humans reported in English language publications from 2008-2021. Overall, 69 publications met our eligibility criteria including 20 animal studies, 35 clinical case reports or case series, and 14 clinical trials. After summarizing safety and toxicity data from these publications, we discuss potential approaches to optimize safety and toxicity monitoring with the therapeutic use of phage moving forward. In our systematic review of the literature, we found some adverse events associated with phage therapy, but serious events were extremely rare. Comprehensive and standardized reporting of potential toxicities associated with phage therapy has generally been lacking in the published literature. Structured safety and tolerability endpoints are necessary when phages are administered as anti-infective therapeutics.","container-title":"Viruses","DOI":"10.3390/v13071268","ISSN":"1999-4915","issue":"7","language":"eng","note":"section: 0","page":"1268","title":"The Safety and Toxicity of Phage Therapy: A Review of Animal and Clinical Studies","volume":"13","author":[{"family":"Liu","given":"Dan"},{"family":"Van Belleghem","given":"Jonas D."},{"family":"Vries","given":"Christiaan R.","non-dropping-particle":"de"},{"family":"Burgener","given":"Elizabeth"},{"family":"Chen","given":"Qingquan"},{"family":"Manasherob","given":"Robert"},{"family":"Aronson","given":"Jenny R."},{"family":"Amanatullah","given":"Derek F."},{"family":"Tamma","given":"Pranita D."},{"family":"Suh","given":"Gina A."}],"issued":{"date-parts":[["2021",6]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->22<!-- [if supportFields]><![endif]-->. Besides, bacteria may forgo virulence in favor of phage resistance, which could have positive effects including decreased antibiotic resistance and improved sensitivity to both phages and antibiotics. Recent research suggests that antibiotic susceptibility may increase in phage-resistant mutants, offering a technique to take advantage of bacterial weaknesses for effective phage therapy <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"gBEhECEe","properties":{"formattedCitation":"\\super 23\\nosupersub{}","plainCitation":"23","noteIndex":0},"citationItems":[{"id":1293,"uris":["http://zotero.org/users/11334842/items/P6WLFGEY"],"itemData":{"id":1293,"type":"article-journal","container-title":"Cell Host & Microbe","DOI":"10.1016/j.chom.2019.01.014","ISSN":"1931-3128","issue":"2","language":"English","note":"section: 0","page":"219–232","title":"Phage Therapy: A Renewed Approach to Combat Antibiotic-Resistant Bacteria","volume":"25","author":[{"family":"Kortright","given":"Kaitlyn E."},{"family":"Chan","given":"Benjamin K."},{"family":"Koff","given":"Jonathan L."},{"family":"Turner","given":"Paul E."}],"issued":{"date-parts":[["2019",2]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->23<!-- [if supportFields]><![endif]-->. Already Used and Proven Effective in Some Places In Egypt, Georgia, and the UK, phage therapy has shown promise in improving wound healing and recovery <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"lZxbbytF","properties":{"formattedCitation":"\\super 24\\nosupersub{}","plainCitation":"24","noteIndex":0},"citationItems":[{"id":1267,"uris":["http://zotero.org/users/11334842/items/5JEVQWSF"],"itemData":{"id":1267,"type":"article-journal","abstract":"Treatment of patients with a burn injury is a complex process involving multicomponent multidirectional intensive therapy of the majority of organs and systems damaged by thermal effects on the skin, alternating with repeated surgical interventions aimed at removing nonviable tissues with subsequent plastic closure of wound defects. After the recovery from the burn shock, local infectious complications are considered to be the leading problem that decelerates the process of recovery and is the main cause of lethal outcomes. Since the skin integrity is broken, microorganisms penetrate readily into the internal environment of the human organism resulting in a septic state with multiple organ failure. A widespread and often uncontrollable use of antibacterial drugs in medical practice has led to the emergence of multiple drug resistance (MDR) in microorganisms. Introduction of drugs made on the basis of bacteriophages into practice is presently becoming increasingly important. This is confirmed by the growing interest in this field of pharmacology, the development of special programs aimed at studying the processes of phage and bacterial cell interaction. This review presents the main types of bacteria pertaining to MDR pathogens, principles of their classification, and the risk factors for infecting patients. The mechanisms of the selective action of phage particles on a bacterial cell and the possibility of using phage therapy in the treatment of burn injury (experimental and clinical data) based on the analysis of foreign literature are demonstrated as well as new positive properties of phages related to the changes in the macroorganism immune status caused by the interaction with bacteriophage particles.","container-title":"Sovremennye Tekhnologii V Meditsine","DOI":"10.17691/stm2020.12.3.12","ISSN":"2309-995X","issue":"3","language":"eng","note":"section: 0","page":"95–103","title":"Application of Phagotherapy in the Treatment of Burn Patients (Review)","volume":"12","author":[{"family":"Leontyev","given":"А. E."},{"family":"Pavlenko","given":"I. V."},{"family":"Kovalishena","given":"О. V."},{"family":"Saperkin","given":"N. V."},{"family":"Tulupov","given":"А. А."},{"family":"Beschastnov","given":"V. V."}],"issued":{"date-parts":[["2021"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->24<!-- [if supportFields]><![endif]-->. Belgium also introduced a framework accepting phages as pharmaceutical ingredients <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"GeqlwNse","properties":{"formattedCitation":"\\super 21\\nosupersub{}","plainCitation":"21","noteIndex":0},"citationItems":[{"id":1121,"uris":["http://zotero.org/users/11334842/items/3UF62TYT"],"itemData":{"id":1121,"type":"article-journal","abstract":"Antibiotic therapy has become increasingly ineffective against bacterial infections due to the rise of resistance. In particular, ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) have caused life-threatening infections in humans and represent a major global health threat due to a high degree of antibiotic resistance. To respond to this urgent call, novel strategies are urgently needed, such as bacteriophages (or phages), phage-encoded enzymes, immunomodulators and monoclonal antibodies. This review critically analyses these promising antimicrobial therapies for the treatment of multidrug-resistant bacterial infections. Recent advances in these novel therapeutic strategies are discussed, focusing on preclinical and clinical investigations, as well as combinatorial approaches. In this 'Bad Bugs, No Drugs' era, novel therapeutic strategies can play a key role in treating deadly infections and help extend the lifetime of antibiotics.","container-title":"Advanced Drug Delivery Reviews","DOI":"10.1016/j.addr.2022.114378","ISSN":"1872-8294","language":"eng","note":"section: 0","page":"114378","title":"Novel antimicrobial agents for combating antibiotic-resistant bacteria","volume":"187","author":[{"family":"Chang","given":"Rachel Yoon Kyung"},{"family":"Nang","given":"Sue C."},{"family":"Chan","given":"Hak-Kim"},{"family":"Li","given":"Jian"}],"issued":{"date-parts":[["2022",8]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->21<!-- [if supportFields]><![endif]-->. Phage potential to strengthen immune systems, lower bacterial loads, and treat pyoseptic issues in burn wounds has been demonstrated in clinical trials 34. Additionally, phages help wounds heal, fight off bacterial biofilms, and have transplant-safe immunosuppressive qualities <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"TAo46BvT","properties":{"formattedCitation":"\\super 24\\nosupersub{}","plainCitation":"24","noteIndex":0},"citationItems":[{"id":1267,"uris":["http://zotero.org/users/11334842/items/5JEVQWSF"],"itemData":{"id":1267,"type":"article-journal","abstract":"Treatment of patients with a burn injury is a complex process involving multicomponent multidirectional intensive therapy of the majority of organs and systems damaged by thermal effects on the skin, alternating with repeated surgical interventions aimed at removing nonviable tissues with subsequent plastic closure of wound defects. After the recovery from the burn shock, local infectious complications are considered to be the leading problem that decelerates the process of recovery and is the main cause of lethal outcomes. Since the skin integrity is broken, microorganisms penetrate readily into the internal environment of the human organism resulting in a septic state with multiple organ failure. A widespread and often uncontrollable use of antibacterial drugs in medical practice has led to the emergence of multiple drug resistance (MDR) in microorganisms. Introduction of drugs made on the basis of bacteriophages into practice is presently becoming increasingly important. This is confirmed by the growing interest in this field of pharmacology, the development of special programs aimed at studying the processes of phage and bacterial cell interaction. This review presents the main types of bacteria pertaining to MDR pathogens, principles of their classification, and the risk factors for infecting patients. The mechanisms of the selective action of phage particles on a bacterial cell and the possibility of using phage therapy in the treatment of burn injury (experimental and clinical data) based on the analysis of foreign literature are demonstrated as well as new positive properties of phages related to the changes in the macroorganism immune status caused by the interaction with bacteriophage particles.","container-title":"Sovremennye Tekhnologii V Meditsine","DOI":"10.17691/stm2020.12.3.12","ISSN":"2309-995X","issue":"3","language":"eng","note":"section: 0","page":"95–103","title":"Application of Phagotherapy in the Treatment of Burn Patients (Review)","volume":"12","author":[{"family":"Leontyev","given":"А. E."},{"family":"Pavlenko","given":"I. V."},{"family":"Kovalishena","given":"О. V."},{"family":"Saperkin","given":"N. V."},{"family":"Tulupov","given":"А. А."},{"family":"Beschastnov","given":"V. V."}],"issued":{"date-parts":[["2021"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->24<!-- [if supportFields]><![endif]-->. The benefits of phage therapy include its efficacy against drug-resistant germs, selectivity, and lack of hazardous side effects <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"rVB1G7xE","properties":{"formattedCitation":"\\super 24\\nosupersub{}","plainCitation":"24","noteIndex":0},"citationItems":[{"id":1267,"uris":["http://zotero.org/users/11334842/items/5JEVQWSF"],"itemData":{"id":1267,"type":"article-journal","abstract":"Treatment of patients with a burn injury is a complex process involving multicomponent multidirectional intensive therapy of the majority of organs and systems damaged by thermal effects on the skin, alternating with repeated surgical interventions aimed at removing nonviable tissues with subsequent plastic closure of wound defects. After the recovery from the burn shock, local infectious complications are considered to be the leading problem that decelerates the process of recovery and is the main cause of lethal outcomes. Since the skin integrity is broken, microorganisms penetrate readily into the internal environment of the human organism resulting in a septic state with multiple organ failure. A widespread and often uncontrollable use of antibacterial drugs in medical practice has led to the emergence of multiple drug resistance (MDR) in microorganisms. Introduction of drugs made on the basis of bacteriophages into practice is presently becoming increasingly important. This is confirmed by the growing interest in this field of pharmacology, the development of special programs aimed at studying the processes of phage and bacterial cell interaction. This review presents the main types of bacteria pertaining to MDR pathogens, principles of their classification, and the risk factors for infecting patients. The mechanisms of the selective action of phage particles on a bacterial cell and the possibility of using phage therapy in the treatment of burn injury (experimental and clinical data) based on the analysis of foreign literature are demonstrated as well as new positive properties of phages related to the changes in the macroorganism immune status caused by the interaction with bacteriophage particles.","container-title":"Sovremennye Tekhnologii V Meditsine","DOI":"10.17691/stm2020.12.3.12","ISSN":"2309-995X","issue":"3","language":"eng","note":"section: 0","page":"95–103","title":"Application of Phagotherapy in the Treatment of Burn Patients (Review)","volume":"12","author":[{"family":"Leontyev","given":"А. E."},{"family":"Pavlenko","given":"I. V."},{"family":"Kovalishena","given":"О. V."},{"family":"Saperkin","given":"N. V."},{"family":"Tulupov","given":"А. А."},{"family":"Beschastnov","given":"V. V."}],"issued":{"date-parts":[["2021"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->24<!-- [if supportFields]><![endif]-->. Accurate agent identification, intracellular pathogen targeting, and routine phage efficacy monitoring present difficulties. Phage therapy offers a targeted and promising infection treatment strategy despite its difficulties <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"ofkVJl1U","properties":{"formattedCitation":"\\super 24\\nosupersub{}","plainCitation":"24","noteIndex":0},"citationItems":[{"id":1267,"uris":["http://zotero.org/users/11334842/items/5JEVQWSF"],"itemData":{"id":1267,"type":"article-journal","abstract":"Treatment of patients with a burn injury is a complex process involving multicomponent multidirectional intensive therapy of the majority of organs and systems damaged by thermal effects on the skin, alternating with repeated surgical interventions aimed at removing nonviable tissues with subsequent plastic closure of wound defects. After the recovery from the burn shock, local infectious complications are considered to be the leading problem that decelerates the process of recovery and is the main cause of lethal outcomes. Since the skin integrity is broken, microorganisms penetrate readily into the internal environment of the human organism resulting in a septic state with multiple organ failure. A widespread and often uncontrollable use of antibacterial drugs in medical practice has led to the emergence of multiple drug resistance (MDR) in microorganisms. Introduction of drugs made on the basis of bacteriophages into practice is presently becoming increasingly important. This is confirmed by the growing interest in this field of pharmacology, the development of special programs aimed at studying the processes of phage and bacterial cell interaction. This review presents the main types of bacteria pertaining to MDR pathogens, principles of their classification, and the risk factors for infecting patients. The mechanisms of the selective action of phage particles on a bacterial cell and the possibility of using phage therapy in the treatment of burn injury (experimental and clinical data) based on the analysis of foreign literature are demonstrated as well as new positive properties of phages related to the changes in the macroorganism immune status caused by the interaction with bacteriophage particles.","container-title":"Sovremennye Tekhnologii V Meditsine","DOI":"10.17691/stm2020.12.3.12","ISSN":"2309-995X","issue":"3","language":"eng","note":"section: 0","page":"95–103","title":"Application of Phagotherapy in the Treatment of Burn Patients (Review)","volume":"12","author":[{"family":"Leontyev","given":"А. E."},{"family":"Pavlenko","given":"I. V."},{"family":"Kovalishena","given":"О. V."},{"family":"Saperkin","given":"N. V."},{"family":"Tulupov","given":"А. А."},{"family":"Beschastnov","given":"V. V."}],"issued":{"date-parts":[["2021"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->24<!-- [if supportFields]><![endif]-->. Support of Normal Flora Diversity The gut microbiome is significantly impacted by phage therapy. Phages support microbial diversity and guard gut mucosal surfaces <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"dEnbTEFt","properties":{"formattedCitation":"\\super 25\\nosupersub{}","plainCitation":"25","noteIndex":0},"citationItems":[{"id":1193,"uris":["http://zotero.org/users/11334842/items/PPF6G9HN"],"itemData":{"id":1193,"type":"article-journal","abstract":"The emergence and spread of antibiotic-resistant bacteria constitute a critical issue for modern medicine. Patients with antibiotic-resistant bacterial infections consume more healthcare resources and have worse clinical outcomes than patients with antibiotic-sensitive bacterial infections. Phages are natural predators of bacteria and may therefore be a source of useful antibacterial drugs. Phage therapy possess availability for oral administration, penetration through the bacteria cell wall, and eradication bacterial biofilms. All of these advantages give phage therapy the possibility to turn into applications for infectious diseases. In this mini-review, we focus on the brief history of lytic phage therapy, the life cycles of lytic phages and the therapeutic effects of lytic phages.","container-title":"Microbial Pathogenesis","DOI":"10.1016/j.micpath.2020.104048","ISSN":"1096-1208","language":"eng","note":"section: 0","page":"104048","title":"Therapeutic applications of lytic phages in human medicine","volume":"142","author":[{"family":"Guo","given":"Zhimin"},{"family":"Lin","given":"Hua"},{"family":"Ji","given":"Xufeng"},{"family":"Yan","given":"Guangmou"},{"family":"Lei","given":"Liancheng"},{"family":"Han","given":"Wenyu"},{"family":"Gu","given":"Jingmin"},{"family":"Huang","given":"Jing"}],"issued":{"date-parts":[["2020",2]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->25<!-- [if supportFields]><![endif]-->. They can target problematic bacteria without disrupting the normal microbiome thanks to their restricted spectrum. According to research, phages may have an impact on diseases like diabetes and inflammatory bowel disease <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"tiUiZipC","properties":{"formattedCitation":"\\super 25\\nosupersub{}","plainCitation":"25","noteIndex":0},"citationItems":[{"id":1193,"uris":["http://zotero.org/users/11334842/items/PPF6G9HN"],"itemData":{"id":1193,"type":"article-journal","abstract":"The emergence and spread of antibiotic-resistant bacteria constitute a critical issue for modern medicine. Patients with antibiotic-resistant bacterial infections consume more healthcare resources and have worse clinical outcomes than patients with antibiotic-sensitive bacterial infections. Phages are natural predators of bacteria and may therefore be a source of useful antibacterial drugs. Phage therapy possess availability for oral administration, penetration through the bacteria cell wall, and eradication bacterial biofilms. All of these advantages give phage therapy the possibility to turn into applications for infectious diseases. In this mini-review, we focus on the brief history of lytic phage therapy, the life cycles of lytic phages and the therapeutic effects of lytic phages.","container-title":"Microbial Pathogenesis","DOI":"10.1016/j.micpath.2020.104048","ISSN":"1096-1208","language":"eng","note":"section: 0","page":"104048","title":"Therapeutic applications of lytic phages in human medicine","volume":"142","author":[{"family":"Guo","given":"Zhimin"},{"family":"Lin","given":"Hua"},{"family":"Ji","given":"Xufeng"},{"family":"Yan","given":"Guangmou"},{"family":"Lei","given":"Liancheng"},{"family":"Han","given":"Wenyu"},{"family":"Gu","given":"Jingmin"},{"family":"Huang","given":"Jing"}],"issued":{"date-parts":[["2020",2]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->25<!-- [if supportFields]><![endif]-->. However, it is unclear how they play a part in disease pathways. The effectiveness of fecal microbiota transplantation for illnesses like Clostridium difficile infection also appears to be influenced by phages <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"afXEjPh4","properties":{"formattedCitation":"\\super 25\\nosupersub{}","plainCitation":"25","noteIndex":0},"citationItems":[{"id":1193,"uris":["http://zotero.org/users/11334842/items/PPF6G9HN"],"itemData":{"id":1193,"type":"article-journal","abstract":"The emergence and spread of antibiotic-resistant bacteria constitute a critical issue for modern medicine. Patients with antibiotic-resistant bacterial infections consume more healthcare resources and have worse clinical outcomes than patients with antibiotic-sensitive bacterial infections. Phages are natural predators of bacteria and may therefore be a source of useful antibacterial drugs. Phage therapy possess availability for oral administration, penetration through the bacteria cell wall, and eradication bacterial biofilms. All of these advantages give phage therapy the possibility to turn into applications for infectious diseases. In this mini-review, we focus on the brief history of lytic phage therapy, the life cycles of lytic phages and the therapeutic effects of lytic phages.","container-title":"Microbial Pathogenesis","DOI":"10.1016/j.micpath.2020.104048","ISSN":"1096-1208","language":"eng","note":"section: 0","page":"104048","title":"Therapeutic applications of lytic phages in human medicine","volume":"142","author":[{"family":"Guo","given":"Zhimin"},{"family":"Lin","given":"Hua"},{"family":"Ji","given":"Xufeng"},{"family":"Yan","given":"Guangmou"},{"family":"Lei","given":"Liancheng"},{"family":"Han","given":"Wenyu"},{"family":"Gu","given":"Jingmin"},{"family":"Huang","given":"Jing"}],"issued":{"date-parts":[["2020",2]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->25<!-- [if supportFields]><![endif]-->. Phage therapy's effects on the gut flora and potential health advantages require further study <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"J9lS0I8e","properties":{"formattedCitation":"\\super 25\\nosupersub{}","plainCitation":"25","noteIndex":0},"citationItems":[{"id":1193,"uris":["http://zotero.org/users/11334842/items/PPF6G9HN"],"itemData":{"id":1193,"type":"article-journal","abstract":"The emergence and spread of antibiotic-resistant bacteria constitute a critical issue for modern medicine. Patients with antibiotic-resistant bacterial infections consume more healthcare resources and have worse clinical outcomes than patients with antibiotic-sensitive bacterial infections. Phages are natural predators of bacteria and may therefore be a source of useful antibacterial drugs. Phage therapy possess availability for oral administration, penetration through the bacteria cell wall, and eradication bacterial biofilms. All of these advantages give phage therapy the possibility to turn into applications for infectious diseases. In this mini-review, we focus on the brief history of lytic phage therapy, the life cycles of lytic phages and the therapeutic effects of lytic phages.","container-title":"Microbial Pathogenesis","DOI":"10.1016/j.micpath.2020.104048","ISSN":"1096-1208","language":"eng","note":"section: 0","page":"104048","title":"Therapeutic applications of lytic phages in human medicine","volume":"142","author":[{"family":"Guo","given":"Zhimin"},{"family":"Lin","given":"Hua"},{"family":"Ji","given":"Xufeng"},{"family":"Yan","given":"Guangmou"},{"family":"Lei","given":"Liancheng"},{"family":"Han","given":"Wenyu"},{"family":"Gu","given":"Jingmin"},{"family":"Huang","given":"Jing"}],"issued":{"date-parts":[["2020",2]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->25<!-- [if supportFields]><![endif]-->. Effective Prototypes Modified S. carnosus phages, from an avirulent strain containing none of the virulence genes of S. aureus phages that could compromise the safe production of phages for therapeutic use, showed a wide host range, with rapid killing, high efficiency in reducing the formation of biofilms, and the prevention of appearance of resistant mutants, with only a small initiating dose required <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"pNxvMTXk","properties":{"formattedCitation":"\\super 26\\nosupersub{}","plainCitation":"26","noteIndex":0},"citationItems":[{"id":1328,"uris":["http://zotero.org/users/11334842/items/9DSUL93H"],"itemData":{"id":1328,"type":"article-journal","abstract":"Phage therapy recently passed a key milestone with success of the first regulated clinical trial using systemic administration. In this single-arm non-comparative safety study, phages were administered intravenously to patients with invasive Staphylococcus aureus infections with no adverse reactions reported. Here, we examined features of 78 lytic S. aureus phages, most of which were propagated using a S. carnosus host modified to be broadly susceptible to staphylococcal phage infection. Use of this host eliminates the threat of contamination with staphylococcal prophage — the main vector of S. aureus horizontal gene transfer. We determined the host range of these phages against an international collection of 185 S. aureus isolates with 56 different multilocus sequence types that included multiple representatives of all epidemic MRSA and MSSA clonal complexes. Forty of our 78 phages were able to infect > 90% of study isolates, 15 were able to infect > 95%, and two could infect all 184 clinical isolates, but not a phage-resistant mutant generated in a previous study. We selected the 10 phages with the widest host range for in vitro characterization by planktonic culture time-kill analysis against four isolates:- modified S. carnosus strain TM300H, methicillin-sensitive isolates D329 and 15981, and MRSA isolate 252. Six of these 10 phages were able to rapidly kill, reducing cell numbers of at least three isolates. The four best-performing phages, in this assay, were further shown to be highly effective in reducing 48 h biofilms on polystyrene formed by eight ST22 and eight ST36 MRSA isolates. Genomes of 22 of the widest host-range phages showed they belonged to the Twortvirinae subfamily of the order Caudovirales in three main groups corresponding to Silviavirus, and two distinct groups of Kayvirus. These genomes assembled as single-linear dsDNAs with an average length of 140 kb and a GC content of c. 30%. Phages that could infect > 96% of S. aureus isolates were found in all three groups, and these have great potential as therapeutic candidates if, in future studies, they can be formulated to maximize their efficacy and eliminate emergence of phage resistance by using appropriate combinations.","container-title":"Frontiers in Cellular and Infection Microbiology","ISSN":"2235-2988","source":"Frontiers","title":"Phenotypic and Genotypic Characterization of Novel Polyvalent Bacteriophages With Potent In Vitro Activity Against an International Collection of Genetically Diverse Staphylococcus aureus","URL":"https://www.frontiersin.org/articles/10.3389/fcimb.2021.698909","volume":"11","author":[{"family":"Whittard","given":"Elliot"},{"family":"Redfern","given":"James"},{"family":"Xia","given":"Guoqing"},{"family":"Millard","given":"Andrew"},{"family":"Ragupathy","given":"Roobinidevi"},{"family":"Malic","given":"Sladjana"},{"family":"Enright","given":"Mark C."}],"accessed":{"date-parts":[["2023",12,6]]},"issued":{"date-parts":[["2021"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->26<!-- [if supportFields]><![endif]-->. Isolated lytic MRSA bacteriophages were shown to have wide host ranges, wide range of temperature, pH and still active at 2.5 kGy doses of gamma radiation, and forcing the MRSA strains to be sensitive after combination with vancomycin and erythromycin <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"jto9qUvq","properties":{"formattedCitation":"\\super 27\\nosupersub{}","plainCitation":"27","noteIndex":0},"citationItems":[{"id":1326,"uris":["http://zotero.org/users/11334842/items/A86J78IU"],"itemData":{"id":1326,"type":"article-journal","abstract":"Although skin infections are usually uncomplicated, it may indicate systemic disease or lead to life-threatening systemic infections. Staphylococcus aureus is the most common cause of skin infections. Treatment is complicated by continuous emergence of resistant S. aureus especially methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant S. aureus (VRSA). Therefore, searching for new alternatives is essential to combat this escalating antibiotic resistance. Bacteriophage therapy is a promising solution in the post antibiotic area. Bacteriophage therapy confers safety and higher rate of success. In the present study, 10 bacteriophages (belonging to the family Siphoviridae and Myoviridae) were isolated with lytic activity against MRSA &VRSA isolated from skin infections. The strongest six of ten phages were characterized morphologically by a JOEL_JEM_1010 electron microscope, physically through evaluating their lytic activity against wide ranges of temperature (35–95° C), PH (3–10) and radiation doses (0.5–2.5kGy) and biologically by evaluating their host ranges and phage longevity (1–120 day) in vitro. Finally, the anti-Staphylococcal effect of the isolated bacteriophages was tested and revealed that they have alone activity (10, 12) and synergistic activity with vancomycin and erythromycin by increasing their inhibition zone diameters (16, 22) mm, respectively.","container-title":"Journal of Radiation Research and Applied Sciences","DOI":"10.1080/16878507.2020.1795564","ISSN":"1687-8507","issue":"1","journalAbbreviation":"Journal of Radiation Research and Applied Sciences","page":"34-43","source":"ScienceDirect","title":"Isolation and characterization of six gamma-irradiated bacteriophages specific for MRSA and VRSA isolated from skin infections","volume":"14","author":[{"family":"Mahmoud","given":"Eman Rashad Ahmed"},{"family":"Ahmed","given":"Hala Ahmed Hussein"},{"family":"Abo-senna","given":"Amal Saeid Mohamad"},{"family":"Riad","given":"Omnia Karem M."},{"family":"Abo- Shadi","given":"Maha Mohamad Abd Al – Rahman"}],"issued":{"date-parts":[["2021",12,1]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->27<!-- [if supportFields]><![endif]-->. Part III: Disadvantages and Ease of Phage Utilization The limitations of phage treatment can be broken down into three main categories: the effect of the phage's special qualities, the absence of suitable regulations, and standards, and the challenges with clinical applications <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"oBqTn7rq","properties":{"formattedCitation":"\\super 24\\nosupersub{}","plainCitation":"24","noteIndex":0},"citationItems":[{"id":1267,"uris":["http://zotero.org/users/11334842/items/5JEVQWSF"],"itemData":{"id":1267,"type":"article-journal","abstract":"Treatment of patients with a burn injury is a complex process involving multicomponent multidirectional intensive therapy of the majority of organs and systems damaged by thermal effects on the skin, alternating with repeated surgical interventions aimed at removing nonviable tissues with subsequent plastic closure of wound defects. After the recovery from the burn shock, local infectious complications are considered to be the leading problem that decelerates the process of recovery and is the main cause of lethal outcomes. Since the skin integrity is broken, microorganisms penetrate readily into the internal environment of the human organism resulting in a septic state with multiple organ failure. A widespread and often uncontrollable use of antibacterial drugs in medical practice has led to the emergence of multiple drug resistance (MDR) in microorganisms. Introduction of drugs made on the basis of bacteriophages into practice is presently becoming increasingly important. This is confirmed by the growing interest in this field of pharmacology, the development of special programs aimed at studying the processes of phage and bacterial cell interaction. This review presents the main types of bacteria pertaining to MDR pathogens, principles of their classification, and the risk factors for infecting patients. The mechanisms of the selective action of phage particles on a bacterial cell and the possibility of using phage therapy in the treatment of burn injury (experimental and clinical data) based on the analysis of foreign literature are demonstrated as well as new positive properties of phages related to the changes in the macroorganism immune status caused by the interaction with bacteriophage particles.","container-title":"Sovremennye Tekhnologii V Meditsine","DOI":"10.17691/stm2020.12.3.12","ISSN":"2309-995X","issue":"3","language":"eng","note":"section: 0","page":"95–103","title":"Application of Phagotherapy in the Treatment of Burn Patients (Review)","volume":"12","author":[{"family":"Leontyev","given":"А. E."},{"family":"Pavlenko","given":"I. V."},{"family":"Kovalishena","given":"О. V."},{"family":"Saperkin","given":"N. V."},{"family":"Tulupov","given":"А. А."},{"family":"Beschastnov","given":"V. V."}],"issued":{"date-parts":[["2021"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->24<!-- [if supportFields]><![endif]-->. An ideal bacteriophage for therapeutic use should have good environmental adaptability and stability, be devoid of endotoxin genes in the genome, be easy to separate from other bacteriophages and to purify, and not harm the host 34. Lack of Adequate Research Despite the benefits of bacteriophage use, we still need to combat several difficulties to unlock their full potential. Clinical research and protocols for administration, dosage, frequency, and treatment duration are often lacking so far <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"BuvwwEji","properties":{"formattedCitation":"\\super 3\\nosupersub{}","plainCitation":"3","noteIndex":0},"citationItems":[{"id":1119,"uris":["http://zotero.org/users/11334842/items/V6FI3YDR"],"itemData":{"id":1119,"type":"article-journal","abstract":"Globally, the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) are the major cause of nosocomial infections. These pathogens are multidrug resistant, and their negative impacts have brought serious health challenges and economic burden on many countries worldwide. Thus, this narrative review exploits different emerging alternative therapeutic strategies including combination antibiotics, antimicrobial peptides ((AMPs), bacteriophage and photodynamic therapies used in the treatment of the ESKAPE pathogens, their merits, limitations, and future prospects. Our findings indicate that ESKAPE pathogens exhibit resistance to drug using different mechanisms including drug inactivation by irreversible enzyme cleavage, drug-binding site alteration, diminution in permeability of drug or drug efflux increment to reduce accumulation of drug as well as biofilms production. However, the scientific community has shown significant interest in using these novel strategies with numerous benefits although they have some limitations including but not limited to instability and toxicity of the therapeutic agents, or the host developing immune response against the therapeutic agents. Thus, comprehension of resistance mechanisms of these pathogens is necessary to further develop or modify these approaches in order to overcome these health challenges including the barriers of bacterial resistance.","container-title":"Microbial Pathogenesis","DOI":"10.1016/j.micpath.2022.105963","ISSN":"1096-1208","language":"eng","note":"section: 0","page":"105963","title":"Coping with the ESKAPE pathogens: Evolving strategies, challenges and future prospects","volume":"175","author":[{"family":"Aloke","given":"Chinyere"},{"family":"Achilonu","given":"Ikechukwu"}],"issued":{"date-parts":[["2023",2]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->3<!-- [if supportFields]><![endif]-->. The number of clinical trials assessing the safety and indications of phage therapy in humans is very limited, and those that have occurred have involved small sample sizes and have relied on data generated by patients <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"VZ95Rpmx","properties":{"formattedCitation":"\\super 9\\nosupersub{}","plainCitation":"9","noteIndex":0},"citationItems":[{"id":1215,"uris":["http://zotero.org/users/11334842/items/KRHR9D2P"],"itemData":{"id":1215,"type":"article-journal","abstract":"Klebsiella spp. are commensals of the human microbiota, and a leading cause of opportunistic nosocomial infections. The incidence of multidrug resistant (MDR) strains of Klebsiella pneumoniae causing serious infections is increasing, and Klebsiella oxytoca is an emerging pathogen. Alternative strategies to tackle infections caused by these bacteria are required as strains become resistant to last-resort antibiotics such as colistin. Bacteriophages (phages) are viruses that can infect and kill bacteria. They and their gene products are now being considered as alternatives or adjuncts to antimicrobial therapies. Several in vitro and in vivo studies have shown the potential for lytic phages to combat MDR K. pneumoniae infections. Ready access to cheap sequencing technologies has led to a large increase in the number of genomes available for Klebsiella-infecting phages, with these phages being heterogeneous at the whole-genome level. This review summarizes our current knowledge on phages of Klebsiella spp. and highlights technological and biological issues relevant to the development of phage-based therapies targeting these bacteria.","container-title":"Journal of Medical Microbiology","DOI":"10.1099/jmm.0.001141","ISSN":"1473-5644","issue":"2","language":"eng","note":"section: 0","page":"176–194","title":"Bacteriophages of Klebsiella spp., their diversity and potential therapeutic uses","volume":"69","author":[{"family":"Herridge","given":"Warren P."},{"family":"Shibu","given":"Preetha"},{"family":"O'Shea","given":"Jessica"},{"family":"Brook","given":"Thomas C."},{"family":"Hoyles","given":"Lesley"}],"issued":{"date-parts":[["2020",2]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->9<!-- [if supportFields]><![endif]-->. The lack of appropriate legal and regulatory frameworks poses a significant challenge to integrating phage therapy into conventional medicine <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"MnG9SWQx","properties":{"formattedCitation":"\\super 3\\nosupersub{}","plainCitation":"3","noteIndex":0},"citationItems":[{"id":1119,"uris":["http://zotero.org/users/11334842/items/V6FI3YDR"],"itemData":{"id":1119,"type":"article-journal","abstract":"Globally, the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) are the major cause of nosocomial infections. These pathogens are multidrug resistant, and their negative impacts have brought serious health challenges and economic burden on many countries worldwide. Thus, this narrative review exploits different emerging alternative therapeutic strategies including combination antibiotics, antimicrobial peptides ((AMPs), bacteriophage and photodynamic therapies used in the treatment of the ESKAPE pathogens, their merits, limitations, and future prospects. Our findings indicate that ESKAPE pathogens exhibit resistance to drug using different mechanisms including drug inactivation by irreversible enzyme cleavage, drug-binding site alteration, diminution in permeability of drug or drug efflux increment to reduce accumulation of drug as well as biofilms production. However, the scientific community has shown significant interest in using these novel strategies with numerous benefits although they have some limitations including but not limited to instability and toxicity of the therapeutic agents, or the host developing immune response against the therapeutic agents. Thus, comprehension of resistance mechanisms of these pathogens is necessary to further develop or modify these approaches in order to overcome these health challenges including the barriers of bacterial resistance.","container-title":"Microbial Pathogenesis","DOI":"10.1016/j.micpath.2022.105963","ISSN":"1096-1208","language":"eng","note":"section: 0","page":"105963","title":"Coping with the ESKAPE pathogens: Evolving strategies, challenges and future prospects","volume":"175","author":[{"family":"Aloke","given":"Chinyere"},{"family":"Achilonu","given":"Ikechukwu"}],"issued":{"date-parts":[["2023",2]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->3<!-- [if supportFields]><![endif]-->. Side Effects Antibiotics are known to have many side effects, but these effects are known, unlike those related to phage treatment <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"1YrqONeN","properties":{"formattedCitation":"\\super 19\\nosupersub{}","plainCitation":"19","noteIndex":0},"citationItems":[{"id":1143,"uris":["http://zotero.org/users/11334842/items/YD3LKXA9"],"itemData":{"id":1143,"type":"article-journal","abstract":"Bacteriophages (simply referred to as Phages) are a class of viruses with the ability to infect and kill prokaryotic cells (bacteria), but are unable to infect mammalian cells. This unique ability to achieve specific infectiousness by bacteriophages has been harnessed in antibacterial treatments dating back almost a decade before the antibiotic era began. Bacteriophages were used as therapeutic agents in treatment of dysentery caused by Shigella dysenteriae as far back as 1919 and in the experimental treatment of a wide variety of other bacterial infections caused by Vibrio cholerae, Staphylococcus sp., Pseudomonas sp. etc, with varying degrees of success. Phage therapy and its many prospects soon fell out of favour in western medicine after the Second World War, with the discovery of penicillin. The Soviet Union and other countries in Eastern Europe however mastered the craft of bacteriophage isolation, purification and cocktail preparation, with phage-based therapeutics becoming widely available over-the-counter. With the recent rise in cases of multi-drug resistant bacterial infections, the clamour for a return to phage therapy, as a potential solution to the anti-microbial resistance (AMR) crisis has grown louder. This review provides an extensive exposé on phage therapy, addressing its historical use, evidences of its safety and efficacy, its pros and cons when compared with antibiotics, cases of compassionate use for treating life-threatening antibiotic-resistant infections, the limitations to its acceptance and how these may be circumvented.","container-title":"AIMS microbiology","DOI":"10.3934/microbiol.2020014","ISSN":"2471-1888","issue":"3","language":"eng","note":"section: 0","page":"204–230","title":"An exegesis of bacteriophage therapy: An emerging player in the fight against anti-microbial resistance","volume":"6","author":[{"family":"Adesanya","given":"Oluwafolajimi"},{"family":"Oduselu","given":"Tolulope"},{"family":"Akin-Ajani","given":"Oluwawapelumi"},{"family":"Adewumi","given":"Olubusuyi M."},{"family":"Ademowo","given":"Olusegun G."}],"issued":{"date-parts":[["2020"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->19<!-- [if supportFields]><![endif]-->. One very important hazard with phages is the risk of anaphylaxis due to the innate ability as viruses to induce an immune reaction <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"LWQjzU8G","properties":{"formattedCitation":"\\super 28\\nosupersub{}","plainCitation":"28","noteIndex":0},"citationItems":[{"id":1177,"uris":["http://zotero.org/users/11334842/items/3SDA35CL"],"itemData":{"id":1177,"type":"article-journal","abstract":"Staphylococcus aureus is a pathogen commonly found in nosocomial environments where infections can easily spread - especially given the reduced immune response of patients and large overlap between personnel in charge of their care. Although antibiotics are available to treat nosocomial infections, the increased occurrence of antibiotic resistance has rendered many treatments ineffective. Such is the case for methicillin resistant S. aureus (MRSA), which has continued to be a threat to public health since its emergence. For this reason, alternative treatment technologies utilizing antimicrobials such as bacteriocins, bacteriophages (phages) and phage endolysins are being developed. These antimicrobials provide an advantage over antibiotics in that many have narrow inhibition spectra, enabling treatments to be selected based on the target (pathogenic) bacterium while allowing for survival of commensal bacteria and thus avoiding collateral damage to the microbiome. Bacterial resistance to these treatments occurs less frequently than with antibiotics, particularly in circumstances where combinatory antimicrobial therapies are used. Phage therapy has been well established in Eastern Europe as an effective treatment against bacterial infections. While there are no Randomized Clinical Trials (RCTs) to our knowledge examining phage treatment of S. aureus infections that have completed all trial phases, numerous clinical trials are underway, and several commercial phage preparations are currently available to treat S. aureus infections. Bacteriocins have primarily been used in the food industry for bio-preservation applications. However, the idea of repurposing bacteriocins for human health is an attractive one considering their efficacy against many bacterial pathogens. There are concerns about the ability of bacteriocins to survive the gastrointestinal tract given their proteinaceous nature, however, this obstacle may be overcome by altering the administration route of the therapy through encapsulation, or by bioengineering protease-resistant variants. Obstacles such as enzymatic digestion are less of an issue for topical/local administration, for example, application to the surface of the skin. Bacteriocins have also shown impressive synergistic effects when used in conjunction with other antimicrobials, including antibiotics, which may allow antibiotic-based therapies to be used more sparingly with less resistance development. This review provides an updated account of known bacteriocins, phages and phage endolysins which have demonstrated an impressive ability to kill S. aureus strains. In particular, examples of antimicrobials with the ability to target MRSA strains and their subsequent use in a clinical setting are outlined.","container-title":"Frontiers in Molecular Biosciences","DOI":"10.3389/fmolb.2021.654038","ISSN":"2296-889X","language":"eng","note":"section: 0","page":"654038","title":"Efficacy of Phage- and Bacteriocin-Based Therapies in Combatting Nosocomial MRSA Infections","volume":"8","author":[{"family":"Walsh","given":"Lauren"},{"family":"Johnson","given":"Crystal N."},{"family":"Hill","given":"Colin"},{"family":"Ross","given":"R. Paul"}],"issued":{"date-parts":[["2021"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->28<!-- [if supportFields]><![endif]-->. Viruses themselves can directly affect the immune system, triggering innate and adaptive responses <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"LJ72QUGV","properties":{"formattedCitation":"\\super 22\\nosupersub{}","plainCitation":"22","noteIndex":0},"citationItems":[{"id":1229,"uris":["http://zotero.org/users/11334842/items/S76547XD"],"itemData":{"id":1229,"type":"article-journal","abstract":"Increasing rates of infection by antibiotic resistant bacteria have led to a resurgence of interest in bacteriophage (phage) therapy. Several phage therapy studies in animals and humans have been completed over the last two decades. We conducted a systematic review of safety and toxicity data associated with phage therapy in both animals and humans reported in English language publications from 2008-2021. Overall, 69 publications met our eligibility criteria including 20 animal studies, 35 clinical case reports or case series, and 14 clinical trials. After summarizing safety and toxicity data from these publications, we discuss potential approaches to optimize safety and toxicity monitoring with the therapeutic use of phage moving forward. In our systematic review of the literature, we found some adverse events associated with phage therapy, but serious events were extremely rare. Comprehensive and standardized reporting of potential toxicities associated with phage therapy has generally been lacking in the published literature. Structured safety and tolerability endpoints are necessary when phages are administered as anti-infective therapeutics.","container-title":"Viruses","DOI":"10.3390/v13071268","ISSN":"1999-4915","issue":"7","language":"eng","note":"section: 0","page":"1268","title":"The Safety and Toxicity of Phage Therapy: A Review of Animal and Clinical Studies","volume":"13","author":[{"family":"Liu","given":"Dan"},{"family":"Van Belleghem","given":"Jonas D."},{"family":"Vries","given":"Christiaan R.","non-dropping-particle":"de"},{"family":"Burgener","given":"Elizabeth"},{"family":"Chen","given":"Qingquan"},{"family":"Manasherob","given":"Robert"},{"family":"Aronson","given":"Jenny R."},{"family":"Amanatullah","given":"Derek F."},{"family":"Tamma","given":"Pranita D."},{"family":"Suh","given":"Gina A."}],"issued":{"date-parts":[["2021",6]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->22<!-- [if supportFields]><![endif]-->. In addition, emergence of phage-neutralizing antibodies could hinder their effectiveness, as observed in some cases after parenteral administration <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"QYuXS81e","properties":{"formattedCitation":"\\super 3\\nosupersub{}","plainCitation":"3","noteIndex":0},"citationItems":[{"id":1119,"uris":["http://zotero.org/users/11334842/items/V6FI3YDR"],"itemData":{"id":1119,"type":"article-journal","abstract":"Globally, the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) are the major cause of nosocomial infections. These pathogens are multidrug resistant, and their negative impacts have brought serious health challenges and economic burden on many countries worldwide. Thus, this narrative review exploits different emerging alternative therapeutic strategies including combination antibiotics, antimicrobial peptides ((AMPs), bacteriophage and photodynamic therapies used in the treatment of the ESKAPE pathogens, their merits, limitations, and future prospects. Our findings indicate that ESKAPE pathogens exhibit resistance to drug using different mechanisms including drug inactivation by irreversible enzyme cleavage, drug-binding site alteration, diminution in permeability of drug or drug efflux increment to reduce accumulation of drug as well as biofilms production. However, the scientific community has shown significant interest in using these novel strategies with numerous benefits although they have some limitations including but not limited to instability and toxicity of the therapeutic agents, or the host developing immune response against the therapeutic agents. Thus, comprehension of resistance mechanisms of these pathogens is necessary to further develop or modify these approaches in order to overcome these health challenges including the barriers of bacterial resistance.","container-title":"Microbial Pathogenesis","DOI":"10.1016/j.micpath.2022.105963","ISSN":"1096-1208","language":"eng","note":"section: 0","page":"105963","title":"Coping with the ESKAPE pathogens: Evolving strategies, challenges and future prospects","volume":"175","author":[{"family":"Aloke","given":"Chinyere"},{"family":"Achilonu","given":"Ikechukwu"}],"issued":{"date-parts":[["2023",2]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->3<!-- [if supportFields]><![endif]-->. Other studies find the implications for such outcomes ambiguous <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"NplZ9gEN","properties":{"formattedCitation":"\\super 21\\nosupersub{}","plainCitation":"21","noteIndex":0},"citationItems":[{"id":1121,"uris":["http://zotero.org/users/11334842/items/3UF62TYT"],"itemData":{"id":1121,"type":"article-journal","abstract":"Antibiotic therapy has become increasingly ineffective against bacterial infections due to the rise of resistance. In particular, ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) have caused life-threatening infections in humans and represent a major global health threat due to a high degree of antibiotic resistance. To respond to this urgent call, novel strategies are urgently needed, such as bacteriophages (or phages), phage-encoded enzymes, immunomodulators and monoclonal antibodies. This review critically analyses these promising antimicrobial therapies for the treatment of multidrug-resistant bacterial infections. Recent advances in these novel therapeutic strategies are discussed, focusing on preclinical and clinical investigations, as well as combinatorial approaches. In this 'Bad Bugs, No Drugs' era, novel therapeutic strategies can play a key role in treating deadly infections and help extend the lifetime of antibiotics.","container-title":"Advanced Drug Delivery Reviews","DOI":"10.1016/j.addr.2022.114378","ISSN":"1872-8294","language":"eng","note":"section: 0","page":"114378","title":"Novel antimicrobial agents for combating antibiotic-resistant bacteria","volume":"187","author":[{"family":"Chang","given":"Rachel Yoon Kyung"},{"family":"Nang","given":"Sue C."},{"family":"Chan","given":"Hak-Kim"},{"family":"Li","given":"Jian"}],"issued":{"date-parts":[["2022",8]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->21<!-- [if supportFields]><![endif]-->. Besides, phage therapy can increase intestinal permeability and induce intestinal barrier dysfunction. Safety concerns in immunocompromised patients remain, but available literature suggests that phage therapy may be safe and effective for this population <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"jkt8lrsQ","properties":{"formattedCitation":"\\super 19\\nosupersub{}","plainCitation":"19","noteIndex":0},"citationItems":[{"id":1143,"uris":["http://zotero.org/users/11334842/items/YD3LKXA9"],"itemData":{"id":1143,"type":"article-journal","abstract":"Bacteriophages (simply referred to as Phages) are a class of viruses with the ability to infect and kill prokaryotic cells (bacteria), but are unable to infect mammalian cells. This unique ability to achieve specific infectiousness by bacteriophages has been harnessed in antibacterial treatments dating back almost a decade before the antibiotic era began. Bacteriophages were used as therapeutic agents in treatment of dysentery caused by Shigella dysenteriae as far back as 1919 and in the experimental treatment of a wide variety of other bacterial infections caused by Vibrio cholerae, Staphylococcus sp., Pseudomonas sp. etc, with varying degrees of success. Phage therapy and its many prospects soon fell out of favour in western medicine after the Second World War, with the discovery of penicillin. The Soviet Union and other countries in Eastern Europe however mastered the craft of bacteriophage isolation, purification and cocktail preparation, with phage-based therapeutics becoming widely available over-the-counter. With the recent rise in cases of multi-drug resistant bacterial infections, the clamour for a return to phage therapy, as a potential solution to the anti-microbial resistance (AMR) crisis has grown louder. This review provides an extensive exposé on phage therapy, addressing its historical use, evidences of its safety and efficacy, its pros and cons when compared with antibiotics, cases of compassionate use for treating life-threatening antibiotic-resistant infections, the limitations to its acceptance and how these may be circumvented.","container-title":"AIMS microbiology","DOI":"10.3934/microbiol.2020014","ISSN":"2471-1888","issue":"3","language":"eng","note":"section: 0","page":"204–230","title":"An exegesis of bacteriophage therapy: An emerging player in the fight against anti-microbial resistance","volume":"6","author":[{"family":"Adesanya","given":"Oluwafolajimi"},{"family":"Oduselu","given":"Tolulope"},{"family":"Akin-Ajani","given":"Oluwawapelumi"},{"family":"Adewumi","given":"Olubusuyi M."},{"family":"Ademowo","given":"Olusegun G."}],"issued":{"date-parts":[["2020"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->19<!-- [if supportFields]><![endif]-->. Furthermore, phage-induced bacterial lysis can result in a rapid release of endotoxins, which may result in inflammatory reactions. It's crucial to keep track of the microorganisms present in phage preparations <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"BHhnuvbf","properties":{"formattedCitation":"\\super 22\\nosupersub{}","plainCitation":"22","noteIndex":0},"citationItems":[{"id":1229,"uris":["http://zotero.org/users/11334842/items/S76547XD"],"itemData":{"id":1229,"type":"article-journal","abstract":"Increasing rates of infection by antibiotic resistant bacteria have led to a resurgence of interest in bacteriophage (phage) therapy. Several phage therapy studies in animals and humans have been completed over the last two decades. We conducted a systematic review of safety and toxicity data associated with phage therapy in both animals and humans reported in English language publications from 2008-2021. Overall, 69 publications met our eligibility criteria including 20 animal studies, 35 clinical case reports or case series, and 14 clinical trials. After summarizing safety and toxicity data from these publications, we discuss potential approaches to optimize safety and toxicity monitoring with the therapeutic use of phage moving forward. In our systematic review of the literature, we found some adverse events associated with phage therapy, but serious events were extremely rare. Comprehensive and standardized reporting of potential toxicities associated with phage therapy has generally been lacking in the published literature. Structured safety and tolerability endpoints are necessary when phages are administered as anti-infective therapeutics.","container-title":"Viruses","DOI":"10.3390/v13071268","ISSN":"1999-4915","issue":"7","language":"eng","note":"section: 0","page":"1268","title":"The Safety and Toxicity of Phage Therapy: A Review of Animal and Clinical Studies","volume":"13","author":[{"family":"Liu","given":"Dan"},{"family":"Van Belleghem","given":"Jonas D."},{"family":"Vries","given":"Christiaan R.","non-dropping-particle":"de"},{"family":"Burgener","given":"Elizabeth"},{"family":"Chen","given":"Qingquan"},{"family":"Manasherob","given":"Robert"},{"family":"Aronson","given":"Jenny R."},{"family":"Amanatullah","given":"Derek F."},{"family":"Tamma","given":"Pranita D."},{"family":"Suh","given":"Gina A."}],"issued":{"date-parts":[["2021",6]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->22<!-- [if supportFields]><![endif]-->. Toxicity A lot of chemical excipients used with phage manufacturing can have their toxicities <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"BgIY41V3","properties":{"formattedCitation":"\\super 29\\nosupersub{}","plainCitation":"29","noteIndex":0},"citationItems":[{"id":1123,"uris":["http://zotero.org/users/11334842/items/73N9P5EC"],"itemData":{"id":1123,"type":"article-journal","abstract":"Antimicrobial resistance (AMR) problems cause an enormous challenge to our world in medicine and in agriculture and many other fields. The current situation makes bacteriophage therapy an attractive therapeutic candidate. Nevertheless, very limited clinical trials on bacteriophage therapy were performed and completed as of presence. Bacteriophage therapy alludes to infecting bacteria with a virus, this often results in a bactericidal effect. The compiled studies support the feasibility of treating AMR with bacteriophage. However, the efficacy of specific bacteriophage strains and the accurate dosage have to be further studied and tested rigorously.","container-title":"Postgraduate Medical Journal","DOI":"10.1136/postgradmedj-2022-141546","ISSN":"1469-0756","language":"eng","note":"section: 0","page":"postgradmedj–2022–141546","title":"Combating antimicrobial resistance: an evidence-based overview of bacteriophage therapy","author":[{"family":"Au","given":"Tsz Yuen"},{"family":"Assavarittirong","given":"Chanika"}],"issued":{"date-parts":[["2022",4]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->29<!-- [if supportFields]><![endif]-->. Preparation often requires purification, often involving cesium chloride (CsCl), which is toxic <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"cWchni3Z","properties":{"formattedCitation":"\\super 29\\nosupersub{}","plainCitation":"29","noteIndex":0},"citationItems":[{"id":1123,"uris":["http://zotero.org/users/11334842/items/73N9P5EC"],"itemData":{"id":1123,"type":"article-journal","abstract":"Antimicrobial resistance (AMR) problems cause an enormous challenge to our world in medicine and in agriculture and many other fields. The current situation makes bacteriophage therapy an attractive therapeutic candidate. Nevertheless, very limited clinical trials on bacteriophage therapy were performed and completed as of presence. Bacteriophage therapy alludes to infecting bacteria with a virus, this often results in a bactericidal effect. The compiled studies support the feasibility of treating AMR with bacteriophage. However, the efficacy of specific bacteriophage strains and the accurate dosage have to be further studied and tested rigorously.","container-title":"Postgraduate Medical Journal","DOI":"10.1136/postgradmedj-2022-141546","ISSN":"1469-0756","language":"eng","note":"section: 0","page":"postgradmedj–2022–141546","title":"Combating antimicrobial resistance: an evidence-based overview of bacteriophage therapy","author":[{"family":"Au","given":"Tsz Yuen"},{"family":"Assavarittirong","given":"Chanika"}],"issued":{"date-parts":[["2022",4]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->29<!