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Left ventricular assist devices (LVAD) are increasingly used for management of heart failure; infection remains a frequent complication. Phage therapy has been successful in a variety of antibiotic refractory infections and is of interest in treating LVAD infections. We performed a retrospective review of four patients that