-- [if supportFields]><![endif]-->. It is removed by anion exchange, which works well for smaller-scale purification<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"UUy0lNND","properties":{"formattedCitation":"\\super 22\\nosupersub{}","plainCitation":"22","noteIndex":0},"citationItems":[{"id":1229,"uris":["http://zotero.org/users/11334842/items/S76547XD"],"itemData":{"id":1229,"type":"article-journal","abstract":"Increasing rates of infection by antibiotic resistant bacteria have led to a resurgence of interest in bacteriophage (phage) therapy. Several phage therapy studies in animals and humans have been completed over the last two decades. We conducted a systematic review of safety and toxicity data associated with phage therapy in both animals and humans reported in English language publications from 2008-2021. Overall, 69 publications met our eligibility criteria including 20 animal studies, 35 clinical case reports or case series, and 14 clinical trials. After summarizing safety and toxicity data from these publications, we discuss potential approaches to optimize safety and toxicity monitoring with the therapeutic use of phage moving forward. In our systematic review of the literature, we found some adverse events associated with phage therapy, but serious events were extremely rare. Comprehensive and standardized reporting of potential toxicities associated with phage therapy has generally been lacking in the published literature. Structured safety and tolerability endpoints are necessary when phages are administered as anti-infective therapeutics.","container-title":"Viruses","DOI":"10.3390/v13071268","ISSN":"1999-4915","issue":"7","language":"eng","note":"section: 0","page":"1268","title":"The Safety and Toxicity of Phage Therapy: A Review of Animal and Clinical Studies","volume":"13","author":[{"family":"Liu","given":"Dan"},{"family":"Van Belleghem","given":"Jonas D."},{"family":"Vries","given":"Christiaan R.","non-dropping-particle":"de"},{"family":"Burgener","given":"Elizabeth"},{"family":"Chen","given":"Qingquan"},{"family":"Manasherob","given":"Robert"},{"family":"Aronson","given":"Jenny R."},{"family":"Amanatullah","given":"Derek F."},{"family":"Tamma","given":"Pranita D."},{"family":"Suh","given":"Gina A."}],"issued":{"date-parts":[["2021",6]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->22<!-- [if supportFields]><![endif]--> .Although typically removed from clinical preparations, safer alternatives like polyethylene glycol, which are not free from toxicity, are used to mitigate risks <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"FtTtB91T","properties":{"formattedCitation":"\\super 29\\nosupersub{}","plainCitation":"29","noteIndex":0},"citationItems":[{"id":1123,"uris":["http://zotero.org/users/11334842/items/73N9P5EC"],"itemData":{"id":1123,"type":"article-journal","abstract":"Antimicrobial resistance (AMR) problems cause an enormous challenge to our world in medicine and in agriculture and many other fields. The current situation makes bacteriophage therapy an attractive therapeutic candidate. Nevertheless, very limited clinical trials on bacteriophage therapy were performed and completed as of presence. Bacteriophage therapy alludes to infecting bacteria with a virus, this often results in a bactericidal effect. The compiled studies support the feasibility of treating AMR with bacteriophage. However, the efficacy of specific bacteriophage strains and the accurate dosage have to be further studied and tested rigorously.","container-title":"Postgraduate Medical Journal","DOI":"10.1136/postgradmedj-2022-141546","ISSN":"1469-0756","language":"eng","note":"section: 0","page":"postgradmedj–2022–141546","title":"Combating antimicrobial resistance: an evidence-based overview of bacteriophage therapy","author":[{"family":"Au","given":"Tsz Yuen"},{"family":"Assavarittirong","given":"Chanika"}],"issued":{"date-parts":[["2022",4]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->29<!-- [if supportFields]><![endif]-->. In addition to chemical toxicity, bacterial proteins and endotoxins present phage preparations may cause inflammation and hypotension. This is because when phages are prepared in the lab, bacteria are used to replicate them. For safety, it is essential to quantify toxin and bacterial particle presence <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"gY2uGVbn","properties":{"formattedCitation":"\\super 22\\nosupersub{}","plainCitation":"22","noteIndex":0},"citationItems":[{"id":1229,"uris":["http://zotero.org/users/11334842/items/S76547XD"],"itemData":{"id":1229,"type":"article-journal","abstract":"Increasing rates of infection by antibiotic resistant bacteria have led to a resurgence of interest in bacteriophage (phage) therapy. Several phage therapy studies in animals and humans have been completed over the last two decades. We conducted a systematic review of safety and toxicity data associated with phage therapy in both animals and humans reported in English language publications from 2008-2021. Overall, 69 publications met our eligibility criteria including 20 animal studies, 35 clinical case reports or case series, and 14 clinical trials. After summarizing safety and toxicity data from these publications, we discuss potential approaches to optimize safety and toxicity monitoring with the therapeutic use of phage moving forward. In our systematic review of the literature, we found some adverse events associated with phage therapy, but serious events were extremely rare. Comprehensive and standardized reporting of potential toxicities associated with phage therapy has generally been lacking in the published literature. Structured safety and tolerability endpoints are necessary when phages are administered as anti-infective therapeutics.","container-title":"Viruses","DOI":"10.3390/v13071268","ISSN":"1999-4915","issue":"7","language":"eng","note":"section: 0","page":"1268","title":"The Safety and Toxicity of Phage Therapy: A Review of Animal and Clinical Studies","volume":"13","author":[{"family":"Liu","given":"Dan"},{"family":"Van Belleghem","given":"Jonas D."},{"family":"Vries","given":"Christiaan R.","non-dropping-particle":"de"},{"family":"Burgener","given":"Elizabeth"},{"family":"Chen","given":"Qingquan"},{"family":"Manasherob","given":"Robert"},{"family":"Aronson","given":"Jenny R."},{"family":"Amanatullah","given":"Derek F."},{"family":"Tamma","given":"Pranita D."},{"family":"Suh","given":"Gina A."}],"issued":{"date-parts":[["2021",6]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->22<!-- [if supportFields]><![endif]-->. Bacterial Resistance Furthermore, bacteria can as well develop resistance to phages <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"V5P30pyx","properties":{"formattedCitation":"\\super 30\\nosupersub{}","plainCitation":"30","noteIndex":0},"citationItems":[{"id":1316,"uris":["http://zotero.org/users/11334842/items/2N9Z2H39"],"itemData":{"id":1316,"type":"article-journal","abstract":"To counteract bacterial defense systems, bacteriophages (phages) make extensive base modifications (substitutions) to block endonuclease restriction. Here we evaluated Type II restriction of three thymidine (T or 5-methyldeoxyuridine, 5mdU) modified phage genomes: Pseudomonas phage M6 with 5-(2-aminoethyl)deoxyuridine (5-NedU), Salmonella phage ViI (Vi1) with 5-(2-aminoethoxy)methyldeoxyuridine (5-NeOmdU) and Delftia phage phi W-14 (a.k.a. ΦW-14) with α-putrescinylthymidine (putT). Among >200 commercially available restriction endonucleases (REases) tested, phage M6, ViI, and phi W-14 genomic DNAs (gDNA) show resistance against 48.4, 71.0, and 68.8% of Type II restrictions, respectively. Inspection of the resistant sites indicates the presence of conserved dinucleotide TG or TC (TS, S=C, or G), implicating the specificity of TS sequence as the target that is converted to modified base in the genomes. We also tested a number of DNA methyltransferases (MTases) on these phage DNAs and found some MTases can fully or partially modify the DNA to confer more resistance to cleavage by REases. Phage M6 restriction fragments can be efficiently ligated by T4 DNA ligase. Phi W-14 restriction fragments show apparent reduced rate in E. coli exonuclease III degradation. This work extends previous studies that hypermodified T derived from 5hmdU provides additional resistance to host-encoded restrictions, in parallel to modified cytosines, guanine, and adenine in phage genomes. The results reported here provide a general guidance to use REases to map and clone phage DNA with hypermodified thymidine.","container-title":"Frontiers in Microbiology","ISSN":"1664-302X","source":"Frontiers","title":"Type II Restriction of Bacteriophage DNA With 5hmdU-Derived Base Modifications","URL":"https://www.frontiersin.org/articles/10.3389/fmicb.2019.00584","volume":"10","author":[{"family":"Flodman","given":"Kiersten"},{"family":"Tsai","given":"Rebecca"},{"family":"Xu","given":"Michael Y."},{"family":"Corrêa","given":"Ivan R."},{"family":"Copelas","given":"Alyssa"},{"family":"Lee","given":"Yan-Jiun"},{"family":"Xu","given":"Ming-Qun"},{"family":"Weigele","given":"Peter"},{"family":"Xu","given":"Shuang-yong"}],"accessed":{"date-parts":[["2023",12,4]]},"issued":{"date-parts":[["2019"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->30<!-- [if supportFields]><![endif]-->. Phages have the capacity to apply considerable evolutionary pressure on bacterial populations, prompting genetic alterations that lead to resistance <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"wcoFHVU9","properties":{"formattedCitation":"\\super 15\\nosupersub{}","plainCitation":"15","noteIndex":0},"citationItems":[{"id":1109,"uris":["http://zotero.org/users/11334842/items/5ZKHMNHA"],"itemData":{"id":1109,"type":"article-journal","abstract":"The emerging resistivity of antibiotic resistance superbugs desire the need to resolve the global problem of antibiotic resistance. Among several other methods currently being adopted, one possible solution may be the development of supplemental therapies for antibiotics. The use of the normal and advanced bactericidal properties of bacteriophages (bacteriophage therapy) may be one of the viable infection control options. It is evident, however, that the safe and regulated application of phage treatment will need extensive knowledge of the characteristics and behaviour of certain phage-bacterium systems. This mini review offers an overview of the potential for phage therapy as well as the constraints and obstacles it faces in becoming a commonly accepted infection management strategy.","container-title":"Frontiers in Pharmacology","DOI":"10.3389/fphar.2023.1036051","ISSN":"1663-9812","language":"eng","note":"section: 0","page":"1036051","title":"Phages against killer superbugs: An enticing strategy against antibiotics-resistant pathogens","volume":"14","author":[{"family":"Baral","given":"Bikash"}],"issued":{"date-parts":[["2023"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->15<!-- [if supportFields]><![endif]-->. For instance, bacteria can employ diverse mechanisms to counteract phages, such as modifying their outer membranes, generating inhibitors that impede phage replication, or modifying the sites that phages target for infection <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Rc4qjr6h","properties":{"formattedCitation":"\\super 15\\nosupersub{}","plainCitation":"15","noteIndex":0},"citationItems":[{"id":1109,"uris":["http://zotero.org/users/11334842/items/5ZKHMNHA"],"itemData":{"id":1109,"type":"article-journal","abstract":"The emerging resistivity of antibiotic resistance superbugs desire the need to resolve the global problem of antibiotic resistance. Among several other methods currently being adopted, one possible solution may be the development of supplemental therapies for antibiotics. The use of the normal and advanced bactericidal properties of bacteriophages (bacteriophage therapy) may be one of the viable infection control options. It is evident, however, that the safe and regulated application of phage treatment will need extensive knowledge of the characteristics and behaviour of certain phage-bacterium systems. This mini review offers an overview of the potential for phage therapy as well as the constraints and obstacles it faces in becoming a commonly accepted infection management strategy.","container-title":"Frontiers in Pharmacology","DOI":"10.3389/fphar.2023.1036051","ISSN":"1663-9812","language":"eng","note":"section: 0","page":"1036051","title":"Phages against killer superbugs: An enticing strategy against antibiotics-resistant pathogens","volume":"14","author":[{"family":"Baral","given":"Bikash"}],"issued":{"date-parts":[["2023"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->15<!-- [if supportFields]><![endif]-->. For example, P. aeruginosa can generate proteins that neutralize phage activity, enabling bacteria to flourish even in the presence of phages <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"QU2yVjif","properties":{"formattedCitation":"\\super 15\\nosupersub{}","plainCitation":"15","noteIndex":0},"citationItems":[{"id":1109,"uris":["http://zotero.org/users/11334842/items/5ZKHMNHA"],"itemData":{"id":1109,"type":"article-journal","abstract":"The emerging resistivity of antibiotic resistance superbugs desire the need to resolve the global problem of antibiotic resistance. Among several other methods currently being adopted, one possible solution may be the development of supplemental therapies for antibiotics. The use of the normal and advanced bactericidal properties of bacteriophages (bacteriophage therapy) may be one of the viable infection control options. It is evident, however, that the safe and regulated application of phage treatment will need extensive knowledge of the characteristics and behaviour of certain phage-bacterium systems. This mini review offers an overview of the potential for phage therapy as well as the constraints and obstacles it faces in becoming a commonly accepted infection management strategy.","container-title":"Frontiers in Pharmacology","DOI":"10.3389/fphar.2023.1036051","ISSN":"1663-9812","language":"eng","note":"section: 0","page":"1036051","title":"Phages against killer superbugs: An enticing strategy against antibiotics-resistant pathogens","volume":"14","author":[{"family":"Baral","given":"Bikash"}],"issued":{"date-parts":[["2023"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->15<!-- [if supportFields]><![endif]-->. Phage therapy typically involves using multiple phages to minimize resistance. Lysogenic phages, which incorporate their DNA into host bacteria, can potentially contribute to horizontal transfer of resistance genes<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"fz8pUkqk","properties":{"formattedCitation":"\\super 19\\nosupersub{}","plainCitation":"19","noteIndex":0},"citationItems":[{"id":1143,"uris":["http://zotero.org/users/11334842/items/YD3LKXA9"],"itemData":{"id":1143,"type":"article-journal","abstract":"Bacteriophages (simply referred to as Phages) are a class of viruses with the ability to infect and kill prokaryotic cells (bacteria), but are unable to infect mammalian cells. This unique ability to achieve specific infectiousness by bacteriophages has been harnessed in antibacterial treatments dating back almost a decade before the antibiotic era began. Bacteriophages were used as therapeutic agents in treatment of dysentery caused by Shigella dysenteriae as far back as 1919 and in the experimental treatment of a wide variety of other bacterial infections caused by Vibrio cholerae, Staphylococcus sp., Pseudomonas sp. etc, with varying degrees of success. Phage therapy and its many prospects soon fell out of favour in western medicine after the Second World War, with the discovery of penicillin. The Soviet Union and other countries in Eastern Europe however mastered the craft of bacteriophage isolation, purification and cocktail preparation, with phage-based therapeutics becoming widely available over-the-counter. With the recent rise in cases of multi-drug resistant bacterial infections, the clamour for a return to phage therapy, as a potential solution to the anti-microbial resistance (AMR) crisis has grown louder. This review provides an extensive exposé on phage therapy, addressing its historical use, evidences of its safety and efficacy, its pros and cons when compared with antibiotics, cases of compassionate use for treating life-threatening antibiotic-resistant infections, the limitations to its acceptance and how these may be circumvented.","container-title":"AIMS microbiology","DOI":"10.3934/microbiol.2020014","ISSN":"2471-1888","issue":"3","language":"eng","note":"section: 0","page":"204–230","title":"An exegesis of bacteriophage therapy: An emerging player in the fight against anti-microbial resistance","volume":"6","author":[{"family":"Adesanya","given":"Oluwafolajimi"},{"family":"Oduselu","given":"Tolulope"},{"family":"Akin-Ajani","given":"Oluwawapelumi"},{"family":"Adewumi","given":"Olubusuyi M."},{"family":"Ademowo","given":"Olusegun G."}],"issued":{"date-parts":[["2020"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->19<!-- [if supportFields]><![endif]-->. However, lysogenic phages can also be modified to convey antibiotic-sensitive genes, offering a potential avenue for restoring antibiotic sensitivity in resistant bacteria <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"lE3A9bVY","properties":{"formattedCitation":"\\super 19\\nosupersub{}","plainCitation":"19","noteIndex":0},"citationItems":[{"id":1143,"uris":["http://zotero.org/users/11334842/items/YD3LKXA9"],"itemData":{"id":1143,"type":"article-journal","abstract":"Bacteriophages (simply referred to as Phages) are a class of viruses with the ability to infect and kill prokaryotic cells (bacteria), but are unable to infect mammalian cells. This unique ability to achieve specific infectiousness by bacteriophages has been harnessed in antibacterial treatments dating back almost a decade before the antibiotic era began. Bacteriophages were used as therapeutic agents in treatment of dysentery caused by Shigella dysenteriae as far back as 1919 and in the experimental treatment of a wide variety of other bacterial infections caused by Vibrio cholerae, Staphylococcus sp., Pseudomonas sp. etc, with varying degrees of success. Phage therapy and its many prospects soon fell out of favour in western medicine after the Second World War, with the discovery of penicillin. The Soviet Union and other countries in Eastern Europe however mastered the craft of bacteriophage isolation, purification and cocktail preparation, with phage-based therapeutics becoming widely available over-the-counter. With the recent rise in cases of multi-drug resistant bacterial infections, the clamour for a return to phage therapy, as a potential solution to the anti-microbial resistance (AMR) crisis has grown louder. This review provides an extensive exposé on phage therapy, addressing its historical use, evidences of its safety and efficacy, its pros and cons when compared with antibiotics, cases of compassionate use for treating life-threatening antibiotic-resistant infections, the limitations to its acceptance and how these may be circumvented.","container-title":"AIMS microbiology","DOI":"10.3934/microbiol.2020014","ISSN":"2471-1888","issue":"3","language":"eng","note":"section: 0","page":"204–230","title":"An exegesis of bacteriophage therapy: An emerging player in the fight against anti-microbial resistance","volume":"6","author":[{"family":"Adesanya","given":"Oluwafolajimi"},{"family":"Oduselu","given":"Tolulope"},{"family":"Akin-Ajani","given":"Oluwawapelumi"},{"family":"Adewumi","given":"Olubusuyi M."},{"family":"Ademowo","given":"Olusegun G."}],"issued":{"date-parts":[["2020"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->19<!-- [if supportFields]><![endif]-->. Nevertheless, phages can be used by bacteria as vectors to transmit their antibiotic and phage resistance genes via genetic transduction, which can further spread resistance against them <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"cDE9YouN","properties":{"formattedCitation":"\\super 28\\nosupersub{}","plainCitation":"28","noteIndex":0},"citationItems":[{"id":1177,"uris":["http://zotero.org/users/11334842/items/3SDA35CL"],"itemData":{"id":1177,"type":"article-journal","abstract":"Staphylococcus aureus is a pathogen commonly found in nosocomial environments where infections can easily spread - especially given the reduced immune response of patients and large overlap between personnel in charge of their care. Although antibiotics are available to treat nosocomial infections, the increased occurrence of antibiotic resistance has rendered many treatments ineffective. Such is the case for methicillin resistant S. aureus (MRSA), which has continued to be a threat to public health since its emergence. For this reason, alternative treatment technologies utilizing antimicrobials such as bacteriocins, bacteriophages (phages) and phage endolysins are being developed. These antimicrobials provide an advantage over antibiotics in that many have narrow inhibition spectra, enabling treatments to be selected based on the target (pathogenic) bacterium while allowing for survival of commensal bacteria and thus avoiding collateral damage to the microbiome. Bacterial resistance to these treatments occurs less frequently than with antibiotics, particularly in circumstances where combinatory antimicrobial therapies are used. Phage therapy has been well established in Eastern Europe as an effective treatment against bacterial infections. While there are no Randomized Clinical Trials (RCTs) to our knowledge examining phage treatment of S. aureus infections that have completed all trial phases, numerous clinical trials are underway, and several commercial phage preparations are currently available to treat S. aureus infections. Bacteriocins have primarily been used in the food industry for bio-preservation applications. However, the idea of repurposing bacteriocins for human health is an attractive one considering their efficacy against many bacterial pathogens. There are concerns about the ability of bacteriocins to survive the gastrointestinal tract given their proteinaceous nature, however, this obstacle may be overcome by altering the administration route of the therapy through encapsulation, or by bioengineering protease-resistant variants. Obstacles such as enzymatic digestion are less of an issue for topical/local administration, for example, application to the surface of the skin. Bacteriocins have also shown impressive synergistic effects when used in conjunction with other antimicrobials, including antibiotics, which may allow antibiotic-based therapies to be used more sparingly with less resistance development. This review provides an updated account of known bacteriocins, phages and phage endolysins which have demonstrated an impressive ability to kill S. aureus strains. In particular, examples of antimicrobials with the ability to target MRSA strains and their subsequent use in a clinical setting are outlined.","container-title":"Frontiers in Molecular Biosciences","DOI":"10.3389/fmolb.2021.654038","ISSN":"2296-889X","language":"eng","note":"section: 0","page":"654038","title":"Efficacy of Phage- and Bacteriocin-Based Therapies in Combatting Nosocomial MRSA Infections","volume":"8","author":[{"family":"Walsh","given":"Lauren"},{"family":"Johnson","given":"Crystal N."},{"family":"Hill","given":"Colin"},{"family":"Ross","given":"R. Paul"}],"issued":{"date-parts":[["2021"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->28<!-- [if supportFields]><![endif]-->. Host Specificity and Polymicrobial Infection The host specificity of phages can also be a limitation, particularly in polymicrobial infections and when broad-spectrum treatment is required <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"tAnB24qB","properties":{"formattedCitation":"\\super 19\\nosupersub{}","plainCitation":"19","noteIndex":0},"citationItems":[{"id":1143,"uris":["http://zotero.org/users/11334842/items/YD3LKXA9"],"itemData":{"id":1143,"type":"article-journal","abstract":"Bacteriophages (simply referred to as Phages) are a class of viruses with the ability to infect and kill prokaryotic cells (bacteria), but are unable to infect mammalian cells. This unique ability to achieve specific infectiousness by bacteriophages has been harnessed in antibacterial treatments dating back almost a decade before the antibiotic era began. Bacteriophages were used as therapeutic agents in treatment of dysentery caused by Shigella dysenteriae as far back as 1919 and in the experimental treatment of a wide variety of other bacterial infections caused by Vibrio cholerae, Staphylococcus sp., Pseudomonas sp. etc, with varying degrees of success. Phage therapy and its many prospects soon fell out of favour in western medicine after the Second World War, with the discovery of penicillin. The Soviet Union and other countries in Eastern Europe however mastered the craft of bacteriophage isolation, purification and cocktail preparation, with phage-based therapeutics becoming widely available over-the-counter. With the recent rise in cases of multi-drug resistant bacterial infections, the clamour for a return to phage therapy, as a potential solution to the anti-microbial resistance (AMR) crisis has grown louder. This review provides an extensive exposé on phage therapy, addressing its historical use, evidences of its safety and efficacy, its pros and cons when compared with antibiotics, cases of compassionate use for treating life-threatening antibiotic-resistant infections, the limitations to its acceptance and how these may be circumvented.","container-title":"AIMS microbiology","DOI":"10.3934/microbiol.2020014","ISSN":"2471-1888","issue":"3","language":"eng","note":"section: 0","page":"204–230","title":"An exegesis of bacteriophage therapy: An emerging player in the fight against anti-microbial resistance","volume":"6","author":[{"family":"Adesanya","given":"Oluwafolajimi"},{"family":"Oduselu","given":"Tolulope"},{"family":"Akin-Ajani","given":"Oluwawapelumi"},{"family":"Adewumi","given":"Olubusuyi M."},{"family":"Ademowo","given":"Olusegun G."}],"issued":{"date-parts":[["2020"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->19<!-- [if supportFields]><![endif]-->. Large-scale production and distribution of phage-based therapeutics can be challenging due to regional specific epidemiology, as phages may be most effective when matched to the local microbial population <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"UfZlIa0l","properties":{"formattedCitation":"\\super 19\\nosupersub{}","plainCitation":"19","noteIndex":0},"citationItems":[{"id":1143,"uris":["http://zotero.org/users/11334842/items/YD3LKXA9"],"itemData":{"id":1143,"type":"article-journal","abstract":"Bacteriophages (simply referred to as Phages) are a class of viruses with the ability to infect and kill prokaryotic cells (bacteria), but are unable to infect mammalian cells. This unique ability to achieve specific infectiousness by bacteriophages has been harnessed in antibacterial treatments dating back almost a decade before the antibiotic era began. Bacteriophages were used as therapeutic agents in treatment of dysentery caused by Shigella dysenteriae as far back as 1919 and in the experimental treatment of a wide variety of other bacterial infections caused by Vibrio cholerae, Staphylococcus sp., Pseudomonas sp. etc, with varying degrees of success. Phage therapy and its many prospects soon fell out of favour in western medicine after the Second World War, with the discovery of penicillin. The Soviet Union and other countries in Eastern Europe however mastered the craft of bacteriophage isolation, purification and cocktail preparation, with phage-based therapeutics becoming widely available over-the-counter. With the recent rise in cases of multi-drug resistant bacterial infections, the clamour for a return to phage therapy, as a potential solution to the anti-microbial resistance (AMR) crisis has grown louder. This review provides an extensive exposé on phage therapy, addressing its historical use, evidences of its safety and efficacy, its pros and cons when compared with antibiotics, cases of compassionate use for treating life-threatening antibiotic-resistant infections, the limitations to its acceptance and how these may be circumvented.","container-title":"AIMS microbiology","DOI":"10.3934/microbiol.2020014","ISSN":"2471-1888","issue":"3","language":"eng","note":"section: 0","page":"204–230","title":"An exegesis of bacteriophage therapy: An emerging player in the fight against anti-microbial resistance","volume":"6","author":[{"family":"Adesanya","given":"Oluwafolajimi"},{"family":"Oduselu","given":"Tolulope"},{"family":"Akin-Ajani","given":"Oluwawapelumi"},{"family":"Adewumi","given":"Olubusuyi M."},{"family":"Ademowo","given":"Olusegun G."}],"issued":{"date-parts":[["2020"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->19<!-- [if supportFields]><![endif]-->. Understanding the regional specificity and targeting phages to prevalent antibiotic-resistant strains can improve the efficacy of phage therapy <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"ytKKrg7r","properties":{"formattedCitation":"\\super 19\\nosupersub{}","plainCitation":"19","noteIndex":0},"citationItems":[{"id":1143,"uris":["http://zotero.org/users/11334842/items/YD3LKXA9"],"itemData":{"id":1143,"type":"article-journal","abstract":"Bacteriophages (simply referred to as Phages) are a class of viruses with the ability to infect and kill prokaryotic cells (bacteria), but are unable to infect mammalian cells. This unique ability to achieve specific infectiousness by bacteriophages has been harnessed in antibacterial treatments dating back almost a decade before the antibiotic era began. Bacteriophages were used as therapeutic agents in treatment of dysentery caused by Shigella dysenteriae as far back as 1919 and in the experimental treatment of a wide variety of other bacterial infections caused by Vibrio cholerae, Staphylococcus sp., Pseudomonas sp. etc, with varying degrees of success. Phage therapy and its many prospects soon fell out of favour in western medicine after the Second World War, with the discovery of penicillin. The Soviet Union and other countries in Eastern Europe however mastered the craft of bacteriophage isolation, purification and cocktail preparation, with phage-based therapeutics becoming widely available over-the-counter. With the recent rise in cases of multi-drug resistant bacterial infections, the clamour for a return to phage therapy, as a potential solution to the anti-microbial resistance (AMR) crisis has grown louder. This review provides an extensive exposé on phage therapy, addressing its historical use, evidences of its safety and efficacy, its pros and cons when compared with antibiotics, cases of compassionate use for treating life-threatening antibiotic-resistant infections, the limitations to its acceptance and how these may be circumvented.","container-title":"AIMS microbiology","DOI":"10.3934/microbiol.2020014","ISSN":"2471-1888","issue":"3","language":"eng","note":"section: 0","page":"204–230","title":"An exegesis of bacteriophage therapy: An emerging player in the fight against anti-microbial resistance","volume":"6","author":[{"family":"Adesanya","given":"Oluwafolajimi"},{"family":"Oduselu","given":"Tolulope"},{"family":"Akin-Ajani","given":"Oluwawapelumi"},{"family":"Adewumi","given":"Olubusuyi M."},{"family":"Ademowo","given":"Olusegun G."}],"issued":{"date-parts":[["2020"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->19<!-- [if supportFields]><![endif]-->. Logistics Raising awareness of phage safety and efficacy is vital for clinical acceptance. Manufacturers must adhere to Good Manufacturing Practice guidelines to ensure phage stability from production to administration <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"V46J0Io0","properties":{"formattedCitation":"\\super 20\\nosupersub{}","plainCitation":"20","noteIndex":0},"citationItems":[{"id":1295,"uris":["http://zotero.org/users/11334842/items/3ZV2PTLG"],"itemData":{"id":1295,"type":"article-journal","abstract":"Bacteriophages (phages) may constitute a natural, safe, and effective strategy to prevent and control multidrug-resistant organisms (MDROs), and ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens in particular. Few clinical studies have assessed the safety and efficacy of phages in patients infected with MDROs. This systematic review summarizes and critically evaluates published studies of phages in clinical practice and presents the appropriate phage selection criteria, as well as recommendations for clinicians and scientists for a successful therapy. Articles were identified through a search of the PubMed, Ovid, EMBASE, and Cochrane Library databases. Among 1102 articles and abstracts, 30 studies were selected and evaluated using selective inclusion criteria, phage criteria, and study characteristics. Most studies showed efficacy (87%) and safety (67%) of the tested phages, but few studies examined phage resistance (35%). Clinical studies and regulatory changes are needed to determine the safety and efficacy of phages and to advance their use in patients with MDRO infections.","container-title":"Clinical Infectious Diseases","DOI":"10.1093/cid/ciy947","ISSN":"1058-4838","issue":"1","note":"section: 0","page":"167–178","title":"A Systematic and Critical Review of Bacteriophage Therapy Against Multidrug-resistant ESKAPE Organisms in Humans","volume":"69","author":[{"family":"El Haddad","given":"Lynn"},{"family":"Harb","given":"Cynthia P"},{"family":"Gebara","given":"Marc A"},{"family":"Stibich","given":"Mark A"},{"family":"Chemaly","given":"Roy F"}],"issued":{"date-parts":[["2019",6]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->20<!-- [if supportFields]><![endif]-->. Phages' personalized nature requires a distinct approach from traditional medicines, with considerations for quick updates in response to bacterial resistance <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"BGqZlwU3","properties":{"formattedCitation":"\\super 20\\nosupersub{}","plainCitation":"20","noteIndex":0},"citationItems":[{"id":1295,"uris":["http://zotero.org/users/11334842/items/3ZV2PTLG"],"itemData":{"id":1295,"type":"article-journal","abstract":"Bacteriophages (phages) may constitute a natural, safe, and effective strategy to prevent and control multidrug-resistant organisms (MDROs), and ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens in particular. Few clinical studies have assessed the safety and efficacy of phages in patients infected with MDROs. This systematic review summarizes and critically evaluates published studies of phages in clinical practice and presents the appropriate phage selection criteria, as well as recommendations for clinicians and scientists for a successful therapy. Articles were identified through a search of the PubMed, Ovid, EMBASE, and Cochrane Library databases. Among 1102 articles and abstracts, 30 studies were selected and evaluated using selective inclusion criteria, phage criteria, and study characteristics. Most studies showed efficacy (87%) and safety (67%) of the tested phages, but few studies examined phage resistance (35%). Clinical studies and regulatory changes are needed to determine the safety and efficacy of phages and to advance their use in patients with MDRO infections.","container-title":"Clinical Infectious Diseases","DOI":"10.1093/cid/ciy947","ISSN":"1058-4838","issue":"1","note":"section: 0","page":"167–178","title":"A Systematic and Critical Review of Bacteriophage Therapy Against Multidrug-resistant ESKAPE Organisms in Humans","volume":"69","author":[{"family":"El Haddad","given":"Lynn"},{"family":"Harb","given":"Cynthia P"},{"family":"Gebara","given":"Marc A"},{"family":"Stibich","given":"Mark A"},{"family":"Chemaly","given":"Roy F"}],"issued":{"date-parts":[["2019",6]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->20<!-- [if supportFields]><![endif]-->. Phages also need for specialized expertise to administer them <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2UnjEWjM","properties":{"formattedCitation":"\\super 15\\nosupersub{}","plainCitation":"15","noteIndex":0},"citationItems":[{"id":1109,"uris":["http://zotero.org/users/11334842/items/5ZKHMNHA"],"itemData":{"id":1109,"type":"article-journal","abstract":"The emerging resistivity of antibiotic resistance superbugs desire the need to resolve the global problem of antibiotic resistance. Among several other methods currently being adopted, one possible solution may be the development of supplemental therapies for antibiotics. The use of the normal and advanced bactericidal properties of bacteriophages (bacteriophage therapy) may be one of the viable infection control options. It is evident, however, that the safe and regulated application of phage treatment will need extensive knowledge of the characteristics and behaviour of certain phage-bacterium systems. This mini review offers an overview of the potential for phage therapy as well as the constraints and obstacles it faces in becoming a commonly accepted infection management strategy.","container-title":"Frontiers in Pharmacology","DOI":"10.3389/fphar.2023.1036051","ISSN":"1663-9812","language":"eng","note":"section: 0","page":"1036051","title":"Phages against killer superbugs: An enticing strategy against antibiotics-resistant pathogens","volume":"14","author":[{"family":"Baral","given":"Bikash"}],"issued":{"date-parts":[["2023"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->15<!-- [if supportFields]><![endif]-->. Ideally, phage therapy offers a potential solution in the fight against multi-drug resistant bacteria in low-income countries, as effective and affordable alternatives to the very expensive and often unavailable antibiotics <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"zfRZPdig","properties":{"formattedCitation":"\\super 19\\nosupersub{}","plainCitation":"19","noteIndex":0},"citationItems":[{"id":1143,"uris":["http://zotero.org/users/11334842/items/YD3LKXA9"],"itemData":{"id":1143,"type":"article-journal","abstract":"Bacteriophages (simply referred to as Phages) are a class of viruses with the ability to infect and kill prokaryotic cells (bacteria), but are unable to infect mammalian cells. This unique ability to achieve specific infectiousness by bacteriophages has been harnessed in antibacterial treatments dating back almost a decade before the antibiotic era began. Bacteriophages were used as therapeutic agents in treatment of dysentery caused by Shigella dysenteriae as far back as 1919 and in the experimental treatment of a wide variety of other bacterial infections caused by Vibrio cholerae, Staphylococcus sp., Pseudomonas sp. etc, with varying degrees of success. Phage therapy and its many prospects soon fell out of favour in western medicine after the Second World War, with the discovery of penicillin. The Soviet Union and other countries in Eastern Europe however mastered the craft of bacteriophage isolation, purification and cocktail preparation, with phage-based therapeutics becoming widely available over-the-counter. With the recent rise in cases of multi-drug resistant bacterial infections, the clamour for a return to phage therapy, as a potential solution to the anti-microbial resistance (AMR) crisis has grown louder. This review provides an extensive exposé on phage therapy, addressing its historical use, evidences of its safety and efficacy, its pros and cons when compared with antibiotics, cases of compassionate use for treating life-threatening antibiotic-resistant infections, the limitations to its acceptance and how these may be circumvented.","container-title":"AIMS microbiology","DOI":"10.3934/microbiol.2020014","ISSN":"2471-1888","issue":"3","language":"eng","note":"section: 0","page":"204–230","title":"An exegesis of bacteriophage therapy: An emerging player in the fight against anti-microbial resistance","volume":"6","author":[{"family":"Adesanya","given":"Oluwafolajimi"},{"family":"Oduselu","given":"Tolulope"},{"family":"Akin-Ajani","given":"Oluwawapelumi"},{"family":"Adewumi","given":"Olubusuyi M."},{"family":"Ademowo","given":"Olusegun G."}],"issued":{"date-parts":[["2020"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->19<!-- [if supportFields]><![endif]-->. However, limited financial resources, lack of political will, and regulatory limitations hinder the exploration of phage therapy in Africa <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"xVyUWEn9","properties":{"formattedCitation":"\\super 19\\nosupersub{}","plainCitation":"19","noteIndex":0},"citationItems":[{"id":1143,"uris":["http://zotero.org/users/11334842/items/YD3LKXA9"],"itemData":{"id":1143,"type":"article-journal","abstract":"Bacteriophages (simply referred to as Phages) are a class of viruses with the ability to infect and kill prokaryotic cells (bacteria), but are unable to infect mammalian cells. This unique ability to achieve specific infectiousness by bacteriophages has been harnessed in antibacterial treatments dating back almost a decade before the antibiotic era began. Bacteriophages were used as therapeutic agents in treatment of dysentery caused by Shigella dysenteriae as far back as 1919 and in the experimental treatment of a wide variety of other bacterial infections caused by Vibrio cholerae, Staphylococcus sp., Pseudomonas sp. etc, with varying degrees of success. Phage therapy and its many prospects soon fell out of favour in western medicine after the Second World War, with the discovery of penicillin. The Soviet Union and other countries in Eastern Europe however mastered the craft of bacteriophage isolation, purification and cocktail preparation, with phage-based therapeutics becoming widely available over-the-counter. With the recent rise in cases of multi-drug resistant bacterial infections, the clamour for a return to phage therapy, as a potential solution to the anti-microbial resistance (AMR) crisis has grown louder. This review provides an extensive exposé on phage therapy, addressing its historical use, evidences of its safety and efficacy, its pros and cons when compared with antibiotics, cases of compassionate use for treating life-threatening antibiotic-resistant infections, the limitations to its acceptance and how these may be circumvented.","container-title":"AIMS microbiology","DOI":"10.3934/microbiol.2020014","ISSN":"2471-1888","issue":"3","language":"eng","note":"section: 0","page":"204–230","title":"An exegesis of bacteriophage therapy: An emerging player in the fight against anti-microbial resistance","volume":"6","author":[{"family":"Adesanya","given":"Oluwafolajimi"},{"family":"Oduselu","given":"Tolulope"},{"family":"Akin-Ajani","given":"Oluwawapelumi"},{"family":"Adewumi","given":"Olubusuyi M."},{"family":"Ademowo","given":"Olusegun G."}],"issued":{"date-parts":[["2020"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->19<!-- [if supportFields]><![endif]-->. The adoption of phage therapy into conventional medicine faces regulatory hurdles due to the lack of a global framework. Its position as a personalized medicine approach challenges existing pharmaceutical regulatory policy <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"DelGfo8N","properties":{"formattedCitation":"\\super 19\\nosupersub{}","plainCitation":"19","noteIndex":0},"citationItems":[{"id":1143,"uris":["http://zotero.org/users/11334842/items/YD3LKXA9"],"itemData":{"id":1143,"type":"article-journal","abstract":"Bacteriophages (simply referred to as Phages) are a class of viruses with the ability to infect and kill prokaryotic cells (bacteria), but are unable to infect mammalian cells. This unique ability to achieve specific infectiousness by bacteriophages has been harnessed in antibacterial treatments dating back almost a decade before the antibiotic era began. Bacteriophages were used as therapeutic agents in treatment of dysentery caused by Shigella dysenteriae as far back as 1919 and in the experimental treatment of a wide variety of other bacterial infections caused by Vibrio cholerae, Staphylococcus sp., Pseudomonas sp. etc, with varying degrees of success. Phage therapy and its many prospects soon fell out of favour in western medicine after the Second World War, with the discovery of penicillin. The Soviet Union and other countries in Eastern Europe however mastered the craft of bacteriophage isolation, purification and cocktail preparation, with phage-based therapeutics becoming widely available over-the-counter. With the recent rise in cases of multi-drug resistant bacterial infections, the clamour for a return to phage therapy, as a potential solution to the anti-microbial resistance (AMR) crisis has grown louder. This review provides an extensive exposé on phage therapy, addressing its historical use, evidences of its safety and efficacy, its pros and cons when compared with antibiotics, cases of compassionate use for treating life-threatening antibiotic-resistant infections, the limitations to its acceptance and how these may be circumvented.","container-title":"AIMS microbiology","DOI":"10.3934/microbiol.2020014","ISSN":"2471-1888","issue":"3","language":"eng","note":"section: 0","page":"204–230","title":"An exegesis of bacteriophage therapy: An emerging player in the fight against anti-microbial resistance","volume":"6","author":[{"family":"Adesanya","given":"Oluwafolajimi"},{"family":"Oduselu","given":"Tolulope"},{"family":"Akin-Ajani","given":"Oluwawapelumi"},{"family":"Adewumi","given":"Olubusuyi M."},{"family":"Ademowo","given":"Olusegun G."}],"issued":{"date-parts":[["2020"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->19<!-- [if supportFields]><![endif]-->. Issues related to intellectual property rights for phage therapy medicinal products (PTMPs) arise because natural bacteriophages cannot be patented, creating challenges for commercial production of phage cocktails <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"9WDEHOva","properties":{"formattedCitation":"\\super 19\\nosupersub{}","plainCitation":"19","noteIndex":0},"citationItems":[{"id":1143,"uris":["http://zotero.org/users/11334842/items/YD3LKXA9"],"itemData":{"id":1143,"type":"article-journal","abstract":"Bacteriophages (simply referred to as Phages) are a class of viruses with the ability to infect and kill prokaryotic cells (bacteria), but are unable to infect mammalian cells. This unique ability to achieve specific infectiousness by bacteriophages has been harnessed in antibacterial treatments dating back almost a decade before the antibiotic era began. Bacteriophages were used as therapeutic agents in treatment of dysentery caused by Shigella dysenteriae as far back as 1919 and in the experimental treatment of a wide variety of other bacterial infections caused by Vibrio cholerae, Staphylococcus sp., Pseudomonas sp. etc, with varying degrees of success. Phage therapy and its many prospects soon fell out of favour in western medicine after the Second World War, with the discovery of penicillin. The Soviet Union and other countries in Eastern Europe however mastered the craft of bacteriophage isolation, purification and cocktail preparation, with phage-based therapeutics becoming widely available over-the-counter. With the recent rise in cases of multi-drug resistant bacterial infections, the clamour for a return to phage therapy, as a potential solution to the anti-microbial resistance (AMR) crisis has grown louder. This review provides an extensive exposé on phage therapy, addressing its historical use, evidences of its safety and efficacy, its pros and cons when compared with antibiotics, cases of compassionate use for treating life-threatening antibiotic-resistant infections, the limitations to its acceptance and how these may be circumvented.","container-title":"AIMS microbiology","DOI":"10.3934/microbiol.2020014","ISSN":"2471-1888","issue":"3","language":"eng","note":"section: 0","page":"204–230","title":"An exegesis of bacteriophage therapy: An emerging player in the fight against anti-microbial resistance","volume":"6","author":[{"family":"Adesanya","given":"Oluwafolajimi"},{"family":"Oduselu","given":"Tolulope"},{"family":"Akin-Ajani","given":"Oluwawapelumi"},{"family":"Adewumi","given":"Olubusuyi M."},{"family":"Ademowo","given":"Olusegun G."}],"issued":{"date-parts":[["2020"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->19<!-- [if supportFields]><![endif]-->. The need for market authorization for PTMPs is unclear, as some argue that they are formulated for specific patient use, while others require industrial-scale production <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"sUHUvYdA","properties":{"formattedCitation":"\\super 19\\nosupersub{}","plainCitation":"19","noteIndex":0},"citationItems":[{"id":1143,"uris":["http://zotero.org/users/11334842/items/YD3LKXA9"],"itemData":{"id":1143,"type":"article-journal","abstract":"Bacteriophages (simply referred to as Phages) are a class of viruses with the ability to infect and kill prokaryotic cells (bacteria), but are unable to infect mammalian cells. This unique ability to achieve specific infectiousness by bacteriophages has been harnessed in antibacterial treatments dating back almost a decade before the antibiotic era began. Bacteriophages were used as therapeutic agents in treatment of dysentery caused by Shigella dysenteriae as far back as 1919 and in the experimental treatment of a wide variety of other bacterial infections caused by Vibrio cholerae, Staphylococcus sp., Pseudomonas sp. etc, with varying degrees of success. Phage therapy and its many prospects soon fell out of favour in western medicine after the Second World War, with the discovery of penicillin. The Soviet Union and other countries in Eastern Europe however mastered the craft of bacteriophage isolation, purification and cocktail preparation, with phage-based therapeutics becoming widely available over-the-counter. With the recent rise in cases of multi-drug resistant bacterial infections, the clamour for a return to phage therapy, as a potential solution to the anti-microbial resistance (AMR) crisis has grown louder. This review provides an extensive exposé on phage therapy, addressing its historical use, evidences of its safety and efficacy, its pros and cons when compared with antibiotics, cases of compassionate use for treating life-threatening antibiotic-resistant infections, the limitations to its acceptance and how these may be circumvented.","container-title":"AIMS microbiology","DOI":"10.3934/microbiol.2020014","ISSN":"2471-1888","issue":"3","language":"eng","note":"section: 0","page":"204–230","title":"An exegesis of bacteriophage therapy: An emerging player in the fight against anti-microbial resistance","volume":"6","author":[{"family":"Adesanya","given":"Oluwafolajimi"},{"family":"Oduselu","given":"Tolulope"},{"family":"Akin-Ajani","given":"Oluwawapelumi"},{"family":"Adewumi","given":"Olubusuyi M."},{"family":"Ademowo","given":"Olusegun G."}],"issued":{"date-parts":[["2020"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->19<!-- [if supportFields]><![endif]-->. Additionally, the unique pharmacodynamic properties of phages as "active drugs" and their potential for self-replication in the body raise additional considerations <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"ewTIwTRD","properties":{"formattedCitation":"\\super 19\\nosupersub{}","plainCitation":"19","noteIndex":0},"citationItems":[{"id":1143,"uris":["http://zotero.org/users/11334842/items/YD3LKXA9"],"itemData":{"id":1143,"type":"article-journal","abstract":"Bacteriophages (simply referred to as Phages) are a class of viruses with the ability to infect and kill prokaryotic cells (bacteria), but are unable to infect mammalian cells. This unique ability to achieve specific infectiousness by bacteriophages has been harnessed in antibacterial treatments dating back almost a decade before the antibiotic era began. Bacteriophages were used as therapeutic agents in treatment of dysentery caused by Shigella dysenteriae as far back as 1919 and in the experimental treatment of a wide variety of other bacterial infections caused by Vibrio cholerae, Staphylococcus sp., Pseudomonas sp. etc, with varying degrees of success. Phage therapy and its many prospects soon fell out of favour in western medicine after the Second World War, with the discovery of penicillin. The Soviet Union and other countries in Eastern Europe however mastered the craft of bacteriophage isolation, purification and cocktail preparation, with phage-based therapeutics becoming widely available over-the-counter. With the recent rise in cases of multi-drug resistant bacterial infections, the clamour for a return to phage therapy, as a potential solution to the anti-microbial resistance (AMR) crisis has grown louder. This review provides an extensive exposé on phage therapy, addressing its historical use, evidences of its safety and efficacy, its pros and cons when compared with antibiotics, cases of compassionate use for treating life-threatening antibiotic-resistant infections, the limitations to its acceptance and how these may be circumvented.","container-title":"AIMS microbiology","DOI":"10.3934/microbiol.2020014","ISSN":"2471-1888","issue":"3","language":"eng","note":"section: 0","page":"204–230","title":"An exegesis of bacteriophage therapy: An emerging player in the fight against anti-microbial resistance","volume":"6","author":[{"family":"Adesanya","given":"Oluwafolajimi"},{"family":"Oduselu","given":"Tolulope"},{"family":"Akin-Ajani","given":"Oluwawapelumi"},{"family":"Adewumi","given":"Olubusuyi M."},{"family":"Ademowo","given":"Olusegun G."}],"issued":{"date-parts":[["2020"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->19<!-- [if supportFields]><![endif]-->. However, there is still much to learn from countries that have not abandoned phage therapy, particularly regarding research, development, policy, and legal considerations, if phage-based therapeutics are to be integrated into modern medicine <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"KqW9luG6","properties":{"formattedCitation":"\\super 19\\nosupersub{}","plainCitation":"19","noteIndex":0},"citationItems":[{"id":1143,"uris":["http://zotero.org/users/11334842/items/YD3LKXA9"],"itemData":{"id":1143,"type":"article-journal","abstract":"Bacteriophages (simply referred to as Phages) are a class of viruses with the ability to infect and kill prokaryotic cells (bacteria), but are unable to infect mammalian cells. This unique ability to achieve specific infectiousness by bacteriophages has been harnessed in antibacterial treatments dating back almost a decade before the antibiotic era began. Bacteriophages were used as therapeutic agents in treatment of dysentery caused by Shigella dysenteriae as far back as 1919 and in the experimental treatment of a wide variety of other bacterial infections caused by Vibrio cholerae, Staphylococcus sp., Pseudomonas sp. etc, with varying degrees of success. Phage therapy and its many prospects soon fell out of favour in western medicine after the Second World War, with the discovery of penicillin. The Soviet Union and other countries in Eastern Europe however mastered the craft of bacteriophage isolation, purification and cocktail preparation, with phage-based therapeutics becoming widely available over-the-counter. With the recent rise in cases of multi-drug resistant bacterial infections, the clamour for a return to phage therapy, as a potential solution to the anti-microbial resistance (AMR) crisis has grown louder. This review provides an extensive exposé on phage therapy, addressing its historical use, evidences of its safety and efficacy, its pros and cons when compared with antibiotics, cases of compassionate use for treating life-threatening antibiotic-resistant infections, the limitations to its acceptance and how these may be circumvented.","container-title":"AIMS microbiology","DOI":"10.3934/microbiol.2020014","ISSN":"2471-1888","issue":"3","language":"eng","note":"section: 0","page":"204–230","title":"An exegesis of bacteriophage therapy: An emerging player in the fight against anti-microbial resistance","volume":"6","author":[{"family":"Adesanya","given":"Oluwafolajimi"},{"family":"Oduselu","given":"Tolulope"},{"family":"Akin-Ajani","given":"Oluwawapelumi"},{"family":"Adewumi","given":"Olubusuyi M."},{"family":"Ademowo","given":"Olusegun G."}],"issued":{"date-parts":[["2020"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->19<!-- [if supportFields]><![endif]-->. Examples from the Literature There are several case reports of unfavorable outcomes with phage treatment. One report discusses the development of reversible transaminitis in a patient with chronic methicillin-resistant S. aureus prosthetic joint infection following phage therapy was probably caused by underlying steatosis and cytokine response <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"S2NUJN9W","properties":{"formattedCitation":"\\super 31\\nosupersub{}","plainCitation":"31","noteIndex":0},"citationItems":[{"id":1329,"uris":["http://zotero.org/users/11334842/items/S7VD2PRQ"],"itemData":{"id":1329,"type":"article-journal","abstract":"This is a case of a 72 year old male with a chronic methicillin-resistant Staphylococcus aureus prosthetic joint infection. After the third intravenous dose of bacteriophage therapy, an unusual, reversible transaminitis prompted stoppage of bacteriophage therapy. Nevertheless, treatment was successful and the patient’s severe chronic infection was eradicated.","container-title":"Antibiotics","DOI":"10.3390/antibiotics9050241","ISSN":"2079-6382","issue":"5","journalAbbreviation":"Antibiotics (Basel)","note":"PMID: 32397354\nPMCID: PMC7277870","page":"241","source":"PubMed Central","title":"Salvage Bacteriophage Therapy for a Chronic MRSA Prosthetic Joint Infection","volume":"9","author":[{"family":"Doub","given":"James B."},{"family":"Ng","given":"Vincent Y."},{"family":"Johnson","given":"Aaron J."},{"family":"Slomka","given":"Magdalena"},{"family":"Fackler","given":"Joseph"},{"family":"Horne","given":"Bri’Anna"},{"family":"Brownstein","given":"Michael J."},{"family":"Henry","given":"Matthew"},{"family":"Malagon","given":"Francisco"},{"family":"Biswas","given":"Biswajit"}],"issued":{"date-parts":[["2020",5,9]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->31<!-- [if supportFields]><![endif]-->. Another describes a diabetic patient with necrotizing pancreatitis and Acinetobacter baumannii infection temporarily required more vasopressors following phage therapy, but things got better after phage therapy was resumed <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"zE8smMcZ","properties":{"formattedCitation":"\\super 22\\nosupersub{}","plainCitation":"22","noteIndex":0},"citationItems":[{"id":1229,"uris":["http://zotero.org/users/11334842/items/S76547XD"],"itemData":{"id":1229,"type":"article-journal","abstract":"Increasing rates of infection by antibiotic resistant bacteria have led to a resurgence of interest in bacteriophage (phage) therapy. Several phage therapy studies in animals and humans have been completed over the last two decades. We conducted a systematic review of safety and toxicity data associated with phage therapy in both animals and humans reported in English language publications from 2008-2021. Overall, 69 publications met our eligibility criteria including 20 animal studies, 35 clinical case reports or case series, and 14 clinical trials. After summarizing safety and toxicity data from these publications, we discuss potential approaches to optimize safety and toxicity monitoring with the therapeutic use of phage moving forward. In our systematic review of the literature, we found some adverse events associated with phage therapy, but serious events were extremely rare. Comprehensive and standardized reporting of potential toxicities associated with phage therapy has generally been lacking in the published literature. Structured safety and tolerability endpoints are necessary when phages are administered as anti-infective therapeutics.","container-title":"Viruses","DOI":"10.3390/v13071268","ISSN":"1999-4915","issue":"7","language":"eng","note":"section: 0","page":"1268","title":"The Safety and Toxicity of Phage Therapy: A Review of Animal and Clinical Studies","volume":"13","author":[{"family":"Liu","given":"Dan"},{"family":"Van Belleghem","given":"Jonas D."},{"family":"Vries","given":"Christiaan R.","non-dropping-particle":"de"},{"family":"Burgener","given":"Elizabeth"},{"family":"Chen","given":"Qingquan"},{"family":"Manasherob","given":"Robert"},{"family":"Aronson","given":"Jenny R."},{"family":"Amanatullah","given":"Derek F."},{"family":"Tamma","given":"Pranita D."},{"family":"Suh","given":"Gina A."}],"issued":{"date-parts":[["2021",6]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->22<!-- [if supportFields]><![endif]-->. During phage therapy, a child with P. aeruginosa bacteremia experienced anaphylaxis-related decompensation, possibly because of developing heart failure or endotoxin release <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"fWGROZjB","properties":{"formattedCitation":"\\super 22\\nosupersub{}","plainCitation":"22","noteIndex":0},"citationItems":[{"id":1229,"uris":["http://zotero.org/users/11334842/items/S76547XD"],"itemData":{"id":1229,"type":"article-journal","abstract":"Increasing rates of infection by antibiotic resistant bacteria have led to a resurgence of interest in bacteriophage (phage) therapy. Several phage therapy studies in animals and humans have been completed over the last two decades. We conducted a systematic review of safety and toxicity data associated with phage therapy in both animals and humans reported in English language publications from 2008-2021. Overall, 69 publications met our eligibility criteria including 20 animal studies, 35 clinical case reports or case series, and 14 clinical trials. After summarizing safety and toxicity data from these publications, we discuss potential approaches to optimize safety and toxicity monitoring with the therapeutic use of phage moving forward. In our systematic review of the literature, we found some adverse events associated with phage therapy, but serious events were extremely rare. Comprehensive and standardized reporting of potential toxicities associated with phage therapy has generally been lacking in the published literature. Structured safety and tolerability endpoints are necessary when phages are administered as anti-infective therapeutics.","container-title":"Viruses","DOI":"10.3390/v13071268","ISSN":"1999-4915","issue":"7","language":"eng","note":"section: 0","page":"1268","title":"The Safety and Toxicity of Phage Therapy: A Review of Animal and Clinical Studies","volume":"13","author":[{"family":"Liu","given":"Dan"},{"family":"Van Belleghem","given":"Jonas D."},{"family":"Vries","given":"Christiaan R.","non-dropping-particle":"de"},{"family":"Burgener","given":"Elizabeth"},{"family":"Chen","given":"Qingquan"},{"family":"Manasherob","given":"Robert"},{"family":"Aronson","given":"Jenny R."},{"family":"Amanatullah","given":"Derek F."},{"family":"Tamma","given":"Pranita D."},{"family":"Suh","given":"Gina A."}],"issued":{"date-parts":[["2021",6]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->22<!-- [if supportFields]><![endif]-->. There is also a case of a patient with P.aeruginosa UTI who experienced fever and chills during phage therapy due to endotoxin release and the antibiotic regimen had to be changed <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"rWpnlJji","properties":{"formattedCitation":"\\super 22\\nosupersub{}","plainCitation":"22","noteIndex":0},"citationItems":[{"id":1229,"uris":["http://zotero.org/users/11334842/items/S76547XD"],"itemData":{"id":1229,"type":"article-journal","abstract":"Increasing rates of infection by antibiotic resistant bacteria have led to a resurgence of interest in bacteriophage (phage) therapy. Several phage therapy studies in animals and humans have been completed over the last two decades. We conducted a systematic review of safety and toxicity data associated with phage therapy in both animals and humans reported in English language publications from 2008-2021. Overall, 69 publications met our eligibility criteria including 20 animal studies, 35 clinical case reports or case series, and 14 clinical trials. After summarizing safety and toxicity data from these publications, we discuss potential approaches to optimize safety and toxicity monitoring with the therapeutic use of phage moving forward. In our systematic review of the literature, we found some adverse events associated with phage therapy, but serious events were extremely rare. Comprehensive and standardized reporting of potential toxicities associated with phage therapy has generally been lacking in the published literature. Structured safety and tolerability endpoints are necessary when phages are administered as anti-infective therapeutics.","container-title":"Viruses","DOI":"10.3390/v13071268","ISSN":"1999-4915","issue":"7","language":"eng","note":"section: 0","page":"1268","title":"The Safety and Toxicity of Phage Therapy: A Review of Animal and Clinical Studies","volume":"13","author":[{"family":"Liu","given":"Dan"},{"family":"Van Belleghem","given":"Jonas D."},{"family":"Vries","given":"Christiaan R.","non-dropping-particle":"de"},{"family":"Burgener","given":"Elizabeth"},{"family":"Chen","given":"Qingquan"},{"family":"Manasherob","given":"Robert"},{"family":"Aronson","given":"Jenny R."},{"family":"Amanatullah","given":"Derek F."},{"family":"Tamma","given":"Pranita D."},{"family":"Suh","given":"Gina A."}],"issued":{"date-parts":[["2021",6]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->22<!-- [if supportFields]><![endif]-->. There are also many clinical trials involving phages. Phage therapy's safety was examined in trials for a variety of illnesses, including endocarditis, UTIs, venous leg ulcers, chronic otitis media, and more <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"KAUJpnpS","properties":{"formattedCitation":"\\super 22\\nosupersub{}","plainCitation":"22","noteIndex":0},"citationItems":[{"id":1229,"uris":["http://zotero.org/users/11334842/items/S76547XD"],"itemData":{"id":1229,"type":"article-journal","abstract":"Increasing rates of infection by antibiotic resistant bacteria have led to a resurgence of interest in bacteriophage (phage) therapy. Several phage therapy studies in animals and humans have been completed over the last two decades. We conducted a systematic review of safety and toxicity data associated with phage therapy in both animals and humans reported in English language publications from 2008-2021. Overall, 69 publications met our eligibility criteria including 20 animal studies, 35 clinical case reports or case series, and 14 clinical trials. After summarizing safety and toxicity data from these publications, we discuss potential approaches to optimize safety and toxicity monitoring with the therapeutic use of phage moving forward. In our systematic review of the literature, we found some adverse events associated with phage therapy, but serious events were extremely rare. Comprehensive and standardized reporting of potential toxicities associated with phage therapy has generally been lacking in the published literature. Structured safety and tolerability endpoints are necessary when phages are administered as anti-infective therapeutics.","container-title":"Viruses","DOI":"10.3390/v13071268","ISSN":"1999-4915","issue":"7","language":"eng","note":"section: 0","page":"1268","title":"The Safety and Toxicity of Phage Therapy: A Review of Animal and Clinical Studies","volume":"13","author":[{"family":"Liu","given":"Dan"},{"family":"Van Belleghem","given":"Jonas D."},{"family":"Vries","given":"Christiaan R.","non-dropping-particle":"de"},{"family":"Burgener","given":"Elizabeth"},{"family":"Chen","given":"Qingquan"},{"family":"Manasherob","given":"Robert"},{"family":"Aronson","given":"Jenny R."},{"family":"Amanatullah","given":"Derek F."},{"family":"Tamma","given":"Pranita D."},{"family":"Suh","given":"Gina A."}],"issued":{"date-parts":[["2021",6]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->22<!-- [if supportFields]><![endif]-->. A study in which healthy persons consumed E.coli phages revealed no changes in the amount of IL-4 in the blood, decreased fecal E.coli burdens, and no significant changes in the gut microbiota <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"dEk7EvOo","properties":{"formattedCitation":"\\super 22\\nosupersub{}","plainCitation":"22","noteIndex":0},"citationItems":[{"id":1229,"uris":["http://zotero.org/users/11334842/items/S76547XD"],"itemData":{"id":1229,"type":"article-journal","abstract":"Increasing rates of infection by antibiotic resistant bacteria have led to a resurgence of interest in bacteriophage (phage) therapy. Several phage therapy studies in animals and humans have been completed over the last two decades. We conducted a systematic review of safety and toxicity data associated with phage therapy in both animals and humans reported in English language publications from 2008-2021. Overall, 69 publications met our eligibility criteria including 20 animal studies, 35 clinical case reports or case series, and 14 clinical trials. After summarizing safety and toxicity data from these publications, we discuss potential approaches to optimize safety and toxicity monitoring with the therapeutic use of phage moving forward. In our systematic review of the literature, we found some adverse events associated with phage therapy, but serious events were extremely rare. Comprehensive and standardized reporting of potential toxicities associated with phage therapy has generally been lacking in the published literature. Structured safety and tolerability endpoints are necessary when phages are administered as anti-infective therapeutics.","container-title":"Viruses","DOI":"10.3390/v13071268","ISSN":"1999-4915","issue":"7","language":"eng","note":"section: 0","page":"1268","title":"The Safety and Toxicity of Phage Therapy: A Review of Animal and Clinical Studies","volume":"13","author":[{"family":"Liu","given":"Dan"},{"family":"Van Belleghem","given":"Jonas D."},{"family":"Vries","given":"Christiaan R.","non-dropping-particle":"de"},{"family":"Burgener","given":"Elizabeth"},{"family":"Chen","given":"Qingquan"},{"family":"Manasherob","given":"Robert"},{"family":"Aronson","given":"Jenny R."},{"family":"Amanatullah","given":"Derek F."},{"family":"Tamma","given":"Pranita D."},{"family":"Suh","given":"Gina A."}],"issued":{"date-parts":[["2021",6]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->22<!-- [if supportFields]><![endif]-->. In another study, healthy volunteers were given a broad-spectrum phage cocktail and experienced back discomfort, gastric acidity, allergic rhinitis, and low-grade fever <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"RkmiCZWy","properties":{"formattedCitation":"\\super 22\\nosupersub{}","plainCitation":"22","noteIndex":0},"citationItems":[{"id":1229,"uris":["http://zotero.org/users/11334842/items/S76547XD"],"itemData":{"id":1229,"type":"article-journal","abstract":"Increasing rates of infection by antibiotic resistant bacteria have led to a resurgence of interest in bacteriophage (phage) therapy. Several phage therapy studies in animals and humans have been completed over the last two decades. We conducted a systematic review of safety and toxicity data associated with phage therapy in both animals and humans reported in English language publications from 2008-2021. Overall, 69 publications met our eligibility criteria including 20 animal studies, 35 clinical case reports or case series, and 14 clinical trials. After summarizing safety and toxicity data from these publications, we discuss potential approaches to optimize safety and toxicity monitoring with the therapeutic use of phage moving forward. In our systematic review of the literature, we found some adverse events associated with phage therapy, but serious events were extremely rare. Comprehensive and standardized reporting of potential toxicities associated with phage therapy has generally been lacking in the published literature. Structured safety and tolerability endpoints are necessary when phages are administered as anti-infective therapeutics.","container-title":"Viruses","DOI":"10.3390/v13071268","ISSN":"1999-4915","issue":"7","language":"eng","note":"section: 0","page":"1268","title":"The Safety and Toxicity of Phage Therapy: A Review of Animal and Clinical Studies","volume":"13","author":[{"family":"Liu","given":"Dan"},{"family":"Van Belleghem","given":"Jonas D."},{"family":"Vries","given":"Christiaan R.","non-dropping-particle":"de"},{"family":"Burgener","given":"Elizabeth"},{"family":"Chen","given":"Qingquan"},{"family":"Manasherob","given":"Robert"},{"family":"Aronson","given":"Jenny R."},{"family":"Amanatullah","given":"Derek F."},{"family":"Tamma","given":"Pranita D."},{"family":"Suh","given":"Gina A."}],"issued":{"date-parts":[["2021",6]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->22<!-- [if supportFields]><![endif]-->. The PhagoBurn burn wound clinical trial examined phage therapy for burn wounds infected with P. aeruginosa. When a phage cocktail was given to the wound, the outcomes were disappointingly poor; this may have been because the phage dose was less than what was intended <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"FDCl24jj","properties":{"formattedCitation":"\\super 23\\nosupersub{}","plainCitation":"23","noteIndex":0},"citationItems":[{"id":1293,"uris":["http://zotero.org/users/11334842/items/P6WLFGEY"],"itemData":{"id":1293,"type":"article-journal","container-title":"Cell Host & Microbe","DOI":"10.1016/j.chom.2019.01.014","ISSN":"1931-3128","issue":"2","language":"English","note":"section: 0","page":"219–232","title":"Phage Therapy: A Renewed Approach to Combat Antibiotic-Resistant Bacteria","volume":"25","author":[{"family":"Kortright","given":"Kaitlyn E."},{"family":"Chan","given":"Benjamin K."},{"family":"Koff","given":"Jonathan L."},{"family":"Turner","given":"Paul E."}],"issued":{"date-parts":[["2019",2]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->23<!-- [if supportFields]><![endif]-->. Possible antagonistic effect with antibiotics Contrary to expectations, antibiotics like streptomycin caused bacterial resistance to phages <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"zPoDS500","properties":{"formattedCitation":"\\super 22\\nosupersub{}","plainCitation":"22","noteIndex":0},"citationItems":[{"id":1229,"uris":["http://zotero.org/users/11334842/items/S76547XD"],"itemData":{"id":1229,"type":"article-journal","abstract":"Increasing rates of infection by antibiotic resistant bacteria have led to a resurgence of interest in bacteriophage (phage) therapy. Several phage therapy studies in animals and humans have been completed over the last two decades. We conducted a systematic review of safety and toxicity data associated with phage therapy in both animals and humans reported in English language publications from 2008-2021. Overall, 69 publications met our eligibility criteria including 20 animal studies, 35 clinical case reports or case series, and 14 clinical trials. After summarizing safety and toxicity data from these publications, we discuss potential approaches to optimize safety and toxicity monitoring with the therapeutic use of phage moving forward. In our systematic review of the literature, we found some adverse events associated with phage therapy, but serious events were extremely rare. Comprehensive and standardized reporting of potential toxicities associated with phage therapy has generally been lacking in the published literature. Structured safety and tolerability endpoints are necessary when phages are administered as anti-infective therapeutics.","container-title":"Viruses","DOI":"10.3390/v13071268","ISSN":"1999-4915","issue":"7","language":"eng","note":"section: 0","page":"1268","title":"The Safety and Toxicity of Phage Therapy: A Review of Animal and Clinical Studies","volume":"13","author":[{"family":"Liu","given":"Dan"},{"family":"Van Belleghem","given":"Jonas D."},{"family":"Vries","given":"Christiaan R.","non-dropping-particle":"de"},{"family":"Burgener","given":"Elizabeth"},{"family":"Chen","given":"Qingquan"},{"family":"Manasherob","given":"Robert"},{"family":"Aronson","given":"Jenny R."},{"family":"Amanatullah","given":"Derek F."},{"family":"Tamma","given":"Pranita D."},{"family":"Suh","given":"Gina A."}],"issued":{"date-parts":[["2021",6]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->22<!-- [if supportFields]><![endif]-->. This is not only limited to streptomycin, as any antibiotic that interferes with protein translation and synthesis can stop the phage replication inside bacterial cells as well, limiting the awaited therapeutic effect <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"bFv5qiSH","properties":{"formattedCitation":"\\super 32\\nosupersub{}","plainCitation":"32","noteIndex":0},"citationItems":[{"id":1341,"uris":["http://zotero.org/users/11334842/items/D6A33LF6"],"itemData":{"id":1341,"type":"article-journal","abstract":"It is becoming increasingly clear that antibiotics can both positively and negatively impact the infectivity of bacteriophages (phage), but the underlying mechanisms often remain unclear. Here we demonstrate that antibiotics that target the protein translation machinery can fundamentally alter the outcome of bacteria–phage interactions by interfering with the production of phage-encoded counter-defense proteins. Specifically, using Pseudomonas aeruginosa PA14 and phage DMS3vir as a model, we show that bacteria with Clustered Regularly Interspaced Short Palindromic Repeat, CRISPR associated (CRISPR-Cas) immune systems have elevated levels of immunity against phage that encode anti-CRISPR (acr) genes when translation inhibitors are present in the environment. CRISPR-Cas are highly prevalent defense systems that enable bacteria to detect and destroy phage genomes in a sequence-specific manner. In response, many phages encode acr genes that are expressed immediately following the infection to inhibit key steps of the CRISPR-Cas immune response. Our data show that while phage-carrying acr genes can amplify efficiently on bacteria with CRISPR-Cas immune systems in the absence of antibiotics, the presence of antibiotics that act on protein translation prevents phage amplification, while protecting bacteria from lysis.","container-title":"Proceedings of the National Academy of Sciences","DOI":"10.1073/pnas.2216084120","issue":"4","note":"publisher: Proceedings of the National Academy of Sciences","page":"e2216084120","source":"pnas.org (Atypon)","title":"Antibiotics that affect translation can antagonize phage infectivity by interfering with the deployment of counter-defenses","volume":"120","author":[{"family":"Pons","given":"Benoit J."},{"family":"Dimitriu","given":"Tatiana"},{"family":"Westra","given":"Edze R."},{"family":"Houte","given":"Stineke","non-dropping-particle":"van"}],"issued":{"date-parts":[["2023",1,24]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->32<!-- [if supportFields]><![endif]-->. Part IV: Administration Route and Dosing The form and route of phage administration is a critical consideration for accurate dosage calculation <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"EC7jSTj8","properties":{"formattedCitation":"\\super 20\\nosupersub{}","plainCitation":"20","noteIndex":0},"citationItems":[{"id":1295,"uris":["http://zotero.org/users/11334842/items/3ZV2PTLG"],"itemData":{"id":1295,"type":"article-journal","abstract":"Bacteriophages (phages) may constitute a natural, safe, and effective strategy to prevent and control multidrug-resistant organisms (MDROs), and ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens in particular. Few clinical studies have assessed the safety and efficacy of phages in patients infected with MDROs. This systematic review summarizes and critically evaluates published studies of phages in clinical practice and presents the appropriate phage selection criteria, as well as recommendations for clinicians and scientists for a successful therapy. Articles were identified through a search of the PubMed, Ovid, EMBASE, and Cochrane Library databases. Among 1102 articles and abstracts, 30 studies were selected and evaluated using selective inclusion criteria, phage criteria, and study characteristics. Most studies showed efficacy (87%) and safety (67%) of the tested phages, but few studies examined phage resistance (35%). Clinical studies and regulatory changes are needed to determine the safety and efficacy of phages and to advance their use in patients with MDRO infections.","container-title":"Clinical Infectious Diseases","DOI":"10.1093/cid/ciy947","ISSN":"1058-4838","issue":"1","note":"section: 0","page":"167–178","title":"A Systematic and Critical Review of Bacteriophage Therapy Against Multidrug-resistant ESKAPE Organisms in Humans","volume":"69","author":[{"family":"El Haddad","given":"Lynn"},{"family":"Harb","given":"Cynthia P"},{"family":"Gebara","given":"Marc A"},{"family":"Stibich","given":"Mark A"},{"family":"Chemaly","given":"Roy F"}],"issued":{"date-parts":[["2019",6]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->20<!-- [if supportFields]><![endif]-->. Some phages are used as ointments on wounds and burns. For that, gel applications have shown better outcomes in comparison to sprays <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"7rgGKBk2","properties":{"formattedCitation":"\\super 20\\nosupersub{}","plainCitation":"20","noteIndex":0},"citationItems":[{"id":1295,"uris":["http://zotero.org/users/11334842/items/3ZV2PTLG"],"itemData":{"id":1295,"type":"article-journal","abstract":"Bacteriophages (phages) may constitute a natural, safe, and effective strategy to prevent and control multidrug-resistant organisms (MDROs), and ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens in particular. Few clinical studies have assessed the safety and efficacy of phages in patients infected with MDROs. This systematic review summarizes and critically evaluates published studies of phages in clinical practice and presents the appropriate phage selection criteria, as well as recommendations for clinicians and scientists for a successful therapy. Articles were identified through a search of the PubMed, Ovid, EMBASE, and Cochrane Library databases. Among 1102 articles and abstracts, 30 studies were selected and evaluated using selective inclusion criteria, phage criteria, and study characteristics. Most studies showed efficacy (87%) and safety (67%) of the tested phages, but few studies examined phage resistance (35%). Clinical studies and regulatory changes are needed to determine the safety and efficacy of phages and to advance their use in patients with MDRO infections.","container-title":"Clinical Infectious Diseases","DOI":"10.1093/cid/ciy947","ISSN":"1058-4838","issue":"1","note":"section: 0","page":"167–178","title":"A Systematic and Critical Review of Bacteriophage Therapy Against Multidrug-resistant ESKAPE Organisms in Humans","volume":"69","author":[{"family":"El Haddad","given":"Lynn"},{"family":"Harb","given":"Cynthia P"},{"family":"Gebara","given":"Marc A"},{"family":"Stibich","given":"Mark A"},{"family":"Chemaly","given":"Roy F"}],"issued":{"date-parts":[["2019",6]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->20<!-- [if supportFields]><![endif]-->. Oral delivery is challenging due to destruction in the stomach due to high acidity, but techniques like gastric fluid neutralization and capsule formulations can enhance absorption<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"9p7ZKdMH","properties":{"formattedCitation":"\\super 33\\nosupersub{}","plainCitation":"33","noteIndex":0},"citationItems":[{"id":1340,"uris":["http://zotero.org/users/11334842/items/29P2Q73H"],"itemData":{"id":1340,"type":"article-journal","abstract":"Introduction\nThere has been renewed interest in the therapeutic use of bacteriophages (phages); however, standardised therapeutic protocols are lacking, and there is a paucity of rigorous clinical trial data assessing efficacy.\n\nMethods and analysis\nWe propose an open-label, single-arm trial investigating a standardised treatment and monitoring protocol for phage therapy. Patients included will have exhausted other therapeutic options for control of their infection and phage therapy will be administered under Australia’s Therapeutic Goods Administration Special Access Scheme. A phage product with high in vitro activity against the targeted pathogen(s) must be available in line with relevant regulatory requirements. We aim to recruit 50–100 patients over 5 years, from any public or private hospitals in Australia. The standardised protocol will specify clinical assessments and biological sampling at scheduled time points. The primary outcome is safety at day 29, assessed by the frequency of adverse events, and overseen by an independent Data Safety Monitoring Board. Secondary outcomes include long-term safety (frequency of adverse events until at least 6 months following phage therapy), and feasibility, measured as the proportion of participants with>80% of minimum data available for analysis. Additional endpoints assessed include clinical response, patient/guardian reported quality of life measures, phage pharmacokinetics, human host immune responses and microbiome analysis. All trial outcomes will be summarised and presented using standard descriptive statistics.\n\nEthics and dissemination\nParticipant inclusion will be dependent on obtaining written informed consent from the patient or guardian. The trial protocol was approved by the Sydney Children’s Hospitals Network Human Research Ethics Committee in December 2021 (Reference 2021/ETH11861). In addition to publication in a peer-reviewed scientific journal, a lay summary of study outcomes will be made available for participants and the public on the Phage Australia website (https://www.phageaustralia.org/).\n\nTrial registration number\nRegistered on ANZCTR, 10 November 2021 (ACTRN12621001526864; WHO Universal Trial Number: U1111-1269-6000).","container-title":"BMJ Open","DOI":"10.1136/bmjopen-2022-065401","ISSN":"2044-6055","issue":"12","journalAbbreviation":"BMJ Open","note":"PMID: 36600337\nPMCID: PMC9743374","page":"e065401","source":"PubMed Central","title":"Standardised treatment and monitoring protocol to assess safety and tolerability of bacteriophage therapy for adult and paediatric patients (STAMP study): protocol for an open-label, single-arm trial","title-short":"Standardised treatment and monitoring protocol to assess safety and tolerability of bacteriophage therapy for adult and paediatric patients (STAMP study)","volume":"12","author":[{"family":"Khatami","given":"Ameneh"},{"family":"Foley","given":"David A"},{"family":"Warner","given":"Morgyn S"},{"family":"Barnes","given":"Elizabeth H"},{"family":"Peleg","given":"Anton Y"},{"family":"Li","given":"Jian"},{"family":"Stick","given":"Stephen"},{"family":"Burke","given":"Nettie"},{"family":"Lin","given":"Ruby C Y"},{"family":"Warning","given":"Julia"},{"family":"Snelling","given":"Thomas L"},{"family":"Tong","given":"Steven Y C"},{"family":"Iredell","given":"Jonathan"}],"issued":{"date-parts":[["2022",12,9]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->33<!-- [if supportFields]><![endif]-->. Intravenous administration is theoretically efficient but may trigger immune responses leading to fever or other constitutional symptoms <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"XUAIG8J1","properties":{"formattedCitation":"\\super 20\\nosupersub{}","plainCitation":"20","noteIndex":0},"citationItems":[{"id":1295,"uris":["http://zotero.org/users/11334842/items/3ZV2PTLG"],"itemData":{"id":1295,"type":"article-journal","abstract":"Bacteriophages (phages) may constitute a natural, safe, and effective strategy to prevent and control multidrug-resistant organisms (MDROs), and ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens in particular. Few clinical studies have assessed the safety and efficacy of phages in patients infected with MDROs. This systematic review summarizes and critically evaluates published studies of phages in clinical practice and presents the appropriate phage selection criteria, as well as recommendations for clinicians and scientists for a successful therapy. Articles were identified through a search of the PubMed, Ovid, EMBASE, and Cochrane Library databases. Among 1102 articles and abstracts, 30 studies were selected and evaluated using selective inclusion criteria, phage criteria, and study characteristics. Most studies showed efficacy (87%) and safety (67%) of the tested phages, but few studies examined phage resistance (35%). Clinical studies and regulatory changes are needed to determine the safety and efficacy of phages and to advance their use in patients with MDRO infections.","container-title":"Clinical Infectious Diseases","DOI":"10.1093/cid/ciy947","ISSN":"1058-4838","issue":"1","note":"section: 0","page":"167–178","title":"A Systematic and Critical Review of Bacteriophage Therapy Against Multidrug-resistant ESKAPE Organisms in Humans","volume":"69","author":[{"family":"El Haddad","given":"Lynn"},{"family":"Harb","given":"Cynthia P"},{"family":"Gebara","given":"Marc A"},{"family":"Stibich","given":"Mark A"},{"family":"Chemaly","given":"Roy F"}],"issued":{"date-parts":[["2019",6]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->20<!-- [if supportFields]><![endif]-->. Current phage therapies don't have standardized formulations and are instead individualized. There are various methods, like as genetic engineering, phage bank expansion, and phage cocktail and antibiotic fusion <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"kA8FNUnV","properties":{"formattedCitation":"\\super 22\\nosupersub{}","plainCitation":"22","noteIndex":0},"citationItems":[{"id":1229,"uris":["http://zotero.org/users/11334842/items/S76547XD"],"itemData":{"id":1229,"type":"article-journal","abstract":"Increasing rates of infection by antibiotic resistant bacteria have led to a resurgence of interest in bacteriophage (phage) therapy. Several phage therapy studies in animals and humans have been completed over the last two decades. We conducted a systematic review of safety and toxicity data associated with phage therapy in both animals and humans reported in English language publications from 2008-2021. Overall, 69 publications met our eligibility criteria including 20 animal studies, 35 clinical case reports or case series, and 14 clinical trials. After summarizing safety and toxicity data from these publications, we discuss potential approaches to optimize safety and toxicity monitoring with the therapeutic use of phage moving forward. In our systematic review of the literature, we found some adverse events associated with phage therapy, but serious events were extremely rare. Comprehensive and standardized reporting of potential toxicities associated with phage therapy has generally been lacking in the published literature. Structured safety and tolerability endpoints are necessary when phages are administered as anti-infective therapeutics.","container-title":"Viruses","DOI":"10.3390/v13071268","ISSN":"1999-4915","issue":"7","language":"eng","note":"section: 0","page":"1268","title":"The Safety and Toxicity of Phage Therapy: A Review of Animal and Clinical Studies","volume":"13","author":[{"family":"Liu","given":"Dan"},{"family":"Van Belleghem","given":"Jonas D."},{"family":"Vries","given":"Christiaan R.","non-dropping-particle":"de"},{"family":"Burgener","given":"Elizabeth"},{"family":"Chen","given":"Qingquan"},{"family":"Manasherob","given":"Robert"},{"family":"Aronson","given":"Jenny R."},{"family":"Amanatullah","given":"Derek F."},{"family":"Tamma","given":"Pranita D."},{"family":"Suh","given":"Gina A."}],"issued":{"date-parts":[["2021",6]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->22<!-- [if supportFields]><![endif]-->. Although the development of topical and inhalable medications shows promise, there are still issues with dose, kinetics, and stability <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"zRNK2uQ4","properties":{"formattedCitation":"\\super 22\\nosupersub{}","plainCitation":"22","noteIndex":0},"citationItems":[{"id":1229,"uris":["http://zotero.org/users/11334842/items/S76547XD"],"itemData":{"id":1229,"type":"article-journal","abstract":"Increasing rates of infection by antibiotic resistant bacteria have led to a resurgence of interest in bacteriophage (phage) therapy. Several phage therapy studies in animals and humans have been completed over the last two decades. We conducted a systematic review of safety and toxicity data associated with phage therapy in both animals and humans reported in English language publications from 2008-2021. Overall, 69 publications met our eligibility criteria including 20 animal studies, 35 clinical case reports or case series, and 14 clinical trials. After summarizing safety and toxicity data from these publications, we discuss potential approaches to optimize safety and toxicity monitoring with the therapeutic use of phage moving forward. In our systematic review of the literature, we found some adverse events associated with phage therapy, but serious events were extremely rare. Comprehensive and standardized reporting of potential toxicities associated with phage therapy has generally been lacking in the published literature. Structured safety and tolerability endpoints are necessary when phages are administered as anti-infective therapeutics.","container-title":"Viruses","DOI":"10.3390/v13071268","ISSN":"1999-4915","issue":"7","language":"eng","note":"section: 0","page":"1268","title":"The Safety and Toxicity of Phage Therapy: A Review of Animal and Clinical Studies","volume":"13","author":[{"family":"Liu","given":"Dan"},{"family":"Van Belleghem","given":"Jonas D."},{"family":"Vries","given":"Christiaan R.","non-dropping-particle":"de"},{"family":"Burgener","given":"Elizabeth"},{"family":"Chen","given":"Qingquan"},{"family":"Manasherob","given":"Robert"},{"family":"Aronson","given":"Jenny R."},{"family":"Amanatullah","given":"Derek F."},{"family":"Tamma","given":"Pranita D."},{"family":"Suh","given":"Gina A."}],"issued":{"date-parts":[["2021",6]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->22<!-- [if supportFields]><![endif]-->. The main challenge here is that phages are able to self-replicate, but if administered in low doses, bacteria can quickly resist them before they can overwhelm bacteria with their numbers. Besides, higher doses can have more side effects <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"bwfCbKrW","properties":{"formattedCitation":"\\super 33\\nosupersub{}","plainCitation":"33","noteIndex":0},"citationItems":[{"id":1340,"uris":["http://zotero.org/users/11334842/items/29P2Q73H"],"itemData":{"id":1340,"type":"article-journal","abstract":"Introduction\nThere has been renewed interest in the therapeutic use of bacteriophages (phages); however, standardised therapeutic protocols are lacking, and there is a paucity of rigorous clinical trial data assessing efficacy.\n\nMethods and analysis\nWe propose an open-label, single-arm trial investigating a standardised treatment and monitoring protocol for phage therapy. Patients included will have exhausted other therapeutic options for control of their infection and phage therapy will be administered under Australia’s Therapeutic Goods Administration Special Access Scheme. A phage product with high in vitro activity against the targeted pathogen(s) must be available in line with relevant regulatory requirements. We aim to recruit 50–100 patients over 5 years, from any public or private hospitals in Australia. The standardised protocol will specify clinical assessments and biological sampling at scheduled time points. The primary outcome is safety at day 29, assessed by the frequency of adverse events, and overseen by an independent Data Safety Monitoring Board. Secondary outcomes include long-term safety (frequency of adverse events until at least 6 months following phage therapy), and feasibility, measured as the proportion of participants with>80% of minimum data available for analysis. Additional endpoints assessed include clinical response, patient/guardian reported quality of life measures, phage pharmacokinetics, human host immune responses and microbiome analysis. All trial outcomes will be summarised and presented using standard descriptive statistics.\n\nEthics and dissemination\nParticipant inclusion will be dependent on obtaining written informed consent from the patient or guardian. The trial protocol was approved by the Sydney Children’s Hospitals Network Human Research Ethics Committee in December 2021 (Reference 2021/ETH11861). In addition to publication in a peer-reviewed scientific journal, a lay summary of study outcomes will be made available for participants and the public on the Phage Australia website (https://www.phageaustralia.org/).\n\nTrial registration number\nRegistered on ANZCTR, 10 November 2021 (ACTRN12621001526864; WHO Universal Trial Number: U1111-1269-6000).","container-title":"BMJ Open","DOI":"10.1136/bmjopen-2022-065401","ISSN":"2044-6055","issue":"12","journalAbbreviation":"BMJ Open","note":"PMID: 36600337\nPMCID: PMC9743374","page":"e065401","source":"PubMed Central","title":"Standardised treatment and monitoring protocol to assess safety and tolerability of bacteriophage therapy for adult and paediatric patients (STAMP study): protocol for an open-label, single-arm trial","title-short":"Standardised treatment and monitoring protocol to assess safety and tolerability of bacteriophage therapy for adult and paediatric patients (STAMP study)","volume":"12","author":[{"family":"Khatami","given":"Ameneh"},{"family":"Foley","given":"David A"},{"family":"Warner","given":"Morgyn S"},{"family":"Barnes","given":"Elizabeth H"},{"family":"Peleg","given":"Anton Y"},{"family":"Li","given":"Jian"},{"family":"Stick","given":"Stephen"},{"family":"Burke","given":"Nettie"},{"family":"Lin","given":"Ruby C Y"},{"family":"Warning","given":"Julia"},{"family":"Snelling","given":"Thomas L"},{"family":"Tong","given":"Steven Y C"},{"family":"Iredell","given":"Jonathan"}],"issued":{"date-parts":[["2022",12,9]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->33<!-- [if supportFields]><![endif]-->. Due to the synergistic effect of some antibiotics and phages, usage of such combos can be utilized to decrease the needed doses of both the phage and the antibiotic. However, it is worth mentioning that just as there exists no universal dose for all antibiotics, phages are very variant and no single dosing regimen fits them all <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"46dsNi1m","properties":{"formattedCitation":"\\super 34\\nosupersub{}","plainCitation":"34","noteIndex":0},"citationItems":[{"id":1339,"uris":["http://zotero.org/users/11334842/items/GI8GCUW3"],"itemData":{"id":1339,"type":"article-journal","abstract":"Infections caused by multidrug-resistant (MDR) bacteria have highlighted the importance of the development of new antimicrobial agents. While bacteriophages (phages) are widely studied as alternative agents to antibiotics, combined treatments using phages and antibiotics have exhibited Phage–Antibiotic Synergy (PAS), in which antibiotics promote phage replication and extraordinary antimicrobial efficacy with reduced development of bacterial resistance. This review paper on the current progress of phage–antibiotic therapy includes aspects of the mechanisms of PAS and the therapeutic performance of PAS in combating multidrug-resistant bacterial infections. The choice of phages and antibiotics, the administration time and sequence, and the concentrations of the two agents impact the bacterial inhibitory effects to different extents.","container-title":"Antibiotics","DOI":"10.3390/antibiotics11050570","ISSN":"2079-6382","issue":"5","journalAbbreviation":"Antibiotics (Basel)","note":"PMID: 35625214\nPMCID: PMC9137994","page":"570","source":"PubMed Central","title":"Phage–Antibiotic Therapy as a Promising Strategy to Combat Multidrug-Resistant Infections and to Enhance Antimicrobial Efficiency","volume":"11","author":[{"family":"Liu","given":"Chengxi"},{"family":"Hong","given":"Qixuan"},{"family":"Chang","given":"Rachel Yoon Kyung"},{"family":"Kwok","given":"Philip Chi Lip"},{"family":"Chan","given":"Hak-Kim"}],"issued":{"date-parts":[["2022",4,25]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->34<!-- [if supportFields]><![endif]-->. Part IV: The Emerging Problem of Multi-Drug Resistant Organisms (MDROs) As mentioned before, MDR emergence is a major challenge in infectious diseases. Pneumonias remain the most common cause to infection-relate mortality <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"0IjS6d58","properties":{"formattedCitation":"\\super 35\\nosupersub{}","plainCitation":"35","noteIndex":0},"citationItems":[{"id":1209,"uris":["http://zotero.org/users/11334842/items/IRMMPZZT"],"itemData":{"id":1209,"type":"article-journal","abstract":"Pneumonia is an acute pulmonary infection whose high hospitalization and mortality rates can, on occasion, bring healthcare systems to the brink of collapse. Both viral and bacterial pneumonia are uncovering many gaps in our understanding of host-pathogen interactions, and are testing the effectiveness of the currently available antimicrobial strategies. In the case of bacterial pneumonia, the main challenge is antibiotic resistance, which is only expected to increase during the current pandemic due to the widespread use of antibiotics to prevent secondary infections in COVID-19 patients. As a result, alternative therapeutics will be necessary to keep this disease under control. This review evaluates the advantages of phage therapy to treat lung bacterial infections, in particular those caused by the Gram-positive bacteria Streptococcus pneumoniae and Staphylococcus aureus, while also highlighting the regulatory impediments that hamper its clinical use and the difficulties associated with phage research.","container-title":"Antibiotics (Basel, Switzerland)","DOI":"10.3390/antibiotics10081000","ISSN":"2079-6382","issue":"8","language":"eng","note":"section: 0","page":"1000","title":"Gram-Positive Pneumonia: Possibilities Offered by Phage Therapy","volume":"10","author":[{"family":"Fernández","given":"Lucía"},{"family":"Cima-Cabal","given":"María Dolores"},{"family":"Duarte","given":"Ana Catarina"},{"family":"Rodríguez","given":"Ana"},{"family":"García-Suárez","given":"María Del Mar"},{"family":"García","given":"Pilar"}],"issued":{"date-parts":[["2021",8]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->35<!-- [if supportFields]><![endif]-->. The risks of death from pneumonia are augmented by antimicrobial resistance, especially in hospital-acquired and ventilator-associated settings <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"HHIz3NSG","properties":{"formattedCitation":"\\super 36\\nosupersub{}","plainCitation":"36","noteIndex":0},"citationItems":[{"id":1167,"uris":["http://zotero.org/users/11334842/items/7BPFI84I"],"itemData":{"id":1167,"type":"article-journal","abstract":"With respiratory infections accounting for significant morbidity and mortality, the issue of antibiotic resistance has added to the gravity of the situation. Treatment of pulmonary infections (bacterial pneumonia, cystic fibrosis-associated bacterial infections, tuberculosis) is more challenging with the involvement of multi-drug resistant bacterial strains, which act as etiological agents. Furthermore, with the dearth of new antibiotics available and old antibiotics losing efficacy, it is prudent to switch to non-antibiotic approaches to fight this battle. Phage therapy represents one such approach that has proven effective against a range of bacterial pathogens including drug resistant strains. Inhaled phage therapy encompasses the use of stable phage preparations given via aerosol delivery. This therapy can be used as an adjunct treatment option in both prophylactic and therapeutic modes. In the present review, we first highlight the role and action of phages against pulmonary pathogens, followed by delineating the different methods of delivery of inhaled phage therapy with evidence of success. The review aims to focus on recent advances and developments in improving the final success and outcome of pulmonary phage therapy. It details the use of electrospray for targeted delivery, advances in nebulization techniques, individualized controlled inhalation with software control, and liposome-encapsulated nebulized phages to take pulmonary phage delivery to the next level. The review expands knowledge on the pulmonary delivery of phages and the advances that have been made for improved outcomes in the treatment of respiratory infections.","container-title":"Frontiers in Cellular and Infection Microbiology","DOI":"10.3389/fcimb.2021.758392","ISSN":"2235-2988","language":"eng","note":"section: 0","page":"758392","title":"Prospects of Inhaled Phage Therapy for Combatting Pulmonary Infections","volume":"11","author":[{"family":"Wang","given":"Xiang"},{"family":"Xie","given":"Zuozhou"},{"family":"Zhao","given":"Jinhong"},{"family":"Zhu","given":"Zhenghua"},{"family":"Yang","given":"Chen"},{"family":"Liu","given":"Yi"}],"issued":{"date-parts":[["2021"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->36<!-- [if supportFields]><![endif]-->. Solid organ transplant and hematopoietic stem cell transplant (HSCT) recipients are highly susceptible to infections and colonization by multidrug-resistant (MDR) pathogens. These MDR pathogens contribute to recurrent hospitalizations and infections, leading to a higher use of antibiotics <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"OooHXYgY","properties":{"formattedCitation":"\\super 37\\nosupersub{}","plainCitation":"37","noteIndex":0},"citationItems":[{"id":1149,"uris":["http://zotero.org/users/11334842/items/3CFTZ7JM"],"itemData":{"id":1149,"type":"article-journal","abstract":"PURPOSE OF REVIEW: Since initial description of the successful use of intravenous bacteriophage therapy in the United States in 2017, there is widespread interest in using bacteriophage therapy for multidrug-resistant (MDR) infections. RECENT FINDINGS: Recent published cases of bacteriophage therapy in transplant candidates and recipients are reviewed highlighting its safety and potential efficacy when used as an adjunct to systemic antibiotics for a variety of clinical indications. An overview of access to bacteriophage therapy in the United States is also provided. SUMMARY: The reviewed cases form the basis for ongoing compassionate use of bacteriophage therapy in transplant candidates and recipients with life-threatening MDR infections until data from clinical trials are available to guide therapy.","container-title":"Current Opinion in Infectious Diseases","DOI":"10.1097/QCO.0000000000000658","ISSN":"1473-6527","issue":"4","language":"eng","note":"section: 0","page":"298–303","title":"Bacteriophage therapy as a treatment option for transplant infections","volume":"33","author":[{"family":"Aslam","given":"Saima"}],"issued":{"date-parts":[["2020",8]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->37<!-- [if supportFields]><![endif]-->. Bacterial prostatitis is also becoming harder to treat due to resistance <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Mz1NKA7J","properties":{"formattedCitation":"\\super 38\\nosupersub{}","plainCitation":"38","noteIndex":0},"citationItems":[{"id":1315,"uris":["http://zotero.org/users/11334842/items/B5Q7CBU9"],"itemData":{"id":1315,"type":"article-journal","abstract":"Chronic bacterial prostatitis (CBP) represents a bacterial infection of the prostate gland. CBP causes an associated symptom complex, the hallmark of which is the occurrence of relapsing urinary tract infections, usually involving the same pathogen.","note":"Publication: Medscape - eMedicine","source":"eMedicine","title":"Chronic Bacterial Prostatitis Treatment & Management: Approach Considerations, Antimicrobial Therapy, Additional Treatments","title-short":"Chronic Bacterial Prostatitis Treatment & Management","URL":"https://emedicine.medscape.com/article/458391-treatment","accessed":{"date-parts":[["2023",12,4]]},"issued":{"date-parts":[["2023",8,17]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->38<!-- [if supportFields]><![endif]-->. The prevalence of MDR infections becomes major in the transplant population, with resistance can range from 14% in kidney transplant to 51% in lung transplant recipients <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"wGxELT30","properties":{"formattedCitation":"\\super 37\\nosupersub{}","plainCitation":"37","noteIndex":0},"citationItems":[{"id":1149,"uris":["http://zotero.org/users/11334842/items/3CFTZ7JM"],"itemData":{"id":1149,"type":"article-journal","abstract":"PURPOSE OF REVIEW: Since initial description of the successful use of intravenous bacteriophage therapy in the United States in 2017, there is widespread interest in using bacteriophage therapy for multidrug-resistant (MDR) infections. RECENT FINDINGS: Recent published cases of bacteriophage therapy in transplant candidates and recipients are reviewed highlighting its safety and potential efficacy when used as an adjunct to systemic antibiotics for a variety of clinical indications. An overview of access to bacteriophage therapy in the United States is also provided. SUMMARY: The reviewed cases form the basis for ongoing compassionate use of bacteriophage therapy in transplant candidates and recipients with life-threatening MDR infections until data from clinical trials are available to guide therapy.","container-title":"Current Opinion in Infectious Diseases","DOI":"10.1097/QCO.0000000000000658","ISSN":"1473-6527","issue":"4","language":"eng","note":"section: 0","page":"298–303","title":"Bacteriophage therapy as a treatment option for transplant infections","volume":"33","author":[{"family":"Aslam","given":"Saima"}],"issued":{"date-parts":[["2020",8]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->37<!-- [if supportFields]><![endif]-->. In HSCT patients, the prevalence of MDR pathogens can also reach up to 50%. These infections are associated with increased mortality and graft loss in transplant recipients <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"X3ivfY9y","properties":{"formattedCitation":"\\super 37\\nosupersub{}","plainCitation":"37","noteIndex":0},"citationItems":[{"id":1149,"uris":["http://zotero.org/users/11334842/items/3CFTZ7JM"],"itemData":{"id":1149,"type":"article-journal","abstract":"PURPOSE OF REVIEW: Since initial description of the successful use of intravenous bacteriophage therapy in the United States in 2017, there is widespread interest in using bacteriophage therapy for multidrug-resistant (MDR) infections. RECENT FINDINGS: Recent published cases of bacteriophage therapy in transplant candidates and recipients are reviewed highlighting its safety and potential efficacy when used as an adjunct to systemic antibiotics for a variety of clinical indications. An overview of access to bacteriophage therapy in the United States is also provided. SUMMARY: The reviewed cases form the basis for ongoing compassionate use of bacteriophage therapy in transplant candidates and recipients with life-threatening MDR infections until data from clinical trials are available to guide therapy.","container-title":"Current Opinion in Infectious Diseases","DOI":"10.1097/QCO.0000000000000658","ISSN":"1473-6527","issue":"4","language":"eng","note":"section: 0","page":"298–303","title":"Bacteriophage therapy as a treatment option for transplant infections","volume":"33","author":[{"family":"Aslam","given":"Saima"}],"issued":{"date-parts":[["2020",8]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->37<!-- [if supportFields]><![endif]-->. COPD and cystic fibrosis predispose to a infections that can be life-threatening and quickly gain resistance <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"QdmDjyDw","properties":{"formattedCitation":"\\super 39\\nosupersub{}","plainCitation":"39","noteIndex":0},"citationItems":[{"id":220,"uris":["http://zotero.org/users/11334842/items/SZ25QFNW"],"itemData":{"id":220,"type":"article-journal","container-title":"Frontiers in Cellular and Infection Microbiology","ISSN":"2235-2988","journalAbbreviation":"Frontiers in Cellular and Infection Microbiology","note":"publisher: Frontiers","page":"1025","title":"Multidrug-resistant Pseudomonas aeruginosa is predisposed to lasR mutation through up-regulated activity of efflux pumps in non-cystic fibrosis bronchiectasis patients","author":[{"family":"Ding","given":"Fengming"},{"family":"Han","given":"Lei"},{"family":"Xue","given":"Yishu"},{"family":"Yang","given":"Iris Tingshiuan"},{"family":"Fan","given":"Xinxin"},{"family":"Tang","given":"Rong"},{"family":"Zhang","given":"Chen"},{"family":"Zhu","given":"Miao"},{"family":"Tian","given":"Xue"},{"family":"Shao","given":"Ping"}],"issued":{"date-parts":[["2022"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->39<!-- [if supportFields]><![endif]-->. These patients have high rates of colonization (up to 73%) with multidrug-resistant (MDR) pathogens, including Pseudomonas aeruginosa and Staphylococcus aureus <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"lEIoidkd","properties":{"formattedCitation":"\\super 37\\nosupersub{}","plainCitation":"37","noteIndex":0},"citationItems":[{"id":1149,"uris":["http://zotero.org/users/11334842/items/3CFTZ7JM"],"itemData":{"id":1149,"type":"article-journal","abstract":"PURPOSE OF REVIEW: Since initial description of the successful use of intravenous bacteriophage therapy in the United States in 2017, there is widespread interest in using bacteriophage therapy for multidrug-resistant (MDR) infections. RECENT FINDINGS: Recent published cases of bacteriophage therapy in transplant candidates and recipients are reviewed highlighting its safety and potential efficacy when used as an adjunct to systemic antibiotics for a variety of clinical indications. An overview of access to bacteriophage therapy in the United States is also provided. SUMMARY: The reviewed cases form the basis for ongoing compassionate use of bacteriophage therapy in transplant candidates and recipients with life-threatening MDR infections until data from clinical trials are available to guide therapy.","container-title":"Current Opinion in Infectious Diseases","DOI":"10.1097/QCO.0000000000000658","ISSN":"1473-6527","issue":"4","language":"eng","note":"section: 0","page":"298–303","title":"Bacteriophage therapy as a treatment option for transplant infections","volume":"33","author":[{"family":"Aslam","given":"Saima"}],"issued":{"date-parts":[["2020",8]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->37<!-- [if supportFields]><![endif]-->. Besides, Burkholderia cepacia complex (BCC) species and Mycobacterium abscessus are associated with high rates of resistance <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"pXj5vqWK","properties":{"formattedCitation":"\\super 37\\nosupersub{}","plainCitation":"37","noteIndex":0},"citationItems":[{"id":1149,"uris":["http://zotero.org/users/11334842/items/3CFTZ7JM"],"itemData":{"id":1149,"type":"article-journal","abstract":"PURPOSE OF REVIEW: Since initial description of the successful use of intravenous bacteriophage therapy in the United States in 2017, there is widespread interest in using bacteriophage therapy for multidrug-resistant (MDR) infections. RECENT FINDINGS: Recent published cases of bacteriophage therapy in transplant candidates and recipients are reviewed highlighting its safety and potential efficacy when used as an adjunct to systemic antibiotics for a variety of clinical indications. An overview of access to bacteriophage therapy in the United States is also provided. SUMMARY: The reviewed cases form the basis for ongoing compassionate use of bacteriophage therapy in transplant candidates and recipients with life-threatening MDR infections until data from clinical trials are available to guide therapy.","container-title":"Current Opinion in Infectious Diseases","DOI":"10.1097/QCO.0000000000000658","ISSN":"1473-6527","issue":"4","language":"eng","note":"section: 0","page":"298–303","title":"Bacteriophage therapy as a treatment option for transplant infections","volume":"33","author":[{"family":"Aslam","given":"Saima"}],"issued":{"date-parts":[["2020",8]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->37<!-- [if supportFields]><![endif]-->. Lung transplantation is often contraindicated in patients with BCC or M. abscessus infections due to the high risk of recurrence and mortality <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"u30TUzeM","properties":{"formattedCitation":"\\super 37\\nosupersub{}","plainCitation":"37","noteIndex":0},"citationItems":[{"id":1149,"uris":["http://zotero.org/users/11334842/items/3CFTZ7JM"],"itemData":{"id":1149,"type":"article-journal","abstract":"PURPOSE OF REVIEW: Since initial description of the successful use of intravenous bacteriophage therapy in the United States in 2017, there is widespread interest in using bacteriophage therapy for multidrug-resistant (MDR) infections. RECENT FINDINGS: Recent published cases of bacteriophage therapy in transplant candidates and recipients are reviewed highlighting its safety and potential efficacy when used as an adjunct to systemic antibiotics for a variety of clinical indications. An overview of access to bacteriophage therapy in the United States is also provided. SUMMARY: The reviewed cases form the basis for ongoing compassionate use of bacteriophage therapy in transplant candidates and recipients with life-threatening MDR infections until data from clinical trials are available to guide therapy.","container-title":"Current Opinion in Infectious Diseases","DOI":"10.1097/QCO.0000000000000658","ISSN":"1473-6527","issue":"4","language":"eng","note":"section: 0","page":"298–303","title":"Bacteriophage therapy as a treatment option for transplant infections","volume":"33","author":[{"family":"Aslam","given":"Saima"}],"issued":{"date-parts":[["2020",8]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->37<!-- [if supportFields]><![endif]-->. As these diseases become harder to combat, we move towards the “post-antibiotic” era” <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"x2OEZ0w1","properties":{"formattedCitation":"\\super 12\\nosupersub{}","plainCitation":"12","noteIndex":0},"citationItems":[{"id":1095,"uris":["http://zotero.org/users/11334842/items/34TH4T66"],"itemData":{"id":1095,"type":"article-journal","abstract":"Interest in the therapeutic use of bacteriophages (phages) has emerged in recent years, driven mainly by the antimicrobial resistance crisis. This review aimed to summarize some important studies addressing the use of phages as a therapeutic alternative for multiresistant bacterial infections. To this end, a literature search was conducted to address the efficacy and versatility of phage therapy, the advantages and disadvantages of its use, and potential limitations for the application of phage therapy that need to be overcome, especially in Western countries. Thus, this review highlights that phage therapy may be a promising route in the treatment of infections caused by multidrug-resistant pathogens and that a combined approach has the potential to prolong the life of the current available antimicrobials. In addition, standardized clinical trials using monoclonal or polyclonal phages, alone or in combination with antimicrobials, are crucial to determine the real potential of these treatments in clinical practice.","container-title":"Archives of Microbiology","DOI":"10.1007/s00203-020-02167-5","ISSN":"1432-072X","issue":"4","language":"eng","note":"section: 0","page":"1271–1279","title":"Phage therapy as strategy to face post-antibiotic era: a guide to beginners and experts","volume":"203","author":[{"family":"Royer","given":"Sabrina"},{"family":"Morais","given":"Aléxia Pinheiro"},{"family":"Fonseca Batistão","given":"Deivid William","non-dropping-particle":"da"}],"issued":{"date-parts":[["2021",5]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->12<!-- [if supportFields]><![endif]-->. A newly growing population, patients with ventricular-assist device (VAD) implantation have very frequent infections approaching 33% pr cases, often caused by Staphylococcus aureus and Pseudomonas aeruginosa<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"scETukLw","properties":{"formattedCitation":"\\super 37\\nosupersub{}","plainCitation":"37","noteIndex":0},"citationItems":[{"id":1149,"uris":["http://zotero.org/users/11334842/items/3CFTZ7JM"],"itemData":{"id":1149,"type":"article-journal","abstract":"PURPOSE OF REVIEW: Since initial description of the successful use of intravenous bacteriophage therapy in the United States in 2017, there is widespread interest in using bacteriophage therapy for multidrug-resistant (MDR) infections. RECENT FINDINGS: Recent published cases of bacteriophage therapy in transplant candidates and recipients are reviewed highlighting its safety and potential efficacy when used as an adjunct to systemic antibiotics for a variety of clinical indications. An overview of access to bacteriophage therapy in the United States is also provided. SUMMARY: The reviewed cases form the basis for ongoing compassionate use of bacteriophage therapy in transplant candidates and recipients with life-threatening MDR infections until data from clinical trials are available to guide therapy.","container-title":"Current Opinion in Infectious Diseases","DOI":"10.1097/QCO.0000000000000658","ISSN":"1473-6527","issue":"4","language":"eng","note":"section: 0","page":"298–303","title":"Bacteriophage therapy as a treatment option for transplant infections","volume":"33","author":[{"family":"Aslam","given":"Saima"}],"issued":{"date-parts":[["2020",8]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->37<!-- [if supportFields]><![endif]-->. Part V: Diseases with Phage Success: Phages offer a good antibiotic alternative, or antibiotic synergistic factor to help combar MDROs. For example, upon the oral administration of phage three times in individuals affected by bronchopneumonia empyema, 82% showed full recovery with a negative culture <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"g73a6NtL","properties":{"formattedCitation":"\\super 8\\nosupersub{}","plainCitation":"8","noteIndex":0},"citationItems":[{"id":1221,"uris":["http://zotero.org/users/11334842/items/IUA99M77"],"itemData":{"id":1221,"type":"article-journal","abstract":"Bacteriophages, highly prevalent in all environments, have found their use in medicine as an alternative or complement to antibiotics. The therapeutic use of bacteriophages was particularly popular in the 1920s and 1930s, until the discovery and introduction of antibiotics. Due to the dynamic growth of antibiotic resistance among bacterial strains, numerous international institutions (such as the FDA) have declared the search for novel treatment modalities to be of the highest priority. To date, bacteriophage therapy has not been registered for general use in Western countries. The regulation of biological medicinal products (within medicinal product regulation) does not contain a specific documentation frame for bacteriophages (only for vaccines, blood derived products, etc.) which, as active substances, need to meet specific requirements. Recently, the FDA allowed bacteriophage therapy to be used in the United States, via the Emergency Investigational New Drug scheme; clinical trials to compare the safety and efficacy of bacteriophage therapy are also permitted. To date, several therapeutic products of this type have made it to phase I or II; some clinical programmes have also been completed. This article cites numerous animal model studies and registered clinical trials, showing the safety and effectiveness of bacteriophage therapy, including infections caused by bacterial strains resistant to antibiotic treatment.","container-title":"Journal of Applied Microbiology","DOI":"10.1111/jam.14535","ISSN":"1365-2672","issue":"4","language":"eng","note":"section: 0","page":"985–1002","title":"Therapeutic bacteriophages as a rescue treatment for drug-resistant infections - an in vivo studies overview","volume":"128","author":[{"family":"Kwiatek","given":"M."},{"family":"Parasion","given":"S."},{"family":"Nakonieczna","given":"A."}],"issued":{"date-parts":[["2020",4]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->8<!-- [if supportFields]><![endif]-->. The pressing need for rapid access to phage therapy in critically ill patients has prompted the initiation of compassionate use case studies in Western countries <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"SUBZCAty","properties":{"formattedCitation":"\\super 21\\nosupersub{}","plainCitation":"21","noteIndex":0},"citationItems":[{"id":1121,"uris":["http://zotero.org/users/11334842/items/3UF62TYT"],"itemData":{"id":1121,"type":"article-journal","abstract":"Antibiotic therapy has become increasingly ineffective against bacterial infections due to the rise of resistance. In particular, ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) have caused life-threatening infections in humans and represent a major global health threat due to a high degree of antibiotic resistance. To respond to this urgent call, novel strategies are urgently needed, such as bacteriophages (or phages), phage-encoded enzymes, immunomodulators and monoclonal antibodies. This review critically analyses these promising antimicrobial therapies for the treatment of multidrug-resistant bacterial infections. Recent advances in these novel therapeutic strategies are discussed, focusing on preclinical and clinical investigations, as well as combinatorial approaches. In this 'Bad Bugs, No Drugs' era, novel therapeutic strategies can play a key role in treating deadly infections and help extend the lifetime of antibiotics.","container-title":"Advanced Drug Delivery Reviews","DOI":"10.1016/j.addr.2022.114378","ISSN":"1872-8294","language":"eng","note":"section: 0","page":"114378","title":"Novel antimicrobial agents for combating antibiotic-resistant bacteria","volume":"187","author":[{"family":"Chang","given":"Rachel Yoon Kyung"},{"family":"Nang","given":"Sue C."},{"family":"Chan","given":"Hak-Kim"},{"family":"Li","given":"Jian"}],"issued":{"date-parts":[["2022",8]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->21<!-- [if supportFields]><![endif]-->. It is known that phages can exist in their lytic or lysogenic phage and that they can both replicate in the targeted pathogen <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"qrhfV97W","properties":{"formattedCitation":"\\super 40\\nosupersub{}","plainCitation":"40","noteIndex":0},"citationItems":[{"id":1175,"uris":["http://zotero.org/users/11334842/items/RUGQE2S7"],"itemData":{"id":1175,"type":"article-journal","abstract":"Prostatitis is a common urinary tract condition but bring innumerable trouble to clinicians in treatment, as well as great financial burden to patients and the society. Bacterial prostatitis (acute bacterial prostatitis plus chronic bacterial prostatitis) accounting for approximately 20% among all prostatitis have made the urological clinics complain about the genital and urinary systems all over the world. The international challenges of antibacterial treatment (emergence of multidrug-resistant bacteria, extended-spectrum beta-lactamase-producing bacteria, bacterial biofilms production and the shift in bacterial etiology) and the transformation of therapeutic strategy for classic therapy have attracted worldwide attention. To the best of our knowledge currently, there is not a single comprehensive review, which can completely elaborate these important topics and the corresponding treatment strategy in an effective way. This review summarizes the general treatment choices for bacterial prostatitis also provides the alternative pharmacological therapies for those patients resistant or intolerant to general treatment.","container-title":"Frontiers in Pharmacology","DOI":"10.3389/fphar.2020.00504","ISSN":"1663-9812","language":"eng","note":"section: 0","page":"504","title":"Pharmacological Interventions for Bacterial Prostatitis","volume":"11","author":[{"family":"Xiong","given":"Situ"},{"family":"Liu","given":"Xiaoqiang"},{"family":"Deng","given":"Wen"},{"family":"Zhou","given":"Zhengtao"},{"family":"Li","given":"Yulei"},{"family":"Tu","given":"Yechao"},{"family":"Chen","given":"Luyao"},{"family":"Wang","given":"Gongxian"},{"family":"Fu","given":"Bin"}],"issued":{"date-parts":[["2020"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->40<!-- [if supportFields]><![endif]-->. Although both cycles can infect the bacterial host, only the lytic phage is used as “the phage therapy”, where the virus binds to the bacteria, injects its genetic material and replicate inside it until it bursts <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"dQARbSjV","properties":{"formattedCitation":"\\super 40\\nosupersub{}","plainCitation":"40","noteIndex":0},"citationItems":[{"id":1175,"uris":["http://zotero.org/users/11334842/items/RUGQE2S7"],"itemData":{"id":1175,"type":"article-journal","abstract":"Prostatitis is a common urinary tract condition but bring innumerable trouble to clinicians in treatment, as well as great financial burden to patients and the society. Bacterial prostatitis (acute bacterial prostatitis plus chronic bacterial prostatitis) accounting for approximately 20% among all prostatitis have made the urological clinics complain about the genital and urinary systems all over the world. The international challenges of antibacterial treatment (emergence of multidrug-resistant bacteria, extended-spectrum beta-lactamase-producing bacteria, bacterial biofilms production and the shift in bacterial etiology) and the transformation of therapeutic strategy for classic therapy have attracted worldwide attention. To the best of our knowledge currently, there is not a single comprehensive review, which can completely elaborate these important topics and the corresponding treatment strategy in an effective way. This review summarizes the general treatment choices for bacterial prostatitis also provides the alternative pharmacological therapies for those patients resistant or intolerant to general treatment.","container-title":"Frontiers in Pharmacology","DOI":"10.3389/fphar.2020.00504","ISSN":"1663-9812","language":"eng","note":"section: 0","page":"504","title":"Pharmacological Interventions for Bacterial Prostatitis","volume":"11","author":[{"family":"Xiong","given":"Situ"},{"family":"Liu","given":"Xiaoqiang"},{"family":"Deng","given":"Wen"},{"family":"Zhou","given":"Zhengtao"},{"family":"Li","given":"Yulei"},{"family":"Tu","given":"Yechao"},{"family":"Chen","given":"Luyao"},{"family":"Wang","given":"Gongxian"},{"family":"Fu","given":"Bin"}],"issued":{"date-parts":[["2020"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->40<!-- [if supportFields]><![endif]-->. Combining various phages with antibiotics to enhance their effectiveness against multidrug-resistant (MDR) bacteria and biofilms has gained significant attention. This strategy aims to augment antibiotic action by utilizing the phage ability to break down the extracellular polymeric substances (EPS) of biofilms and increase their permeability, enhancing antibiotic efficacy<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"36diig0g","properties":{"formattedCitation":"\\super 41\\nosupersub{}","plainCitation":"41","noteIndex":0},"citationItems":[{"id":1318,"uris":["http://zotero.org/users/11334842/items/3F3D9QEG"],"itemData":{"id":1318,"type":"article-journal","abstract":"We documented the adjunctive bacteriophage therapy to treat a chronic relapsing periprosthetic joint infection of the knee and chronic osteomyelitis of the femur caused by multidrug-resistant Pseudomonas aeruginosa The combined antibiotic-phage treatment eradicated the infection, and no side effects to phages were observed.","container-title":"Antimicrobial Agents and Chemotherapy","DOI":"10.1128/AAC.00924-19","ISSN":"1098-6596","issue":"1","journalAbbreviation":"Antimicrob Agents Chemother","language":"eng","note":"PMID: 31527029\nPMCID: PMC7187616","page":"e00924-19","source":"PubMed","title":"Bacteriophages as Adjuvant to Antibiotics for the Treatment of Periprosthetic Joint Infection Caused by Multidrug-Resistant Pseudomonas aeruginosa","volume":"64","author":[{"family":"Tkhilaishvili","given":"Tamta"},{"family":"Winkler","given":"Tobias"},{"family":"Müller","given":"Michael"},{"family":"Perka","given":"Carsten"},{"family":"Trampuz","given":"Andrej"}],"issued":{"date-parts":[["2019",12,20]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->41<!-- [if supportFields]><![endif]-->. Tkhilaishvili et al. demonstrated that bacteriophages, administered alongside antibiotics, successfully inhibited MDR P. aeruginosa biofilm in a patient with diabetes, joint infection, and osteomyelitis <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"VkASs40u","properties":{"formattedCitation":"\\super 41\\nosupersub{}","plainCitation":"41","noteIndex":0},"citationItems":[{"id":1318,"uris":["http://zotero.org/users/11334842/items/3F3D9QEG"],"itemData":{"id":1318,"type":"article-journal","abstract":"We documented the adjunctive bacteriophage therapy to treat a chronic relapsing periprosthetic joint infection of the knee and chronic osteomyelitis of the femur caused by multidrug-resistant Pseudomonas aeruginosa The combined antibiotic-phage treatment eradicated the infection, and no side effects to phages were observed.","container-title":"Antimicrobial Agents and Chemotherapy","DOI":"10.1128/AAC.00924-19","ISSN":"1098-6596","issue":"1","journalAbbreviation":"Antimicrob Agents Chemother","language":"eng","note":"PMID: 31527029\nPMCID: PMC7187616","page":"e00924-19","source":"PubMed","title":"Bacteriophages as Adjuvant to Antibiotics for the Treatment of Periprosthetic Joint Infection Caused by Multidrug-Resistant Pseudomonas aeruginosa","volume":"64","author":[{"family":"Tkhilaishvili","given":"Tamta"},{"family":"Winkler","given":"Tobias"},{"family":"Müller","given":"Michael"},{"family":"Perka","given":"Carsten"},{"family":"Trampuz","given":"Andrej"}],"issued":{"date-parts":[["2019",12,20]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->41<!-- [if supportFields]><![endif]-->. In another study, the combination of phage PEV20 and ciprofloxacin was employed to combat P. aeruginosa biofilm sourced from wound and cystic fibrosis patients. The study revealed that the joint application of antibiotics and phages exhibited superior biofilm eradication compared to the use of ciprofloxacin alone <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"CENxcptW","properties":{"formattedCitation":"\\super 42\\nosupersub{}","plainCitation":"42","noteIndex":0},"citationItems":[{"id":1321,"uris":["http://zotero.org/users/11334842/items/P23YPJC2"],"itemData":{"id":1321,"type":"article-journal","abstract":"Aims: To identify enzymes associated with bacteriophages infecting cystic fibrosis (CF) strains of Pseudomonas aeruginosa that are able to degrade extracellular alginic acids elaborated by the host bacterium. Methods and Results: Plaques produced by 21 Ps. aeruginosa-specific phages were screened for the presence of haloes, an indicator of capsule hydrolytic activity. Four phages produced haloed plaques, and one (PT-6) was investigated further. PT-6 was shown by electron microscopy to belong to Podoviridae family C1, to reduce the viscosity of four alginate preparations using a rolling ball viscometer and to release uronic acid-containing fragments from the polymers, as judged by spectrophotometry and thin layer chromatography. The alginase was partially purified by gel filtration chromatography and shown to be a 37 kDa polypeptide. Conclusions: Infection of CF strains of Ps. aeruginosa by phage PT-6 involves hydrolysis of the exopolysaccharide secreted by the host. Significance and Impact of the Study: The alginase produced by PT-6 has the potential to increase the well-being of CF suffers by improving the surface properties of sputum, accelerating phagocytic uptake of bacteria and perturbing bacterial growth in biofilms.","container-title":"Journal of Applied Microbiology","DOI":"10.1111/j.1365-2672.2009.04469.x","ISSN":"1365-2672","issue":"2","language":"en","license":"© 2009 The Authors. Journal compilation © 2009 The Society for Applied Microbiology","note":"_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2672.2009.04469.x","page":"695-702","source":"Wiley Online Library","title":"Bacteriophage-derived enzyme that depolymerizes the alginic acid capsule associated with cystic fibrosis isolates of Pseudomonas aeruginosa","volume":"108","author":[{"family":"Glonti","given":"T."},{"family":"Chanishvili","given":"N."},{"family":"Taylor","given":"P.w."}],"issued":{"date-parts":[["2010"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->42<!-- [if supportFields]><![endif]-->. Furthermore, phages are stable and can be stored at room temperature for months. They can survive stomach acidity, making them useful for treating intestinal colonization by bacteria like E. coli, Salmonella, Campylobacter, and Helicobacter <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"5MNfS0CI","properties":{"formattedCitation":"\\super 3\\nosupersub{}","plainCitation":"3","noteIndex":0},"citationItems":[{"id":1119,"uris":["http://zotero.org/users/11334842/items/V6FI3YDR"],"itemData":{"id":1119,"type":"article-journal","abstract":"Globally, the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) are the major cause of nosocomial infections. These pathogens are multidrug resistant, and their negative impacts have brought serious health challenges and economic burden on many countries worldwide. Thus, this narrative review exploits different emerging alternative therapeutic strategies including combination antibiotics, antimicrobial peptides ((AMPs), bacteriophage and photodynamic therapies used in the treatment of the ESKAPE pathogens, their merits, limitations, and future prospects. Our findings indicate that ESKAPE pathogens exhibit resistance to drug using different mechanisms including drug inactivation by irreversible enzyme cleavage, drug-binding site alteration, diminution in permeability of drug or drug efflux increment to reduce accumulation of drug as well as biofilms production. However, the scientific community has shown significant interest in using these novel strategies with numerous benefits although they have some limitations including but not limited to instability and toxicity of the therapeutic agents, or the host developing immune response against the therapeutic agents. Thus, comprehension of resistance mechanisms of these pathogens is necessary to further develop or modify these approaches in order to overcome these health challenges including the barriers of bacterial resistance.","container-title":"Microbial Pathogenesis","DOI":"10.1016/j.micpath.2022.105963","ISSN":"1096-1208","language":"eng","note":"section: 0","page":"105963","title":"Coping with the ESKAPE pathogens: Evolving strategies, challenges and future prospects","volume":"175","author":[{"family":"Aloke","given":"Chinyere"},{"family":"Achilonu","given":"Ikechukwu"}],"issued":{"date-parts":[["2023",2]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->3<!-- [if supportFields]><![endif]-->. Many factors must be taken into account to optimize therapeutic outcomes. The patient's clinical status should guide the treatment duration, especially for those with multiple co-morbidities <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"M5FARqAI","properties":{"formattedCitation":"\\super 20\\nosupersub{}","plainCitation":"20","noteIndex":0},"citationItems":[{"id":1295,"uris":["http://zotero.org/users/11334842/items/3ZV2PTLG"],"itemData":{"id":1295,"type":"article-journal","abstract":"Bacteriophages (phages) may constitute a natural, safe, and effective strategy to prevent and control multidrug-resistant organisms (MDROs), and ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens in particular. Few clinical studies have assessed the safety and efficacy of phages in patients infected with MDROs. This systematic review summarizes and critically evaluates published studies of phages in clinical practice and presents the appropriate phage selection criteria, as well as recommendations for clinicians and scientists for a successful therapy. Articles were identified through a search of the PubMed, Ovid, EMBASE, and Cochrane Library databases. Among 1102 articles and abstracts, 30 studies were selected and evaluated using selective inclusion criteria, phage criteria, and study characteristics. Most studies showed efficacy (87%) and safety (67%) of the tested phages, but few studies examined phage resistance (35%). Clinical studies and regulatory changes are needed to determine the safety and efficacy of phages and to advance their use in patients with MDRO infections.","container-title":"Clinical Infectious Diseases","DOI":"10.1093/cid/ciy947","ISSN":"1058-4838","issue":"1","note":"section: 0","page":"167–178","title":"A Systematic and Critical Review of Bacteriophage Therapy Against Multidrug-resistant ESKAPE Organisms in Humans","volume":"69","author":[{"family":"El Haddad","given":"Lynn"},{"family":"Harb","given":"Cynthia P"},{"family":"Gebara","given":"Marc A"},{"family":"Stibich","given":"Mark A"},{"family":"Chemaly","given":"Roy F"}],"issued":{"date-parts":[["2019",6]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->20<!-- [if supportFields]><![endif]-->. For instance, patients with conditions such as diabetes mellitus, cystic fibrosis, obesity, smoking habits, or compromised immune systems might necessitate extended treatment periods <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"67Vc1kxH","properties":{"formattedCitation":"\\super 20\\nosupersub{}","plainCitation":"20","noteIndex":0},"citationItems":[{"id":1295,"uris":["http://zotero.org/users/11334842/items/3ZV2PTLG"],"itemData":{"id":1295,"type":"article-journal","abstract":"Bacteriophages (phages) may constitute a natural, safe, and effective strategy to prevent and control multidrug-resistant organisms (MDROs), and ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens in particular. Few clinical studies have assessed the safety and efficacy of phages in patients infected with MDROs. This systematic review summarizes and critically evaluates published studies of phages in clinical practice and presents the appropriate phage selection criteria, as well as recommendations for clinicians and scientists for a successful therapy. Articles were identified through a search of the PubMed, Ovid, EMBASE, and Cochrane Library databases. Among 1102 articles and abstracts, 30 studies were selected and evaluated using selective inclusion criteria, phage criteria, and study characteristics. Most studies showed efficacy (87%) and safety (67%) of the tested phages, but few studies examined phage resistance (35%). Clinical studies and regulatory changes are needed to determine the safety and efficacy of phages and to advance their use in patients with MDRO infections.","container-title":"Clinical Infectious Diseases","DOI":"10.1093/cid/ciy947","ISSN":"1058-4838","issue":"1","note":"section: 0","page":"167–178","title":"A Systematic and Critical Review of Bacteriophage Therapy Against Multidrug-resistant ESKAPE Organisms in Humans","volume":"69","author":[{"family":"El Haddad","given":"Lynn"},{"family":"Harb","given":"Cynthia P"},{"family":"Gebara","given":"Marc A"},{"family":"Stibich","given":"Mark A"},{"family":"Chemaly","given":"Roy F"}],"issued":{"date-parts":[["2019",6]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->20<!-- [if supportFields]><![endif]-->. The severity and type of infection also play a role in determining treatment duration. Smokers, for instance, may require up to 18 weeks of phage therapy compared to non-smokers who might only need less than 4 weeks. However, immunocompromised patients might develop bacterial resistance after a few weeks of phage therapy, as observed in a lung transplant recipient with Pseudomonas aeruginosa pneumonia <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"62egjrDl","properties":{"formattedCitation":"\\super 20\\nosupersub{}","plainCitation":"20","noteIndex":0},"citationItems":[{"id":1295,"uris":["http://zotero.org/users/11334842/items/3ZV2PTLG"],"itemData":{"id":1295,"type":"article-journal","abstract":"Bacteriophages (phages) may constitute a natural, safe, and effective strategy to prevent and control multidrug-resistant organisms (MDROs), and ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens in particular. Few clinical studies have assessed the safety and efficacy of phages in patients infected with MDROs. This systematic review summarizes and critically evaluates published studies of phages in clinical practice and presents the appropriate phage selection criteria, as well as recommendations for clinicians and scientists for a successful therapy. Articles were identified through a search of the PubMed, Ovid, EMBASE, and Cochrane Library databases. Among 1102 articles and abstracts, 30 studies were selected and evaluated using selective inclusion criteria, phage criteria, and study characteristics. Most studies showed efficacy (87%) and safety (67%) of the tested phages, but few studies examined phage resistance (35%). Clinical studies and regulatory changes are needed to determine the safety and efficacy of phages and to advance their use in patients with MDRO infections.","container-title":"Clinical Infectious Diseases","DOI":"10.1093/cid/ciy947","ISSN":"1058-4838","issue":"1","note":"section: 0","page":"167–178","title":"A Systematic and Critical Review of Bacteriophage Therapy Against Multidrug-resistant ESKAPE Organisms in Humans","volume":"69","author":[{"family":"El Haddad","given":"Lynn"},{"family":"Harb","given":"Cynthia P"},{"family":"Gebara","given":"Marc A"},{"family":"Stibich","given":"Mark A"},{"family":"Chemaly","given":"Roy F"}],"issued":{"date-parts":[["2019",6]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->20<!-- [if supportFields]><![endif]-->. Understanding Phage-Antibiotic Synergy (PAS) is pivotal for leveraging bacteriophage therapy in eradicating difficult to treat infections like osteoarticular infections <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"nWowdXGp","properties":{"formattedCitation":"\\super 43\\nosupersub{}","plainCitation":"43","noteIndex":0},"citationItems":[{"id":1265,"uris":["http://zotero.org/users/11334842/items/DYIAGN6C"],"itemData":{"id":1265,"type":"article-journal","abstract":"Infection after fracture fixation (IAFF) in orthopaedic surgery is a significant complication that can lead to disability due to chronic infection and/or relapsing disease, non-union necessitating revision surgery. Management of IAFF is a major challenge facing orthopaedic surgeons across the world due to two key pathogenic mechanisms of Biofilm formation and antimicrobial resistance (AMR) against traditional antibiotics. Advanced prophylactic and treatment strategies to help eradicate established infections and prevent the development of such infections are necessary. Bacteriophage therapy represents an innovative modality to treat IAFF due to multi-drug resistant organisms. We assess the current role and potential therapeutic applications of the novel bacteriophage therapy in the management of these recalcitrant infections to achieve a successful outcome.","container-title":"Journal of Clinical Orthopaedics and Trauma","DOI":"10.1016/j.jcot.2022.102067","ISSN":"0976-5662","language":"en","note":"section: 0","page":"102067","title":"Bacteriophage therapy in infection after fracture fixation (IAFF) in orthopaedic surgery","volume":"35","author":[{"family":"Jeyaraman","given":"Madhan"},{"family":"Jain","given":"Vijay Kumar"},{"family":"Iyengar","given":"Karthikeyan P."}],"issued":{"date-parts":[["2022",12]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->43<!-- [if supportFields]><![endif]-->. PAS has been demonstrated to curb the development of multi-drug resistant organisms by employing bactericidal mechanisms <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"0Fp8ndP7","properties":{"formattedCitation":"\\super 43\\nosupersub{}","plainCitation":"43","noteIndex":0},"citationItems":[{"id":1265,"uris":["http://zotero.org/users/11334842/items/DYIAGN6C"],"itemData":{"id":1265,"type":"article-journal","abstract":"Infection after fracture fixation (IAFF) in orthopaedic surgery is a significant complication that can lead to disability due to chronic infection and/or relapsing disease, non-union necessitating revision surgery. Management of IAFF is a major challenge facing orthopaedic surgeons across the world due to two key pathogenic mechanisms of Biofilm formation and antimicrobial resistance (AMR) against traditional antibiotics. Advanced prophylactic and treatment strategies to help eradicate established infections and prevent the development of such infections are necessary. Bacteriophage therapy represents an innovative modality to treat IAFF due to multi-drug resistant organisms. We assess the current role and potential therapeutic applications of the novel bacteriophage therapy in the management of these recalcitrant infections to achieve a successful outcome.","container-title":"Journal of Clinical Orthopaedics and Trauma","DOI":"10.1016/j.jcot.2022.102067","ISSN":"0976-5662","language":"en","note":"section: 0","page":"102067","title":"Bacteriophage therapy in infection after fracture fixation (IAFF) in orthopaedic surgery","volume":"35","author":[{"family":"Jeyaraman","given":"Madhan"},{"family":"Jain","given":"Vijay Kumar"},{"family":"Iyengar","given":"Karthikeyan P."}],"issued":{"date-parts":[["2022",12]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->43<!-- [if supportFields]><![endif]-->. There have been reports of successful outcomes in cystic fibrosis and lung transplant patients with MDR infections when treated with bacteriophage therapy in addition to systemic antibiotics <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"5vBc2rMG","properties":{"formattedCitation":"\\super 37\\nosupersub{}","plainCitation":"37","noteIndex":0},"citationItems":[{"id":1149,"uris":["http://zotero.org/users/11334842/items/3CFTZ7JM"],"itemData":{"id":1149,"type":"article-journal","abstract":"PURPOSE OF REVIEW: Since initial description of the successful use of intravenous bacteriophage therapy in the United States in 2017, there is widespread interest in using bacteriophage therapy for multidrug-resistant (MDR) infections. RECENT FINDINGS: Recent published cases of bacteriophage therapy in transplant candidates and recipients are reviewed highlighting its safety and potential efficacy when used as an adjunct to systemic antibiotics for a variety of clinical indications. An overview of access to bacteriophage therapy in the United States is also provided. SUMMARY: The reviewed cases form the basis for ongoing compassionate use of bacteriophage therapy in transplant candidates and recipients with life-threatening MDR infections until data from clinical trials are available to guide therapy.","container-title":"Current Opinion in Infectious Diseases","DOI":"10.1097/QCO.0000000000000658","ISSN":"1473-6527","issue":"4","language":"eng","note":"section: 0","page":"298–303","title":"Bacteriophage therapy as a treatment option for transplant infections","volume":"33","author":[{"family":"Aslam","given":"Saima"}],"issued":{"date-parts":[["2020",8]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->37<!-- [if supportFields]><![endif]-->. Case reports have also shown the safety and probable efficacy of intravenous bacteriophage therapy in pretransplant and posttransplant settings, with some patients also receiving nebulized phage <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"epMVnxNv","properties":{"formattedCitation":"\\super 37\\nosupersub{}","plainCitation":"37","noteIndex":0},"citationItems":[{"id":1149,"uris":["http://zotero.org/users/11334842/items/3CFTZ7JM"],"itemData":{"id":1149,"type":"article-journal","abstract":"PURPOSE OF REVIEW: Since initial description of the successful use of intravenous bacteriophage therapy in the United States in 2017, there is widespread interest in using bacteriophage therapy for multidrug-resistant (MDR) infections. RECENT FINDINGS: Recent published cases of bacteriophage therapy in transplant candidates and recipients are reviewed highlighting its safety and potential efficacy when used as an adjunct to systemic antibiotics for a variety of clinical indications. An overview of access to bacteriophage therapy in the United States is also provided. SUMMARY: The reviewed cases form the basis for ongoing compassionate use of bacteriophage therapy in transplant candidates and recipients with life-threatening MDR infections until data from clinical trials are available to guide therapy.","container-title":"Current Opinion in Infectious Diseases","DOI":"10.1097/QCO.0000000000000658","ISSN":"1473-6527","issue":"4","language":"eng","note":"section: 0","page":"298–303","title":"Bacteriophage therapy as a treatment option for transplant infections","volume":"33","author":[{"family":"Aslam","given":"Saima"}],"issued":{"date-parts":[["2020",8]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->37<!-- [if supportFields]><![endif]-->. Some reports highlight successful outcomes in the treatment of extended-spectrum β-lactamase-positive Klebsiella pneumoniae infections <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"YhWXJGX9","properties":{"formattedCitation":"\\super 37\\nosupersub{}","plainCitation":"37","noteIndex":0},"citationItems":[{"id":1149,"uris":["http://zotero.org/users/11334842/items/3CFTZ7JM"],"itemData":{"id":1149,"type":"article-journal","abstract":"PURPOSE OF REVIEW: Since initial description of the successful use of intravenous bacteriophage therapy in the United States in 2017, there is widespread interest in using bacteriophage therapy for multidrug-resistant (MDR) infections. RECENT FINDINGS: Recent published cases of bacteriophage therapy in transplant candidates and recipients are reviewed highlighting its safety and potential efficacy when used as an adjunct to systemic antibiotics for a variety of clinical indications. An overview of access to bacteriophage therapy in the United States is also provided. SUMMARY: The reviewed cases form the basis for ongoing compassionate use of bacteriophage therapy in transplant candidates and recipients with life-threatening MDR infections until data from clinical trials are available to guide therapy.","container-title":"Current Opinion in Infectious Diseases","DOI":"10.1097/QCO.0000000000000658","ISSN":"1473-6527","issue":"4","language":"eng","note":"section: 0","page":"298–303","title":"Bacteriophage therapy as a treatment option for transplant infections","volume":"33","author":[{"family":"Aslam","given":"Saima"}],"issued":{"date-parts":[["2020",8]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->37<!-- [if supportFields]><![endif]-->. In one case, a kidney transplant recipient with recurrent urinary tract infection and epididymitis was treated with a combination of phages, administered orally and directly into the bladder via a urinary catheter for 12 weeks, alongside antibiotics. Another case involved a nontransplant recipient with a recurrent UTI caused by an extensively drug-resistant K. pneumoniae strain <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"HUHoECYP","properties":{"formattedCitation":"\\super 37\\nosupersub{}","plainCitation":"37","noteIndex":0},"citationItems":[{"id":1149,"uris":["http://zotero.org/users/11334842/items/3CFTZ7JM"],"itemData":{"id":1149,"type":"article-journal","abstract":"PURPOSE OF REVIEW: Since initial description of the successful use of intravenous bacteriophage therapy in the United States in 2017, there is widespread interest in using bacteriophage therapy for multidrug-resistant (MDR) infections. RECENT FINDINGS: Recent published cases of bacteriophage therapy in transplant candidates and recipients are reviewed highlighting its safety and potential efficacy when used as an adjunct to systemic antibiotics for a variety of clinical indications. An overview of access to bacteriophage therapy in the United States is also provided. SUMMARY: The reviewed cases form the basis for ongoing compassionate use of bacteriophage therapy in transplant candidates and recipients with life-threatening MDR infections until data from clinical trials are available to guide therapy.","container-title":"Current Opinion in Infectious Diseases","DOI":"10.1097/QCO.0000000000000658","ISSN":"1473-6527","issue":"4","language":"eng","note":"section: 0","page":"298–303","title":"Bacteriophage therapy as a treatment option for transplant infections","volume":"33","author":[{"family":"Aslam","given":"Saima"}],"issued":{"date-parts":[["2020",8]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->37<!-- [if supportFields]><![endif]-->. Phage therapy also shows promise in treating infections in burn patients, by tackling problems brought on by bacteria that are resistant to antibiotics <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"hTQJ9YXj","properties":{"formattedCitation":"\\super 24\\nosupersub{}","plainCitation":"24","noteIndex":0},"citationItems":[{"id":1267,"uris":["http://zotero.org/users/11334842/items/5JEVQWSF"],"itemData":{"id":1267,"type":"article-journal","abstract":"Treatment of patients with a burn injury is a complex process involving multicomponent multidirectional intensive therapy of the majority of organs and systems damaged by thermal effects on the skin, alternating with repeated surgical interventions aimed at removing nonviable tissues with subsequent plastic closure of wound defects. After the recovery from the burn shock, local infectious complications are considered to be the leading problem that decelerates the process of recovery and is the main cause of lethal outcomes. Since the skin integrity is broken, microorganisms penetrate readily into the internal environment of the human organism resulting in a septic state with multiple organ failure. A widespread and often uncontrollable use of antibacterial drugs in medical practice has led to the emergence of multiple drug resistance (MDR) in microorganisms. Introduction of drugs made on the basis of bacteriophages into practice is presently becoming increasingly important. This is confirmed by the growing interest in this field of pharmacology, the development of special programs aimed at studying the processes of phage and bacterial cell interaction. This review presents the main types of bacteria pertaining to MDR pathogens, principles of their classification, and the risk factors for infecting patients. The mechanisms of the selective action of phage particles on a bacterial cell and the possibility of using phage therapy in the treatment of burn injury (experimental and clinical data) based on the analysis of foreign literature are demonstrated as well as new positive properties of phages related to the changes in the macroorganism immune status caused by the interaction with bacteriophage particles.","container-title":"Sovremennye Tekhnologii V Meditsine","DOI":"10.17691/stm2020.12.3.12","ISSN":"2309-995X","issue":"3","language":"eng","note":"section: 0","page":"95–103","title":"Application of Phagotherapy in the Treatment of Burn Patients (Review)","volume":"12","author":[{"family":"Leontyev","given":"А. E."},{"family":"Pavlenko","given":"I. V."},{"family":"Kovalishena","given":"О. V."},{"family":"Saperkin","given":"N. V."},{"family":"Tulupov","given":"А. А."},{"family":"Beschastnov","given":"V. V."}],"issued":{"date-parts":[["2021"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->24<!-- [if supportFields]><![endif]-->. Many other case reports on successful phage treatments exist. P. aeruginosa bacteremia was detected in a youngster who had Pseudomonas sepsis, where a phage cocktail was used when antibiotics proved ineffective to lessen the infection in the blood but not completely eradicate it <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"4bexZJ2j","properties":{"formattedCitation":"\\super 23\\nosupersub{}","plainCitation":"23","noteIndex":0},"citationItems":[{"id":1293,"uris":["http://zotero.org/users/11334842/items/P6WLFGEY"],"itemData":{"id":1293,"type":"article-journal","container-title":"Cell Host & Microbe","DOI":"10.1016/j.chom.2019.01.014","ISSN":"1931-3128","issue":"2","language":"English","note":"section: 0","page":"219–232","title":"Phage Therapy: A Renewed Approach to Combat Antibiotic-Resistant Bacteria","volume":"25","author":[{"family":"Kortright","given":"Kaitlyn E."},{"family":"Chan","given":"Benjamin K."},{"family":"Koff","given":"Jonathan L."},{"family":"Turner","given":"Paul E."}],"issued":{"date-parts":[["2019",2]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->23<!-- [if supportFields]><![endif]-->. In another report, multiple phage cocktails were utilized in a case of necrotizing pancreatitis caused by an MDR A. baumannii-infected pseudocyst. A novel mixture proved successful in treating the infection over a 12-week period despite the emergence of resistance <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Lp7dw8NE","properties":{"formattedCitation":"\\super 23\\nosupersub{}","plainCitation":"23","noteIndex":0},"citationItems":[{"id":1293,"uris":["http://zotero.org/users/11334842/items/P6WLFGEY"],"itemData":{"id":1293,"type":"article-journal","container-title":"Cell Host & Microbe","DOI":"10.1016/j.chom.2019.01.014","ISSN":"1931-3128","issue":"2","language":"English","note":"section: 0","page":"219–232","title":"Phage Therapy: A Renewed Approach to Combat Antibiotic-Resistant Bacteria","volume":"25","author":[{"family":"Kortright","given":"Kaitlyn E."},{"family":"Chan","given":"Benjamin K."},{"family":"Koff","given":"Jonathan L."},{"family":"Turner","given":"Paul E."}],"issued":{"date-parts":[["2019",2]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->23<!-- [if supportFields]><![endif]-->. P. aeruginosa was also targeted in an aortic graft: This infection proved resistant to conventional therapy. The local administration of ceftazidime along with phage OMKO1 successfully resolved the infection <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"WmHI7KUk","properties":{"formattedCitation":"\\super 23\\nosupersub{}","plainCitation":"23","noteIndex":0},"citationItems":[{"id":1293,"uris":["http://zotero.org/users/11334842/items/P6WLFGEY"],"itemData":{"id":1293,"type":"article-journal","container-title":"Cell Host & Microbe","DOI":"10.1016/j.chom.2019.01.014","ISSN":"1931-3128","issue":"2","language":"English","note":"section: 0","page":"219–232","title":"Phage Therapy: A Renewed Approach to Combat Antibiotic-Resistant Bacteria","volume":"25","author":[{"family":"Kortright","given":"Kaitlyn E."},{"family":"Chan","given":"Benjamin K."},{"family":"Koff","given":"Jonathan L."},{"family":"Turner","given":"Paul E."}],"issued":{"date-parts":[["2019",2]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->23<!-- [if supportFields]><![endif]-->. Successful cases show how well phage treatment and antibiotics work together. Using a phage cocktail and trimethoprim-sulfamethoxazole, a patient with a UTI caused by the highly drug-resistant Klebsiella pneumoniae was able to get rid of the infection and avoid recurrence for six months <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"5fJLzOvy","properties":{"formattedCitation":"\\super 44\\nosupersub{}","plainCitation":"44","noteIndex":0},"citationItems":[{"id":1271,"uris":["http://zotero.org/users/11334842/items/7CFWW6JZ"],"itemData":{"id":1271,"type":"article-journal","abstract":"Emergence of antibiotic resistance presents a major setback to global health, and shortage of antibiotic pipelines has created an urgent need for development of alternative therapeutic strategies. Bacteriophage (phage) therapy is considered as a potential approach for treatment of the increasing number of antibiotic-resistant pathogens. Phage-antibiotic synergy (PAS) refers to sublethal concentrations of certain antibiotics that enhance release of progeny phages from bacterial cells. A combination of phages and antibiotics is a promising strategy to reduce the dose of antibiotics and the development of antibiotic resistance during treatment. In this review, we highlight the state-of-the-art advancements of PAS studies, including the analysis of bacterial-killing enhancement, bacterial resistance reduction, and anti-biofilm effect, at both in vitro and in vivo levels. A comprehensive review of the genetic and molecular mechanisms of phage antibiotic synergy is provided, and synthetic biology approaches used to engineer phages, and design novel therapies and diagnostic tools are discussed. In addition, the role of engineered phages in reducing pathogenicity of bacteria is explored.","container-title":"International Journal of Biological Sciences","DOI":"10.7150/ijbs.60551","ISSN":"1449-2288","issue":"13","language":"eng","note":"section: 0","page":"3573–3582","title":"A combination therapy of Phages and Antibiotics: Two is better than one","volume":"17","author":[{"family":"Li","given":"Xianghui"},{"family":"He","given":"Yuhua"},{"family":"Wang","given":"Zhili"},{"family":"Wei","given":"Jiacun"},{"family":"Hu","given":"Tongxin"},{"family":"Si","given":"Jiangzhe"},{"family":"Tao","given":"Guangzhao"},{"family":"Zhang","given":"Lei"},{"family":"Xie","given":"Longxiang"},{"family":"Abdalla","given":"Abualgasim Elgaili"},{"family":"Wang","given":"Guoying"},{"family":"Li","given":"Yanzhang"},{"family":"Teng","given":"Tieshan"}],"issued":{"date-parts":[["2021"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->44<!-- [if supportFields]><![endif]-->. Similarly, a Georgia phage in combination with meropenem successfully treated an infection in a renal transplant patient, resulting in symptom relief and a year-long recovery. Depending on the kind, different phages and antibiotics interact differently. <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"IA9lHZGf","properties":{"formattedCitation":"\\super 44\\nosupersub{}","plainCitation":"44","noteIndex":0},"citationItems":[{"id":1271,"uris":["http://zotero.org/users/11334842/items/7CFWW6JZ"],"itemData":{"id":1271,"type":"article-journal","abstract":"Emergence of antibiotic resistance presents a major setback to global health, and shortage of antibiotic pipelines has created an urgent need for development of alternative therapeutic strategies. Bacteriophage (phage) therapy is considered as a potential approach for treatment of the increasing number of antibiotic-resistant pathogens. Phage-antibiotic synergy (PAS) refers to sublethal concentrations of certain antibiotics that enhance release of progeny phages from bacterial cells. A combination of phages and antibiotics is a promising strategy to reduce the dose of antibiotics and the development of antibiotic resistance during treatment. In this review, we highlight the state-of-the-art advancements of PAS studies, including the analysis of bacterial-killing enhancement, bacterial resistance reduction, and anti-biofilm effect, at both in vitro and in vivo levels. A comprehensive review of the genetic and molecular mechanisms of phage antibiotic synergy is provided, and synthetic biology approaches used to engineer phages, and design novel therapies and diagnostic tools are discussed. In addition, the role of engineered phages in reducing pathogenicity of bacteria is explored.","container-title":"International Journal of Biological Sciences","DOI":"10.7150/ijbs.60551","ISSN":"1449-2288","issue":"13","language":"eng","note":"section: 0","page":"3573–3582","title":"A combination therapy of Phages and Antibiotics: Two is better than one","volume":"17","author":[{"family":"Li","given":"Xianghui"},{"family":"He","given":"Yuhua"},{"family":"Wang","given":"Zhili"},{"family":"Wei","given":"Jiacun"},{"family":"Hu","given":"Tongxin"},{"family":"Si","given":"Jiangzhe"},{"family":"Tao","given":"Guangzhao"},{"family":"Zhang","given":"Lei"},{"family":"Xie","given":"Longxiang"},{"family":"Abdalla","given":"Abualgasim Elgaili"},{"family":"Wang","given":"Guoying"},{"family":"Li","given":"Yanzhang"},{"family":"Teng","given":"Tieshan"}],"issued":{"date-parts":[["2021"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->44<!-- [if supportFields]><![endif]-->. S. aureus phages can also be used as a coating on prosthetic medical devices, in combination with antibiotics, as anti-biofilm formation strategies <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"QkA4HUQe","properties":{"formattedCitation":"\\super 45\\nosupersub{}","plainCitation":"45","noteIndex":0},"citationItems":[{"id":1257,"uris":["http://zotero.org/users/11334842/items/D99FAKML"],"itemData":{"id":1257,"type":"article-journal","abstract":"Unconstrained consumption of antibiotics throughout the expanse of the 21st century has resulted in increased antimicrobial resistance (AMR) among bacterial pathogens, a transpiring predicament affecting the public healthcare sector. The upsurge of multidrug-resistant pathogens, including Staphylococcus aureus, synchronously with the breakdown of the conventional antibiotic pipeline has led to the exploration of alternate strategies. Phage therapy applications have thus gained immense prominence among the scientific community to conquer this notorious pathogen associated with wide-ranging clinical manifestations, especially in immunosuppressed individuals. In this direction, a plethora of phage formulations like topical solutions, medicated dressings impregnated with phages, liposomal entrapments, etc., have been considered as an effective and upcoming strategy. Owing to the synergistic effect of phages with other antibacterial agents, they can be easily exploited for biomedical application. This review primarily focuses on the therapeutic implications of S. aureus phages in the biotechnological and medical arena. Through this review article, we have also discussed the current status and the incurring challenges in phage therapy.","container-title":"Journal of Applied Microbiology","DOI":"10.1111/jam.15462","ISSN":"1365-2672","issue":"5","language":"eng","note":"section: 0","page":"3515–3532","title":"Exploring the therapeutic potential of staphylococcal phage formulations: Current challenges and applications in phage therapy","volume":"132","author":[{"family":"Khullar","given":"Lavanya"},{"family":"Harjai","given":"Kusum"},{"family":"Chhibber","given":"Sanjay"}],"issued":{"date-parts":[["2022",5]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->45<!-- [if supportFields]><![endif]-->. Clinical trials have also been conducted on this topic. The Otitis Clinical Trial started in 2009 showed that phage treatment for persistent P. aeruginosa otitis dramatically lowered bacterial counts after treatment for 23 days. No significant adverse events were seen, and safety was established <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"97z0uOY3","properties":{"formattedCitation":"\\super 23\\nosupersub{}","plainCitation":"23","noteIndex":0},"citationItems":[{"id":1293,"uris":["http://zotero.org/users/11334842/items/P6WLFGEY"],"itemData":{"id":1293,"type":"article-journal","container-title":"Cell Host & Microbe","DOI":"10.1016/j.chom.2019.01.014","ISSN":"1931-3128","issue":"2","language":"English","note":"section: 0","page":"219–232","title":"Phage Therapy: A Renewed Approach to Combat Antibiotic-Resistant Bacteria","volume":"25","author":[{"family":"Kortright","given":"Kaitlyn E."},{"family":"Chan","given":"Benjamin K."},{"family":"Koff","given":"Jonathan L."},{"family":"Turner","given":"Paul E."}],"issued":{"date-parts":[["2019",2]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->23<!-- [if supportFields]><![endif]-->. In another trial in Bengladesh, phage mixtures were used to treat pathogenic E.coli in cases of diarrhea and failed to show benefot. The low-pH stomach environment may have an effect on viral viability, <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"hZYS2P0O","properties":{"formattedCitation":"\\super 23\\nosupersub{}","plainCitation":"23","noteIndex":0},"citationItems":[{"id":1293,"uris":["http://zotero.org/users/11334842/items/P6WLFGEY"],"itemData":{"id":1293,"type":"article-journal","container-title":"Cell Host & Microbe","DOI":"10.1016/j.chom.2019.01.014","ISSN":"1931-3128","issue":"2","language":"English","note":"section: 0","page":"219–232","title":"Phage Therapy: A Renewed Approach to Combat Antibiotic-Resistant Bacteria","volume":"25","author":[{"family":"Kortright","given":"Kaitlyn E."},{"family":"Chan","given":"Benjamin K."},{"family":"Koff","given":"Jonathan L."},{"family":"Turner","given":"Paul E."}],"issued":{"date-parts":[["2019",2]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->23<!-- [if supportFields]><![endif]-->. Part VIL: Real Life Applications In a systemic review published in 2022, from 27 chosen studies that encompassed a patient cohort of 165 individuals, the analyzed data showed that 85% of cases exhibited decreased bacterial loads or complete eradication, coupled with improved clinical indicators, while 15% (24 cases) saw no positive impact from Phage Treatment (PT). A mere 21% (35 patients) underwent combined PT and antibiotic treatment, achieving a 100% success rate. Among the remaining 79% who exclusively received PT, the success rate reached 81%. Notably, within the 27 examined studies, 6 reported instances of bacterial resistance to phages 46. In another review, 5 randomized clinical trials were included. One focused on chronic otitis where BT yielded significant positive clinical results 29. The other trials suggested that the bacteriophage concentration might have been too low to trigger a significant therapeutic effect, raising the need for dose optimization 29. Additionally, two trials exploring topical bacteriophage use yielded discouraging results due to phages' susceptibility to environmental factors 29. Variations in phage variants, conditions, concentrations, and approaches in these trials make it challenging to draw definitive conclusions about bacteriophage efficacy 29. The effectiveness of phage therapy relies heavily on selecting precise bacteriophages for individual bacterial species and strains due to their host cell specificity. This necessity underscores the need for extensive phage libraries to tailor treatments accordingly 46. Phages carry diverse proteins crucial for their replication cycle, encompassing functions from host recognition to cell lysis 47. Among these, phage-encoded proteins like receptor binding proteins, Virion-associated peptidoglycan hydrolases (VAPGHs), endolysins, anti-CRISPR proteins, spanins and holins are being explored as potential tools to combat antibiotic-resistant bacteria 47. The effectiveness of phage-encoded proteins as therapeutics relies on their serum half-life, with longer half-lives generally considered preferable 47. Besides, safety and cost-effectiveness are important considerations throughout the production process, including host selection, endotoxin removal, and regulatory approval 47. The proper selection of phages for clinical application emerges as a pivotal factor in the success of phage therapy. This selection process is influenced by factors such as the type of infection, the timing of treatment, the patient's clinical status, and the attributes of the phages themselves 20. The reviewed studies underscore that appropriate phage selection is an essential consideration for successful clinical phage therapy. Effective phages should possess traits such as safety, strict lytic behavior, polyvalency, stability, ability to replicate within the host, and compatibility within phage cocktails to curb bacterial resistance 20. The absence of significant side effects in the reviewed studies can be attributed to the inherent composition of phages, primarily composed of DNA and proteins that do not provoke allergic or toxic reactions in humans, and their targeted specificity towards specific bacteria 20. Ensuring phage purity and appropriate dilution further enhances their safety profile by eliminating potential immune reactions and constitutional symptoms arising from bacterial lysates or toxins 20. Moreover, the risk of virulence or drug resistance genes within phage genomes is mitigated by employing naturally occurring, strictly lytic phages, as they lack integration with bacterial genomes and the dissemination of harmful genes 20. Industrial-scale phage production requires standardized methods and regulatory frameworks lack global consensus 18. Raising awareness about phages' natural presence, safety, and potential efficacy is therefore crucial. Manufacturers must follow protocols, and regulations should ensure phage stability 18. To address resistance, genetically engineered phages are being developed to enhance effectiveness and decrease immunogenicity 43. Notably, the US FDA has approved phage therapy under the "Emergency Investigational New Drug Scheme," with the European Medicines Agency considering genetically modified phages as advanced therapeutic medicinal products 43. Purification and dilution methods further enhanced phage safety by removing bacterial toxins and lysates 11. To ensure phage stability, it is crucial to use strictly lytic phages that do not carry resistance genes 11. Genome sequencing can help identify the presence or absence of resistance elements, guiding appropriate phage selection 11. Genetically engineered phages offer customization options, and they have demonstrated efficacy in reducing bacterial titers. In cases of phage resistance, the use of polyvalent phage cocktails in alternation can be considered 11. The administration of compassionate phage therapy typically involves a collaborative approach, bringing together experts from various fields, including infectious disease specialists, microbiologists, phage biologists, and pharmacologists 21. A standardized protocol for phage selection, production, purification, dosing, and treatment methods could immensely facilitate the broader implementation of compassionate phage therapy on a global scale. This would streamline the process and provide more uniform and effective treatments for critically-ill patients 21. Topical phage products have emerged as some of the first to reach the market, with Gladskin (lysin SA.100) by Micreos gaining approval from the European Medicines Agency 21. Gladskin targets S. aureus for treating skin conditions like eczema, rosacea, psoriasis, and acne 21. Micreos is also developing endolysin XZ.700 for atopic dermatitis. iNtRON Biotechnology completed a phase I clinical study for intravenous N-Rephasin SAL200, demonstrating its tolerability and safety 21. The endolysin exebacase CF-301 by ContraFect is being evaluated in COVID-19 patients with persistent MRSA bacteraemia, showcasing its effectiveness against a broad range of S. aureus isolates, including biofilms 21. Combination therapy, involving the use of both antibiotics and phage therapy, has shown synergistic effects in treating bacterial infections 11. Sublethal concentrations of antibiotics can enhance the production of lytic phages, leading to faster destruction of bacterial cells 11. In the reviewed studies, combination therapy was tested for S. aureus infections, with one study including P. aeruginosa. The results demonstrated mostly synergistic effects, such as improved survival, protection from lethal infection, biofilm degradation, and reduced bacterial load 11. However, factors such as administration methods, dosage, and choice of antibiotic can influence the practicality and effectiveness of the approach 11. Currently, there are two main approaches to bacteriophage therapy in the United States. The first approach is personalized phage therapy, where a large phage library is developed and maintained 37. The patient's bacterial isolate is tested against various phages in the library to select the most effective ones 37. These phages are then used to create a personalized combination for the patient. Initially, finding matching phages took time as they were isolated from environmental and sewage samples 37. However, now there are commercial entities and academic laboratories with large phage banks, reducing the time to find active options 37. The second approach is the use of a fixed phage combination as an off-the-shelf product. This involves developing a product with a predetermined combination of phages that are active against a broad range of bacterial strains within a specific species 37. Genetically modified phages that can overcome bacterial resistance mechanisms can also be explored for this purpose 37. While not all patients can be treated with this approach, the goal is to be able to treat a majority of patients with susceptible bacterial infections 37. Unlike antibiotics, a single phage dosage may be able to completely eradicate the bacterial population 48. However, the method phages are given out directly affects how effective they are as a treatment. High quantities of phages must be delivered near to the target pathogen using the right dose and delivery techniques in order to obtain the best results 48. Antibiotic and phage interactions can have positive or negative consequences. Rifampicin exhibits antagonistic behavior with some phages by reducing bacterial growth and phage replication through the host RNA polymerase 44. Rifampicin can work better when combined with phages that have their own RNA polymerase, such as the P. aeruginosa phage KZ 44. Utilizing a variety of phages from nature is essential to preventing the emergence of phage resistance. Phage cocktails, which are combinations of several viruses, are used to boost therapeutic efficacy and immune system evasion 49. These combinations are effective because they dramatically lower the development of multi-resistance because even if bacterial cells develop resistance to one phage, they remain susceptible to the others in the mixture 49. Various formulations of phages have been reported that have different routes of administration to enhance bioavailability and target specificity, including topical applications, liposomal entrapments, immobilization of active phages on bandages, hydrogels, prosthetic devices and nanofibers. Encapsulating the phages in the liposome improves gastric resistance and stability, and protects it from antibodies 45. One of the modes of administration is through nebulizers, which permits topical delivery of phages directly to the site of infection in patients with cystic fibrosis or pulmonary bacterial infections. In non-cystic fibrosis patients, inhaling small particles such as dry powders can incite irritation and bronchoconstriction, and thus extra caution is needed 45. In one study, upon five nebulized administrations of pyophage cocktail, which included an anti-Staphylococcal phage, the patient suffering from cystic fibrosis became culture negative 50. Pyo bacteriophage preparation plays a role in wound healing in patients with diabetic foot ulcers colonized with MRSA and fully eliminate the infection, with the condition that it must be preceded with removal of necrotic tissue and antiseptic solution that doesn’t affect the phage’s titers, and continuous monitoring and the stopping of treatment only after the bacteria has immensely decreased 50. Topical preparation of staphylococcal phage Sb-1 once a week for seven weeks was shown to be more effective in toe ulcers treatment than antibiotics, but with a delay caused by osteomyelitis. Trials have also shown that S. aureus phages as a treatment for chronic venous leg ulcers are safe to use and with minimal side effects 50. Part VII: ESKAPE Organisms and Phages In the treatment of infections caused by ESKAPE pathogens, phages have shown promise. Studies have demonstrated the effectiveness of phages against pathogens like Enterococcus faecalis and Staphylococcus aureus, where bacteriophage-based drugs have halted bacterial growth in both planktonic and biofilm stages <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"3LWhEmpv","properties":{"formattedCitation":"\\super 3\\nosupersub{}","plainCitation":"3","noteIndex":0},"citationItems":[{"id":1119,"uris":["http://zotero.org/users/11334842/items/V6FI3YDR"],"itemData":{"id":1119,"type":"article-journal","abstract":"Globally, the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) are the major cause of nosocomial infections. These pathogens are multidrug resistant, and their negative impacts have brought serious health challenges and economic burden on many countries worldwide. Thus, this narrative review exploits different emerging alternative therapeutic strategies including combination antibiotics, antimicrobial peptides ((AMPs), bacteriophage and photodynamic therapies used in the treatment of the ESKAPE pathogens, their merits, limitations, and future prospects. Our findings indicate that ESKAPE pathogens exhibit resistance to drug using different mechanisms including drug inactivation by irreversible enzyme cleavage, drug-binding site alteration, diminution in permeability of drug or drug efflux increment to reduce accumulation of drug as well as biofilms production. However, the scientific community has shown significant interest in using these novel strategies with numerous benefits although they have some limitations including but not limited to instability and toxicity of the therapeutic agents, or the host developing immune response against the therapeutic agents. Thus, comprehension of resistance mechanisms of these pathogens is necessary to further develop or modify these approaches in order to overcome these health challenges including the barriers of bacterial resistance.","container-title":"Microbial Pathogenesis","DOI":"10.1016/j.micpath.2022.105963","ISSN":"1096-1208","language":"eng","note":"section: 0","page":"105963","title":"Coping with the ESKAPE pathogens: Evolving strategies, challenges and future prospects","volume":"175","author":[{"family":"Aloke","given":"Chinyere"},{"family":"Achilonu","given":"Ikechukwu"}],"issued":{"date-parts":[["2023",2]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->3<!-- [if supportFields]><![endif]-->. Combining lytic enzymes with cell-penetrating peptides, such as homing peptides, has been explored to target intracellular pathogens like E. coli, S. aureus, and L. monocytogenes <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"etTztLPM","properties":{"formattedCitation":"\\super 47\\nosupersub{}","plainCitation":"47","noteIndex":0},"citationItems":[{"id":1147,"uris":["http://zotero.org/users/11334842/items/89U9EXRN"],"itemData":{"id":1147,"type":"article-journal","abstract":"INTRODUCTION: The mounting incidence of multidrug-resistant bacterial strains and the dearth of novel antibiotics demand alternate therapies to manage the infections caused by resistant superbugs. Bacteriophages and phage=derived proteins are considered as potential alternates to treat such infections, and have several applications in health care systems. The aim of this review is to explore the hidden potential of bacteriophage proteins which may be a practical alternative approach to manage the threat of antibiotic resistance. RESULTS: Clinical trials are in progress for the use of phage therapy as a tool for routine medical use; however, the existing regulations may hamper their development of routine antimicrobial agents. The advancement of molecular techniques and the advent of sequencing have opened new potentials for the design of engineered bacteriophages as well as recombinant bacteriophage proteins. The phage enzymes and proteins encoded by the lysis cassette genes, especially endolysins, holins, and spanins, have shown plausible potentials as therapeutic candidates. CONCLUSION: This review offers an integrated viewpoint that aims to decipher the insights and abilities of bacteriophages and their derived proteins as potential alternatives to antibiotics.","container-title":"Infectious Diseases and Therapy","DOI":"10.1007/s40121-021-00446-2","ISSN":"2193-8229","issue":"3","language":"eng","note":"section: 0","page":"1171–1193","title":"Bacteriophage Proteome: Insights and Potentials of an Alternate to Antibiotics","volume":"10","author":[{"family":"Aslam","given":"Bilal"},{"family":"Arshad","given":"Muhammad Imran"},{"family":"Aslam","given":"Muhammad Aamir"},{"family":"Muzammil","given":"Saima"},{"family":"Siddique","given":"Abu Baker"},{"family":"Yasmeen","given":"Nafeesa"},{"family":"Khurshid","given":"Mohsin"},{"family":"Rasool","given":"Maria"},{"family":"Ahmad","given":"Moeed"},{"family":"Rasool","given":"Muhammad Hidayat"},{"family":"Fahim","given":"Mohammad"},{"family":"Hussain","given":"Riaz"},{"family":"Xia","given":"Xueshan"},{"family":"Baloch","given":"Zulqarnain"}],"issued":{"date-parts":[["2021",9]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->47<!-- [if supportFields]><![endif]-->. Data has demonstrated the safety profile of certain endolysins, suggesting their potential for therapeutic use. Moreover, endolysins like lysostaphin can be modified to create lysibodies, aiding in the opsonization of pathogens like S. aureus<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"x5sUy0ps","properties":{"formattedCitation":"\\super 47\\nosupersub{}","plainCitation":"47","noteIndex":0},"citationItems":[{"id":1147,"uris":["http://zotero.org/users/11334842/items/89U9EXRN"],"itemData":{"id":1147,"type":"article-journal","abstract":"INTRODUCTION: The mounting incidence of multidrug-resistant bacterial strains and the dearth of novel antibiotics demand alternate therapies to manage the infections caused by resistant superbugs. Bacteriophages and phage=derived proteins are considered as potential alternates to treat such infections, and have several applications in health care systems. The aim of this review is to explore the hidden potential of bacteriophage proteins which may be a practical alternative approach to manage the threat of antibiotic resistance. RESULTS: Clinical trials are in progress for the use of phage therapy as a tool for routine medical use; however, the existing regulations may hamper their development of routine antimicrobial agents. The advancement of molecular techniques and the advent of sequencing have opened new potentials for the design of engineered bacteriophages as well as recombinant bacteriophage proteins. The phage enzymes and proteins encoded by the lysis cassette genes, especially endolysins, holins, and spanins, have shown plausible potentials as therapeutic candidates. CONCLUSION: This review offers an integrated viewpoint that aims to decipher the insights and abilities of bacteriophages and their derived proteins as potential alternatives to antibiotics.","container-title":"Infectious Diseases and Therapy","DOI":"10.1007/s40121-021-00446-2","ISSN":"2193-8229","issue":"3","language":"eng","note":"section: 0","page":"1171–1193","title":"Bacteriophage Proteome: Insights and Potentials of an Alternate to Antibiotics","volume":"10","author":[{"family":"Aslam","given":"Bilal"},{"family":"Arshad","given":"Muhammad Imran"},{"family":"Aslam","given":"Muhammad Aamir"},{"family":"Muzammil","given":"Saima"},{"family":"Siddique","given":"Abu Baker"},{"family":"Yasmeen","given":"Nafeesa"},{"family":"Khurshid","given":"Mohsin"},{"family":"Rasool","given":"Maria"},{"family":"Ahmad","given":"Moeed"},{"family":"Rasool","given":"Muhammad Hidayat"},{"family":"Fahim","given":"Mohammad"},{"family":"Hussain","given":"Riaz"},{"family":"Xia","given":"Xueshan"},{"family":"Baloch","given":"Zulqarnain"}],"issued":{"date-parts":[["2021",9]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->47<!-- [if supportFields]><![endif]-->. El Haddad et al. assessed the present utilization of phages as a therapeutic approach in Western countries by a systemic review. The majority of the reviewed research demonstrated that various phages and phage cocktails exhibited significant effectiveness against certain ESKAPE pathogens, while also maintaining a high level of safety <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"OCiVVJYd","properties":{"formattedCitation":"\\super 20\\nosupersub{}","plainCitation":"20","noteIndex":0},"citationItems":[{"id":1295,"uris":["http://zotero.org/users/11334842/items/3ZV2PTLG"],"itemData":{"id":1295,"type":"article-journal","abstract":"Bacteriophages (phages) may constitute a natural, safe, and effective strategy to prevent and control multidrug-resistant organisms (MDROs), and ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens in particular. Few clinical studies have assessed the safety and efficacy of phages in patients infected with MDROs. This systematic review summarizes and critically evaluates published studies of phages in clinical practice and presents the appropriate phage selection criteria, as well as recommendations for clinicians and scientists for a successful therapy. Articles were identified through a search of the PubMed, Ovid, EMBASE, and Cochrane Library databases. Among 1102 articles and abstracts, 30 studies were selected and evaluated using selective inclusion criteria, phage criteria, and study characteristics. Most studies showed efficacy (87%) and safety (67%) of the tested phages, but few studies examined phage resistance (35%). Clinical studies and regulatory changes are needed to determine the safety and efficacy of phages and to advance their use in patients with MDRO infections.","container-title":"Clinical Infectious Diseases","DOI":"10.1093/cid/ciy947","ISSN":"1058-4838","issue":"1","note":"section: 0","page":"167–178","title":"A Systematic and Critical Review of Bacteriophage Therapy Against Multidrug-resistant ESKAPE Organisms in Humans","volume":"69","author":[{"family":"El Haddad","given":"Lynn"},{"family":"Harb","given":"Cynthia P"},{"family":"Gebara","given":"Marc A"},{"family":"Stibich","given":"Mark A"},{"family":"Chemaly","given":"Roy F"}],"issued":{"date-parts":[["2019",6]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->20<!-- [if supportFields]><![endif]-->. Notably, all patients enrolled in the review possessed bacterial strains resistant to conventional antibiotics. In approximately 87% of these cases, bacteriophage therapy exhibited positive outcomes, leading to reductions in bacterial concentrations, biofilm degradation, wound healing, and overall improvements in health <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"sIepaxHB","properties":{"formattedCitation":"\\super 20\\nosupersub{}","plainCitation":"20","noteIndex":0},"citationItems":[{"id":1295,"uris":["http://zotero.org/users/11334842/items/3ZV2PTLG"],"itemData":{"id":1295,"type":"article-journal","abstract":"Bacteriophages (phages) may constitute a natural, safe, and effective strategy to prevent and control multidrug-resistant organisms (MDROs), and ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens in particular. Few clinical studies have assessed the safety and efficacy of phages in patients infected with MDROs. This systematic review summarizes and critically evaluates published studies of phages in clinical practice and presents the appropriate phage selection criteria, as well as recommendations for clinicians and scientists for a successful therapy. Articles were identified through a search of the PubMed, Ovid, EMBASE, and Cochrane Library databases. Among 1102 articles and abstracts, 30 studies were selected and evaluated using selective inclusion criteria, phage criteria, and study characteristics. Most studies showed efficacy (87%) and safety (67%) of the tested phages, but few studies examined phage resistance (35%). Clinical studies and regulatory changes are needed to determine the safety and efficacy of phages and to advance their use in patients with MDRO infections.","container-title":"Clinical Infectious Diseases","DOI":"10.1093/cid/ciy947","ISSN":"1058-4838","issue":"1","note":"section: 0","page":"167–178","title":"A Systematic and Critical Review of Bacteriophage Therapy Against Multidrug-resistant ESKAPE Organisms in Humans","volume":"69","author":[{"family":"El Haddad","given":"Lynn"},{"family":"Harb","given":"Cynthia P"},{"family":"Gebara","given":"Marc A"},{"family":"Stibich","given":"Mark A"},{"family":"Chemaly","given":"Roy F"}],"issued":{"date-parts":[["2019",6]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->20<!-- [if supportFields]><![endif]-->. There is ongoing interest in using nebulized phage for outpatient management of P. aeruginosa infections in cystic fibrosis patients, particularly during cystic fibrosis flares <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"tG6c9W6s","properties":{"formattedCitation":"\\super 37\\nosupersub{}","plainCitation":"37","noteIndex":0},"citationItems":[{"id":1149,"uris":["http://zotero.org/users/11334842/items/3CFTZ7JM"],"itemData":{"id":1149,"type":"article-journal","abstract":"PURPOSE OF REVIEW: Since initial description of the successful use of intravenous bacteriophage therapy in the United States in 2017, there is widespread interest in using bacteriophage therapy for multidrug-resistant (MDR) infections. RECENT FINDINGS: Recent published cases of bacteriophage therapy in transplant candidates and recipients are reviewed highlighting its safety and potential efficacy when used as an adjunct to systemic antibiotics for a variety of clinical indications. An overview of access to bacteriophage therapy in the United States is also provided. SUMMARY: The reviewed cases form the basis for ongoing compassionate use of bacteriophage therapy in transplant candidates and recipients with life-threatening MDR infections until data from clinical trials are available to guide therapy.","container-title":"Current Opinion in Infectious Diseases","DOI":"10.1097/QCO.0000000000000658","ISSN":"1473-6527","issue":"4","language":"eng","note":"section: 0","page":"298–303","title":"Bacteriophage therapy as a treatment option for transplant infections","volume":"33","author":[{"family":"Aslam","given":"Saima"}],"issued":{"date-parts":[["2020",8]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->37<!-- [if supportFields]><![endif]-->. Efforts are also underway to develop a BCC phage library and a mycobacterial phage library targeting M. abscessus, M. tuberculosis, and M. avium species <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"ApRtew7k","properties":{"formattedCitation":"\\super 37\\nosupersub{}","plainCitation":"37","noteIndex":0},"citationItems":[{"id":1149,"uris":["http://zotero.org/users/11334842/items/3CFTZ7JM"],"itemData":{"id":1149,"type":"article-journal","abstract":"PURPOSE OF REVIEW: Since initial description of the successful use of intravenous bacteriophage therapy in the United States in 2017, there is widespread interest in using bacteriophage therapy for multidrug-resistant (MDR) infections. RECENT FINDINGS: Recent published cases of bacteriophage therapy in transplant candidates and recipients are reviewed highlighting its safety and potential efficacy when used as an adjunct to systemic antibiotics for a variety of clinical indications. An overview of access to bacteriophage therapy in the United States is also provided. SUMMARY: The reviewed cases form the basis for ongoing compassionate use of bacteriophage therapy in transplant candidates and recipients with life-threatening MDR infections until data from clinical trials are available to guide therapy.","container-title":"Current Opinion in Infectious Diseases","DOI":"10.1097/QCO.0000000000000658","ISSN":"1473-6527","issue":"4","language":"eng","note":"section: 0","page":"298–303","title":"Bacteriophage therapy as a treatment option for transplant infections","volume":"33","author":[{"family":"Aslam","given":"Saima"}],"issued":{"date-parts":[["2020",8]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->37<!-- [if supportFields]><![endif]-->. Other antibiotic-resistant respiratory infection-causing microbes like Acinetobacter, Achromobacter, Staphylococcus, and Burkholderia species have also been successfully treated with phage therapy <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"puVbD42B","properties":{"formattedCitation":"\\super 50\\nosupersub{}","plainCitation":"50","noteIndex":0},"citationItems":[{"id":1225,"uris":["http://zotero.org/users/11334842/items/W8CIDIJE"],"itemData":{"id":1225,"type":"article-journal","abstract":"The looming antibiotic resistance crisis is forcing clinicians to consider alternative approaches to treating bacterial infections. As the window of use for current antimicrobial agents becomes ever narrower, we consider if looking back will now be the way forward. Conceptually, phage therapy is simple and specific; a targeted treatment to control bacterial overgrowth. In this article we discuss bacteriophage and potential use in future therapy.","container-title":"Paediatric Respiratory Reviews","DOI":"10.1016/j.prrv.2022.02.001","ISSN":"1526-0550","language":"eng","note":"section: 0","page":"70–77","title":"The potential of bacteriophage therapy in the treatment of paediatric respiratory infections","volume":"44","author":[{"family":"Jones","given":"J. D."},{"family":"Varghese","given":"D."},{"family":"Pabary","given":"R."},{"family":"Langley","given":"R. J."}],"issued":{"date-parts":[["2022",12]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->50<!-- [if supportFields]><![endif]-->. Aerosolized phage therapy has been shown to be effective against the Burkholderia cepacia complex in mice <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"p58VBYIJ","properties":{"formattedCitation":"\\super 50\\nosupersub{}","plainCitation":"50","noteIndex":0},"citationItems":[{"id":1225,"uris":["http://zotero.org/users/11334842/items/W8CIDIJE"],"itemData":{"id":1225,"type":"article-journal","abstract":"The looming antibiotic resistance crisis is forcing clinicians to consider alternative approaches to treating bacterial infections. As the window of use for current antimicrobial agents becomes ever narrower, we consider if looking back will now be the way forward. Conceptually, phage therapy is simple and specific; a targeted treatment to control bacterial overgrowth. In this article we discuss bacteriophage and potential use in future therapy.","container-title":"Paediatric Respiratory Reviews","DOI":"10.1016/j.prrv.2022.02.001","ISSN":"1526-0550","language":"eng","note":"section: 0","page":"70–77","title":"The potential of bacteriophage therapy in the treatment of paediatric respiratory infections","volume":"44","author":[{"family":"Jones","given":"J. D."},{"family":"Varghese","given":"D."},{"family":"Pabary","given":"R."},{"family":"Langley","given":"R. J."}],"issued":{"date-parts":[["2022",12]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->50<!-- [if supportFields]><![endif]-->. Careful phage selection is essential for phage mixtures to work well. Due to their wide host range and quick lytic cycle, the Myoviridae family is the main focus of most cocktails used to treat staphylococcal infections <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Y0MsLeDX","properties":{"formattedCitation":"\\super 49\\nosupersub{}","plainCitation":"49","noteIndex":0},"citationItems":[{"id":1219,"uris":["http://zotero.org/users/11334842/items/M8IK4MUX"],"itemData":{"id":1219,"type":"article-journal","abstract":"Despite occurring at the microscopic scale, the armed race between phages and their bacterial hosts involves multiple mechanisms, some of which are just starting to be understood. On the one hand, bacteria have evolved strategies that can stop the viral infection at different stages (adsorption, DNA injection and replication, biosynthesis and assembly of the viral progeny and/or release of the newly formed virions); on the other, phages have gradually evolved counterattack strategies that allow them to continue infecting their prey. This co-evolutionary process has played a major role in the development of microbial populations in both natural and man-made environments. Notably, understanding the parameters of this microscopic war will be paramount to fully benefit from the application of phage therapy against dangerous, antibiotic-resistant human pathogens. This review gathers the current knowledge regarding the mechanisms of phage resistance in the Staphylococcus genus, which includes Staphylococcus aureus, one of the most concerning microorganisms in terms of antibiotic resistance acquisition. Some of these strategies involve permanent changes to the bacterial cell via mutations, while others are transient, adaptive changes whose expression depends on certain environmental cues or the growth phase. Finally, we discuss the most plausible strategies to limit the impact of phage resistance on therapy, with a special emphasis on the importance of a rational design of phage cocktails in order to thwart therapeutic failure.","container-title":"Viruses","DOI":"10.3390/v14051061","ISSN":"1999-4915","issue":"5","language":"eng","note":"section: 0","page":"1061","title":"Understanding the Mechanisms That Drive Phage Resistance in Staphylococci to Prevent Phage Therapy Failure","volume":"14","author":[{"family":"Jurado","given":"Andrea"},{"family":"Fernández","given":"Lucía"},{"family":"Rodríguez","given":"Ana"},{"family":"García","given":"Pilar"}],"issued":{"date-parts":[["2022",5]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->49<!-- [if supportFields]><![endif]-->. Products like Pyophage, which contains a myovirus and a podovirus, are examples of exceptions. Although aggressive variants of these phages can be exploited, siphoviridae family phages are less frequently used due to their temperate lifestyle <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"VYyH8pq5","properties":{"formattedCitation":"\\super 49\\nosupersub{}","plainCitation":"49","noteIndex":0},"citationItems":[{"id":1219,"uris":["http://zotero.org/users/11334842/items/M8IK4MUX"],"itemData":{"id":1219,"type":"article-journal","abstract":"Despite occurring at the microscopic scale, the armed race between phages and their bacterial hosts involves multiple mechanisms, some of which are just starting to be understood. On the one hand, bacteria have evolved strategies that can stop the viral infection at different stages (adsorption, DNA injection and replication, biosynthesis and assembly of the viral progeny and/or release of the newly formed virions); on the other, phages have gradually evolved counterattack strategies that allow them to continue infecting their prey. This co-evolutionary process has played a major role in the development of microbial populations in both natural and man-made environments. Notably, understanding the parameters of this microscopic war will be paramount to fully benefit from the application of phage therapy against dangerous, antibiotic-resistant human pathogens. This review gathers the current knowledge regarding the mechanisms of phage resistance in the Staphylococcus genus, which includes Staphylococcus aureus, one of the most concerning microorganisms in terms of antibiotic resistance acquisition. Some of these strategies involve permanent changes to the bacterial cell via mutations, while others are transient, adaptive changes whose expression depends on certain environmental cues or the growth phase. Finally, we discuss the most plausible strategies to limit the impact of phage resistance on therapy, with a special emphasis on the importance of a rational design of phage cocktails in order to thwart therapeutic failure.","container-title":"Viruses","DOI":"10.3390/v14051061","ISSN":"1999-4915","issue":"5","language":"eng","note":"section: 0","page":"1061","title":"Understanding the Mechanisms That Drive Phage Resistance in Staphylococci to Prevent Phage Therapy Failure","volume":"14","author":[{"family":"Jurado","given":"Andrea"},{"family":"Fernández","given":"Lucía"},{"family":"Rodríguez","given":"Ana"},{"family":"García","given":"Pilar"}],"issued":{"date-parts":[["2022",5]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->49<!-- [if supportFields]><![endif]-->. Staphylococcus Aureus Another member of the ESKAPE family is Staphylococcus aureus. S. aureus is one of the main global contributors to both community and hospital-acquired illnesses. It is a highly adaptable pathogen that causes a wide range of illnesses, from minor skin and soft-tissue infections to fatal invasive infections <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"pdii3of0","properties":{"formattedCitation":"\\super 26\\nosupersub{}","plainCitation":"26","noteIndex":0},"citationItems":[{"id":1328,"uris":["http://zotero.org/users/11334842/items/9DSUL93H"],"itemData":{"id":1328,"type":"article-journal","abstract":"Phage therapy recently passed a key milestone with success of the first regulated clinical trial using systemic administration. In this single-arm non-comparative safety study, phages were administered intravenously to patients with invasive Staphylococcus aureus infections with no adverse reactions reported. Here, we examined features of 78 lytic S. aureus phages, most of which were propagated using a S. carnosus host modified to be broadly susceptible to staphylococcal phage infection. Use of this host eliminates the threat of contamination with staphylococcal prophage — the main vector of S. aureus horizontal gene transfer. We determined the host range of these phages against an international collection of 185 S. aureus isolates with 56 different multilocus sequence types that included multiple representatives of all epidemic MRSA and MSSA clonal complexes. Forty of our 78 phages were able to infect > 90% of study isolates, 15 were able to infect > 95%, and two could infect all 184 clinical isolates, but not a phage-resistant mutant generated in a previous study. We selected the 10 phages with the widest host range for in vitro characterization by planktonic culture time-kill analysis against four isolates:- modified S. carnosus strain TM300H, methicillin-sensitive isolates D329 and 15981, and MRSA isolate 252. Six of these 10 phages were able to rapidly kill, reducing cell numbers of at least three isolates. The four best-performing phages, in this assay, were further shown to be highly effective in reducing 48 h biofilms on polystyrene formed by eight ST22 and eight ST36 MRSA isolates. Genomes of 22 of the widest host-range phages showed they belonged to the Twortvirinae subfamily of the order Caudovirales in three main groups corresponding to Silviavirus, and two distinct groups of Kayvirus. These genomes assembled as single-linear dsDNAs with an average length of 140 kb and a GC content of c. 30%. Phages that could infect > 96% of S. aureus isolates were found in all three groups, and these have great potential as therapeutic candidates if, in future studies, they can be formulated to maximize their efficacy and eliminate emergence of phage resistance by using appropriate combinations.","container-title":"Frontiers in Cellular and Infection Microbiology","ISSN":"2235-2988","source":"Frontiers","title":"Phenotypic and Genotypic Characterization of Novel Polyvalent Bacteriophages With Potent In Vitro Activity Against an International Collection of Genetically Diverse Staphylococcus aureus","URL":"https://www.frontiersin.org/articles/10.3389/fcimb.2021.698909","volume":"11","author":[{"family":"Whittard","given":"Elliot"},{"family":"Redfern","given":"James"},{"family":"Xia","given":"Guoqing"},{"family":"Millard","given":"Andrew"},{"family":"Ragupathy","given":"Roobinidevi"},{"family":"Malic","given":"Sladjana"},{"family":"Enright","given":"Mark C."}],"accessed":{"date-parts":[["2023",12,6]]},"issued":{"date-parts":[["2021"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->26<!-- [if supportFields]><![endif]-->. Methicillin resistant and vancomycin resistant S. aureus strains have emerged , which led to the emergence of bacteriophages infecting S.aureus as a potential treatment <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"S5lM0OfQ","properties":{"formattedCitation":"\\super 49\\nosupersub{}","plainCitation":"49","noteIndex":0},"citationItems":[{"id":1219,"uris":["http://zotero.org/users/11334842/items/M8IK4MUX"],"itemData":{"id":1219,"type":"article-journal","abstract":"Despite occurring at the microscopic scale, the armed race between phages and their bacterial hosts involves multiple mechanisms, some of which are just starting to be understood. On the one hand, bacteria have evolved strategies that can stop the viral infection at different stages (adsorption, DNA injection and replication, biosynthesis and assembly of the viral progeny and/or release of the newly formed virions); on the other, phages have gradually evolved counterattack strategies that allow them to continue infecting their prey. This co-evolutionary process has played a major role in the development of microbial populations in both natural and man-made environments. Notably, understanding the parameters of this microscopic war will be paramount to fully benefit from the application of phage therapy against dangerous, antibiotic-resistant human pathogens. This review gathers the current knowledge regarding the mechanisms of phage resistance in the Staphylococcus genus, which includes Staphylococcus aureus, one of the most concerning microorganisms in terms of antibiotic resistance acquisition. Some of these strategies involve permanent changes to the bacterial cell via mutations, while others are transient, adaptive changes whose expression depends on certain environmental cues or the growth phase. Finally, we discuss the most plausible strategies to limit the impact of phage resistance on therapy, with a special emphasis on the importance of a rational design of phage cocktails in order to thwart therapeutic failure.","container-title":"Viruses","DOI":"10.3390/v14051061","ISSN":"1999-4915","issue":"5","language":"eng","note":"section: 0","page":"1061","title":"Understanding the Mechanisms That Drive Phage Resistance in Staphylococci to Prevent Phage Therapy Failure","volume":"14","author":[{"family":"Jurado","given":"Andrea"},{"family":"Fernández","given":"Lucía"},{"family":"Rodríguez","given":"Ana"},{"family":"García","given":"Pilar"}],"issued":{"date-parts":[["2022",5]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->49<!-- [if supportFields]><![endif]-->. The prevalence of S. aureus (SA) phages in the environment is widespread <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"SPYAiR9R","properties":{"formattedCitation":"\\super 45\\nosupersub{}","plainCitation":"45","noteIndex":0},"citationItems":[{"id":1257,"uris":["http://zotero.org/users/11334842/items/D99FAKML"],"itemData":{"id":1257,"type":"article-journal","abstract":"Unconstrained consumption of antibiotics throughout the expanse of the 21st century has resulted in increased antimicrobial resistance (AMR) among bacterial pathogens, a transpiring predicament affecting the public healthcare sector. The upsurge of multidrug-resistant pathogens, including Staphylococcus aureus, synchronously with the breakdown of the conventional antibiotic pipeline has led to the exploration of alternate strategies. Phage therapy applications have thus gained immense prominence among the scientific community to conquer this notorious pathogen associated with wide-ranging clinical manifestations, especially in immunosuppressed individuals. In this direction, a plethora of phage formulations like topical solutions, medicated dressings impregnated with phages, liposomal entrapments, etc., have been considered as an effective and upcoming strategy. Owing to the synergistic effect of phages with other antibacterial agents, they can be easily exploited for biomedical application. This review primarily focuses on the therapeutic implications of S. aureus phages in the biotechnological and medical arena. Through this review article, we have also discussed the current status and the incurring challenges in phage therapy.","container-title":"Journal of Applied Microbiology","DOI":"10.1111/jam.15462","ISSN":"1365-2672","issue":"5","language":"eng","note":"section: 0","page":"3515–3532","title":"Exploring the therapeutic potential of staphylococcal phage formulations: Current challenges and applications in phage therapy","volume":"132","author":[{"family":"Khullar","given":"Lavanya"},{"family":"Harjai","given":"Kusum"},{"family":"Chhibber","given":"Sanjay"}],"issued":{"date-parts":[["2022",5]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->45<!-- [if supportFields]><![endif]-->. These include Siphovoridae, a temperate bacteriophage, but which may turn virulent, and Myoviridae and Podoviridae, which are virulent ones, have a wide host range, and are more preferred as they ensure the death of the infected bacteria <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"0GGawZXa","properties":{"formattedCitation":"\\super 49\\nosupersub{}","plainCitation":"49","noteIndex":0},"citationItems":[{"id":1219,"uris":["http://zotero.org/users/11334842/items/M8IK4MUX"],"itemData":{"id":1219,"type":"article-journal","abstract":"Despite occurring at the microscopic scale, the armed race between phages and their bacterial hosts involves multiple mechanisms, some of which are just starting to be understood. On the one hand, bacteria have evolved strategies that can stop the viral infection at different stages (adsorption, DNA injection and replication, biosynthesis and assembly of the viral progeny and/or release of the newly formed virions); on the other, phages have gradually evolved counterattack strategies that allow them to continue infecting their prey. This co-evolutionary process has played a major role in the development of microbial populations in both natural and man-made environments. Notably, understanding the parameters of this microscopic war will be paramount to fully benefit from the application of phage therapy against dangerous, antibiotic-resistant human pathogens. This review gathers the current knowledge regarding the mechanisms of phage resistance in the Staphylococcus genus, which includes Staphylococcus aureus, one of the most concerning microorganisms in terms of antibiotic resistance acquisition. Some of these strategies involve permanent changes to the bacterial cell via mutations, while others are transient, adaptive changes whose expression depends on certain environmental cues or the growth phase. Finally, we discuss the most plausible strategies to limit the impact of phage resistance on therapy, with a special emphasis on the importance of a rational design of phage cocktails in order to thwart therapeutic failure.","container-title":"Viruses","DOI":"10.3390/v14051061","ISSN":"1999-4915","issue":"5","language":"eng","note":"section: 0","page":"1061","title":"Understanding the Mechanisms That Drive Phage Resistance in Staphylococci to Prevent Phage Therapy Failure","volume":"14","author":[{"family":"Jurado","given":"Andrea"},{"family":"Fernández","given":"Lucía"},{"family":"Rodríguez","given":"Ana"},{"family":"García","given":"Pilar"}],"issued":{"date-parts":[["2022",5]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->49<!-- [if supportFields]><![endif]-->. The efficacy of SA phages in the treatment of human infections was first reported after the regression of an infection within only 24-48 hours after the SA phages’ local injection in a surgically open wound <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"JfwwYsko","properties":{"formattedCitation":"\\super 51\\nosupersub{}","plainCitation":"51","noteIndex":0},"citationItems":[{"id":1243,"uris":["http://zotero.org/users/11334842/items/N7UUSKJC"],"itemData":{"id":1243,"type":"article-journal","abstract":"Introduction Staphylococcus aureus is a common human pathogen that causes various diseases including infections on the skin, in the bloodstream and the lower respiratory tracts. The emergence of methicillin-resistant S. aureus (MRSA) made the treatment of the bacterial infection more difficult, calling for development of new therapeutics. Compared with conventional antibiotic therapy, phage therapy offers a promising alternative to combat infections caused by MRSA. Results Here we showed that phage VB_SauS_SH-St 15644 isolated from sewage inhibited MRSA isolates in vitro and in the murine skin infection model. Phage VB_SauS_SH-St 15644 belongs to Siphoviridae. The genome of the phage is a linear, 45,111 bp double-stranded DNA with GC content of 33.35%. Among the 37 clinical MRSA isolates tested, 12 (32%) were lysed by the phage in vitro. The phage was relatively stable at temperatures up to 40 °C or between pH 6 and 9. However, the phage was sensitive to UV light. 80% of the phage was approximately adsorbed to the host MRSA isolate in 4 min. The one-step growth curve showed that the latent period was about 12 min followed by the growth period (about 9 min). The burst size was estimated at 13 PFU per infected cell. Furthermore, in a murine skin infection model, the phage significantly inhibited MRSA infection. Conclusions Our study suggested that phage VB_SauS_SH-St 15644 has a potential to inhibit MRSA skin infection.","container-title":"Microbial Pathogenesis","DOI":"10.1016/j.micpath.2020.104317","ISSN":"0882-4010","language":"en","note":"section: 0","page":"104317","title":"Identification of a novel phage targeting methicillin-resistant Staphylococcus aureus In vitro and In vivo","volume":"149","author":[{"family":"Ji","given":"Jiawei"},{"family":"Liu","given":"Qian"},{"family":"Wang","given":"Rui"},{"family":"Luo","given":"Tingting"},{"family":"Guo","given":"Xiaokui"},{"family":"Xu","given":"Mengsha"},{"family":"Yin","given":"Qian"},{"family":"Wang","given":"Xuetong"},{"family":"Zhou","given":"Min"},{"family":"Li","given":"Min"},{"family":"He","given":"Ping"}],"issued":{"date-parts":[["2020",12]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->51<!-- [if supportFields]><![endif]-->. Trials on bacteriophage therapy against acute and chronic staphylococcal infections resulted in complete resolution of the diseases in 40% of patients after bacteriophage monotherapy, with better results (70%) after bacteriophage/antibiotic combination treatment, with the bacteriophage therapy being efficient in children, especially infants (aged 1–12 months) with staphylococcal infections <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"H4Rbqogj","properties":{"formattedCitation":"\\super 8\\nosupersub{}","plainCitation":"8","noteIndex":0},"citationItems":[{"id":1221,"uris":["http://zotero.org/users/11334842/items/IUA99M77"],"itemData":{"id":1221,"type":"article-journal","abstract":"Bacteriophages, highly prevalent in all environments, have found their use in medicine as an alternative or complement to antibiotics. The therapeutic use of bacteriophages was particularly popular in the 1920s and 1930s, until the discovery and introduction of antibiotics. Due to the dynamic growth of antibiotic resistance among bacterial strains, numerous international institutions (such as the FDA) have declared the search for novel treatment modalities to be of the highest priority. To date, bacteriophage therapy has not been registered for general use in Western countries. The regulation of biological medicinal products (within medicinal product regulation) does not contain a specific documentation frame for bacteriophages (only for vaccines, blood derived products, etc.) which, as active substances, need to meet specific requirements. Recently, the FDA allowed bacteriophage therapy to be used in the United States, via the Emergency Investigational New Drug scheme; clinical trials to compare the safety and efficacy of bacteriophage therapy are also permitted. To date, several therapeutic products of this type have made it to phase I or II; some clinical programmes have also been completed. This article cites numerous animal model studies and registered clinical trials, showing the safety and effectiveness of bacteriophage therapy, including infections caused by bacterial strains resistant to antibiotic treatment.","container-title":"Journal of Applied Microbiology","DOI":"10.1111/jam.14535","ISSN":"1365-2672","issue":"4","language":"eng","note":"section: 0","page":"985–1002","title":"Therapeutic bacteriophages as a rescue treatment for drug-resistant infections - an in vivo studies overview","volume":"128","author":[{"family":"Kwiatek","given":"M."},{"family":"Parasion","given":"S."},{"family":"Nakonieczna","given":"A."}],"issued":{"date-parts":[["2020",4]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->8<!-- [if supportFields]><![endif]-->. Klebsiella Pneumoniae K. pneumoniae is a gram-negative bacterium that causes nosocomial antimicrobial-resistant opportunistic infections, including wound infections, pneumonia, meningitis, septicemia, and UTI <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"8IsD8Hp9","properties":{"formattedCitation":"\\super 21\\nosupersub{}","plainCitation":"21","noteIndex":0},"citationItems":[{"id":1121,"uris":["http://zotero.org/users/11334842/items/3UF62TYT"],"itemData":{"id":1121,"type":"article-journal","abstract":"Antibiotic therapy has become increasingly ineffective against bacterial infections due to the rise of resistance. In particular, ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) have caused life-threatening infections in humans and represent a major global health threat due to a high degree of antibiotic resistance. To respond to this urgent call, novel strategies are urgently needed, such as bacteriophages (or phages), phage-encoded enzymes, immunomodulators and monoclonal antibodies. This review critically analyses these promising antimicrobial therapies for the treatment of multidrug-resistant bacterial infections. Recent advances in these novel therapeutic strategies are discussed, focusing on preclinical and clinical investigations, as well as combinatorial approaches. In this 'Bad Bugs, No Drugs' era, novel therapeutic strategies can play a key role in treating deadly infections and help extend the lifetime of antibiotics.","container-title":"Advanced Drug Delivery Reviews","DOI":"10.1016/j.addr.2022.114378","ISSN":"1872-8294","language":"eng","note":"section: 0","page":"114378","title":"Novel antimicrobial agents for combating antibiotic-resistant bacteria","volume":"187","author":[{"family":"Chang","given":"Rachel Yoon Kyung"},{"family":"Nang","given":"Sue C."},{"family":"Chan","given":"Hak-Kim"},{"family":"Li","given":"Jian"}],"issued":{"date-parts":[["2022",8]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->21<!-- [if supportFields]><![endif]-->. Regardless of antibiotic therapy, these infections can have a high mortality rate due to its incidence in neonates and immunocompromised patients. Over the last few decades, the rise in antibiotic resistance has resulted in the emergence of multidrug-resistant (MDR) strains, especially the Carbapenem-resistant K. Pneumoniae (CRKP), which pose a significant challenge in the treatment of infections. Facing antibiotic resistance, alternative methods of treatment are needed such as phage therapy, a promising tool yet in need of more research <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"oSdHDfWA","properties":{"formattedCitation":"\\super 21,52\\nosupersub{}","plainCitation":"21,52","noteIndex":0},"citationItems":[{"id":1121,"uris":["http://zotero.org/users/11334842/items/3UF62TYT"],"itemData":{"id":1121,"type":"article-journal","abstract":"Antibiotic therapy has become increasingly ineffective against bacterial infections due to the rise of resistance. In particular, ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) have caused life-threatening infections in humans and represent a major global health threat due to a high degree of antibiotic resistance. To respond to this urgent call, novel strategies are urgently needed, such as bacteriophages (or phages), phage-encoded enzymes, immunomodulators and monoclonal antibodies. This review critically analyses these promising antimicrobial therapies for the treatment of multidrug-resistant bacterial infections. Recent advances in these novel therapeutic strategies are discussed, focusing on preclinical and clinical investigations, as well as combinatorial approaches. In this 'Bad Bugs, No Drugs' era, novel therapeutic strategies can play a key role in treating deadly infections and help extend the lifetime of antibiotics.","container-title":"Advanced Drug Delivery Reviews","DOI":"10.1016/j.addr.2022.114378","ISSN":"1872-8294","language":"eng","note":"section: 0","page":"114378","title":"Novel antimicrobial agents for combating antibiotic-resistant bacteria","volume":"187","author":[{"family":"Chang","given":"Rachel Yoon Kyung"},{"family":"Nang","given":"Sue C."},{"family":"Chan","given":"Hak-Kim"},{"family":"Li","given":"Jian"}],"issued":{"date-parts":[["2022",8]]}}},{"id":1253,"uris":["http://zotero.org/users/11334842/items/C7NB8T9E"],"itemData":{"id":1253,"type":"article-journal","abstract":"Klebsiella pneumoniae, a multidrug resistant bacterium that causes nosocomial infections including septicemia, pneumonia etc. Bacteriophages are potential antimicrobial agents for the treatment of antibiotic resistant bacteria. In this study, a novel bacteriophage IME184, was isolated from hospital sewage against clinical multi-drug resistant Klebsiella pneumoniae. Transmission electron microscopy and genomic characterization exhibited this phage belongs to the Molineuxvirinae genus, Autographiviridae family. Phage IME184 possessed a double-stranded DNA genome composed of 44,598 bp with a GC content of 50.3%. The phage genome encodes 57 open reading frames, out of 26 are hypothetical proteins while 31 had assigned putative functions. No tRNA, virulence related or antibiotic resistance genes were found in phage genome. Comparative genomic analysis showed that phage IME184 has 94% similarity with genomic sequence of Klebsiella phage K1-ULIP33 (MK380014.1). Multiplicity of infection, one step growth curve and host range of phage were also measured. According to findings, Phage IME184 is a promising biological agent that infects Klebsiella pneumoniae and can be used in future phage therapies.","container-title":"Virus Research","DOI":"10.1016/j.virusres.2022.198873","ISSN":"0168-1702","language":"en","note":"section: 0","page":"198873","title":"Isolation and genomic characterization of a novel Autographiviridae bacteriophage IME184 with lytic activity against Klebsiella pneumoniae","volume":"319","author":[{"family":"Li","given":"Fei"},{"family":"Tian","given":"Fengjuan"},{"family":"Nazir","given":"Amina"},{"family":"Sui","given":"Shujing"},{"family":"Li","given":"Mengzhe"},{"family":"Cheng","given":"Dongxiao"},{"family":"Nong","given":"Siqin"},{"family":"Ali","given":"Azam"},{"family":"KaKar","given":"Mohib-Ullah"},{"family":"Li","given":"Lu"},{"family":"Feng","given":"Qiang"},{"family":"Tong","given":"Yigang"}],"issued":{"date-parts":[["2022",10]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->21,52<!-- [if supportFields]><![endif]-->. There are few trials where Klebsiella bacteriophages were used in human subjects in EU and UK though nearly all the trials done were successful to treat MDR Klebsiella. This small number of trials is because the use of bacteriophage by physicians is hindered by the lack of regulations and rules regarding their safety <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"WUDwxstX","properties":{"formattedCitation":"\\super 9\\nosupersub{}","plainCitation":"9","noteIndex":0},"citationItems":[{"id":1215,"uris":["http://zotero.org/users/11334842/items/KRHR9D2P"],"itemData":{"id":1215,"type":"article-journal","abstract":"Klebsiella spp. are commensals of the human microbiota, and a leading cause of opportunistic nosocomial infections. The incidence of multidrug resistant (MDR) strains of Klebsiella pneumoniae causing serious infections is increasing, and Klebsiella oxytoca is an emerging pathogen. Alternative strategies to tackle infections caused by these bacteria are required as strains become resistant to last-resort antibiotics such as colistin. Bacteriophages (phages) are viruses that can infect and kill bacteria. They and their gene products are now being considered as alternatives or adjuncts to antimicrobial therapies. Several in vitro and in vivo studies have shown the potential for lytic phages to combat MDR K. pneumoniae infections. Ready access to cheap sequencing technologies has led to a large increase in the number of genomes available for Klebsiella-infecting phages, with these phages being heterogeneous at the whole-genome level. This review summarizes our current knowledge on phages of Klebsiella spp. and highlights technological and biological issues relevant to the development of phage-based therapies targeting these bacteria.","container-title":"Journal of Medical Microbiology","DOI":"10.1099/jmm.0.001141","ISSN":"1473-5644","issue":"2","language":"eng","note":"section: 0","page":"176–194","title":"Bacteriophages of Klebsiella spp., their diversity and potential therapeutic uses","volume":"69","author":[{"family":"Herridge","given":"Warren P."},{"family":"Shibu","given":"Preetha"},{"family":"O'Shea","given":"Jessica"},{"family":"Brook","given":"Thomas C."},{"family":"Hoyles","given":"Lesley"}],"issued":{"date-parts":[["2020",2]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->9<!-- [if supportFields]><![endif]-->. There are many bacteriophages targeting different components of the K. pneumoniae, most of them were tested in vitro or on animal models. For example, bacteriophage TSK1 produced a depolymerase enzyme and targeted the biofilm's capsular polysaccharides, resulting in a 99-100% reduction in the in-vitro developed K. pneumoniae biofilm <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"TloA9paZ","properties":{"formattedCitation":"\\super 1\\nosupersub{}","plainCitation":"1","noteIndex":0},"citationItems":[{"id":1103,"uris":["http://zotero.org/users/11334842/items/UV9M5H9G"],"itemData":{"id":1103,"type":"article-journal","abstract":"INTRODUCTION: The quest to combat bacterial infections has dreaded humankind for centuries. Infections involving ESKAPE (Enterococcus spp., Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) impose therapeutic challenges due to the emergence of antimicrobial drug resistance. Recently, investigations with bacteriophages have led to the development of novel strategies against ESKAPE infections. Also, bacteriophages have been demonstrated to be instrumental in the dissemination of virulence markers in ESKAPE pathogens. AREAS COVERED: The review highlights the potential of bacteriophage in and against the pathogenicity of antibiotic-resistant ESKAPE pathogens. The review also emphasizes the challenges of employing bacteriophage in treating ESKAPE pathogens and the knowledge gap in the bacteriophage mediated antibiotic resistance and pathogenicity in ESKAPE infections. EXPERT OPINION: Bacteriophage infection can kill the host bacteria but in survivors can transfer genes that contribute toward the survival of the pathogens in the host and resistance toward multiple antimicrobials. The knowledge on the dual role of bacteriophages in the treatment and pathogenicity will assist in the prediction and development of novel therapeutics targeting antimicrobial-resistant ESKAPE. Therefore, extensive investigations on the efficacy of synthetic bacteriophage, bacteriophage cocktails, and bacteriophage in combination with antibiotics are needed to develop effective therapeutics against ESKAPE infections.","container-title":"Expert Review of Anti-Infective Therapy","DOI":"10.1080/14787210.2021.1858800","ISSN":"1744-8336","issue":"7","language":"eng","note":"section: 0","page":"845–865","title":"Bacteriophages for ESKAPE: role in pathogenicity and measures of control","volume":"19","author":[{"family":"Patil","given":"Amrita"},{"family":"Banerji","given":"Rajashri"},{"family":"Kanojiya","given":"Poonam"},{"family":"Koratkar","given":"Santosh"},{"family":"Saroj","given":"Sunil"}],"issued":{"date-parts":[["2021",7]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->1<!-- [if supportFields]><![endif]-->. Bacteriophage cocktail, targeting many MDR bacteria, can also be effective after only 45 minutes of injections of isolates of 6 pathogens (including K. pneumoniae). Likewise, injection of the cocktail treatment involving bacteriophage ECP311, KPP235, and ELP140 displayed a 100 % survival rate when injected into an infected larva <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"EDBzzNvA","properties":{"formattedCitation":"\\super 1\\nosupersub{}","plainCitation":"1","noteIndex":0},"citationItems":[{"id":1103,"uris":["http://zotero.org/users/11334842/items/UV9M5H9G"],"itemData":{"id":1103,"type":"article-journal","abstract":"INTRODUCTION: The quest to combat bacterial infections has dreaded humankind for centuries. Infections involving ESKAPE (Enterococcus spp., Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) impose therapeutic challenges due to the emergence of antimicrobial drug resistance. Recently, investigations with bacteriophages have led to the development of novel strategies against ESKAPE infections. Also, bacteriophages have been demonstrated to be instrumental in the dissemination of virulence markers in ESKAPE pathogens. AREAS COVERED: The review highlights the potential of bacteriophage in and against the pathogenicity of antibiotic-resistant ESKAPE pathogens. The review also emphasizes the challenges of employing bacteriophage in treating ESKAPE pathogens and the knowledge gap in the bacteriophage mediated antibiotic resistance and pathogenicity in ESKAPE infections. EXPERT OPINION: Bacteriophage infection can kill the host bacteria but in survivors can transfer genes that contribute toward the survival of the pathogens in the host and resistance toward multiple antimicrobials. The knowledge on the dual role of bacteriophages in the treatment and pathogenicity will assist in the prediction and development of novel therapeutics targeting antimicrobial-resistant ESKAPE. Therefore, extensive investigations on the efficacy of synthetic bacteriophage, bacteriophage cocktails, and bacteriophage in combination with antibiotics are needed to develop effective therapeutics against ESKAPE infections.","container-title":"Expert Review of Anti-Infective Therapy","DOI":"10.1080/14787210.2021.1858800","ISSN":"1744-8336","issue":"7","language":"eng","note":"section: 0","page":"845–865","title":"Bacteriophages for ESKAPE: role in pathogenicity and measures of control","volume":"19","author":[{"family":"Patil","given":"Amrita"},{"family":"Banerji","given":"Rajashri"},{"family":"Kanojiya","given":"Poonam"},{"family":"Koratkar","given":"Santosh"},{"family":"Saroj","given":"Sunil"}],"issued":{"date-parts":[["2021",7]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->1<!-- [if supportFields]><![endif]-->. K. pneumoniae bacteriophages have different host ranges, for instance, phage φBO1E recognizes and targets specifically K. pneumoniae of the pandemic clonal group 258 (CG258) clade II lineage, rendering it a narrow spectrum bacteriophage <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"JzRp3wcC","properties":{"formattedCitation":"\\super 9\\nosupersub{}","plainCitation":"9","noteIndex":0},"citationItems":[{"id":1215,"uris":["http://zotero.org/users/11334842/items/KRHR9D2P"],"itemData":{"id":1215,"type":"article-journal","abstract":"Klebsiella spp. are commensals of the human microbiota, and a leading cause of opportunistic nosocomial infections. The incidence of multidrug resistant (MDR) strains of Klebsiella pneumoniae causing serious infections is increasing, and Klebsiella oxytoca is an emerging pathogen. Alternative strategies to tackle infections caused by these bacteria are required as strains become resistant to last-resort antibiotics such as colistin. Bacteriophages (phages) are viruses that can infect and kill bacteria. They and their gene products are now being considered as alternatives or adjuncts to antimicrobial therapies. Several in vitro and in vivo studies have shown the potential for lytic phages to combat MDR K. pneumoniae infections. Ready access to cheap sequencing technologies has led to a large increase in the number of genomes available for Klebsiella-infecting phages, with these phages being heterogeneous at the whole-genome level. This review summarizes our current knowledge on phages of Klebsiella spp. and highlights technological and biological issues relevant to the development of phage-based therapies targeting these bacteria.","container-title":"Journal of Medical Microbiology","DOI":"10.1099/jmm.0.001141","ISSN":"1473-5644","issue":"2","language":"eng","note":"section: 0","page":"176–194","title":"Bacteriophages of Klebsiella spp., their diversity and potential therapeutic uses","volume":"69","author":[{"family":"Herridge","given":"Warren P."},{"family":"Shibu","given":"Preetha"},{"family":"O'Shea","given":"Jessica"},{"family":"Brook","given":"Thomas C."},{"family":"Hoyles","given":"Lesley"}],"issued":{"date-parts":[["2020",2]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->9<!-- [if supportFields]><![endif]-->. On the other hand, phage KPO1K2, specific for K. pneumoniae B5055, is also able to infect multiple strains of K. pneumoniae, as well as some E. coli strains and, therefore, has a relatively broader host spectrum. Phages with a narrow host range are inappropriate for presumptive or prophylactic treatment <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"r1zKYXUS","properties":{"formattedCitation":"\\super 9\\nosupersub{}","plainCitation":"9","noteIndex":0},"citationItems":[{"id":1215,"uris":["http://zotero.org/users/11334842/items/KRHR9D2P"],"itemData":{"id":1215,"type":"article-journal","abstract":"Klebsiella spp. are commensals of the human microbiota, and a leading cause of opportunistic nosocomial infections. The incidence of multidrug resistant (MDR) strains of Klebsiella pneumoniae causing serious infections is increasing, and Klebsiella oxytoca is an emerging pathogen. Alternative strategies to tackle infections caused by these bacteria are required as strains become resistant to last-resort antibiotics such as colistin. Bacteriophages (phages) are viruses that can infect and kill bacteria. They and their gene products are now being considered as alternatives or adjuncts to antimicrobial therapies. Several in vitro and in vivo studies have shown the potential for lytic phages to combat MDR K. pneumoniae infections. Ready access to cheap sequencing technologies has led to a large increase in the number of genomes available for Klebsiella-infecting phages, with these phages being heterogeneous at the whole-genome level. This review summarizes our current knowledge on phages of Klebsiella spp. and highlights technological and biological issues relevant to the development of phage-based therapies targeting these bacteria.","container-title":"Journal of Medical Microbiology","DOI":"10.1099/jmm.0.001141","ISSN":"1473-5644","issue":"2","language":"eng","note":"section: 0","page":"176–194","title":"Bacteriophages of Klebsiella spp., their diversity and potential therapeutic uses","volume":"69","author":[{"family":"Herridge","given":"Warren P."},{"family":"Shibu","given":"Preetha"},{"family":"O'Shea","given":"Jessica"},{"family":"Brook","given":"Thomas C."},{"family":"Hoyles","given":"Lesley"}],"issued":{"date-parts":[["2020",2]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->9<!-- [if supportFields]><![endif]-->. Successful phage therapy in combination with antibiotics is demonstrated by clinical examples. A phage cocktail and antibiotics were used to treat a patient with a UTI caused by Klebsiella pneumoniae and eradicate the infection for six months <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"UCHubMEw","properties":{"formattedCitation":"\\super 44\\nosupersub{}","plainCitation":"44","noteIndex":0},"citationItems":[{"id":1271,"uris":["http://zotero.org/users/11334842/items/7CFWW6JZ"],"itemData":{"id":1271,"type":"article-journal","abstract":"Emergence of antibiotic resistance presents a major setback to global health, and shortage of antibiotic pipelines has created an urgent need for development of alternative therapeutic strategies. Bacteriophage (phage) therapy is considered as a potential approach for treatment of the increasing number of antibiotic-resistant pathogens. Phage-antibiotic synergy (PAS) refers to sublethal concentrations of certain antibiotics that enhance release of progeny phages from bacterial cells. A combination of phages and antibiotics is a promising strategy to reduce the dose of antibiotics and the development of antibiotic resistance during treatment. In this review, we highlight the state-of-the-art advancements of PAS studies, including the analysis of bacterial-killing enhancement, bacterial resistance reduction, and anti-biofilm effect, at both in vitro and in vivo levels. A comprehensive review of the genetic and molecular mechanisms of phage antibiotic synergy is provided, and synthetic biology approaches used to engineer phages, and design novel therapies and diagnostic tools are discussed. In addition, the role of engineered phages in reducing pathogenicity of bacteria is explored.","container-title":"International Journal of Biological Sciences","DOI":"10.7150/ijbs.60551","ISSN":"1449-2288","issue":"13","language":"eng","note":"section: 0","page":"3573–3582","title":"A combination therapy of Phages and Antibiotics: Two is better than one","volume":"17","author":[{"family":"Li","given":"Xianghui"},{"family":"He","given":"Yuhua"},{"family":"Wang","given":"Zhili"},{"family":"Wei","given":"Jiacun"},{"family":"Hu","given":"Tongxin"},{"family":"Si","given":"Jiangzhe"},{"family":"Tao","given":"Guangzhao"},{"family":"Zhang","given":"Lei"},{"family":"Xie","given":"Longxiang"},{"family":"Abdalla","given":"Abualgasim Elgaili"},{"family":"Wang","given":"Guoying"},{"family":"Li","given":"Yanzhang"},{"family":"Teng","given":"Tieshan"}],"issued":{"date-parts":[["2021"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->44<!-- [if supportFields]><![endif]-->. In another instance, K. pneumoniae infection responded favorably to a Georgia phage and meropenem, resulting in relief and a year-long recovery. Acinetobacter baumannii A. baumannii causes nosocomial infections notably ventilator-associated pneumonia, meningitis, catheter-associated urinary tract infections and surgical site infections <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"krcARz70","properties":{"formattedCitation":"\\super 53\\nosupersub{}","plainCitation":"53","noteIndex":0},"citationItems":[{"id":1171,"uris":["http://zotero.org/users/11334842/items/ZQTX4N5V"],"itemData":{"id":1171,"type":"article-journal","abstract":"Hospital-acquired infections are on the rise and are a substantial cause of clinical and financial burden for healthcare systems. While infection control plays a major role in curtailing the spread of outbreak organisms, it is not always successful. One organism of particular concern is Acinetobacter baumannii, due to both its persistence in the hospital setting and its ability to acquire antibiotic resistance. A. baumannii has emerged as a nosocomial pathogen that exhibits high levels of resistance to antibiotics, and remains resilient against traditional cleaning measures with resistance to Colistin increasingly reported. Given the magnitude and costs associated with hospital acquired infections, and the increase in multidrug-resistant organisms, it is worth re-evaluating our current approaches and looking for alternatives or adjuncts to traditional antibiotics therapies. The aims of this review are to look at how this organism is spread within the hospital setting, discuss current treatment modalities, and propose alternative methods of outbreak management.","container-title":"Infection Prevention in Practice","DOI":"10.1016/j.infpip.2020.100077","ISSN":"2590-0889","issue":"3","language":"en","note":"section: 0","page":"100077","title":"Control and management of multidrug resistant Acinetobacter baumannii: A review of the evidence and proposal of novel approaches","volume":"2","author":[{"family":"Weinberg","given":"S. E."},{"family":"Villedieu","given":"A."},{"family":"Bagdasarian","given":"N."},{"family":"Karah","given":"N."},{"family":"Teare","given":"L."},{"family":"Elamin","given":"W. F."}],"issued":{"date-parts":[["2020",9]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->53<!-- [if supportFields]><![endif]-->. It has become a significant concern in hospital settings due to its. In recent years, the bacteria has become more resistant to Colistin, a last resort antibiotic, making it more difficult to treat <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"QR2ZL9vQ","properties":{"formattedCitation":"\\super 53\\nosupersub{}","plainCitation":"53","noteIndex":0},"citationItems":[{"id":1171,"uris":["http://zotero.org/users/11334842/items/ZQTX4N5V"],"itemData":{"id":1171,"type":"article-journal","abstract":"Hospital-acquired infections are on the rise and are a substantial cause of clinical and financial burden for healthcare systems. While infection control plays a major role in curtailing the spread of outbreak organisms, it is not always successful. One organism of particular concern is Acinetobacter baumannii, due to both its persistence in the hospital setting and its ability to acquire antibiotic resistance. A. baumannii has emerged as a nosocomial pathogen that exhibits high levels of resistance to antibiotics, and remains resilient against traditional cleaning measures with resistance to Colistin increasingly reported. Given the magnitude and costs associated with hospital acquired infections, and the increase in multidrug-resistant organisms, it is worth re-evaluating our current approaches and looking for alternatives or adjuncts to traditional antibiotics therapies. The aims of this review are to look at how this organism is spread within the hospital setting, discuss current treatment modalities, and propose alternative methods of outbreak management.","container-title":"Infection Prevention in Practice","DOI":"10.1016/j.infpip.2020.100077","ISSN":"2590-0889","issue":"3","language":"en","note":"section: 0","page":"100077","title":"Control and management of multidrug resistant Acinetobacter baumannii: A review of the evidence and proposal of novel approaches","volume":"2","author":[{"family":"Weinberg","given":"S. E."},{"family":"Villedieu","given":"A."},{"family":"Bagdasarian","given":"N."},{"family":"Karah","given":"N."},{"family":"Teare","given":"L."},{"family":"Elamin","given":"W. F."}],"issued":{"date-parts":[["2020",9]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->53<!-- [if supportFields]><![endif]-->. Hospital-acquired infections caused by A. baumannii pose a significant risk to patients and can result in increased healthcare costs <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"ZccAMJNZ","properties":{"formattedCitation":"\\super 53\\nosupersub{}","plainCitation":"53","noteIndex":0},"citationItems":[{"id":1171,"uris":["http://zotero.org/users/11334842/items/ZQTX4N5V"],"itemData":{"id":1171,"type":"article-journal","abstract":"Hospital-acquired infections are on the rise and are a substantial cause of clinical and financial burden for healthcare systems. While infection control plays a major role in curtailing the spread of outbreak organisms, it is not always successful. One organism of particular concern is Acinetobacter baumannii, due to both its persistence in the hospital setting and its ability to acquire antibiotic resistance. A. baumannii has emerged as a nosocomial pathogen that exhibits high levels of resistance to antibiotics, and remains resilient against traditional cleaning measures with resistance to Colistin increasingly reported. Given the magnitude and costs associated with hospital acquired infections, and the increase in multidrug-resistant organisms, it is worth re-evaluating our current approaches and looking for alternatives or adjuncts to traditional antibiotics therapies. The aims of this review are to look at how this organism is spread within the hospital setting, discuss current treatment modalities, and propose alternative methods of outbreak management.","container-title":"Infection Prevention in Practice","DOI":"10.1016/j.infpip.2020.100077","ISSN":"2590-0889","issue":"3","language":"en","note":"section: 0","page":"100077","title":"Control and management of multidrug resistant Acinetobacter baumannii: A review of the evidence and proposal of novel approaches","volume":"2","author":[{"family":"Weinberg","given":"S. E."},{"family":"Villedieu","given":"A."},{"family":"Bagdasarian","given":"N."},{"family":"Karah","given":"N."},{"family":"Teare","given":"L."},{"family":"Elamin","given":"W. F."}],"issued":{"date-parts":[["2020",9]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->53<!-- [if supportFields]><![endif]-->. One target of phage therapy is the breakdown of bacterial biofilm, in one study that evaluated lytic phage on 15 isolates of bacteria <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"T5WqRbSn","properties":{"formattedCitation":"\\super 4\\nosupersub{}","plainCitation":"4","noteIndex":0},"citationItems":[{"id":1205,"uris":["http://zotero.org/users/11334842/items/8SHEUGH9"],"itemData":{"id":1205,"type":"article-journal","abstract":"Introduction Acinetobacter baumannii is responsible for most nosocomial infections in hospitals. It can form biofilms and has a high degree of antibiotic resistance. Colistin is one of the last therapeutic options for the treatment of MDR infections. Recently, strains of this pathogen resistance to the colistin were reported increasingly. Therefore, alternative antibacterial methods, such as phage therapy, are being researched. This study aims to survey the efficacy of isolated Myoviridae bacteriophage against biofilm embedded colistin-resistant Acinetobacter baumannii. Method In this study, 15 isolates of bacteria were isolated, and their biofilm was measured using violet crystal staining, and their MIC was measured using the broth microdilution method. On the other hand, lytic phage was isolated and purified from wastewater. Finally, the effect of phage on bacteria was calculated using MTT staining method. Results From 15 MDR A. baumannii clinical isolates, 26.6% were resistant to colistin, 80% were able to produce strong biofilm, and 20% have weak biofilm. The isolated lytic phage (IsfAB78) was able to reduce the biofilm by up to 87%. Conclusions This study showed that the isolated lytic phage impacted the biofilm of MDR A. baumannii. Phage IsfAB78 is the right candidate for this purpose.","container-title":"Gene Reports","DOI":"10.1016/j.genrep.2020.100984","ISSN":"2452-0144","language":"en","note":"section: 0","page":"100984","title":"Efficacy of isolated bacteriophage against biofilm embedded colistin-resistant Acinetobacter baumannii","volume":"22","author":[{"family":"Ebrahimi","given":"Saeedeh"},{"family":"Sisakhtpour","given":"Behnam"},{"family":"Mirzaei","given":"Arezoo"},{"family":"Karbasizadeh","given":"Vajihe"},{"family":"Moghim","given":"Sharareh"}],"issued":{"date-parts":[["2021",3]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->4<!-- [if supportFields]><![endif]-->. The study's data analysis revealed that the isolated lytic phage decreased by 87%. This finding indicates that bacteriophages can be valuable in breaking down biofilms on the surface of medical devices <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"6GxkZD5k","properties":{"formattedCitation":"\\super 4\\nosupersub{}","plainCitation":"4","noteIndex":0},"citationItems":[{"id":1205,"uris":["http://zotero.org/users/11334842/items/8SHEUGH9"],"itemData":{"id":1205,"type":"article-journal","abstract":"Introduction Acinetobacter baumannii is responsible for most nosocomial infections in hospitals. It can form biofilms and has a high degree of antibiotic resistance. Colistin is one of the last therapeutic options for the treatment of MDR infections. Recently, strains of this pathogen resistance to the colistin were reported increasingly. Therefore, alternative antibacterial methods, such as phage therapy, are being researched. This study aims to survey the efficacy of isolated Myoviridae bacteriophage against biofilm embedded colistin-resistant Acinetobacter baumannii. Method In this study, 15 isolates of bacteria were isolated, and their biofilm was measured using violet crystal staining, and their MIC was measured using the broth microdilution method. On the other hand, lytic phage was isolated and purified from wastewater. Finally, the effect of phage on bacteria was calculated using MTT staining method. Results From 15 MDR A. baumannii clinical isolates, 26.6% were resistant to colistin, 80% were able to produce strong biofilm, and 20% have weak biofilm. The isolated lytic phage (IsfAB78) was able to reduce the biofilm by up to 87%. Conclusions This study showed that the isolated lytic phage impacted the biofilm of MDR A. baumannii. Phage IsfAB78 is the right candidate for this purpose.","container-title":"Gene Reports","DOI":"10.1016/j.genrep.2020.100984","ISSN":"2452-0144","language":"en","note":"section: 0","page":"100984","title":"Efficacy of isolated bacteriophage against biofilm embedded colistin-resistant Acinetobacter baumannii","volume":"22","author":[{"family":"Ebrahimi","given":"Saeedeh"},{"family":"Sisakhtpour","given":"Behnam"},{"family":"Mirzaei","given":"Arezoo"},{"family":"Karbasizadeh","given":"Vajihe"},{"family":"Moghim","given":"Sharareh"}],"issued":{"date-parts":[["2021",3]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->4<!-- [if supportFields]><![endif]-->. Nonetheless, the phage was not entirely successful in removing the biofilms of some isolates. Thus, to achieve optimal results and completely eradicate biofilms, a combination of multiple lytic phages or a combination of phages with antibiotics could prove beneficial <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"QnSXGwzc","properties":{"formattedCitation":"\\super 4\\nosupersub{}","plainCitation":"4","noteIndex":0},"citationItems":[{"id":1205,"uris":["http://zotero.org/users/11334842/items/8SHEUGH9"],"itemData":{"id":1205,"type":"article-journal","abstract":"Introduction Acinetobacter baumannii is responsible for most nosocomial infections in hospitals. It can form biofilms and has a high degree of antibiotic resistance. Colistin is one of the last therapeutic options for the treatment of MDR infections. Recently, strains of this pathogen resistance to the colistin were reported increasingly. Therefore, alternative antibacterial methods, such as phage therapy, are being researched. This study aims to survey the efficacy of isolated Myoviridae bacteriophage against biofilm embedded colistin-resistant Acinetobacter baumannii. Method In this study, 15 isolates of bacteria were isolated, and their biofilm was measured using violet crystal staining, and their MIC was measured using the broth microdilution method. On the other hand, lytic phage was isolated and purified from wastewater. Finally, the effect of phage on bacteria was calculated using MTT staining method. Results From 15 MDR A. baumannii clinical isolates, 26.6% were resistant to colistin, 80% were able to produce strong biofilm, and 20% have weak biofilm. The isolated lytic phage (IsfAB78) was able to reduce the biofilm by up to 87%. Conclusions This study showed that the isolated lytic phage impacted the biofilm of MDR A. baumannii. Phage IsfAB78 is the right candidate for this purpose.","container-title":"Gene Reports","DOI":"10.1016/j.genrep.2020.100984","ISSN":"2452-0144","language":"en","note":"section: 0","page":"100984","title":"Efficacy of isolated bacteriophage against biofilm embedded colistin-resistant Acinetobacter baumannii","volume":"22","author":[{"family":"Ebrahimi","given":"Saeedeh"},{"family":"Sisakhtpour","given":"Behnam"},{"family":"Mirzaei","given":"Arezoo"},{"family":"Karbasizadeh","given":"Vajihe"},{"family":"Moghim","given":"Sharareh"}],"issued":{"date-parts":[["2021",3]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->4<!-- [if supportFields]><![endif]-->. The goal of phage therapy is to ultimately be used for personalized clinical treatment of patients. Multiple trials have attempted to do so, where phage therapy successfully eliminated the Acinetobacter pneumonia with full recovery <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"7ODb8VRs","properties":{"formattedCitation":"\\super 5\\nosupersub{}","plainCitation":"5","noteIndex":0},"citationItems":[{"id":1303,"uris":["http://zotero.org/users/11334842/items/IMCDGVZV"],"itemData":{"id":1303,"type":"article-journal","container-title":"Antimicrobial Agents and Chemotherapy","DOI":"10.1128/aac.00954-17","issue":"10","language":"en","page":"00954–17","title":"Development and Use of Personalized Bacteriophage-Based Therapeutic Cocktails To Treat a Patient with a Disseminated Resistant Acinetobacter baumannii Infection","volume":"61","author":[{"family":"Schooley","given":"R.T."},{"family":"Biswas","given":"B."},{"family":"Gill","given":"J.J."},{"family":"Hernandez-Morales","given":"A."},{"family":"Lancaster","given":"J."},{"family":"Lessor","given":"L."},{"family":"Barr","given":"J.J."},{"family":"Reed","given":"S.L."},{"family":"Rohwer","given":"F."},{"family":"Benler","given":"S."},{"family":"Segall","given":"A.M."},{"family":"Taplitz","given":"R."},{"family":"Smith","given":"D.M."},{"family":"Kerr","given":"K."},{"family":"Kumaraswamy","given":"M."},{"family":"Nizet","given":"V."},{"family":"Lin","given":"L."},{"family":"McCauley","given":"M.D."},{"family":"Strathdee","given":"S.A."},{"family":"Hamilton","given":"T."}],"issued":{"date-parts":[["2017"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->5<!-- [if supportFields]><![endif]-->. In another trial, phage therapy was administered to four severely ill COVID-19 patients with A. baumannii pulmonary infections. Out of the four patients, three showed positive clinical results and were discharged home, however one died of respiratory failure a month later <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"VMjM68Sa","properties":{"formattedCitation":"\\super 54\\nosupersub{}","plainCitation":"54","noteIndex":0},"citationItems":[{"id":1165,"uris":["http://zotero.org/users/11334842/items/VZV4QKP8"],"itemData":{"id":1165,"type":"article-journal","abstract":"Nosocomial infections (NIs) are hospital-acquired infections which pose a high healthcare burden worldwide. The impact of NIs is further aggravated by the global spread of antimicrobial resistance (AMR). Conventional treatment and disinfection agents are often insufficient to catch up with the increasing AMR and tolerance of the pathogenic bacteria. This has resulted in a need for alternative approaches and raised new interest in therapeutic bacteriophages (phages). In contrast to the limited clinical options available against AMR bacteria, the extreme abundance and biodiversity of phages in nature provides an opportunity to establish an ever-expanding phage library that collectively provides sustained broad-spectrum and poly microbial coverage. Given the specificity of phage-host interactions, phage susceptibility testing can serve as a rapid and cost-effective method for bacterial subtyping. The library can also provide a database for routine monitoring of nosocomial infections as a prelude to preparing ready-to-use phages for patient treatment and environmental sterilization. Despite the remaining obstacles for clinical application of phages, the establishment of phage libraries, pre-stocked phage vials prepared to good manufacturing practice (GMP) standards, and pre-optimized phage screening technology will facilitate efforts to make phages available as modern medicine. This may provide the breakthrough needed to demonstrate the great potential in nosocomial infection management.","container-title":"Frontiers in Microbiology","DOI":"10.3389/fmicb.2021.638094","ISSN":"1664-302X","language":"eng","note":"section: 0","page":"638094","title":"Potential of Therapeutic Bacteriophages in Nosocomial Infection Management","volume":"12","author":[{"family":"Wu","given":"Nannan"},{"family":"Zhu","given":"Tongyu"}],"issued":{"date-parts":[["2021"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->54<!-- [if supportFields]><![endif]-->. Clinical administration of phage therapy in A. baumannii patients has been safe so far, with reported side effects including hypotension after phage administration, without the need for vasopressor administration <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"hRio00Sb","properties":{"formattedCitation":"\\super 55\\nosupersub{}","plainCitation":"55","noteIndex":0},"citationItems":[{"id":1217,"uris":["http://zotero.org/users/11334842/items/2G6W7PYN"],"itemData":{"id":1217,"type":"article-journal","abstract":"Acinetobacter baumannii has become a major concern for scientific attention due to extensive antimicrobial resistance. This resistance causes an increase in mortality rate because strains resistant to antimicrobial agents are a major challenge for physicians and healthcare workers regarding the eradication of either hospital or community-based infections. These strains with emerging resistance are a serious issue for patients in the intensive care unit (ICU). Antibiotic resistance has increased because of the acquirement of mobile genetic elements such as transposons, plasmids, and integrons and causes the prevalence of multidrug resistance strains (MDR). In addition, an increase in carbapenem resistance, which is used as last line antibiotic treatment to eliminate infections with multidrug-resistant Gram-negative bacteria, is a major concern. Carbapenems resistant A. baumannii (CR-Ab) is a worldwide problem. Because these strains are often resistant to all other commonly used antibiotics. Therefore, pathogenic multi-drug resistance A. baumannii (MDR-Ab) associated infections become hard to eradicate. Plasmid-mediated resistance causes outbreaks of extensive drug-resistant. A. baumannii (XDR-Ab). In addition, recent outbreaks relating to livestock and community settings illustrate the existence of large MDR-Ab strain reservoirs within and outside hospital settings. The purpose of this review, proper monitoring, prevention, and treatment are required to control (XDR-Ab) infections. Attachment, the formation of biofilms and the secretion of toxins, and low activation of inflammatory responses are mechanisms used by pathogenic A. baumannii strain. This review will discuss some aspects associated with antibiotics resistance in A. baumannii as well as cover briefly phage therapy as an alternative therapeutic treatment.","container-title":"Molecular Biology Reports","DOI":"10.1007/s11033-021-06690-6","ISSN":"1573-4978","issue":"10","language":"eng","note":"section: 0","page":"6987–6998","title":"Multidrug-resistant Acinetobacter baumannii as an emerging concern in hospitals","volume":"48","author":[{"family":"Ibrahim","given":"Susan"},{"family":"Al-Saryi","given":"Nadal"},{"family":"Al-Kadmy","given":"Israa M. S."},{"family":"Aziz","given":"Sarah Naji"}],"issued":{"date-parts":[["2021",10]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->55<!-- [if supportFields]><![endif]-->. Some notable limitations of phage treatment include a decreasing susceptibility to the phage over time, requiring multiple doses <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"ufmSfEN0","properties":{"formattedCitation":"\\super 5\\nosupersub{}","plainCitation":"5","noteIndex":0},"citationItems":[{"id":1303,"uris":["http://zotero.org/users/11334842/items/IMCDGVZV"],"itemData":{"id":1303,"type":"article-journal","container-title":"Antimicrobial Agents and Chemotherapy","DOI":"10.1128/aac.00954-17","issue":"10","language":"en","page":"00954–17","title":"Development and Use of Personalized Bacteriophage-Based Therapeutic Cocktails To Treat a Patient with a Disseminated Resistant Acinetobacter baumannii Infection","volume":"61","author":[{"family":"Schooley","given":"R.T."},{"family":"Biswas","given":"B."},{"family":"Gill","given":"J.J."},{"family":"Hernandez-Morales","given":"A."},{"family":"Lancaster","given":"J."},{"family":"Lessor","given":"L."},{"family":"Barr","given":"J.J."},{"family":"Reed","given":"S.L."},{"family":"Rohwer","given":"F."},{"family":"Benler","given":"S."},{"family":"Segall","given":"A.M."},{"family":"Taplitz","given":"R."},{"family":"Smith","given":"D.M."},{"family":"Kerr","given":"K."},{"family":"Kumaraswamy","given":"M."},{"family":"Nizet","given":"V."},{"family":"Lin","given":"L."},{"family":"McCauley","given":"M.D."},{"family":"Strathdee","given":"S.A."},{"family":"Hamilton","given":"T."}],"issued":{"date-parts":[["2017"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->5<!-- [if supportFields]><![endif]-->. Another is the development of anti-phage antibodies, which could deactivate the lytic phages and impede their efficacy. This anti-phage humoral immunity was evident after 2-3 weeks of oral phage therapy for patients with A. baumannii, K. pneumoniae, or P. aeruginosa infections. Subsequent administration of phage treatment (3-5 courses) resulted in an increase in the levels of antibodies. Interestingly, there is no clear link between the strength of the immune response against the phage and the effectiveness of the phage therapy, hence this requires further investigation into its clinical significance <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"BetCC7Kd","properties":{"formattedCitation":"\\super 21\\nosupersub{}","plainCitation":"21","noteIndex":0},"citationItems":[{"id":1121,"uris":["http://zotero.org/users/11334842/items/3UF62TYT"],"itemData":{"id":1121,"type":"article-journal","abstract":"Antibiotic therapy has become increasingly ineffective against bacterial infections due to the rise of resistance. In particular, ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) have caused life-threatening infections in humans and represent a major global health threat due to a high degree of antibiotic resistance. To respond to this urgent call, novel strategies are urgently needed, such as bacteriophages (or phages), phage-encoded enzymes, immunomodulators and monoclonal antibodies. This review critically analyses these promising antimicrobial therapies for the treatment of multidrug-resistant bacterial infections. Recent advances in these novel therapeutic strategies are discussed, focusing on preclinical and clinical investigations, as well as combinatorial approaches. In this 'Bad Bugs, No Drugs' era, novel therapeutic strategies can play a key role in treating deadly infections and help extend the lifetime of antibiotics.","container-title":"Advanced Drug Delivery Reviews","DOI":"10.1016/j.addr.2022.114378","ISSN":"1872-8294","language":"eng","note":"section: 0","page":"114378","title":"Novel antimicrobial agents for combating antibiotic-resistant bacteria","volume":"187","author":[{"family":"Chang","given":"Rachel Yoon Kyung"},{"family":"Nang","given":"Sue C."},{"family":"Chan","given":"Hak-Kim"},{"family":"Li","given":"Jian"}],"issued":{"date-parts":[["2022",8]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->21 Pseudomonas aeruginosa Pseudomonas aeruginosa is capable of evading the immune system by using its antiphagocytic polysaccharide capsule, biofilm formation and intracellular survival, causing fatal bacteremia and pneumonia <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"n0lYqzcb","properties":{"formattedCitation":"\\super 11\\nosupersub{}","plainCitation":"11","noteIndex":0},"citationItems":[{"id":1309,"uris":["http://zotero.org/users/11334842/items/EP6UHW6W"],"itemData":{"id":1309,"type":"article-journal","container-title":"Viruses","DOI":"10.3390/v13010051.","issue":"1","language":"en","page":"51","title":"Bacteriophage Treatment: Critical Evaluation of Its Application on World Health Organization Priority Pathogens","volume":"13","author":[{"family":"Al-Ishak","given":"R."},{"family":"Skariah","given":"S."},{"family":"Busselberg","given":"D."}],"issued":{"date-parts":[["2020"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->11<!-- [if supportFields]><![endif]-->. It is capable of causing extensive tissue damage by using its virulence factors acquired in hospitals where it is known to be the most common cause of ventilator acquired pneumonia <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Ri0Vc3Jt","properties":{"formattedCitation":"\\super 2\\nosupersub{}","plainCitation":"2","noteIndex":0},"citationItems":[{"id":1145,"uris":["http://zotero.org/users/11334842/items/XVQ9IE9G"],"itemData":{"id":1145,"type":"article-journal","abstract":"Multi-Drug Resistant (MDR) Pseudomonas aeruginosa is one of the most important bacterial pathogens that causes infection with a high mortality rate due to resistance to different antibiotics. This bacterium prompts extensive tissue damage with varying factors of virulence, and its biofilm production causes chronic and antibiotic-resistant infections. Therefore, due to the non-applicability of antibiotics for the destruction of P. aeruginosa biofilm, alternative approaches have been considered by researchers, and phage therapy is one of these new therapeutic solutions. Bacteriophages can be used to eradicate P. aeruginosa biofilm by destroying the extracellular matrix, increasing the permeability of antibiotics into the inner layer of biofilm, and inhibiting its formation by stopping the quorum-sensing activity. Furthermore, the combined use of bacteriophages and other compounds with anti-biofilm properties such as nanoparticles, enzymes, and natural products can be of more interest because they invade the biofilm by various mechanisms and can be more effective than the one used alone. On the other hand, the use of bacteriophages for biofilm destruction has some limitations such as limited host range, high-density biofilm, sub-populate phage resistance in biofilm, and inhibition of phage infection via quorum sensing in biofilm. Therefore, in this review, we specifically discuss the use of phage therapy for inhibition of P. aeruginosa biofilm in clinical and in vitro studies to identify different aspects of this treatment for broader use.","container-title":"Annals of Clinical Microbiology and Antimicrobials","DOI":"10.1186/s12941-020-00389-5","ISSN":"1476-0711","issue":"1","language":"eng","note":"section: 0","page":"45","title":"Bacteriophage therapy against Pseudomonas aeruginosa biofilms: a review","volume":"19","author":[{"family":"Chegini","given":"Zahra"},{"family":"Khoshbayan","given":"Amin"},{"family":"Taati Moghadam","given":"Majid"},{"family":"Farahani","given":"Iman"},{"family":"Jazireian","given":"Parham"},{"family":"Shariati","given":"Aref"}],"issued":{"date-parts":[["2020",9]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->2<!-- [if supportFields]><![endif]--> (VAP). A recent study done by the US center for Diseases Control and Prevention (CDC), showed that there are roughly 51,000 health care associated infections reported to be caused by P. aeruginosa every year, 13% of these infections are multidrug resistant causing about 400 deaths per year. P. aeruginosa is found to have an increasing number of strains that are multidrug resistant without any effective antibiotic to stop this bacterium <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"EsibePaY","properties":{"formattedCitation":"\\super 2\\nosupersub{}","plainCitation":"2","noteIndex":0},"citationItems":[{"id":1145,"uris":["http://zotero.org/users/11334842/items/XVQ9IE9G"],"itemData":{"id":1145,"type":"article-journal","abstract":"Multi-Drug Resistant (MDR) Pseudomonas aeruginosa is one of the most important bacterial pathogens that causes infection with a high mortality rate due to resistance to different antibiotics. This bacterium prompts extensive tissue damage with varying factors of virulence, and its biofilm production causes chronic and antibiotic-resistant infections. Therefore, due to the non-applicability of antibiotics for the destruction of P. aeruginosa biofilm, alternative approaches have been considered by researchers, and phage therapy is one of these new therapeutic solutions. Bacteriophages can be used to eradicate P. aeruginosa biofilm by destroying the extracellular matrix, increasing the permeability of antibiotics into the inner layer of biofilm, and inhibiting its formation by stopping the quorum-sensing activity. Furthermore, the combined use of bacteriophages and other compounds with anti-biofilm properties such as nanoparticles, enzymes, and natural products can be of more interest because they invade the biofilm by various mechanisms and can be more effective than the one used alone. On the other hand, the use of bacteriophages for biofilm destruction has some limitations such as limited host range, high-density biofilm, sub-populate phage resistance in biofilm, and inhibition of phage infection via quorum sensing in biofilm. Therefore, in this review, we specifically discuss the use of phage therapy for inhibition of P. aeruginosa biofilm in clinical and in vitro studies to identify different aspects of this treatment for broader use.","container-title":"Annals of Clinical Microbiology and Antimicrobials","DOI":"10.1186/s12941-020-00389-5","ISSN":"1476-0711","issue":"1","language":"eng","note":"section: 0","page":"45","title":"Bacteriophage therapy against Pseudomonas aeruginosa biofilms: a review","volume":"19","author":[{"family":"Chegini","given":"Zahra"},{"family":"Khoshbayan","given":"Amin"},{"family":"Taati Moghadam","given":"Majid"},{"family":"Farahani","given":"Iman"},{"family":"Jazireian","given":"Parham"},{"family":"Shariati","given":"Aref"}],"issued":{"date-parts":[["2020",9]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->2<!-- [if supportFields]><![endif]-->. As mentioned previously, the key to phage therapy is the binding of the phage to its receptor and this phage-receptor relationship is widely affected by the environment of the phage itself. The presence of the phage receptors is influenced by their lipid surroundings that will affect their structure and function <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"tKe1xBWJ","properties":{"formattedCitation":"\\super 7\\nosupersub{}","plainCitation":"7","noteIndex":0},"citationItems":[{"id":1245,"uris":["http://zotero.org/users/11334842/items/XSBXTJXR"],"itemData":{"id":1245,"type":"article-journal","abstract":"Pseudomonas aeruginosa is an important Gram-negative pathogen with intrinsic resistance to many clinically used antibiotics. It is particularly troublesome in nosocomial infections, immunocompromised patients, and individuals with cystic fibrosis. Antimicrobial resistance (AMR) is a huge threat to global health, with a predicted 10 million people dying from resistant infections by 2050. A promising therapy for combatting AMR infections is phage therapy. However, more research is required to investigate mechanisms that may influence the efficacy of phage therapy. An important overlooked aspect is the impact of membrane lipid remodelling on phage binding ability. P. aeruginosa undergoes changes in membrane lipids when it encounters phosphorus stress, an environmental perturbation that is likely to occur during infection. Lipid changes include the substitution of glycerophospholipids with surrogate glycolipids and the over-production of ornithine-containing aminolipids. Given that membrane lipids are known to influence the structure and function of membrane proteins, we propose that changes in the composition of membrane lipids during infection may alter phage binding and subsequent phage infection dynamics. Consideration of such effects needs to be urgently prioritised in order to develop the most effective phage therapy strategies for P. aeruginosa infections.","container-title":"Environmental Microbiology","DOI":"10.1111/1462-2920.16136","ISSN":"1462-2920","issue":"10","language":"eng","note":"section: 0","page":"4533–4546","title":"Membrane lipid renovation in Pseudomonas aeruginosa - implications for phage therapy?","volume":"24","author":[{"family":"Lyon","given":"Rhiannon"},{"family":"Jones","given":"Rebekah A."},{"family":"Shropshire","given":"Holly"},{"family":"Aberdeen","given":"Isabel"},{"family":"Scanlan","given":"David J."},{"family":"Millard","given":"Andrew"},{"family":"Chen","given":"Yin"}],"issued":{"date-parts":[["2022",10]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->7<!-- [if supportFields]><![endif]-->. A slight change in the receptor can prevent phage binding, which means that it will not allow the phage to act as a bactericidal agent <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Kg4JjUGM","properties":{"formattedCitation":"\\super 7\\nosupersub{}","plainCitation":"7","noteIndex":0},"citationItems":[{"id":1245,"uris":["http://zotero.org/users/11334842/items/XSBXTJXR"],"itemData":{"id":1245,"type":"article-journal","abstract":"Pseudomonas aeruginosa is an important Gram-negative pathogen with intrinsic resistance to many clinically used antibiotics. It is particularly troublesome in nosocomial infections, immunocompromised patients, and individuals with cystic fibrosis. Antimicrobial resistance (AMR) is a huge threat to global health, with a predicted 10 million people dying from resistant infections by 2050. A promising therapy for combatting AMR infections is phage therapy. However, more research is required to investigate mechanisms that may influence the efficacy of phage therapy. An important overlooked aspect is the impact of membrane lipid remodelling on phage binding ability. P. aeruginosa undergoes changes in membrane lipids when it encounters phosphorus stress, an environmental perturbation that is likely to occur during infection. Lipid changes include the substitution of glycerophospholipids with surrogate glycolipids and the over-production of ornithine-containing aminolipids. Given that membrane lipids are known to influence the structure and function of membrane proteins, we propose that changes in the composition of membrane lipids during infection may alter phage binding and subsequent phage infection dynamics. Consideration of such effects needs to be urgently prioritised in order to develop the most effective phage therapy strategies for P. aeruginosa infections.","container-title":"Environmental Microbiology","DOI":"10.1111/1462-2920.16136","ISSN":"1462-2920","issue":"10","language":"eng","note":"section: 0","page":"4533–4546","title":"Membrane lipid renovation in Pseudomonas aeruginosa - implications for phage therapy?","volume":"24","author":[{"family":"Lyon","given":"Rhiannon"},{"family":"Jones","given":"Rebekah A."},{"family":"Shropshire","given":"Holly"},{"family":"Aberdeen","given":"Isabel"},{"family":"Scanlan","given":"David J."},{"family":"Millard","given":"Andrew"},{"family":"Chen","given":"Yin"}],"issued":{"date-parts":[["2022",10]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->7<!-- [if supportFields]><![endif]-->. Nevertheless, case reports have shown the clearance of P.aeruginosa using phage therapy in several types of infections and has also been able to prove the safety of this therapy in a randomized, double blinded placebo-controlled clinical trial <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"vTTAt32c","properties":{"formattedCitation":"\\super 7,7\\nosupersub{}","plainCitation":"7,7","dontUpdate":true,"noteIndex":0},"citationItems":[{"id":1245,"uris":["http://zotero.org/users/11334842/items/XSBXTJXR"],"itemData":{"id":1245,"type":"article-journal","abstract":"Pseudomonas aeruginosa is an important Gram-negative pathogen with intrinsic resistance to many clinically used antibiotics. It is particularly troublesome in nosocomial infections, immunocompromised patients, and individuals with cystic fibrosis. Antimicrobial resistance (AMR) is a huge threat to global health, with a predicted 10 million people dying from resistant infections by 2050. A promising therapy for combatting AMR infections is phage therapy. However, more research is required to investigate mechanisms that may influence the efficacy of phage therapy. An important overlooked aspect is the impact of membrane lipid remodelling on phage binding ability. P. aeruginosa undergoes changes in membrane lipids when it encounters phosphorus stress, an environmental perturbation that is likely to occur during infection. Lipid changes include the substitution of glycerophospholipids with surrogate glycolipids and the over-production of ornithine-containing aminolipids. Given that membrane lipids are known to influence the structure and function of membrane proteins, we propose that changes in the composition of membrane lipids during infection may alter phage binding and subsequent phage infection dynamics. Consideration of such effects needs to be urgently prioritised in order to develop the most effective phage therapy strategies for P. aeruginosa infections.","container-title":"Environmental Microbiology","DOI":"10.1111/1462-2920.16136","ISSN":"1462-2920","issue":"10","language":"eng","note":"section: 0","page":"4533–4546","title":"Membrane lipid renovation in Pseudomonas aeruginosa - implications for phage therapy?","volume":"24","author":[{"family":"Lyon","given":"Rhiannon"},{"family":"Jones","given":"Rebekah A."},{"family":"Shropshire","given":"Holly"},{"family":"Aberdeen","given":"Isabel"},{"family":"Scanlan","given":"David J."},{"family":"Millard","given":"Andrew"},{"family":"Chen","given":"Yin"}],"issued":{"date-parts":[["2022",10]]}}},{"id":1245,"uris":["http://zotero.org/users/11334842/items/XSBXTJXR"],"itemData":{"id":1245,"type":"article-journal","abstract":"Pseudomonas aeruginosa is an important Gram-negative pathogen with intrinsic resistance to many clinically used antibiotics. It is particularly troublesome in nosocomial infections, immunocompromised patients, and individuals with cystic fibrosis. Antimicrobial resistance (AMR) is a huge threat to global health, with a predicted 10 million people dying from resistant infections by 2050. A promising therapy for combatting AMR infections is phage therapy. However, more research is required to investigate mechanisms that may influence the efficacy of phage therapy. An important overlooked aspect is the impact of membrane lipid remodelling on phage binding ability. P. aeruginosa undergoes changes in membrane lipids when it encounters phosphorus stress, an environmental perturbation that is likely to occur during infection. Lipid changes include the substitution of glycerophospholipids with surrogate glycolipids and the over-production of ornithine-containing aminolipids. Given that membrane lipids are known to influence the structure and function of membrane proteins, we propose that changes in the composition of membrane lipids during infection may alter phage binding and subsequent phage infection dynamics. Consideration of such effects needs to be urgently prioritised in order to develop the most effective phage therapy strategies for P. aeruginosa infections.","container-title":"Environmental Microbiology","DOI":"10.1111/1462-2920.16136","ISSN":"1462-2920","issue":"10","language":"eng","note":"section: 0","page":"4533–4546","title":"Membrane lipid renovation in Pseudomonas aeruginosa - implications for phage therapy?","volume":"24","author":[{"family":"Lyon","given":"Rhiannon"},{"family":"Jones","given":"Rebekah A."},{"family":"Shropshire","given":"Holly"},{"family":"Aberdeen","given":"Isabel"},{"family":"Scanlan","given":"David J."},{"family":"Millard","given":"Andrew"},{"family":"Chen","given":"Yin"}],"issued":{"date-parts":[["2022",10]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->7<!-- [if supportFields]><![endif]-->. Various studies have demonstrated the promising potential of using bacteriophages against multidrug-resistant (MDR) Pseudomonas aeruginosa infections, particularly in cases of chronic otitis media, cystic fibrosis, and burn wounds <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"LMldE6gS","properties":{"formattedCitation":"\\super 2\\nosupersub{}","plainCitation":"2","noteIndex":0},"citationItems":[{"id":1145,"uris":["http://zotero.org/users/11334842/items/XVQ9IE9G"],"itemData":{"id":1145,"type":"article-journal","abstract":"Multi-Drug Resistant (MDR) Pseudomonas aeruginosa is one of the most important bacterial pathogens that causes infection with a high mortality rate due to resistance to different antibiotics. This bacterium prompts extensive tissue damage with varying factors of virulence, and its biofilm production causes chronic and antibiotic-resistant infections. Therefore, due to the non-applicability of antibiotics for the destruction of P. aeruginosa biofilm, alternative approaches have been considered by researchers, and phage therapy is one of these new therapeutic solutions. Bacteriophages can be used to eradicate P. aeruginosa biofilm by destroying the extracellular matrix, increasing the permeability of antibiotics into the inner layer of biofilm, and inhibiting its formation by stopping the quorum-sensing activity. Furthermore, the combined use of bacteriophages and other compounds with anti-biofilm properties such as nanoparticles, enzymes, and natural products can be of more interest because they invade the biofilm by various mechanisms and can be more effective than the one used alone. On the other hand, the use of bacteriophages for biofilm destruction has some limitations such as limited host range, high-density biofilm, sub-populate phage resistance in biofilm, and inhibition of phage infection via quorum sensing in biofilm. Therefore, in this review, we specifically discuss the use of phage therapy for inhibition of P. aeruginosa biofilm in clinical and in vitro studies to identify different aspects of this treatment for broader use.","container-title":"Annals of Clinical Microbiology and Antimicrobials","DOI":"10.1186/s12941-020-00389-5","ISSN":"1476-0711","issue":"1","language":"eng","note":"section: 0","page":"45","title":"Bacteriophage therapy against Pseudomonas aeruginosa biofilms: a review","volume":"19","author":[{"family":"Chegini","given":"Zahra"},{"family":"Khoshbayan","given":"Amin"},{"family":"Taati Moghadam","given":"Majid"},{"family":"Farahani","given":"Iman"},{"family":"Jazireian","given":"Parham"},{"family":"Shariati","given":"Aref"}],"issued":{"date-parts":[["2020",9]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->2<!-- [if supportFields]><![endif]-->. These studies have emphasized that phages need sufficient exposure time to penetrate biofilm exopolysaccharides and effectively clear P. aeruginosa. Overall, these pre-clinical studies highlight the potential of bacteriophages as a therapeutic approach for controlling MDR P. aeruginosa infections, particularly those associated with biofilm formation. A Pseudomonas aeruginosa infection in an aortic graft was successfully treated with phage OMKO1 and ceftazidime <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"sPKvC06v","properties":{"formattedCitation":"\\super 44\\nosupersub{}","plainCitation":"44","noteIndex":0},"citationItems":[{"id":1271,"uris":["http://zotero.org/users/11334842/items/7CFWW6JZ"],"itemData":{"id":1271,"type":"article-journal","abstract":"Emergence of antibiotic resistance presents a major setback to global health, and shortage of antibiotic pipelines has created an urgent need for development of alternative therapeutic strategies. Bacteriophage (phage) therapy is considered as a potential approach for treatment of the increasing number of antibiotic-resistant pathogens. Phage-antibiotic synergy (PAS) refers to sublethal concentrations of certain antibiotics that enhance release of progeny phages from bacterial cells. A combination of phages and antibiotics is a promising strategy to reduce the dose of antibiotics and the development of antibiotic resistance during treatment. In this review, we highlight the state-of-the-art advancements of PAS studies, including the analysis of bacterial-killing enhancement, bacterial resistance reduction, and anti-biofilm effect, at both in vitro and in vivo levels. A comprehensive review of the genetic and molecular mechanisms of phage antibiotic synergy is provided, and synthetic biology approaches used to engineer phages, and design novel therapies and diagnostic tools are discussed. In addition, the role of engineered phages in reducing pathogenicity of bacteria is explored.","container-title":"International Journal of Biological Sciences","DOI":"10.7150/ijbs.60551","ISSN":"1449-2288","issue":"13","language":"eng","note":"section: 0","page":"3573–3582","title":"A combination therapy of Phages and Antibiotics: Two is better than one","volume":"17","author":[{"family":"Li","given":"Xianghui"},{"family":"He","given":"Yuhua"},{"family":"Wang","given":"Zhili"},{"family":"Wei","given":"Jiacun"},{"family":"Hu","given":"Tongxin"},{"family":"Si","given":"Jiangzhe"},{"family":"Tao","given":"Guangzhao"},{"family":"Zhang","given":"Lei"},{"family":"Xie","given":"Longxiang"},{"family":"Abdalla","given":"Abualgasim Elgaili"},{"family":"Wang","given":"Guoying"},{"family":"Li","given":"Yanzhang"},{"family":"Teng","given":"Tieshan"}],"issued":{"date-parts":[["2021"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->44<!-- [if supportFields]><![endif]-->. Phage-antibiotic interactions can be antagonistic or synergistic, as in the case of the P. aeruginosa phage KZ with rifampicin <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"ISZDs2Je","properties":{"formattedCitation":"\\super 44\\nosupersub{}","plainCitation":"44","noteIndex":0},"citationItems":[{"id":1271,"uris":["http://zotero.org/users/11334842/items/7CFWW6JZ"],"itemData":{"id":1271,"type":"article-journal","abstract":"Emergence of antibiotic resistance presents a major setback to global health, and shortage of antibiotic pipelines has created an urgent need for development of alternative therapeutic strategies. Bacteriophage (phage) therapy is considered as a potential approach for treatment of the increasing number of antibiotic-resistant pathogens. Phage-antibiotic synergy (PAS) refers to sublethal concentrations of certain antibiotics that enhance release of progeny phages from bacterial cells. A combination of phages and antibiotics is a promising strategy to reduce the dose of antibiotics and the development of antibiotic resistance during treatment. In this review, we highlight the state-of-the-art advancements of PAS studies, including the analysis of bacterial-killing enhancement, bacterial resistance reduction, and anti-biofilm effect, at both in vitro and in vivo levels. A comprehensive review of the genetic and molecular mechanisms of phage antibiotic synergy is provided, and synthetic biology approaches used to engineer phages, and design novel therapies and diagnostic tools are discussed. In addition, the role of engineered phages in reducing pathogenicity of bacteria is explored.","container-title":"International Journal of Biological Sciences","DOI":"10.7150/ijbs.60551","ISSN":"1449-2288","issue":"13","language":"eng","note":"section: 0","page":"3573–3582","title":"A combination therapy of Phages and Antibiotics: Two is better than one","volume":"17","author":[{"family":"Li","given":"Xianghui"},{"family":"He","given":"Yuhua"},{"family":"Wang","given":"Zhili"},{"family":"Wei","given":"Jiacun"},{"family":"Hu","given":"Tongxin"},{"family":"Si","given":"Jiangzhe"},{"family":"Tao","given":"Guangzhao"},{"family":"Zhang","given":"Lei"},{"family":"Xie","given":"Longxiang"},{"family":"Abdalla","given":"Abualgasim Elgaili"},{"family":"Wang","given":"Guoying"},{"family":"Li","given":"Yanzhang"},{"family":"Teng","given":"Tieshan"}],"issued":{"date-parts":[["2021"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->44<!-- [if supportFields]><![endif]-->. Due to its antibiotic resistance, Pseudomonas aeruginosa is a primary target for respiratory phage therapy <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"lmh4jYbN","properties":{"formattedCitation":"\\super 50\\nosupersub{}","plainCitation":"50","noteIndex":0},"citationItems":[{"id":1225,"uris":["http://zotero.org/users/11334842/items/W8CIDIJE"],"itemData":{"id":1225,"type":"article-journal","abstract":"The looming antibiotic resistance crisis is forcing clinicians to consider alternative approaches to treating bacterial infections. As the window of use for current antimicrobial agents becomes ever narrower, we consider if looking back will now be the way forward. Conceptually, phage therapy is simple and specific; a targeted treatment to control bacterial overgrowth. In this article we discuss bacteriophage and potential use in future therapy.","container-title":"Paediatric Respiratory Reviews","DOI":"10.1016/j.prrv.2022.02.001","ISSN":"1526-0550","language":"eng","note":"section: 0","page":"70–77","title":"The potential of bacteriophage therapy in the treatment of paediatric respiratory infections","volume":"44","author":[{"family":"Jones","given":"J. D."},{"family":"Varghese","given":"D."},{"family":"Pabary","given":"R."},{"family":"Langley","given":"R. J."}],"issued":{"date-parts":[["2022",12]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->50<!-- [if supportFields]><![endif]-->. Phage treatment has been used to successfully treat respiratory P. aeruginosa infections, including those in CF patients, with minimal side effects <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"EGCEiXeY","properties":{"formattedCitation":"\\super 50\\nosupersub{}","plainCitation":"50","noteIndex":0},"citationItems":[{"id":1225,"uris":["http://zotero.org/users/11334842/items/W8CIDIJE"],"itemData":{"id":1225,"type":"article-journal","abstract":"The looming antibiotic resistance crisis is forcing clinicians to consider alternative approaches to treating bacterial infections. As the window of use for current antimicrobial agents becomes ever narrower, we consider if looking back will now be the way forward. Conceptually, phage therapy is simple and specific; a targeted treatment to control bacterial overgrowth. In this article we discuss bacteriophage and potential use in future therapy.","container-title":"Paediatric Respiratory Reviews","DOI":"10.1016/j.prrv.2022.02.001","ISSN":"1526-0550","language":"eng","note":"section: 0","page":"70–77","title":"The potential of bacteriophage therapy in the treatment of paediatric respiratory infections","volume":"44","author":[{"family":"Jones","given":"J. D."},{"family":"Varghese","given":"D."},{"family":"Pabary","given":"R."},{"family":"Langley","given":"R. J."}],"issued":{"date-parts":[["2022",12]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->50<!-- [if supportFields]><![endif]-->. Enterobacter & Enterococcus The upsurge of antimicrobial resistance with sophisticated mechanisms has challenged the current fight against multi-drug resistant bacteria, in particular to VRE (Vancomycin-Resistant Enterococcus). PlyV12 lysin has shown strong lytic activity in vitro against multiple bacteria, including VRE <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"LClj5i72","properties":{"formattedCitation":"\\super 56\\nosupersub{}","plainCitation":"56","noteIndex":0},"citationItems":[{"id":608,"uris":["http://zotero.org/users/11334842/items/L24BVQ9F"],"itemData":{"id":608,"type":"article-journal","container-title":"Journal of Global Antimicrobial Resistance","ISSN":"2213-7165","journalAbbreviation":"Journal of Global Antimicrobial Resistance","note":"publisher: Elsevier","page":"228-235","title":"Bacterial bloodstream infections and patterns of resistance in patients with haematological malignancies at a tertiary centre in Lebanon over 10 years","volume":"27","author":[{"family":"Haddad","given":"Sara"},{"family":"Jabbour","given":"Jean-Francois"},{"family":"Hindy","given":"Joya-Rita"},{"family":"Makki","given":"Maha"},{"family":"Sabbagh","given":"Ali"},{"family":"Nayfeh","given":"Malek"},{"family":"Boustany","given":"Mickael"},{"family":"El-Zein","given":"Saeed"},{"family":"Tamim","given":"Hani"},{"family":"El Zakhem","given":"Aline"}],"issued":{"date-parts":[["2021"]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->56<!-- [if supportFields]><![endif]-->. Other phages of the Siphoviridae & Myoviridae have been successfully used in vitro to eradicate Enterococcus faecalis <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"DvNvbIKL","properties":{"formattedCitation":"\\super 57\\nosupersub{}","plainCitation":"57","noteIndex":0},"citationItems":[{"id":1277,"uris":["http://zotero.org/users/11334842/items/L84NT5A9"],"itemData":{"id":1277,"type":"article-journal","abstract":"Phage therapy is revolving to address the issues mainly dealing with antibiotic resistance in the pathogenic bacteria. Among the drug-resistant microbial populations, the bacterial species have been categorized as high-priority or critical-priority bacteria. This review summarizes the efficiency and development in phage therapy used against these drug-resistant bacteria in the past few years mainly belonging to the critical- and high-priority list. Phage therapy is more than just an alternative to antibiotics as it not only kills the target microbial population directly but also leads to the chemical and physical modifications in bacterial cell structures. These phage-mediated modifications in the bacterial cell may make them antibiotic sensitive. Application of phage therapy in antibiotic-resistant foodborne bacteria and possible modulation in gut microbes has also been explored. Further, the phage cocktail antibiotic formulation, containing more than one type of phage with antibiotics, has also been discussed.","container-title":"Food and Environmental Virology","DOI":"10.1007/s12560-021-09483-z","ISSN":"1867-0342","issue":"4","language":"eng","note":"section: 0","page":"433–446","title":"Bacteriophage Therapy for Critical and High-Priority Antibiotic-Resistant Bacteria and Phage Cocktail-Antibiotic Formulation Perspective","volume":"13","author":[{"family":"Kaur","given":"Gursneh"},{"family":"Agarwal","given":"Ritika"},{"family":"Sharma","given":"Rakesh Kumar"}],"issued":{"date-parts":[["2021",12]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->57<!-- [if supportFields]><![endif]-->. The advent of phage therapy comes with an interesting evolutionary genetic trade-off in E. faecalis, whereby induction of phage resistance comes at the cost of regaining antibiotic susceptibility, in what has been described the “seesaw effect”. This possibly promotes the idea of antibiotic-phage combinations when handling these superbugs <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"3nlIUW6t","properties":{"formattedCitation":"\\super 58\\nosupersub{}","plainCitation":"58","noteIndex":0},"citationItems":[{"id":1287,"uris":["http://zotero.org/users/11334842/items/C3K2EPBW"],"itemData":{"id":1287,"type":"article-journal","abstract":"Multidrug-resistant organisms have caused a marked depletion of effective antimicrobials, and the narrow pipeline of antibiotics has demanded the need to find novel therapeutic alternatives including nonantibiotic agents. Bacteriophages (phages) are viruses that use the bacterial machinery to infect, replicate, and kill bacterial cells. Although a marked decline in their use was driven by the discovery of antibiotics, the era of antibiotic resistance has led to a resurgence of phage therapy into clinical practice. The term phage-antibiotic synergy (PAS) was coined just over a decade ago and described that sublethal concentrations of antibiotics could stimulate phage production by bacterial cells. Recent literature has described PAS and other encouraging interactions with various phage and antibiotic combinations against a variety of bacterial strains. The primary objective of this review is to discuss the positive interactions between phage and antibiotic combinations, with an emphasis on PAS, reductions in bacterial growth or minimum inhibitory concentrations, enhanced biofilm eradication, and alterations in the emergence of bacterial resistance. A peer-reviewed literature search was conducted (1890-2019) using the PubMed, Medline, and Google Scholar databases. Although more investigation is certainly needed, the combination of bacteriophages with antibiotics is a promising strategy to target organisms with limited or no therapeutic options. This approach may also foster the ability to lower the antibiotic dose and may reduce the potential for antibiotic resistance emergence during therapy.","container-title":"Pharmacotherapy","DOI":"10.1002/phar.2358","ISSN":"1875-9114","issue":"2","language":"eng","note":"section: 0","page":"153–168","title":"Bacteriophage Therapeutics: A Primer for Clinicians on Phage-Antibiotic Combinations","volume":"40","author":[{"family":"Morrisette","given":"Taylor"},{"family":"Kebriaei","given":"Razieh"},{"family":"Lev","given":"Katherine L."},{"family":"Morales","given":"S"},{"literal":"ra"},{"family":"Rybak","given":"Michael J."}],"issued":{"date-parts":[["2020",2]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->58<!-- [if supportFields]><![endif]-->. Alternatively, studies demonstrating phage-resistant Enterococcus faecalis have been handled by isolating yet another lytic phage against the bacteria, proposing cocktails of mixed phages<!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"x4pezoTy","properties":{"formattedCitation":"\\super 57\\nosupersub{}","plainCitation":"57","noteIndex":0},"citationItems":[{"id":1277,"uris":["http://zotero.org/users/11334842/items/L84NT5A9"],"itemData":{"id":1277,"type":"article-journal","abstract":"Phage therapy is revolving to address the issues mainly dealing with antibiotic resistance in the pathogenic bacteria. Among the drug-resistant microbial populations, the bacterial species have been categorized as high-priority or critical-priority bacteria. This review summarizes the efficiency and development in phage therapy used against these drug-resistant bacteria in the past few years mainly belonging to the critical- and high-priority list. Phage therapy is more than just an alternative to antibiotics as it not only kills the target microbial population directly but also leads to the chemical and physical modifications in bacterial cell structures. These phage-mediated modifications in the bacterial cell may make them antibiotic sensitive. Application of phage therapy in antibiotic-resistant foodborne bacteria and possible modulation in gut microbes has also been explored. Further, the phage cocktail antibiotic formulation, containing more than one type of phage with antibiotics, has also been discussed.","container-title":"Food and Environmental Virology","DOI":"10.1007/s12560-021-09483-z","ISSN":"1867-0342","issue":"4","language":"eng","note":"section: 0","page":"433–446","title":"Bacteriophage Therapy for Critical and High-Priority Antibiotic-Resistant Bacteria and Phage Cocktail-Antibiotic Formulation Perspective","volume":"13","author":[{"family":"Kaur","given":"Gursneh"},{"family":"Agarwal","given":"Ritika"},{"family":"Sharma","given":"Rakesh Kumar"}],"issued":{"date-parts":[["2021",12]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->57<!-- [if supportFields]><![endif]-->. Most of what is known regarding efficacy of bacteriophage therapy on Enterobacter spp., a facultative anaerobic rod-shaped bacilli responsible for bacteremia & sepsis in the context of nosocomial infection, has been limited to animal studies <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"hVp0yhWf","properties":{"formattedCitation":"\\super 59\\nosupersub{}","plainCitation":"59","noteIndex":0},"citationItems":[{"id":1137,"uris":["http://zotero.org/users/11334842/items/8WLBRF7L"],"itemData":{"id":1137,"type":"article-journal","abstract":"The authors emphasize how extremely important it is to highlight the role played by animal models in an attempt to determine possible phage interactions with the organism into which it was introduced as well as to determine the safety and effectiveness of phage therapy in vivo taking into account the individual conditions of a given organism and its physiology. Animal models in which phages are used make it possible, among other things, to evaluate the effective therapeutic dose and to choose the possible route of phage administration depending on the type of infection developed. These results cannot be applied in detail to the human body, but the knowledge gained from animal experiments is invaluable and very helpful. We would like to highlight how useful animal models may be for the possible effectiveness evaluation of phage therapy in the case of infections caused by gram-negative bacteria from the ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species) group of pathogens. In this review, we focus specifically on the data from the last few years.","container-title":"Microorganisms","DOI":"10.3390/microorganisms9020206","ISSN":"2076-2607","issue":"2","language":"eng","note":"section: 0","page":"206","title":"Animal Models in the Evaluation of the Effectiveness of Phage Therapy for Infections Caused by Gram-Negative Bacteria from the ESKAPE Group and the Reliability of Its Use in Humans","volume":"9","author":[{"family":"Cieślik","given":"Martyna"},{"family":"Bagińska","given":"Natalia"},{"family":"Górski","given":"Andrzej"},{"family":"Jończyk-Matysiak","given":"Ewa"}],"issued":{"date-parts":[["2021",1]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->59<!-- [if supportFields]><![endif]-->. There have been novel investigations of two bacteriophages ELP140 & GAP161 on survival rates of infected G. mellonella larvaes with the genus, both resulting in complete survival rates <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"XoNX6zoC","properties":{"formattedCitation":"\\super 59\\nosupersub{}","plainCitation":"59","noteIndex":0},"citationItems":[{"id":1137,"uris":["http://zotero.org/users/11334842/items/8WLBRF7L"],"itemData":{"id":1137,"type":"article-journal","abstract":"The authors emphasize how extremely important it is to highlight the role played by animal models in an attempt to determine possible phage interactions with the organism into which it was introduced as well as to determine the safety and effectiveness of phage therapy in vivo taking into account the individual conditions of a given organism and its physiology. Animal models in which phages are used make it possible, among other things, to evaluate the effective therapeutic dose and to choose the possible route of phage administration depending on the type of infection developed. These results cannot be applied in detail to the human body, but the knowledge gained from animal experiments is invaluable and very helpful. We would like to highlight how useful animal models may be for the possible effectiveness evaluation of phage therapy in the case of infections caused by gram-negative bacteria from the ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species) group of pathogens. In this review, we focus specifically on the data from the last few years.","container-title":"Microorganisms","DOI":"10.3390/microorganisms9020206","ISSN":"2076-2607","issue":"2","language":"eng","note":"section: 0","page":"206","title":"Animal Models in the Evaluation of the Effectiveness of Phage Therapy for Infections Caused by Gram-Negative Bacteria from the ESKAPE Group and the Reliability of Its Use in Humans","volume":"9","author":[{"family":"Cieślik","given":"Martyna"},{"family":"Bagińska","given":"Natalia"},{"family":"Górski","given":"Andrzej"},{"family":"Jończyk-Matysiak","given":"Ewa"}],"issued":{"date-parts":[["2021",1]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->59<!-- [if supportFields]><![endif]-->. As colistin is being increasingly used as a last resort for antimicrobial resistance, an alternative in phage therapy is being considered to colistin-resistant bacteria, which would otherwise pose a health concern <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Z96zhY53","properties":{"formattedCitation":"\\super 60\\nosupersub{}","plainCitation":"60","noteIndex":0},"citationItems":[{"id":1324,"uris":["http://zotero.org/users/11334842/items/EYQ3KM83"],"itemData":{"id":1324,"type":"article-journal","abstract":"Endolysins are double-stranded DNA bacteriophage-encoded peptidoglycan hydrolases produced in phage-infected bacterial cells toward the end of the lytic cycle. They reach the peptidoglycan through membrane lesions formed by holins and cleave it, thus, inducing lysis of the bacterial cell and enabling progeny virions to be released. Endolysins are also capable of degrading peptidoglycan when applied externally (as purified recombinant proteins) to the bacterial cell wall, which also results in a rapid lysis of the bacterial cell. The unique ability of endolysins to rapidly cleave peptidoglycan in a generally species-specific manner renders them promising potential antibacterial agents. Originally developed with a view to killing bacteria colonizing mucous membranes (with the first report published in 2001), endolysins also hold promise for the treatment of systemic infections. As potential antibacterials, endolysins possess several important features, for instance, a novel mode of action, a narrow antibacterial spectrum, activity against bacteria regardless of their antibiotic sensitivity, and a low probability of developing resistance. However, there is only one report directly comparing the activity of an endolysin with that of an antibiotic, and no general conclusions can be drawn regarding whether lysins are more effective than traditional antibiotics. The results of the first preclinical studies indicate that the most apparent potential problems associated with endolysin therapy (e.g., their immunogenicity, the release of proinflammatory components during bacteriolysis, or the development of resistance), in fact, may not seriously hinder their use. However, all data regarding the safety and therapeutic effectiveness of endolysins obtained from preclinical studies must be ultimately verified by clinical trials. This review discusses the prophylactic and therapeutic applications of endolysins, especially with respect to their potential use in human medicine. Additionally, we outline current knowledge regarding the structure and natural function of the enzymes in phage biology, including the most recent findings.","container-title":"Experimental Biology and Medicine (Maywood, N.J.)","DOI":"10.1177/153537020623100402","ISSN":"1535-3702","issue":"4","journalAbbreviation":"Exp Biol Med (Maywood)","language":"eng","note":"PMID: 16565432","page":"366-377","source":"PubMed","title":"Bacteriophage endolysins as a novel class of antibacterial agents","volume":"231","author":[{"family":"Borysowski","given":"Jan"},{"family":"Weber-Dabrowska","given":"Beata"},{"family":"Górski","given":"Andrzej"}],"issued":{"date-parts":[["2006",4]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->60<!-- [if supportFields]><![endif]-->. Isolation studies have succeeded in identifying lytic myPSH1140 phage against four colistin-resistant Enterobacter spp6. Multi-drug resistant strains of Enterobacter are quite common in E. cloacae & E. aerogenes, with phages belonging to the Podoviridae & Myoviridae respectively having been isolated <!-- [if supportFields]> ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"jXWP6DIO","properties":{"formattedCitation":"\\super 57\\nosupersub{}","plainCitation":"57","noteIndex":0},"citationItems":[{"id":1277,"uris":["http://zotero.org/users/11334842/items/L84NT5A9"],"itemData":{"id":1277,"type":"article-journal","abstract":"Phage therapy is revolving to address the issues mainly dealing with antibiotic resistance in the pathogenic bacteria. Among the drug-resistant microbial populations, the bacterial species have been categorized as high-priority or critical-priority bacteria. This review summarizes the efficiency and development in phage therapy used against these drug-resistant bacteria in the past few years mainly belonging to the critical- and high-priority list. Phage therapy is more than just an alternative to antibiotics as it not only kills the target microbial population directly but also leads to the chemical and physical modifications in bacterial cell structures. These phage-mediated modifications in the bacterial cell may make them antibiotic sensitive. Application of phage therapy in antibiotic-resistant foodborne bacteria and possible modulation in gut microbes has also been explored. Further, the phage cocktail antibiotic formulation, containing more than one type of phage with antibiotics, has also been discussed.","container-title":"Food and Environmental Virology","DOI":"10.1007/s12560-021-09483-z","ISSN":"1867-0342","issue":"4","language":"eng","note":"section: 0","page":"433–446","title":"Bacteriophage Therapy for Critical and High-Priority Antibiotic-Resistant Bacteria and Phage Cocktail-Antibiotic Formulation Perspective","volume":"13","author":[{"family":"Kaur","given":"Gursneh"},{"family":"Agarwal","given":"Ritika"},{"family":"Sharma","given":"Rakesh Kumar"}],"issued":{"date-parts":[["2021",12]]}}}],"schema":"https://github.com/citation-style-language/schema/raw/master/csl-citation.json"} <![endif]-->57<!-- [if supportFields]><![endif]-->. Discussion In the recent years, many articles have emerged in the literature discussing phages as potential non-antibiotic antimicrobials that can offer an alternative treatment option for infections, especially MDRO-induced disease 61. These viruses have been a source of attraction for many researchers and drug developers, due to their sturdiness, bacterial host specificity and ability to self-replicate 62. This offers several advantages, like a minimal side effect profile due to extreme specificity, an ease of storage and a possible 1 dose regimen 63. With the increase in MDROs and the paralleled increased mortality due to infectious diseases, phage studies have shifted from basic science and animal-based studies to human-based trials 63. This led to a great abundance of new information, especially about effectiveness, side effects, form of administration and dosing. For example, we have learned that now there are nebulized, IV, oral and topical phages 64. We have also learned that they minimally affect the gut microbiome and that they can be very effective in treating bacteria, sometimes outstanding antibiotics 65. This becomes especially evident in pan drug resistance and biofilms where antibiotics are least effective 66. However, with more phage utilization, we discover new obstacles. Finding the right dose is very difficult in the absence of sufficient data. Besides, while specificity is a phage’s biggest advantage, it can be its enemy, where slight target modification can lead to resistance. Bacteria can also produce restriction enzymes to fight off their own “viral parasites” 62. While this can be combatted with the administration of polyvalent phages, their non-self-proteins are almost always immunogenic, which can trigger an immune reaction towards them, rendering them ineffective 67. Besides, bacterial cells are the breeding milieu for these viruses and thus phage therapy purification is key to avoid co-administration of bacterial remnants to avoid severe reactions such as anaphylaxis. This is less of a problem with topical or inhaled phages. Another obstacle is oral phages overcoming the stomach acidity barrier, which can be done by using liposomes and/or special capsules 68. The promising thing is that now we have two potential antimicrobial options: phages and antibiotics. This does not mean that one is to replace the other, but rather as an added weapon to our war on infectious diseases. Therefore, we can have phage-antibiotic combos that would have synergistic effects, maximizing the effect of phages and antibiotics and minimizing their doses and side effects 69. This is especially true with antibiotics that target cell structures such as the cell wall or cell membrane. It is worth noting, however, that phages rely on cell machinery to make their own proteins, and by such antibiotics that target protein synthesis can have antagonistic effects to phages 69. We now have an arsenal of experimental phages, but the data regarding them is still lacking. We need more large, randomized trials on phages to fully establish their dosing, side effect profile and efficacy so that we can move to large phase III trials. This way, we would be proactive in our battles against antimicrobial resistance, especially after finding new antibiotic classes or agents becomes more of a challenge 70. With our current technology we have made huge steps in genome sequencing and molecular microbiology that we are, more than ever, capable of achieving that by manipulating viral genomes in the way we find appropriate 71. This is why this era of antimicrobials is progressing to what some describe as the “post-antibiotic” or the “bacteriophage” era 72. Conclusion With the constant increase in antibiotic resistance, there is a need for new agents to fight off MDROs and increase cure rates and survivability with less side effects. This led to the revival of an idea that was long suppressed due to the ease of access to antibiotics: bacteriophages. However, antibiotics are gradually being overthrown by bacteria and now we have the technology to venture to molecular microbiology, making phages a possibility that has proven itself promising on multiple occasions. Therefore, more studies and funding are needed towards this field, that offers us a promising salvation from the antimicrobial resistance pandemic. Declarations Author contributions All authors contributed equally and validated the final version of record. Conflicts Of Interest The Author(s) declare(s) that there is no conflict of interest. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. 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Quality of life following Covid-19 vaccination in Lebanese adults
Background: This study investigates the quality of life (QoL) among individuals in Lebanon post-COVID-19 vaccination, focusing on various demographic and lifestyle factors influencing physical, psychological, social, and environmental health domains. Objective: To explore the associations between COVID-19 vaccination status and QoL across four sub-scales: physical health, psychological health, social relationships, and environmental quality, examining the impact of gender, tobacco and alcohol consumption, chronic diseases, physical activity, employment status, education level, geographic location, and marital status. Methods: A cross-sectional study was conducted involving 507 Lebanese adults who completed a structured questionnaire. The questionnaire collected data on demographics, lifestyle factors, and QoL using a standardized measurement tool. Statistical analysis, including bivariate analysis, was performed to determine significant associations between independent variables and QoL scores across the four domains. Results: The majority of participants were female (71.6%), non-smokers (83%), and non-drinkers (76.7%). Most had no chronic diseases (83%), and 42.4% engaged in regular physical activity. High educational attainment (80.5% with graduate or professional degrees) and full-time employment (77%) were prevalent. Significant associations were found between gender and all QoL domains, with males reporting higher scores. Physical health scores were higher among non-drinkers, the physically active, independent workers, and vaccinated individuals. Psychological health was better in males, the physically active, and independent workers. Social relationships were stronger among males, independent workers, and those in relationships. Environmental quality was higher among males, non-drinkers, independent workers, and those with no formal education. Vaccination status positively influenced physical health and showed near-significant effects on social relationships and environmental quality. Conclusion: COVID-19 vaccination is associated with improved QoL in Lebanon, particularly in physical health. The findings highlight the importance of considering socio-economic factors and lifestyle choices in public health strategies to enhance overall well-being. Future research should explore longitudinal impacts and address the specific needs of diverse populations. Introduction COVID-19 is an acute respiratory infection caused by the potentially serious SARS-CoV-2, with high transmissibility and global distribution(1). The coronavirus pandemic has had a significant negative impact on human mental health and quality of life. Physical separation and other preventative measures exacerbate psychological distress. The COVID-19 vaccine is predicted to lower both the incidence and severity of illnesses. Therefore, the creation of vaccines played a role in the conclusion of the pandemic. Scientific evidence is available on the impact of the Covid-19 vaccine and the outcome of infected patients. However, a lack of information exists concerning the effect of vaccination on the quality of life of people worldwide and specifically in Lebanon. Considering the previous observations, the objective of this study is to determine the Quality of life (QoL) post-COVID-19 vaccinated patients and to assess post-COVID-19 patients' QoL by interpolating health and social characteristics. Regarding how vaccines affect the well-being of individuals, a study on the impact of a 2-dose COVID-19 vaccination campaign on reducing incidence, hospitalizations and deaths in the United States is developed based on an agent-based model of the severe acute respiratory syndrome coronavirus (SARS-CoV-2) transmission and parameterized with US demographics and age-specific COVID-19 outcomes. A vaccine efficacy of 95% against the disease after 2 doses administered 21 days apart, reaching a vaccination coverage of 40% of the entire population in 284 days. Vaccination reduced the overall attack rate to 4.6% versus 9.0% without vaccination, over 300 days. Vaccination significantly reduced adverse events, with non-intensive care unit and intensive care unit hospitalizations and deaths decreasing by 63.5%, 65.6%, and 69.3%, respectively, over the same period. These results indicate that vaccination can have a substantial impact on mitigating COVID-19 outbreaks, even with limited protection against infection(2). Another study from Poland aimed to assess the effects of vaccination on respondents' mental well-being, their attitudes towards following government recommendations limiting viral transmission, and to identify factors that may influence the decision to get vaccinated. Standardized psychometric tools were used in the survey: the Generalized Anxiety Disorder Assessment (GAD-7) and the Manchester Quality of Life Abbreviated Assessment (MANSA). The survey involved 1,696 respondents, the vast majority of whom were women between the ages of 18 and 29. Immunization status was reported by 1677 respondents (98.9%). Fully vaccinated individuals had lower anxiety levels, higher MANSA scores, and lower subjective anxiety of being infected with COVID-19 than those awaiting vaccination or those with an incomplete vaccination schedule.(3) When it comes to pandemic fear and anxiety, there is a clearly distinct group of individuals who are unwilling to get vaccinated. Their reported level of fear and anxiety related to a possible SARS-CoV-2 infection is significantly lower than that of others, whether or not they have already been vaccinated, as confirmed by post-hoc analysis. Considering the entire GAD-7 questionnaire, the differences between the groups border on statistical significance. fully vaccinated people rated their level of anxiety as lower than other participants. On the MANSA questionnaire, fully vaccinated respondents were more satisfied with their lives than single-dose vaccinates, unvaccinated and those who did not intend to vaccinate (62.81 vs 60.22 vs 59 .38 versus 60.26; p=0.0017). Those who were unwilling to get vaccinated had a similar total score to single-dose vaccinates, while those who intended to get vaccinated had the lowest scores. Post hoc analysis revealed a statistically significant difference between those fully vaccinated and those awaiting vaccination (p=0.0006). In the analysis of individual questions included in the questionnaire, the highest subjective sense of security was reported by fully vaccinated individuals, while the lowest was reported by single-dose vaccinated individuals (post-hoc analysis p = 0.014). Unvaccinated obtained intermediate scores (p = 0.022); there were no statistically significant differences between the other groups The results of this study indicate that vaccination affects mental well-being and level of anxiety about SARS-CoV-2 infection. Fully vaccinated people have lower levels of anxiety than single-dose vaccinated people or unvaccinated people intending to get vaccinated. The exceptions are those who do not wish to be vaccinated against COVID-19; their level of anxiety (subjective score and GAD-7) is significantly lower compared to the other groups. The results of the GAD-7 questionnaire, and questions about subjective anxiety about being infected or anxiety about quarantining or isolating people from the immediate environment, indicate a significant reduction in anxiety among fully vaccinated versus single dose or unvaccinated. Fully vaccinated people are the most satisfied with their lives, as well as their mental health and financial situation, both compared to those who do not wish to be vaccinated and those vaccinated with a single dose. These variables overlap with factors that increase the likelihood of making the decision to vaccinate.(4) Preliminary research suggests that vaccination against Covid-19 of people who already have a long Covid could reduce the severity of their symptoms.(3) To support these results, the researchers used data from the ComPaRe Covid long cohort to carry out a study aimed at emulating a clinical trial evaluating the effect of vaccination against Covid-19 on the symptoms and impact of Covid long.(5) The researchers used data from 455 pairs of people (vaccinated and unvaccinated) matched on several variables such as age, sex, level of education, comorbidities, hospitalization during the acute phase of Covid-19 and the severity of their long Covid. Covid-19 vaccines were developed by Astra-Zeneca, Pfizer-BioNTech, Johnson & Johnson and Moderna. The mechanisms of actions of each vaccine are different. Moderna and Pfizer-BioNTech created mRNA vaccines that specifically target the SARS-CoV-2 surface protein. Johnson & Johnson and Astra-Zeneca employed already-existing technologies in conjunction with an adenovirus vector to elicit an immune response and provide defense against further infection. Along with further variations like administration and side effects, each vaccine has exhibited varying reactions to the variants(5). The researchers compared patients vaccinated for the first time with one of these vaccines with those who remained unvaccinated. The average age of the participants was 47 years and most (733; 80.5%) were women. Participants rated the severity of their symptoms and the impact of long Covid on their quality of life every 60 days using validated scales. Vaccination was associated with a slight reduction in the average number of symptoms at 120 days: 13 different symptoms of long Covid in those vaccinated and 14.8 in those who were not. Twice as many vaccinated patients reported remission of all their long Covid symptoms: 57 (nearly 17%) versus 27 (7.5%) of the unvaccinated. Some of the vaccinated patients (26 out of 455, or nearly 6%) reported side effects, 4 of which were considered serious, 2 of which required hospitalization; in 13 others, symptoms worsened. A systematic review of 16 observational studies from 5 countries, conclude that COVID-19 vaccines could both protect against and help treat the symptoms of long Covid, provided there is more good quality evidence.(6) This study seeks to answer the following research question: How does COVID-19 vaccination influence the quality of life in Lebanese adults, considering the interaction with various health and social characteristics? The primary objective of this study is to assess the QOL in post-COVID-19 vaccinated individuals in Lebanon and to explore how various health and social characteristics interact with QoL. Methods and Materials Population and study design This cross-sectional study consisted of 507 Lebanese adults from various regions, including Mount Lebanon, North Lebanon, Bekaa, South Lebanon, and Beirut. Participants were selected to represent a diverse cross-section of the population in terms of gender, age, educational level, employment status, and health conditions. The sample size was computed as 385 using online EpiInfo Software, vesrion7.3, keeping confidence level of 95%. However, the sample size was rounded off to 500 to prevent errors in data analysis due to drop-off. Procedure Participants were recruited through a combination of online and in-person methods to ensure inclusivity. In-Person Recruitment: Participants were recruited in person across various public locations frequented by adults in Lebanon, such as shopping centers, universities, workplaces, and community centers. Trained data collectors approached individuals and provided them with information about the study, inviting them to participate. Those who agreed were asked to complete the survey on-site or were given a link to complete it online at their convenience. Online invitations were distributed via social media platforms. Sampling Method A combination of convenience sampling and snowball sampling methods was employed. Convenience sampling allowed us to reach participants easily accessible in various public locations, while snowball sampling enabled us to expand the sample size by encouraging initial participants to refer others who met the inclusion criteria. Ensuring Representativeness To ensure the representativeness of the sample, we took several steps. First, we aimed for diversity in terms of age, gender, and socioeconomic status by recruiting participants from various urban and rural areas across Lebanon. Second, we monitored the demographic composition of the sample throughout the data collection process and made efforts to reach underrepresented groups through targeted recruitment strategies, such as focusing on specific communities or social media networks. Data collection was carried out over a period of three months, during which participants completed a detailed questionnaire that included the WHOQOL-BREF(7) ,(8) demographic information, and health-related behaviors such as tobacco and alcohol consumption, physical activity, and COVID-19 vaccination status. The WHOQOL-BREF questionnaire was translated into Arabic to ensure accessibility and comprehension for all participants. The translation process followed standard procedures to maintain the validity and reliability of the instrument. Structure of the Questionnaire Section 1: Demographic Information: This section collects basic demographic data, including age, gender, marital status, education level, employment status, and geographic location (urban or rural). This information is crucial for understanding the demographic profile of the participants and for stratifying the data in the analysis. Section 2: Health Status: Participants are asked about their vaccination status (number of doses received), history of chronic diseases, current health conditions, and any history of COVID-19 infection. This section is essential for examining the relationship between health status and QoL. Section 3: Lifestyle Behaviors: This section includes questions about lifestyle factors such as smoking, alcohol consumption, physical activity, and diet. These variables are important as they may influence both health outcomes and QoL. Section 4: Quality of Life (QoL) Assessment: The core of the questionnaire is the QoL assessment, which is based on the WHOQOL-BREF instrument, a widely recognized tool for measuring QoL across four domains: Physical Health, Psychological Health, Social Relationships, and Environment. Each domain is assessed through a series of Likert-scale questions, where participants rate their experiences over the past two weeks. The WHOQOL-BREF instrument used in the questionnaire is a validated tool with established reliability in various cultural contexts, including Lebanon. The internal consistency of the instrument, measured by Cronbach’s alpha, typically ranges between 0.70 and 0.90 across different domains (Physical Health = 0.842, Psychological Health =0.785, Social Relationships = 0.814, Environment =0.89), indicating good reliability. Scoring Instructions The WHO Quality of Life Scale-Brief (WHOQOL-BREF), a subset of 26 items from the WHOQOL-100, was used to assess participants' quality of life across four domains: physical health, psychological health, social relationships, and environment. The WHOQOL-BREF does not have facet scores, and mean substitutions were recommended for Domain 1 (Physical Health) and Domain 4 (Environment) if no more than one item was missing. Three items (Q3, Q4, Q26) needed to be reversed before scoring. Each item on the WHOQOL-BREF was scored from 1 to 5, with higher scores indicating better quality of life. Domain scores were calculated by averaging the item scores within each domain, reversing the specified items, and multiplying by 4 to standardize the score. The domain scores were then converted to a 0-100 scale, where 0 represented the worst possible health status and 100 the best possible. Score calculation Physical health = 4x ((6 – Q3) + (6 – Q4) + Q10 + Q15 + Q16 + Q17 + Q18)/7 Psychological health = 4x (Q5 + Q6 + Q7 + Q11 + Q19 + (6 – Q26))/6 Social relations = 4x (Q20 + Q21 + Q22)/3 Environment = 4x (Q8 + Q9 + Q12 + Q13 + Q14 + Q23 + Q24 + Q25)/8 These domain scores were converted to a scale of 0 to 100 using the formula: Converted score= (domain score−4) ×(100/16) (7). Statistical Analysis Descriptive analysis will be performed to provide an overview of the dataset and the demographic characteristics of the study participants. The dataset consisted of a total of 507 participants. Summary statistics, including means, standard deviations, frequencies, and proportions, were calculated for continuous and categorical variables, respectively. These statistics will be computed using the Descriptives and Frequencies procedures in IBM SPSS Statistics version 27. Bivariate analysis will be used to explore the relationships between variables in the study and to identify any potential associations or differences between these variables and the scores in the study. The statistical analyses were conducted using the Independent Samples T-Test, One-Way ANOVA and the Pearson correlation test for parametric tests. Ethical Considerations The study was conducted in accordance with ethical standards for research involving human participants. Informed consent was obtained from all participants, and confidentiality of their data was assured. The study protocol was reviewed and approved by the ethics committee at Holy Family University Batroun-Lebanon. Results The descriptive table provides data on the demographics and other independent characteristics of participants in the study on quality-of-life following COVID-19 vaccination. The majority of participants are female (71.6%), and most do not consume tobacco (83%) or alcohol (76.7%). A significant portion (83%) does not suffer from chronic diseases, and 42.4% engage in at least 2.5 hours of physical activity per week. Employment status shows that 60.2% work in the private sector, with 77% employed full-time. The educational level is high, with 80.5% having a graduate or professional degree. Geographically, 52.3% of participants are from Northern Lebanon. Regarding marital status, 49.2% are married, and 41.1% are single. An overwhelming majority (93.9%) are vaccinated against COVID-19, predominantly with the Pfizer vaccine (79%). The average age of participants is 35.01 years. Quality of life scores vary across domains, with the highest average in the psychological domain (57.05) (table 1). Physical health domain Table 2 explores the association between various independent variables and the physical health scale scores among the study participants. Gender shows a significant difference (P=0.04), with males (54.19 ± 12.78) scoring higher than females (51.71 ± 10.50). Tobacco consumption and the presence of chronic diseases do not significantly affect physical health scores, with P values of 0.704 for both variables. However, alcohol consumption does show a significant difference (P=0.045), where non-drinkers (52.96 ± 11.24) have higher physical health scores than drinkers (50.60 ± 11.09). Physical activity has a significant impact (P=0.007), with those engaging in at least 2.5 hours of physical activity per week (53.97 ± 11.83) having higher scores than those who do not (51.26 ± 10.65). Employment status is also significant (P=0.028), with independent workers (55.95 ± 12.27) scoring highest, followed by those not working (53.17 ± 11.64), private sector employees (51.55 ± 10.77), and those unable to find work (50.95 ± 10.97). Work time does not significantly affect the scores (P=0.727). Educational level shows a significant association (P=0.0001), with high school graduates (60.40 ± 10.65) having the highest scores, followed by those with no formal education (57.14 ± 9.44). Participants with graduate/professional degrees have the lowest scores (51.51 ± 10.74). Geographic location is significant (P=0.002), with Beirut residents scoring highest (56.92 ± 11.75) and participants from the North scoring lowest (50.63 ± 11.02). Marital status does not show a significant difference (P=0.576). Vaccination status is significant (P=0.014), with vaccinated individuals (52.69 ± 11.08) scoring higher than unvaccinated ones (47.11 ± 13.62). The number of vaccine doses does not significantly affect physical health scores (P=0.529). Finally, age shows a weak positive correlation with physical health scores (Pearson=0.076, P=0.096), but it is not statistically significant (Table 2). Psychological health domain When examining the relationship between various independent variables and psychological health scores among the study participants, gender shows a significant difference (P=0.001), with males (59.80 ± 11.61) having higher psychological health scores than females (55.96 ± 11.03). Tobacco consumption and the presence of chronic diseases do not significantly affect psychological health scores, with P values of 0.705 for both variables. Alcohol consumption does not show a significant difference (P=0.19), though non-drinkers (57.42 ± 10.84) have slightly higher scores than drinkers (55.86 ± 12.75). Physical activity significantly impacts psychological health (P=0.041), with those engaging in at least 2.5 hours of physical activity per week (58.25 ± 11.45) having higher scores than those who do not (56.17 ± 11.15). Employment status reveals significant differences (P=0.004), with independent workers (60.58 ± 11.17) having the highest scores, followed by those not working (57.07 ± 10.55), private sector employees (56.85 ± 11.39), and those unable to find work (51.66 ± 11.71). However, when employment is categorized as working versus not working, the difference is not significant (P=0.577). Work time does not show a significant difference in scores (P=0.158). Educational level shows a marginal significance (P=0.063), with high school graduates (61.66 ± 10.29) having the highest scores and those with no formal education (49.16 ± 7.45) having the lowest. Geographic location does not show significant differences (P=0.2), although Beirut residents (58.71 ± 12.81) have the highest scores. Marital status is near significance (P=0.053), with those in a relationship (61.03 ± 13.4) having the highest scores and widowed individuals (52.43 ± 9.8) having the lowest. Vaccination status does not significantly affect psychological health scores (P=0.249), though vaccinated individuals (57.10 ± 11.39) have higher scores than unvaccinated ones (54.48 ± 8.81). The number of vaccine doses does not significantly affect scores (P=0.272). Finally, age shows a weak and non-significant positive correlation with psychological health scores (Pearson=0.036, P=0.421) (Table 3). Social Relations domain The bivariate analysis reveals significant associations between various independent variables and social relationship scores among the study participants. Gender shows a highly significant difference, with males (53.06 ± 17.37) reporting higher social relationship scores than females (45.63 ± 15.61) (P=0.0001). Tobacco consumption and chronic disease status do not significantly impact social relationship scores, both with P values of 0.941. Alcohol consumption also does not show a significant effect (P=0.599), although those who consume alcohol (48.44 ± 16.23) have slightly higher scores than non-drinkers (47.53 ± 16.54). Physical activity does not significantly influence social relationship scores (P=0.294), with physically active individuals (48.64 ± 17.88) having marginally higher scores than those who are not physically active (47.08 ± 15.32). Employment status shows significant differences (P=0.0001), with independent workers (53.43 ± 17.12) having the highest social relationship scores, followed by private sector employees (48.11 ± 15.86), those not working (45.94 ± 16.33), and those unable to find work (38.61 ± 17.15). Work time shows significant differences (P=0.004), with those working part-time (49.13 ± 16.35) scoring higher than those working full-time (47.4 ± 16.53). Educational level does not show significant differences (P=0.708), although college graduates (50.53 ± 15.86) have the highest social relationship scores, and elementary school graduates (43.75 ± 15.12) have the lowest. Geographic location shows significant differences (P=0.046), with Bekaa residents (55.83 ± 20.78) having the highest social relationship scores, followed by Beirut (50.5 ± 18.27) and Mount Lebanon (49.2 ± 15.87). North residents have the lowest scores (46.06 ± 16.26). Marital status shows significant differences (P=0.002), with individuals in a relationship (51.12 ± 19.16) and married individuals (50.06 ± 14.79) having higher social relationship scores compared to singles (44.63 ± 17.02) and widowed individuals (45.13 ± 21.74). Vaccination status shows a near significant difference (P=0.069), with vaccinated individuals (47.95 ± 16.21) having higher social relationship scores than unvaccinated ones (41.98 ± 17.39). The number of vaccine doses does not significantly affect social relationship scores (P=0.853). Age shows a weak and non-significant positive correlation with social relationship scores (Pearson=0.029, P=0.532). Environment Domain The bivariate analysis explores the relationship between various independent variables and the environment quality scores. Gender reveals a significant difference (P=0.009), with males (56.35 ± 12.95) reporting higher environment quality scores compared to females (53.13 ± 10.79). Tobacco consumption and the presence of chronic diseases do not significantly affect environment quality scores, both having P values of 0.164. However, alcohol consumption shows a significant effect (P=0.007), with non-drinkers (54.80 ± 11.46) having higher scores than drinkers (51.56 ± 11.42). Engaging in physical activity does not significantly impact environment quality scores (P=0.249), though those who practice physical activity (54.73 ± 12.8) report slightly higher scores than those who do not (53.54 ± 10.47). Employment status shows significant differences (P=0.001), with independent workers (57.49 ± 10.70) having the highest scores, followed by those not working (55.96 ± 11.61), private sector employees (53.18 ± 11.38), and those unable to find work (48.64 ± 11.65). Work time also does not show a significant difference (P=0.668), with full-time workers (54.18 ± 11.66) and part-time workers (53.47 ± 11.21) having similar scores. Educational level shows significant differences (P=0.003), with individuals having no formal education reporting the highest scores (65 ± 11.35), while those with graduate or professional degrees report the lowest (53.19 ± 11.05). District shows non-significant differences (P=0.131), with slight variations across regions, such as the South (55.31 ± 11.78) and Bekaa (54.84 ± 13.8) reporting higher scores than North (52.94 ± 11.52) and Beirut (54.04 ± 11.52). Marital status does not significantly affect environment quality scores (P=0.579), though those who are single (54.7 ± 12.64) report higher scores than married (53.77 ± 10.56) and widowed (50.52 ± 11.21) individuals. Vaccination status shows a non-significant difference (P=0.153), with vaccinated individuals (54.14 ± 11.31) reporting higher environment quality scores compared to unvaccinated individuals (50.84 ± 13.73). The number of vaccine doses does not significantly affect scores (P=0.269). Age shows a weak and non-significant positive correlation with environment quality scores (Pearson=0.079, P=0.081) (Table 5). When stratifying the number of doses in the analysis of the four QoL domains—Physical Health, Psychological Health, Social Relations, and Environment—it reveals that there is no statistically significant difference in QoL scores based on the number of COVID-19 vaccine doses received. Although the mean scores show slight variations across the different dose groups, the p-values for each domain (Physical Health: 0.089, Psychological Health: 0.261, Social Relations: 0.353, and Environment: 0.262) all exceed the conventional threshold of 0.05 for statistical significance (Table 6). Discussion Vaccination and Quality of Life Our study aimed to explore the quality of life (QoL) among post-COVID-19 vaccinated individuals in Lebanon, enriching the global understanding of the vaccine's benefits beyond mere infection prevention. The literature robustly supports that COVID-19 vaccination significantly reduces infection rates, severity of the illness, and mortality, as demonstrated by Mahony et al. (9) The interaction between vaccination status and mental health, particularly anxiety and life satisfaction, has been a focal point in our analysis. Consistent with findings from Babicki et al. (2021) in Poland,(10) our study confirms that fully vaccinated individuals exhibit lower levels of anxiety and higher overall life satisfaction. This aligns with the hypothesis that vaccination alleviates the psychological burden imposed by the fear of contracting severe illness. However, unique to our study is how these psychological benefits manifest in the Lebanese population, a region beset by economic instability and political unrest, which are factors known to exacerbate mental health struggles (11). A particularly novel aspect of our study relates to the impact of vaccination on long COVID symptoms. Echoing the preliminary international data presented by LongCovidSOS (2021) and the systematic review by BMJ Med (2022), our local analysis suggests a slight reduction in the number and severity of long COVID symptoms post-vaccination.(6,12). This finding is pivotal as it suggests vaccination as a potential therapeutic avenue not just for prevention but also as a part of the management strategy for long COVID, a rapidly emerging public health concern. Furthermore, an unexpected yet significant finding from our study was the persistently lower anxiety levels among individuals who were hesitant or refused vaccination. This subgroup displayed a distinct psychological profile compared to both unvaccinated individuals intending to vaccinate and those already fully vaccinated. This finding suggests complex underlying factors, including personal beliefs about health and government trust, which influence vaccination decisions. These aspects merit further investigation to effectively address vaccination hesitancy from a public health communication perspective(13). These findings align with existing literature indicating that higher education levels, stable employment, and physical activity correlate with better quality of life.(14) Studies from the US and Poland similarly show that fully vaccinated individuals experience lower anxiety and higher life satisfaction.(15,4) The high vaccination rate and associated improvements in quality of life observed in this study are consistent with global trends demonstrating the positive impact of COVID-19 vaccination on mental health and overall well-being. The data also reflect the significant role of vaccination in reducing the severity of long COVID symptoms, contributing to improved quality of life for those affected (6,16). Gender differences are evident across all four domains, with males consistently reporting higher scores than females. For physical health, this aligns with studies suggesting men may perceive their physical health more positively than women, potentially due to different health-seeking behaviors and societal expectations.(17,3) Similarly, males report higher psychological health scores, which aligns with studies suggesting men often report higher psychological well-being, possibly due to different coping mechanisms and societal roles.(18) In terms of social relationships, men report higher scores, consistent with literature indicating men often report better social well-being due to different socialization patterns and societal roles.(19) For environmental quality, men also report higher scores, possibly due to different lifestyle and occupational exposures (20). Furthermore, the impact of tobacco consumption and chronic diseases is non-significant across all four domains. This contrasts with studies that typically show these factors negatively impacting physical and psychological health, as well as social relationships and environmental perceptions.(21) The discrepancy might be due to the specific characteristics or size of the sample used in this study. Alcohol consumption shows a significant negative impact on physical health and environmental quality, aligning with broader research linking alcohol use to various health problems and poorer perceptions of one's environment due to associated health and social issues (22,23). However, its impact on psychological health and social relationships is non-significant, although the mean psychological health scores are slightly higher for non-compared to drinkers, this difference is not statistically significant, Therefore, no firm conclusions can be drawn regarding the impact of alcohol consumption on psychological health based on these results consistent with studies linking alcohol use to poorer mental health outcomes (24). Also, physical activity's positive association with better physical health scores is well-documented, highlighting the benefits of regular exercise on overall well-being.(25) This positive impact extends to psychological health, with extensive research supporting that regular exercise significantly enhances mental well-being.(19) However, physical activity does not show a significant impact on social relationships and environmental quality in this study, contrasting with numerous studies that highlight the social and environmental benefits of regular exercise. This indicates a need for further investigation into the context and nature of physical activities undertaken by the sample population (25,26). Noting that the employment status significantly affects all four domains. Independent workers report the highest physical health and psychological health scores, reflecting findings that stable and fulfilling work contributes to better mental and physical health (27). For social relationships, independent workers also report the highest scores, supporting research suggesting that fulfilling and stable work environments enhance social well-being.(19,27) In terms of environmental quality, independent workers again report the highest scores, possibly due to greater autonomy and satisfaction (28). When categorizing employment into working versus not working, or considering work time, the impact is less clear, suggesting that the quality and nature of employment might be more critical than employment status or hours worked (6). Educational level shows significant associations with physical health, psychological health, and environmental quality. Higher educational attainment generally correlates with better health outcomes, corroborating findings from studies emphasizing the role of socioeconomic factors in health (10,20). Interestingly, those with no formal education report the highest environmental quality scores, challenging the expectation that higher education correlates with better environmental perceptions. This may reflect different expectations or coping mechanisms among those with varying education levels. For social relationships, the impact is non-significant, although the trend suggests higher scores with higher education, supporting the notion that education enhances social capital and relationships (19). Moreover, geographical disparities are evident across the domains. Beirut residents report better physical health and psychological health scores, possibly reflecting differences in healthcare access, lifestyle, and environmental factors across regions.(11) For social relationships, the Bekaa region has the highest scores, possibly due to stronger community ties and social networks in rural. For environmental quality, geographic variations suggest regional differences in perceptions, though these differences are not statistically significant.(28) Marital status significantly affects psychological health and social relationships. Being in a relationship or married is associated with higher scores, supporting extensive research emphasizing the positive impact of close social bonds and support systems on mental and social well-being.(7) For physical health and environmental quality, the impact is less clear, with marital status showing no significant effect on physical health and only marginal differences in environmental quality scores.(17) Besides, vaccination status shows a significant positive impact on physical health scores, supporting research demonstrating the health benefits of vaccination beyond just preventing infection.(29) While not significantly impacting psychological health, vaccinated individuals report higher psychological health scores, aligning with studies indicating that vaccination reduces anxiety and improves mental health by providing a sense of security and protection against COVID-19.(30) Vaccination status shows a difference that is close to the statistical significance threshold, with a p-value of 0.069. However, the difference is not considered statistically significant., Contrarily, other research suggests that vaccination might enhance social interactions and reduce social anxiety related to COVID-19.(31) In terms of environmental quality, the near-significant impact of vaccination status suggests that health security can enhance overall well-being and perceptions of one's environment.(32) The number of vaccine doses did not significantly affect any of the four domains, indicating that the act of being vaccinated, rather than the number of doses, might be more crucial. Finally, the non-significant correlation between age and physical, psychological, and social relationship scores suggests that age alone does not heavily influence these aspects of well-being in this sample. This aligns with some research but contrasts with other studies that find varying impacts across different age groups.(33) For environmental quality, the correlation with age shows a positive trend, though not statistically significant, indicating a need for further exploration with a larger sample size to confirm any potential age-related differences.(26) The number of vaccine doses does not have a significant impact on the overall quality of life in the studied population. This suggests that while there may be observable trends, such as a slight increase in Physical Health and Environment scores with more doses, these differences are not strong enough to be considered statistically meaningful. Therefore, it can be inferred that the number of vaccine doses does not have a significant impact on the overall quality of life in the studied population. This finding is consistent with the work of Qiao Liu et al. (2021), which showed that while COVID-19 vaccination was effective in preventing severe outcomes, it did not have a significant impact on the overall quality of life based on the number of doses. Further research might be necessary to explore these relationships in more depth, potentially considering additional variables or a larger sample size to detect subtler effects.(34) Limitations and Future Research Our study, while informative, is not without limitations. The self-reported nature of quality of life and mental health data may introduce bias. Additionally, the specific socio-economic context of Lebanon might limit the generalizability of our findings to other regions. Future research should focus on longitudinal studies to track the evolution of quality of life over time post-vaccination and explore the long-term effects of vaccination on mental health and well-being. Our study contributes to the growing body of evidence supporting the multifaceted benefits of COVID-19 vaccination. By enhancing our understanding of how vaccinations influence quality of life and mental health, particularly in contexts as challenging as Lebanon, we can better tailor public health initiatives to meet the needs of diverse populations facing a global health crisis. Conclusion This study explored the relationship between various independent variables and environment quality scores, revealing several significant associations. From a policy standpoint, our findings underscore the need for comprehensive public health strategies that not only promote vaccination uptake but also address the broader implications of the pandemic on mental health and quality of life. Implementing supportive policies that enhance healthcare accessibility, mental health services, and public health education could mitigate the long-term impacts of the pandemic. The high educational attainment and employment rates suggest that interventions aimed at increasing vaccination rates and improving quality of life could be effectively communicated through workplace initiatives and educational institutions. Moreover, targeted efforts might be needed in regions with lower socioeconomic status or access to information, such as Bekaa and South Lebanon. The analysis of lifestyle factors like tobacco and alcohol use in relation to vaccination status could help tailor public health messages that resonate with specific subgroups' existing health beliefs and behaviors. Encouraging physical activity as part of a holistic approach to health could be a dual strategy to enhance both physical and mental health outcomes post-vaccination. Overall, the findings highlight the complex interplay of various factors affecting environment quality perceptions, corroborating and challenging existing literature. The significant positive impacts of employment status, particularly independent work, and the potential influence of vaccination underscore the importance of socio-economic stability and health interventions in enhancing environmental quality perceptions. The non-significant findings for physical activity, tobacco use, and chronic diseases indicate areas for further research to better understand their roles in shaping environmental perceptions. Declarations Authorship statement All authors contributed equally and validated the final version of record. Conflicts Of Interest The Author(s) declare(s) that there is no conflict of interest. Funding statement This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Registration No registration applicable. Data availability statement The data that support the findings of this study are available from the corresponding author upon reasonable request. 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Influenza Associated Pulmonary Aspergillosis: A Retrospective Study from a Tertiary Care Center in Lebanon
Introduction Influenza-associated pulmonary aspergillosis (IAPA) has been reported in multiple cohort studies, typically in the immunocompromised host. Limited data is available from the Middle Eastern region. Methods This is a retrospective study conducted at the American University of Beirut Medical Center (AUBMC) between January 1 2014 and March 1 2019, to describe the clinical characteristics, risk factors and outcomes of patients with influenza and invasive pulmonary aspergillosis (IPA). Six hundred fifty six patients were admitted with influenza pneumonia. Data about positive cultures for Aspergillus sp. isolated from sputum, deep tracheal aspirates (DTA) or bronchoalveolar lavage (BAL) or a positive aspergillus galactomannan test (GM) in serum or BAL was collected. Cases were identified based on the definitions and criteria for influenza and invasive aspergillosis suggested by the European Organization for Research and Treatment of Cancer/Mycoses study Group (EORTC/MSG), EORTC/MSG intensive care unit (EORTC/MSGERC ICU) Working Group, and IAPA definition. Results Nine patients had a positive result for Aspergillus sp. in culture or GM. Based on the EORTC/MSG criteria, 7 patients were classified as probable cases of IPA, and one as a possible case. On the other hand, only 2 patients were classified as probable cases of invasive fungal infection (IFI) based on the IAPA criteria. Only 1 out of 9 patients died. There was a preponderance of aspergillosis among immunocompromised patients. Conclusion Our study showed that the incidence of IPA in influenza patients was low compared to the data reported from European countries. This calls for national and regional surveillance to better understand the epidemiological variation in the regions. Introduction The association between influenza and superimposed pulmonary aspergillosis has been described as early as 1979.[1] Influenza-associated pulmonary aspergillosis (IAPA) has been reported in multiple cohort studies.[2, 3] The associated mortality is high ranging between 22.2% to 100%, especially in patients admitted to the intensive care unit (ICU).[4] While invasive pulmonary aspergillosis (IPA) typically occurs in immunocompromised hosts and isolation of Aspergillus species in immunocompetent patients is most often considered a colonization,[5] IAPA has been described in many patients without the traditional risk factors for IPA, including immunocompetent individuals.[6] Since the associated mortality of IAPA is 51% compared to 28% in patients with influenza admitted to the ICU without IAPA, criteria have been proposed for the diagnosis and early identification of IAPA.[7-11] Limited data on IAPA is available from the Arab countries in the Middle East region. In Lebanon, a country with low vaccination rates for influenza, seasonal influenza is a significant burden on the population, with a hospital admission rate in one center estimated at 26.6%.[12] The purpose of this study is to describe the clinical characteristics, risk factors and outcomes of patients with influenza who had Aspergillus sp. isolated from cultures of respiratory specimens or positive aspergillus galactomannan (GM) test. Methods Study design This is a retrospective chart review conducted at the American University of Beirut Medical Center (AUBMC), a teaching hospital with 364 beds and 50 adult ICU beds. We reviewed the electronic medical records of patients hospitalized between January 1, 2014, and March 1, 2019, before the severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) pandemic started. We included those with a primary diagnosis of influenza (confirmed either by a reverse transcriptase polymerase-chain-reaction (RT-PCR) or by a rapid antigen tests). We then checked which patients had positive cultures for Aspergillus sp. isolated from sputum, deep tracheal aspirates (DTA) or bronchoalveolar lavage (BAL) or a positive aspergillus GM in serum or BAL in patients who had worsening respiratory symptoms. Until 2020, our center had not been speciating the Aspergillus sp. nor had access to 1,3- β-D-Glucan (BDG). We collected data on patients characteristics including age, gender, Charlson’s score, body mass index (BMI), presence of neutropenia with neutrophils count at the time of influenza diagnosis (<500 neutrophils/mm3), bacterial co-infection at the time of influenza diagnosis, presence of type II diabetes mellitus (DM II), chronic kidney disease (CKD), hemodialysis use, chronic lung disease (chronic obstructive pulmonary disease COPD, asthma and other lung diseases like bronchiectasis), active hematological or solid organ malignancy, and active chemotherapy intake. Reviewed hospitalization course included length of hospital stay in days, intake of neuraminidase-inhibitor and/ or corticosteroids, radiographic characteristics of the lung findings, the need for oxygen supplementation, and the need for invasive or non-invasive mechanical ventilation. In-hospital mortality was defined as mortality anytime during the hospital stay. The study protocol was approved by the AUBMC Institutional Review Board under number BIO-2019-0166 and informed consents were waived due to the retrospective nature of the study. Case definitions and analysis Cases were identified by clinical, microbiological and radiological criteria based on the definitions and criteria for influenza and invasive aspergillosis suggested by the European Organization for Research and Treatment of Cancer/Mycoses study Group (EORTC/MSG), [7] European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium (EORTC/MSGERC) ICU Working Group [9] and IAPA definition (supplementary material 1). [8] According to EORTC/MSG criteria, patients were classified into three types of IAPA (proven IPA, probable IPA, and possible IPA). [7] The EORTC/MSERG ICU working group updated definitions specifically for invasive candidiasis and invasive aspergillosis that are relevant for ICU patients, focusing on the host factors. [9] As for IAPA, although patients were classified as either proven or probable, authors suggested that clinicians should not distinguish between proven and probable disease and might consider these differences only for clinical trials [8]. Two categories were included in this definition: Invasive Aspergillus tracheobronchitis (ATB) and IAPA without ATB, based on expert consensus. [8] Since our study population included all hospitalized patients and not only those admitted to the ICU, we opted to include all the aforementioned definitions to assess our patients. Results During the study period, we identified a total of 656 cases of severe influenza pneumonia requiring hospital admission. Of these, nine patients had a positive result for Aspergillus sp. in culture or positive GM. The clinical and laboratory characteristics of the 9 patients are presented in Table 1. Based on the EORTC/MSG criteria, 7 patients were classified as probable cases of IPA, and one as a possible case. On the other hand, only 3/9 patients were admitted to the ICU and thus met the entry criteria for the IAPA definition and 2 were classified as probable cases of IAPA. (Table 2). Seven patients were infected by influenza virus A and 2 patients by influenza virus B. Five patients had influenza confirmed by PCR and 4 by a positive rapid respiratory antigen test and had a typical clinical presentation. The mean time from influenza diagnosis to positive aspergillus test in respiratory samples was 4.66 days (interquartile range (IQR) 0–9 days). The mean age of patients was 52.5 years (standard deviation [SD] 16.9). Four out of 9 patients were males. Six patients had underlying medical conditions classically considered risk factors for IPA, including malignancy under treatment. Three patients had no immune compromising conditions, but two of them had chronic lung disease. None of the patients had DM and one had CKD. Three patients were treated in ICUs, one of which required mechanical ventilation, with a length of ICU stay of 5, 5 and 23 days respectively. There were 5 patients who underwent bronchoscopy, all of which had a positive GM in BAL, 4 of which had a GM index ≥1.0. Two of those patients grew Aspergillus sp. from BAL culture in addition to sputum culture, however they had a negative GM in serum. A total of 5 Aspergillus isolates were cultured from 5 different patients. As mentioned previously, during the study period speciation of Aspergillus sp. was not available at our center. Among those who did not undergo bronchoscopy, 3 patients had an elevated serum GM >0.5 while 1 had a positive sputum culture for Aspergillus sp. None of the patients had evidence of ATB by bronchoscopy. All patients demonstrated radiologic abnormalities. One patient had a cavitary lesion on chest computed tomography (CT), 6 patients had dense circumscribed lesions, and none showed a halo sign (Table 2). Prednisone at a dose of 40 mg per day had been administered to 4/9 patients for an average duration of 3 days prior to the positive fungal results. All patients were treated with voriconazole at the recommended dose. Only one of the 9 patients died from respiratory failure during the hospital stay. Seven patients were treated with antibiotics for superimposed bacterial infections, mostly consisting of quinolones alone or in combination with extended spectrum beta-lactam antibiotics. Discussion This is the first case series from the Arab countries of the Middle East region describing the association between influenza pneumonia and pulmonary aspergillosis and providing added insight to the regional epidemiology of this disease. Our results demonstrated a low incidence of concurrent influenza infection and pulmonary aspergillosis (1.4%) in our hospitalized patients with influenza and a subsequent low mortality in these patients (1/9). Eight out of the 9 patients met the criteria for definitions set by the EORTC/MSG and/or the IAPA criteria, resulting in a cumulative incidence rate of only 1.2%. Two very recent systematic review/meta-analyses have been published; one summarizing the clinical characteristics of IAPA in critically ill patients, and the second in all hospitalized patients.[4, 13] Studies on hospitalized patients with a sample size >50 were included and all were observational except for one randomized control trial (RCT).[4] These studies were mostly conducted in Europe and China.[4] Therefore, more high-quality evidence needs to be generated globally, particularly in regions such as the Middle East and Africa in which there is a paucity of data. Our results demonstrated a very low incidence rate of IAPA in comparison to other published studies. This could partly be explained by the fact that we explored the incidence in all hospitalized patients, and not only those admitted to the ICU. Most studies reporting on the incidence of IAPA have focused on critically ill patients. The proportion of IAPA among this population varies across studies, with as high as 32% in immunocompromised individuals.Even in the non-immunocompromised, the reported incidence was 14% in the same study, including 7 ICUs from the Netherlands and Belgium.[6] However, other studies have also expanded the analysis to include all patients hospitalized for influenza (including those requiring ICU admission). One large scale study from the United States which analyzed 477,556 hospitalizations identified with the principal diagnosis of influenza, found that IAPA was diagnosed in 823 (0.17%) of total admissions. [14]Another study on the total number of influenza admissions in a Chinese institution showed an incidence rate of 5.4%.[15] One cohort study from Canada also found an incidence of 7.2% in ICU patients.[16] Thus, the rates of IAPA are variable according to the countries. Low rates could be partly due to underdiagnosis of aspergillosis probably from the lack of physicians’ awareness of the relationship between influenza and aspergillosis. This has been observed globally, with Thevissen et. al reporting that outside Europe, only a minority of physicians have heard of or diagnosed IAPA in the past 5 years (17% in the United States and 39% in other countries) and lower respiratory sampling were performed less often. Additionally, while 39% of respondents globally did take lower respiratory samples for microbiologic analysis, the majority of respondents (79%) rarely requested GM from BAL samples.[17] The unavailability and the cost of GM particularly in low and middle income countries might play a role in underdiagnosing IAPA. In the absence of a high degree of suspicion physicians may have opted not to pursue the diagnosis of IAPA especially given the low mortality rate in our patient population. Another possible explanation to the low incidence in our study is that our population of admitted influenza patients might be less sick than in other studies as AUBMC is a private hospital and not unfrequently patients are admitted for IV hydration and antipyretics, whereas conditions for admitting influenza patients might be stricter in other settings. The mean or median ages of hospitalized patients in pooled studies in a systematic review ranged from 52 to 65 years, and the proportions of males ranged from 50.6% to 69.3%.[4] Although we had a low number of patients, this was similar to our findings, where the average age was 52.5. Additionally, the systematic review done by Shi et al found that development of IAPA was significantly associated with a history of DM, COPD, and presence of EORTC/MSGERC host factors.[4] Our study also demonstrated a preponderance of IPA among immunocompromised patients. Only one case occurred in a patient with no risk factors. In our study, four patients were receiving steroids. In the meta-analysis on critically ill patients in particular, pooled studies comparing those with IAPA and no IAPA, showed that significantly more patients with IAPA were on chronic corticosteroids whereas there was no significant difference in pre-existing chronic lung diseases, DM and solid/hematological cancer. Thus, the concerning factors with IAPA despite the variations in prevalence, is the fact that it can manifest in patients without traditional risk factors for aspergillosis. Our population included mostly hospitalized non-critically ill patients and in general, this group of patients represents a challenge in classification, diagnosis as well as management. The EORTC/MSGERC consensus definitions in combination with the ICU working groups’ definition captured the most patients (7 out of 9, 77.7%) in this case series. Compared to the EORTC/MSGERC definitions, the IAPA definition is more useful in an immunocompetent patient population. However, restricting the inclusion criteria to critically ill patients limits its use in the larger demographic of non-critically ill patients who may still incur significant morbidity such as a prolonged hospital stay. Indeed, studies have shown that in both total hospitalized patients and those only admitted to the ICU, the mortality rate, use of mechanical ventilation, and length of hospital stay are significantly increased in patients with IAPA versus patients without IAPA.[4, 13] Though these results mostly stem from observational data, the available evidence does seem to suggest that infection with aspergillosis in patients with influenza is independently associated with mortality, and not just a marker of clinical severity. [18] Our results showed that the interval from the diagnosis of influenza to Aspergillus growth was on average 4.6 days and is consistent with other studies frequently demonstrating a median time to diagnosis of up to 5 days.[19-22] This relatively short interval suggests that the patient might have been colonized by Aspergillus sp. preceding hospital admission through inhalation of spores. Therefore, the environmental surroundings will incur a differential risk to each patient and can also be center specific given differences in ventilation systems. A recent systematic review summarized the available evidence on the diagnostic performance of the various definitions for the diagnosis of IPA in non-hematological, non-solid organ transplant, critically ill patients. There was significant heterogeneity across studies in terms of population, prevalence, used reference definitions for IPA, (non-standardized) ad hoc variations of reference definitions, limiting comparisons across studies.[23] A proven diagnosis of IAPA in both the EORTC/MSGERC and the IAPA definition requires invasive procedures, though experts generally agree that the distinction between proven and probable IAPA is more important for clinical trials rather than clinical practice.[8] A presumptive diagnosis of IAPA can therefore be established in a relatively easier and quicker manner. This is important to consider, since early initiation of antifungal treatment has been shown to improve outcomes in critically ill patients,[24] however more evidence should be generated to assess early treatment benefit in non-critically ill patients. In our study, all patients received voriconazole as the first line agent, which is the appropriate initial antifungal therapy for IPA as per guidelines.[24] There is uncertainty as to whether patients with influenza admitted to the ICU would benefit from prophylactic therapy against infection with Aspergillus sp.. One recent randomized control trial assessed posaconazole as a prophylactic agent. The majority of patients were diagnosed within 48 hours of ICU admission, excluding them from the modified intention-to-treat population, while in the remaining patients the incidence of IAPA was not significantly reduced compared to those receiving standard of care.[25] This study was limited by its retrospective nature, small sample size and single center experience. Additionally, some pulmonary aspergillosis cases could have been missed since diagnostic testing may not have been ordered if a physician did not suspect the diagnosis. We did not compare patients with influenza who developed pulmonary aspergillosis versus those who didn’t, which limits the ability to form associations of the different patient factors with outcomes. Conclusion Although influenza associated aspergillosis was less common in our study than reported elsewhere, the heterogeneity of incidence rates across studies published in the literature highlights the importance of conducting national and regional surveillance studies to better understand the epidemiological variations. Moreover, there are important differences between hospitalized patients on regular wards and those in the ICU, and the lack of data in the former group warrants more studies in order to optimize diagnosis and management in different patient populations. List of abbreviations: IAPA, Influenza-associated aspergillosis; ICU, Intensive care unit; IPA, Invasive pulmonary aspergillosis; GM, galactomannan; AUBMC, American University of Beirut Medical Center; RT-PCR, Reverse transcriptase polymerase-chain-reaction; DTA, Deep tracheal aspirate; BAL, Bronchioalveolar lavage; BDG, 1,3- β-D-Glucan; BMI, Body mass index; DM II, Type II diabetes mellitus; CKD, Chronic kidney disease; COPD, Chronic obstructive pulmonary disease; EORTC/MSG, European Organization for Research and Treatment of Cancer/Mycoses study Group; EORTC/MSGERC, European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium; ATB, Aspergillus tracheobronchitis; SARS-COV-2, Severe acute respiratory syndrome coronavirus 2; IQR, Interquartile range; SD, Standard deviation; CT, Computed tomography; NSLC, Non-small cell lung cancer ; BIPAP, Bi-level positive airway pressure; IFI, Invasive fungal infection; RCT, Randomized controlled trial. Declarations Authorship statement Fatima Allaw and Rozana El Eid contributed equally. Michel Almardini and Nabih Habib contributed equally. All authors validated the final version of record. Conflicts Of Interest The Author(s) declare(s) that there is no conflict of interest. Funding statement This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Registration No registration applicable. Data availability statement The data that support the findings of this study are available from the corresponding author upon reasonable request. Ethical approval The study was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. The study protocol was approved by the AUBMC institutional Review Board under number BIO-2019-0166. Patient consent was waived due to the retrospective nature of the study. References 1. Fischer JJ, Walker DH. Invasive pulmonary aspergillosis associated with influenza. JAMA. 1979;241(14):1493-4. 2. Duan Y, Ou X, Chen Y, Liang B, Ou X. Severe Influenza With Invasive Pulmonary Aspergillosis in Immunocompetent Hosts: A Retrospective Cohort Study. Front Med. 2021;7:602732. https://doi.org/10.3389/fmed.2020.602732. 3. Waldeck F, Boroli F, Suh N, Wendel Garcia PD, Flury D, Notter J, et al. Influenza-associated aspergillosis in critically-ill patients-a retrospective bicentric cohort study. Eur J Clin Microbiol Infect Dis. 2020;39(10):1915-23. https://doi.org/10.1007/s10096-020-03923-7. 4. Shi C, Shan Q, Xia J, Wang L, Wang L, Qiu L, et al. Incidence, risk factors and mortality of invasive pulmonary aspergillosis in patients with influenza: A systematic review and meta-analysis. Mycoses. 2022;65(2):152-63. https://doi.org/10.1111/myc.13410. 5. Patterson TF, Thompson GR, 3rd, Denning DW, Fishman JA, Hadley S, Herbrecht R, et al. Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;63(4):e1-e60. https://doi.org/10.1093/cid/ciw326. 6. Schauwvlieghe A, Rijnders BJA, Philips N, Verwijs R, Vanderbeke L, Van Tienen C, et al. Invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study. Lancet Respir Med. 2018;6(10):782-92. https://doi.org/10.1016/s2213-2600(18)30274-1 7. Donnelly JP, Chen SC, Kauffman CA, Steinbach WJ, Baddley JW, Verweij PE, et al. Revision and Update of the Consensus Definitions of Invasive Fungal Disease From the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium. Clin Infect Dis. 2019;71(6):1367-76. https://doi.org/10.1093/cid/ciz1008. 8. Verweij PE, Rijnders BJA, Brüggemann RJM, Azoulay E, Bassetti M, Blot S, et al. Review of influenza-associated pulmonary aspergillosis in ICU patients and proposal for a case definition: an expert opinion. Intensive Care Med. 2020;46(8):1524-35. https://doi.org/10.1007/s00134-020-06091-6. 9. Bassetti M, Azoulay E, Kullberg BJ, Ruhnke M, Shoham S, Vazquez J, et al. EORTC/MSGERC Definitions of Invasive Fungal Diseases: Summary of Activities of the Intensive Care Unit Working Group. Clin Infect Dis. 2021 Mar 15;72(Supplement_2):S121–7. https://doi.org/10.1093/cid/ciaa1751. 10. Hamam J, Navellou J-C, Bellanger A-P, Bretagne S, Winiszewski H, Scherer E, et al. New clinical algorithm including fungal biomarkers to better diagnose probable invasive pulmonary aspergillosis in ICU. Ann Intensive Care. 2021;11(1):41. https://doi.org/10.1186/s13613-021-00827-3. 11. Blot SI, Taccone FS, Van den Abeele AM, Bulpa P, Meersseman W, Brusselaers N, et al. A clinical algorithm to diagnose invasive pulmonary aspergillosis in critically ill patients. Am J Respir Crit Care Med. 2012;186(1):56-64. https://doi.org/10.1164/rccm.201111-1978OC. 12. Assaf-Casals A, Saleh Z, Khafaja S, Fayad D, Ezzeddine H, Saleh M, et al. The burden of laboratory-confirmed influenza infection in Lebanon between 2008 and 2016: a single tertiary care center experience. BMC Infect Dis. 2020;20(1):339. https://doi.org/10.1186/s12879-020-05013-7. 13. Chong WH, Saha BK, Tan CK. Clinical characteristics and outcomes of influenza-associated pulmonary aspergillosis among critically ill patients: a systematic review and meta-analysis. J Hosp Infect. 2022;120:98-109. https://doi.org/10.1016/j.jhin.2021.11.016. 14. Robinson KM. Mechanistic Basis of Super-Infection: Influenza-Associated Invasive Pulmonary Aspergillosis. J Fungi (Basel). 2022;8(5). https://doi.org/10.3390/jof8050428. 15. Zou P, Wang C, Zheng S, Guo F, Yang L, Zhang Y, et al. Invasive Pulmonary Aspergillosis in Adults With Avian Influenza A (H7N9) Pneumonia in China: A Retrospective Study. J Infect Dis. 2020;221(Suppl 2):S193-s7. https://doi.org/10.1093/infdis/jiz682. 16. Schwartz IS, Friedman DZP, Zapernick L, Dingle TC, Lee N, Sligl W, et al. High Rates of Influenza-Associated Invasive Pulmonary Aspergillosis May Not Be Universal: A Retrospective Cohort Study from Alberta, Canada. Clin Infect Dis. 2020;71(7):1760-3. https://doi.org/10.1093/cid/ciaa007. 17. Thevissen K, Jacobs C, Holtappels M, Toda M, Verweij P, Wauters J. International survey on influenza-associated pulmonary aspergillosis (IAPA) in intensive care units: responses suggest low awareness and potential underdiagnosis outside Europe. Crit Care. 2020;24(1):84. https://doi.org/10.1186/s13054-020-2808-8. 18. Rijnders BJA, Schauwvlieghe A, Wauters J. Influenza-Associated Pulmonary Aspergillosis: A Local or Global Lethal Combination? Clin Infect Dis. 2020;71(7):1764-7. https://doi.org/10.1093/cid/ciaa010. 19. Wauters J, Baar I, Meersseman P, Meersseman W, Dams K, De Paep R, et al. Invasive pulmonary aspergillosis is a frequent complication of critically ill H1N1 patients: a retrospective study. Intensive Care Med. 2012;38(11):1761-8. https://doi.org/10.1007/s00134-012-2673-2. 20. van de Veerdonk FL, Kolwijck E, Lestrade PP, Hodiamont CJ, Rijnders BJ, van Paassen J, et al. Influenza-Associated Aspergillosis in Critically Ill Patients. Am J Respir Crit Care Med. 2017;196(4):524-7. https://doi.org/10.1164/rccm.201612-2540LE. 21. Ku YH, Chan KS, Yang CC, Tan CK, Chuang YC, Yu WL. Higher mortality of severe influenza patients with probable aspergillosis than those with and without other coinfections. J Formos Med Assoc. 2017;116(9):660-70. https://doi.org/10.1016/j.jfma.2017.06.002. 22. Wu CJ, Cia CT, Wang HC, Chen CW, Lin WC, Lee JC, et al. Clinical and Microbiological Characteristics of Culture-Positive, Influenza-Associated Pulmonary Aspergillosis: A Single-Center Study in Southern Taiwan, 2016-2019. J Fungi (Basel). 2022;8(1). https://doi.org/10.3390/jof8010049. 23. Bassetti M, Giacobbe DR, Grecchi C, Rebuffi C, Zuccaro V, Scudeller L, et al. Performance of existing definitions and tests for the diagnosis of invasive aspergillosis in critically ill, adult patients: A systematic review with qualitative evidence synthesis. J Infect. 2020;81(1):131-46. https://doi.org/10.1016/j.jinf.2020.03.065. 24. Cadena J, Thompson GR, 3rd, Patterson TF. Invasive Aspergillosis: Current Strategies for Diagnosis and Management. Infect Dis Clin North Am. 2016;30(1):125-42. https://doi.org/10.1016/j.idc.2015.10.015. 25. Vanderbeke L, Janssen NAF, Bergmans D, Bourgeois M, Buil JB, Debaveye Y, et al. Posaconazole for prevention of invasive pulmonary aspergillosis in critically ill influenza patients (POSA-FLU): a randomised, open-label, proof-of-concept trial. Intensive Care Med. 2021;47(6):674-86. https://doi.org/10.1007/s00134-021-06431-0.
Lemierre Syndrome in a Pediatric Patient with Nephrotic Syndrome: a Case Report
Lemierre syndrome is a rare thrombotic complication of head and neck infections. Nephrotic syndrome is sometimes treated by immunosuppressive medications that can present with severe infections without a fever. The association of the two diseases is extremely rare. We report the first case, to our knowledge, of Lemierre syndrome in an eleven-year-old patient with nephrotic syndrome on Tacrolimus. A patient with nephrotic syndrome is at higher risk for all kinds of thrombotic events. Also, being on immunosuppressive therapy can lead to late presentation and the absence of fever. A low level of suspicion in those patients can lead to timely diagnosis and early treatment. Key Messages: Ø What is already known on this topic – Nephrotic syndrome is a thrombophilic condition and Lemierre syndrome is a rare complication of head and neck infections. Ø What this study adds – We report the first case of Lemierre syndrome, to our knowledge, occurring in a child with nephrotic syndrome on immunosuppressive therapy. Ø How this study might affect research, practice, or policy – Patients of immunotherapy and with nephrotic syndrome might be at a higher risk of developing Lemierre syndrome. Introduction Lemierre syndrome (LS) is a rare complication of head and neck infections in the pediatric population. Classically the syndrome consists of suppurative thrombophlebitis of the internal jugular veins secondary to infection of the oropharynx with Fusobacterium necrophorum bacteremia (1). The bacterial pharyngitis is usually seen with peritonsillar abscess which can rupture and spread to the carotid sheath that contains the internal carotid artery and internal jugular vein. This leads to seeding of the internal jugular vein with bacteria and the formation of thrombophlebitis which can then spread systemically. Typical presentation includes recent oropharyngeal symptoms which may resolve followed by progression to high fever, headache, neck pain, and respiratory symptoms (2). Infection may occur in previously healthy children and in individuals with chronic conditions such as systemic lupus erythematosus and antiphospholipid syndrome (3). Nephrotic syndrome (NS) is defined as proteinuria of > 3 g/day and hypoalbuminemia (<30 g/L). The protein loss leads to loss in Immunoglobulins which predisposes patients to infections. NS is also associated with hypercoagulability and patients are at increased risk of venous thrombosis. The incidence of venous and arterial thromboembolism is low in children occurring in only 2-3% of cases (4). Only one pediatric case report of thrombosis of the internal jugular vein in a child with NS without any evidence of infection, has been published (5). After a literature review using MeSH and keywords (Lemierre syndrome, NS, thrombophlebitis) in PubMed, we report the first case of LS, to our knowledge, occurring in a child with NS on immunosuppressive therapy. Case presentation 11-year-old boy, known for NS treated with Tacrolimus, presented for headache and neck pain of 2 weeks duration with decreased oral intake and urine output. He had previously sought medical attention twice but was diagnosed with muscular neck sprain and discharged home. His symptoms progressed and he was brought to the emergency department. At triage, the patient was in severe pain, appeared uncomfortable and was found to have a stiff neck. He was afebrile and his vital signs were normal. On further history and physical exam, the boy looked tired and was complaining of occipital headache and sore throat. The patient had a muffled voice and right sided peritonsillar swelling. Laboratory tests showed a white blood cell count of 14100 cells/microliter with 82.9% neutrophils, high C-Reactive Protein of 122 mg/L (12.2 mg/dL) and 0.3 g/L of protein in the urine, the other tests including electrolytes were normal. Computed tomography angiogram was obtained and showed a large retropharyngeal abscess with acute thrombosis of the proximal third of the right intrajugular vein (Fig. 1). The patient was started on piperacillin tazobactam and sent to the operation room for emergent drainage. After the drainage, the patient was started on anticoagulation, but his stay was complicated by reformation of the abscess that required repeat incision and drainage. He was discharge home on day 8 of admission with close follow up with ENT. Discussion We describe the first known case of LS in a patient with NS. Despite reduction in mortality from LS with antimicrobial therapy (6), there are reports of increasing rates of F necrophorum infections (1) and clinicians need to be aware of this aggressive infection as early diagnosis and therapy is critical. There are several published case studies over the past years that report cases of LS in previously healthy individuals and associated thrombosis in different sites, including lungs, bones, and brain. Also, LS was described in patients with different medical conditions including systemic lupus erythematosus, different types of arthritis among others (7, 8). The emergency physician should have a low threshold for LS in any patient with such conditions presenting with neck pain, sore throat, fever, or high inflammatory markers to the emergency department. LS has been reported in all ages, but approximately 70% of the documented cases were in adolescents and young adults between 16-25 years old. Typically, patients present with infection in the oropharynx, fever, neck stiffness, cervical lymphadenopathy which invades the lateral pharyngeal space leading to serious complications. Fusobacterium necrophorum is the most common cause of LS. It is an anaerobic, nonmotile, pleomorphic, gram-negative bacillus that exists in normal oral flora. It becomes pathogenic when there is a break in the oral mucosa with infections such as pharyngitis. The pathophysiology of the thrombotic events in LS remains unclear. Some studies attribute it to underlying inherited thrombophilia whereas in other cases, it is believed to be caused by a cascade of enzymes activities triggered by the bacteria. The thrombotic process caused by fusobacterium is multifactorial. Like any thrombosis event, it is mainly the result of Virchow’s triad: systemic hypercoagulability, venous stasis by vessel occlusion caused by inflammation, and endothelial damage by the direct endovascular invasion of the bacteria. F necrophorum consists of multiple virulence factors, including lipopolysaccharide endotoxin, leucocidin, hemolysin, lipase, hemagglutinin, and a cytoplasmic toxin, all contribute to the thrombotic process. These enzymes may produce endothelial damage and diffuse intravascular coagulation by promoting platelet aggregation in an anaerobic environment, which also permits F necrophorum to grow (9). In our case, the patient is known for NS, he was at higher risk of developing complications of LS. As it is commonly known, NS is defined by increased urinary protein losses, edema, hypoalbuminemia, hyperlipidemia, and can be complicated by infectious and thromboembolic manifestations. The pathogenesis of platelet hyperaggregability and its association with NS has been widely reported throughout the years. It is reported that hypoalbuminemia leads to increased thromboxane A2 production in platelets, which trigger platelet aggregation. Also, increased levels of low-density lipoprotein may induce platelet aggregation (4). Patients with NS characteristically lose plasma proteins in the urine (factors IX, X, and XII, prothrombin, antithrombin, and α2-antiplasmin), which inhibit the systemic hemostasis. On the other hand, high molecular weight proteins are exceedingly synthesized and primarily promote thrombosis. These proteins include factor V, factor VIII, von Willebrand factor, fibrinogen, and α2-macroglobulin accumulate. Factor VII has an essential role in starting the coagulation cascade. It is shown that increased factor VIII led to an increase in the risk factor for thromboembolism in nephrotic patients (10). So, with all these factors, a patient with NS is at higher risk for all kinds of thrombotic events, especially that our patient was also on immunosuppressive therapy which can explain his late presentation and the absence of fever. Conclusion We describe a case of LS in a child with NS. LS is a rare disease that has a high morbidity and mortality if not diagnosed and treated early. Patients with NS are at higher risk for thrombotic event including thromboembolism of the internal jugular vein. A low level of suspicion in those patients can lead to timely diagnosis and early treatment. Declarations Author contributions All authors contributed equally and validated the final version of record. Conflicts Of Interest The Author(s) declare(s) that there is no conflict of interest. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Registration No registration applicable Data availability statement The data that support the findings of this study are available from the corresponding author upon reasonable request. Ethical approval Ethical approval for this study was not required. References 1. Ramirez S, Hild TG, Rudolph CN, Sty JR, Kehl SC, Havens P, et al. Increased diagnosis of Lemierre syndrome and other Fusobacterium necrophorum infections at a Children's Hospital. Pediatrics. 2003;112(5):e380. https://doi.org/10.1542/peds.112.5.e380 2. Lu MD, Vasavada Z, Tanner C. Lemierre syndrome following oropharyngeal infection: a case series. J Am Board Fam Med. 2009;22(1):79-83. https://doi.org/10.3122/jabfm.2009.01.07024 3. Cho YP, Choi SJ, Jung BH, Hwang JW, Han MS, Kim YH, et al. Lemierre's syndrome in a patient with antiphospholipid syndrome. Ann Vasc Surg. 2006;20(2):274-7. https://doi.org/10.1007/s10016-006-9004-4 4. Kerlin BA, Ayoob R, Smoyer WE. Epidemiology and pathophysiology of nephrotic syndrome-associated thromboembolic disease. Clin J Am Soc Nephrol. 2012;7(3):513-20. https://doi.org/10.2215/cjn.10131011 5. Vyas V, Kapoor S, Panda M, Mandal Ravi RN. Thrombosis of internal jugular vein in nephrotic syndrome presenting as neck pain. Indian J Pediatr. 2012;79(10):1388. https://doi.org/10.1007/s12098-012-0705-0 6. Screaton NJ, Ravenel JG, Lehner PJ, Heitzman ER, Flower CD. Lemierre syndrome: forgotten but not extinct--report of four cases. Radiology. 1999;213(2):369-74. https://doi.org/10.1148/radiology.213.2.r99nv09369 7. Fujii T, Iwabuchi Y, Moriyama T, Uchida K, Nitta K. A case of Lemierre syndrome combined with a suspected systemic lupus erythematosus flare. SAGE Open Med Case Rep. 2019;7:2050313X19871782. https://doi.org/10.1177/2050313x19871782 8. Hagiya H, Haruki Y, Otsuka F. Lemierre syndrome involving external jugular vein. Acute Med Surg. 2015;2(1):64-8. https://doi.org/10.1002/ams2.61 9. Tan ZL, Nagaraja TG, Chengappa MM. Fusobacterium necrophorum infections: virulence factors, pathogenic mechanism and control measures. Vet Res Commun. 1996;20(2):113-40. https://doi.org/10.1007/bf00385634 10. Cristina L, Benilde C, Michela C, Mirella F, Giuliana G, Gualtiero P. High plasma levels of factor VIII and risk of recurrence of venous thromboembolism. Br J Haematol. 2004;124(4):504-10. https://doi.org/10.1046/j.1365-2141.2003.04795.x
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Heart rate, a poor predictor of Pulmonary Embolism
Objective: To determine if there is a significant difference in vital signs between patients with confirmed and excluded pulmonary embolism (PE) throughout their Emergency Department presentation. Methods: We conducted a retrospective cohort study with patients presenting with suspected PE to Monash Health Emergency Departments between July 2014 and July 2019. Vital signs were compared between patients with confirmed or excluded PE as determined by imaging (CTPA or VQ). Vital signs were compared at three unique data points: initial, minimum, and maximum values. Results: 3549 patients met inclusion criteria, 922 with confirmed PE and 2627 with excluded PE based on CTPA or VQ. Patients with PE had significant elevations in mean respiratory rates, systolic blood pressures and reduced oxygen saturations compared to patients without PE. Heart rate was not significantly different at initial and maximum datapoints. Conclusion: Vital signs were demonstrated to be poor predictors of acute PE. Receiver operating characteristic curve analysis suggests that heart rate has poor discriminative power. AUC values for heart rate were: 0.516 (initial), 0.549 (maximum) and 0.519 (minimum). Furthermore, 95% of patients with confirmed PE did not exceed heart rates of 100 BPM during presentation to Emergency. The utility of elevated heart rate and other vital signs in predicting PE were not substantiated in this study. Introduction A pulmonary embolism (PE) refers to a blockage in the lung’s arterial network due to the migration of clot material (1-2). Although uncommon, with a reported incidence of 60 to 70 per 100,000, mortality rates can range from up to 1% for small PEs, and between 18 to 65% in massive PEs (1). Patient with suspected PE report symptoms of dyspnoea, haemoptysis, and pleuritic chest pain. On examination, patients may also exhibit abnormal vital signs, such as tachycardia (3,4), tachypnoea (5) and hypotension (5, 6). 20 per cent of patients with suspected PE return positive diagnoses, hence, the diagnostic workflow for PE must employ safe, timely and primarily non-invasive methods (7). Definitive investigations for PE may include a ventilation-perfusion scintigraphy (V/Q scan) or computed tomography pulmonary angiography (CTPA) (2). To minimise inappropriate use, risk stratification tools are utilised to exclude PE in low-risk patients. These include the Wells’ criteria, revised Geneva score (rGeneva) and PERC rule, all of which employ vital signs to stratify risk of PE (8-11). The Wells’ criteria have been validated in numerous clinical settings to provide an estimated pre-test probability and risk stratification for PE – assisting clinicians in selecting appropriate investigations (10). To establish pre-test probability, the Wells’ criteria allocate points to clinical factors, such as tachycardia (>100 BPM) and evidence of deep vein thrombosis (DVT) (12). The rGeneva similarly quantifies risk but enables a finer level of stratification by ascribing greater weight to heart rates (HR) exceeding 95 BPM, compared to 75-94 BPM. The PERC rule increases suspicion for PE in patients with HR greater than 100 BPM and oxygen saturations less than 95 per cent (8). However, a meta-analysis demonstrated the inadequacy of these scores in the final exclusion of PE (13). Non-specific tachycardia in emergency department (ED) patients has reportedly led to false positive screening and unnecessary diagnostic tests (14, 15). Despite associations between abnormal vital signs and PE, these derangements are unpredictable, transient, and may even normalise during an ED stay. Thus, for a theoretically accurate stratification of risk, vital signs need to be robust and persistent, suggesting potentially limited clinical utility. Mortality rates in patients with confirmed PE can be estimated with the Pulmonary Embolism Severity Index (PESI) and BOVA score (16, 17). These tools utilise vital signs to inform the necessity of inpatient management. The BOVA score utilises HR and systolic blood pressure (SBP), whilst the PESI utilises HR, SBP, respiratory rate (RR), temperature, and oxygen saturation (16, 17). These scores also rely on the persistence of deranged vital signs, which suggests that they are a potentially inaccurate representation of a patient’s evolving clinical state. Hence, appraising these scores against the stability and trend of a patient’s vital signs is necessary. The adoption of the D-dimer was thought to revolutionise the diagnostic approach for PE and reduce unnecessary diagnostic imaging. However, as the D-dimer has inherently low specificity and excellent sensitivity, there is potential for false positivity that has been criticised in the literature (18-20). There is an evolving body of research focused on advancing and optimising the diagnostic approach for PE, resulting in novel technologies, such as focused cardiac ultrasound. However, current practice continues to place significance on vital sign derangements, which could potentially impede development of novel clinical approaches (21). The impact of PE on vital sign derangements are diverse and unpredictable, due to the marked variation of emboli size and obstructive location (22). Smaller emboli may remain asymptomatic, while larger and more proximal emboli may result in striking changes to a patient’s clinical state, with acute hypotension, tachycardia, and reduced saturation (3, 4, 22, 23). Considering the heterogeneity of PE presentations, an evaluation of the clinical utility of vital signs is prudent. Methods Population and study design This retrospective cohort study included adults investigated for PE attending Monash Health EDs from July 2014 to July 2019. Monash Health is in south-east Melbourne, with approximately 230,000 annual presentations across several institutions. This study was approved by Monash Health and the Monash University Human Research and Ethics Committees (Ref: RES-19-0000-535Q). Selection Eligible cases were identified through Emergency medical records (Symphony, EMIS Health, Leeds, UK) by filtering for patients who were suspected and investigated for a PE between July 2014 to July 2019. The rationale to perform confirmatory imaging with VQ or CTPA was based on risk stratification on clinical presentation, vital signs, and pertinent risk factors. Patients deemed low risk, as established by a PERC rule score of 0, did not undergo imaging. Patients deemed moderate risk, commonly had D-dimer levels measured, where normal levels did not necessitate imaging, and elevations were consequently investigated. Patients deemed high risk all underwent confirmatory imaging to further investigate PE. To supplement the study population, data was extracted from two datasets of patients presenting to Monash Health EDs between July 2014 to July 2019. The first dataset included patients with a provisional diagnosis of PE on presentation, who were then risk stratified and investigated with VQ or CTPA imaging if deemed appropriate. The second dataset of patients included those who underwent VQ scans to rule out a diagnosis of PE, where CTPA was contraindicated. Duplicate entries were collated. Patient were excluded if they did not undergo confirmatory imaging. Data gathered during presentations included age, gender, presenting complaint, vital signs, provisional diagnosis, confirmed diagnosis, tests ordered and subsequent results. Reported vital signs included: HR, RR, SBP, oxygen saturation and temperature. Patients with confirmatory imaging (VQ scans or CTPA) and serum biomarkers (D dimer) were identified. Patient imaging was retrieved from Carestream (Carestream Radiography Software, Carestream Health, Inc, Rochester, NY). Patients were excluded if any of the following criteria were applicable: incomplete or missing vital signs, repeat presentations for a previously diagnosed PE, self-discharge against medical advice without investigation, death prior to imaging, having PE diagnosed in a non-Monash Health hospital, or having a history of known chronic PE. Following exclusion, eligible patients with a confirmed PE diagnosis via CTPA or VQ were compared to those with excluded PE. This is summarised in Figure 1. Statistical analysis Observations that were recorded included: HR, SBP, RR, oxygen saturation and temperature. For each vital sign, the following datapoints were recorded: initial observations at presentation, the highest recorded observation, and the lowest recorded observation. The Shapiro-Wilk test was employed, with any non-normal data logarithmically transformed. The difference in mean vital signs between patients with confirmed PE and excluded PE were analysed at the corresponding initial, maximum and minimum datapoints using the Mann-Whitney U Test. The difference in means between sex (Male or Female) and age (Age > 50 or Age < 50) groups were also conducted. A value of p < 0.05 was considered statistically significant. An Area Under the Receiver Operating Characteristic curve (AUC-ROC) approach was utilised to appraise the discriminative power of the following observations: HR, BO, O2 saturation and RR. Computational statistical analysis was completed using IBM® SPSS® Statistics (v27). Results A total of 3,549 patients met inclusion criteria; 684 (19.27%) were diagnosed with PE through CTPA, and 238 (6.71%) were diagnosed through VQ scan. Patients with negative PE on confirmatory imaging formed the control group 2627 (74.02%). 272 (7.66%) patients had PE excluded on CTPA and 2355 (66.36%) were excluded on VQ scan. Patients with confirmed PE had significantly higher mean HR than patients with excluded PE at the minimum data point: 73.80 (15.26) versus 71.04 (13.02), p < 0.001 (Table 1,2). The difference in means at maximum HR, 97.92 (19.43) versus 97.01 (18.46), p = 0.153, and initial HR, 92.95 (19.88) versus 92.06 (19.85), p = 0.181, were not significant (Table 1,2). Mean SBP, RR and O2 saturations were all significantly different in patients with confirmed PE compared to those with excluded PE at initial, maximum, and minimum datapoints (Table 2). Mean temperature was significantly different at maximum and minimum data points between the two groups (Table 2). Mean HR was significantly higher in female patients with confirmed PE compared to males at the minimum data point only (Table 3). Mean temperature was significantly higher in female patients with confirmed PE compared to males at the initial, maximum, and minimum data points (Table 3). Oxygen saturation was significantly higher in female patients with confirmed PE compared to males at maximum and minimum data points (Table 3). Mean HR was significantly lower in patients aged > 50 years with confirmed PE, compared to patients < 50 years at the initial and maximum data point (Table 4). Mean SBP was significantly higher in patients aged > 50 years with confirmed PE, compared to patients < 50 years at the initial, maximum, and minimum data points (Table 4). Mean RR was significantly higher in patients aged > 50 years with confirmed PE, compared to patients <50 years at the minimum data point (Table 4). Mean oxygen saturation was significantly lower in patients aged > 50 years with confirmed PE, compared to patients <50 years at the initial, maximum, and minimum data points (Table 4). An Area Under the Receiver Operating Characteristic Curve (AUC-ROC) approach was employed to determine the discriminative power of HR, SBP, RR and oxygen saturation in predicting PE (Figure 2) (Table 5). The AUC for mean HR was 0.516 (initial), 0.549 (maximum) and 0.519 (minimum). The AUC for mean SBP was 0.568 (initial), 0.605 (maximum) and 0.569 (minimum). The AUC for mean RR was 0.339 (initial), 0.346 (maximum) and 0.313 (minimum). The AUC for mean oxygen saturation was 0.559 (initial), 0.598 (maximum) and 0.557 (minimum). Discussion Our study demonstrates that HR is not statistically different at initial (p = 0.181) and maximum (p = 0.153) data points between patients with confirmed and excluded PE (Table 1,2). While the minimum data point was significantly different (p < 0.001) between groups, ROC analysis suggests that HR has poor discriminative power and predicts PE slightly better than chance, with AUC values of 0.516 (initial), 0.549 (maximum) and 0.519 (minimum) (Table 5). Thus, while these differences between groups are statistically significant, they are not clinically useful. The effectiveness of other vital signs in predicting acute PE were also poor. The corresponding AUC values were: 0.568 (initial), 0.605 (maximum) and 0.569 (minimum) for SBP, 0.339 (initial), 0.346 (maximum) and 0.313 (minimum) for RR, and 0.559 (initial), 0.598 (maximum) and 0.557 (minimum) for oxygen saturation. This study also determined that 95% of all patients with confirmed PE at Monash Health EDs have a maximum HR between the values of 96.64 and 99.19 BPM (Table 1). This suggests that most patients in the study population with confirmed PE would not satisfy the HR component of the Wells’, PERC, PESI and BOVA risk stratification tools (8-11,16,17). Furthermore, patients with confirmed PE that were >50 years of age had a significantly lower mean HR at initial, maximum, and minimum data points compared to patients <50 years of age (Table 4). This may indicate that an increase in age of greater than 50 years further reduces the efficacy of HR in predicting acute PE. Our study suggests that the use of HR >100 or >110 BPM, in several risk stratification tools does not reliably or strongly predict acute PE. In agreement with our findings, a cohort study by Meneveau et al. (24), found that HR >100 BPM in patients with confirmed PE was not an independent predictor of adverse outcomes such as inpatient death, bleeding, or recurrent PE. Specifically, in all adverse events HR >100 BPM was found in 55% of patients, whilst in cases without adverse events, HR >100 BPM was found 42% of patients (p = 0.11) (24). Similarly, Wicki et al. (25) found that patients with confirmed PE with HR >100 BPM compared to those with HR <100 BPM had no significant difference in adverse outcomes (p = 0.051). While our study suggests that higher cut offs are not predictive of PE, a study by Keller et al. (26), found that a HR value of 86 BPM may acceptably predict right ventricular dysfunction in acute PE (AUC = 0.706). This study has several strengths and limitations. The strengths include the large population size, multi-centre study design and age and sex subgroups. The main limitation is the retrospective and observational nature of our study and the inability to follow up patient outcomes. In our data collection process, our study design did not account for patients that were negative for PE by imaging, but subsequently died from misdiagnosed PE – this diagnostic outcome would benefit from analysis in future studies. Our study has the potential for measurement error in obtaining vital signs, due to variation in technique, equipment, and personnel. Conclusion Differences in vital signs between patients with confirmed and excluded PE were inconsistently significant and poor clinical predictors of acute pathology. This study suggests that the utilisation of elevations in HR of >100 and >110 BPM within risk stratification tools are potentially poor predictors of acute PE. Future investigations into lower HR thresholds, as well as considering age in risk stratification could prove to be beneficial in optimising the diagnosis and prediction of PE. Declarations Author contributions All authors contributed equally and validated the final version of record. Conflicts Of Interest The Author(s) declare(s) that there is no conflict of interest. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Registration No registration applicable Data availability statement The data that support the findings of this study are available from the corresponding author upon reasonable request. Ethical approval This study was approved by Monash Health and the Monash University Human Research and Ethics Committees (Ref: RES-19-0000-535Q). References 1. Bĕlohlávek J, Dytrych V, Linhart A. Pulmonary embolism, part I: Epidemiology, risk factors and risk stratification, pathophysiology, clinical presentation, diagnosis and nonthrombotic pulmonary embolism. Exp Clin Cardiol. 2013;18(2):129-38. 2. Lavorini F, Di Bello V, De Rimini ML, Lucignani G, Marconi L, Palareti G, et al. Diagnosis and treatment of pulmonary embolism: a multidisciplinary approach. 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Association between septic shock prehospital hemodynamic parameters improvement and 28-day mortality
Objective: The early hemodynamic optimization of septic shock patients is a cornerstone of care to hope for a better outcome, e.g., mortality decrease. However, in the prehospital setting, hemodynamic evaluation is restricted to micro and macrocirculatory clinical parameters. This study aims to assess the relationship between micro and macrocirculatory hemodynamic parameters improvement and 30-days mortality among septic shock patients being taken care of for by a mobile intensive care unit (mICU) in the prehospital setting. Methods: We performed a retrospective multicenter study, from January 2015 to November 2019 including septic shock patients requiring pre-hospital mICU intervention. Results: Three hundred thirty-seven patients were analyzed. The mean age was 69 ± 15-years-old and 226 of which 67% were male patients. One hundred thirty-six patients (40%) had previous hypertension. Pulmonary infection was the main cause of septic shock (46%) and 30-days mortality reached 30%. After propensity score analysis, for the macrocirculation: when systolic blood pressure increased by at least 30mmHg the odd ratio (OR) for 30-days mortality was 0.77 [0.65-0.84], when diastolic blood pressure increased by at least 5mmHg, the OR for 30-days mortality was 0.95 [0.88-0.99], when mean blood pressure increased by at least 30%, the OR for 30-days mortality was 0.88 [0.77-0.92] and when the heart rate decreased by at least 30 bpm, the OR for 30-days mortality was 0.62 [0.55-0.76]. For microcirculation, when the mottling score decreased by at least 2 points, the OR for 30-days mortality was 0.83 [0.75-0.91]. Conclusion: In this study, we report that prehospital improvement in micro and macrocirculatory parameters are associated with 30-days mortality rate decrease. Introduction Each year, 30 million people worldwide [1–3] suffer from sepsis, leading to around 11 million deaths [3] approximately one third of in-hospital deaths [4]. Sepsis mortality rate varies from 10 to 20% for sepsis and even up to 50% - 60% for septic shock, the most severe form of sepsis [5–7]. Among the factors that have made it possible to improve patient survival, we find early diagnosis, early referral to an appropriate facility, and the implementation of adequate therapies [8]. A comprehensive management strategy combining the above factors, "bundle of care", has proven its effectiveness in improving the outcome of septic shock [8–15]. The management of sepsis requires a dynamic approach constantly adapted to the severity of the patient [16,17]. For the more serious forms, the more rapid and aggressive management is the most effective [18]. Previous studies have identified that 70% of sepsis are present before arrival at the hospital, justifying the need to implement early diagnostic and therapeutic strategies from prehospital care [19]. From a pathophysiological point of view, a sufficient tissue perfusion pressure, assessed by mean arterial pressure (MAP), is necessary for antibiotic therapy to diffuse in infected tissues [18,20]. Obtaining a correct MAP requires hemodynamic optimization, including vascular filling in the first hours, even norepinephrine administration if necessary [8]. Hypertension is associated with mortality and morbidity rise [21]. In addition, hypertension is the main medical diagnosis in patients with septic shock [22]. A recommended target MAP of 65 mmHg is probably not suitable for all patients with chronic hypertension [8,23–25]. The aim of this retrospective observational study was to assess the relationship between hemodynamic parameters improvement during the pre-hospital phase of septic shock and 30-days mortality rate after hospital admission. Patients and methods The specificity of the French out-of-hospital emergency and care system is based on the French prehospital emergency system; the SAMU (Service d’Aide Medicale Urgente). The SAMU organization allows prehospital care equivalent to an intensive care unit by an emergency physician and a nurse. In the context of septic shock, fluid volume expansion, norepinephrine administration and antibiotic therapy can be addressed in the prehospital setting according to the recommendations [26]. We performed a retrospective, multicenter study, from January 2015 to November 2019, including patients with septic shock, treated in prehospital setting by a mICU team from Toulouse hospital, Necker hospital, Lariboisière, Pitié Salpêtrière hospital, Hôtel Dieu and Paris Fire Brigade. The patients received care according to the recommendations of the protocols and habits of the pre-hospital and hospital teams. The patients included in the study were those treated by a mICU team for prehospital septic shock, according to the definition of the “sepsis 3” conference in 2016 [17]. Underage patients, deprived of their liberty, under guardianship or curatorship as well as pregnant women were not included in the study. The data analyzed included demographic data (age, weight, height), medical history, current treatments, suspected origin of sepsis, and schedules related to the pre-hospital care phase (time of call from the SAMU, time of arrival on site of the mICU team and time of arrival at the hospital), the data of the clinical examination collected at the initial stage of the prehospital setting (1st contact with the patient) and at the end of the pre-hospital phase (last values before hospital admission) - heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP), pulsed oxygen saturation (SpO2), respiratory rate (RR), Glasgow coma scale (GCS), body core temperature, capillary blood sugar, capillary refill time, skin mottling score [27] - and lactatemia at the start of pre-hospital. Skin mottling score is a clinical score ranging from 0 to 5 associated with sepsis-outcome. The data describing the treatments administered were also collected (vascular filling (products, volume), use of vasopressors (products, dosage), mechanical ventilation parameters if applicable, antibiotic therapy (qualitative and quantitative). IGS II, SAPS II and SOFA scores were calculated from hospital data on day 1 [28,29]. These scores are used to predict sepsis outcome among patients admitted in ICU. The study was approved by the ethics committee of the French Society of Anesthesia and Resuscitation on December 12, 2017 (reference number: IRB 00010254-2017-026). Statistical analysis The primary outcome was the 30-days mortality after hospital admission. The absolute variations (initial value in the prehospital setting – final value before hospital admission) of SBP, DBP, MAP and HR were calculated in order to evaluate the treatment effect on the macrocirculation. An increase of 30 mmHg of SBP, 5 mmHg of DBP and 30% MAP as well as a decrease of 30 beats per minute during pre-hospital care, were chosen at the beginning because of their clinical relevance representing the positive effect on hemodynamic treatment of septic shock. For microcirculation, an absolute variation in the mottling score of at least 2 points was considered to be significantly representative of a positive treatment effect of pre-hospital hemodynamic management of septic shock. The components of the hemodynamic treatment, vascular filling and/or administration of norepinephrine, were not analyzed individually but as a whole, given the absence of protocolization (possibility of using one and/or other therapies left to the discretion of the team in charge of the patient). Univariate and multivariate analysis were performed to assess the relationship between each covariate and 30-days mortality. The results are expressed as an absolute value with relative percentage for the qualitative variables, as a mean with standard deviation for the quantitative variables of normal distribution and as a median with interquartile range (1st quartile - 3rd quartile) for the quantitative variables of non-Gaussian distribution. Univariate analysis comparisons were made using Student's t-test for quantitative variables of normal distribution, Wilcoxon's test for continuous variables of non-Gaussian distribution, and Chi-square test for categorical variables. In order to reduce the potential effect of confounding covariates on the relationship between 30-days mortality and changes in SBP, DBP, MAP, HR and mottling score, a propensity score analysis was performed. The propensity score was estimated using a logistic regression based on confounding covariates on 30-days mortality: pre-hospital duration, vascular filling volume, norepinephrine infusion, initial values of SBP, DBP, MAP, HR, and skin mottling score. The “nearest neighbor matching” method was used to match patients from the logit of the propensity score [30]. A threshold of 10% of the absolute differences of the means was used to estimate the balance of covariates after matching [31]. After matching, the association between 30-days mortality and micro and macrocirculation parameters was evaluated by logistic regression. The tests performed are two-sided with a p-value <0.05 defining the significance of the difference. Statistical analyzes were performed using R software version 3,4,2 (http://www.R-project,org; the R Foundation for Statistical Computing, Vienna, Austria). Results In this study, 337 patients with septic shock, according to the definition of the consensus conference “sepsis 3” of 2016, were retrospectively analyzed [17]. Global characteristics of the population are summarized in Table 1. Suspected origin of septic shock during pre-hospital care was mainly pulmonary (n=153, 46%), digestive (n=78, 23%) and urinary (n=52, 15%). Univariate analysis The results of the univariate analysis are summarized in Table 2. Multivariate analysis After matching by propensity score, the association between 30-days mortality and micro and macrocirculation parameters were evaluated by logistic regression. The balance of covariates after matching is represented by Figures 1, 2, 3, 4 and 5 for SBP, DBP, MAP, HR and skin mottling score respectively. * Micro-circulation For microcirculation, when the skin mottling score decreased by at least 2 points, then the OR of death at D30 was 0.83 [0.75-0.91]. * Macro-circulation Thus, for macrocirculation, between the start and the end of pre-hospital care: - when the SBP increased by at least 30mmHg then the OR of death on D30 was 0.77 [0.65-0.84], - when the DBP increased by at least 5mmHg then the OR of death on D30 was 0.95 [0.88-0.99], - when the MAP increased by at least 30% then the OR of death on D30 was 0.88 [0.77-0.92], - when the HR decreased by at least 30 beats per minute then the OR of death at D30 was 0.62 [0.55-0.76]. Discussion In this study, we observed that the improvement in the micro and macrocirculatory hemodynamic parameters of patients with septic shock treated in pre-hospital setting by a mICU team is associated with a 30-days mortality decrease. Indeed, data from previous studies had reported that circulatory, clinical or biological failures are associated with worsening of the patient [32–36]. From a pathophysiological point of view, the inflammation caused by sepsis is associated with vasodilation and vascular permeability as reflected by micro and macrocirculatory parameters [37]. In prehospital setting, only clinical parameters are available to assess the micro and macrocirculatory. For macro-circulation, MAP being considered to reflect tissue perfusion, the importance of maintaining or restoring it to reduce the occurrence or worsening of organ failures appears essential. Since invasive monitoring is rarely possible in pre-hospital, a non-invasive MAP measurement is the only one that can be used in pre-hospital. For microcirculation, the advisability of considering clinical parameters as a therapeutic target has already been reported for skin mottling score and capillary refill time [38]. For optimal management, the "sepsis 3" conference of 2016 [17], recommends a fluid volume expansion initiated in the first hours, followed by the administration of norepinephrine even if the MAP remains below 65 mmHg [8,17]. However, recent studies show the benefits of using norepinephrine earlier in order to reduce the time to target MAP and improve survival [39–41]. A MAP target of 65 mmHg for all patients without taking into account their personal history does not appear physiologically logical. Indeed, among patients suffering from, pathophysiological changes aim to allow adaptation to the higher blood pressure regimen [42–44]. Previous studies have reported the benefit of a higher blood pressure target in hypertensive population without altering heart function [45–47], microcirculation [48] and kidney function [23]. Thus, Lee et al. reported that a MAP target between 75 and 85 mmHg is associated with increased survival in hypertensive patients with septic shock [49]. In addition, it has been reported that the shorter the duration of the period of low blood pressure, e.g., hypoperfusion, the better is the survival [50]. However, this study has limitations. First, this is a retrospective study. Second, the study was conducted in an adult population exclusively; therefore, the results cannot be extrapolated directly to a pediatric population. Third, the external validity is low due to the specificity of the French pre-hospital emergency medical system. Fourth, the study population is represented by septic shock, therefore the results cannot be extrapolated to non-septic shock patients, i.e., sepsis. Nevertheless, the micro and macrocirculatory hemodynamic parameters reported in this study are simple and accessible since the prehospital setting to assess the severity and the treatment effect of septic shock cared for by a mICU team. Further studies are needed to confirm whether these parameters could be used to increase prehospital management and triage of septic shock. Conclusion In this study, we report an association between survival and micro and macrocirculatory hemodynamic parameters improvement among septic shock patients cared for by a mICU team in the prehospital setting. An early intervention, from the prehospital setting, personalized mean arterial pressure management appears desirable among hypertensive patients. Author contributions All authors contributed equally and validated the final version of record. Conflicts Of Interest The Author(s) declare(s) that there is no conflict of interest. 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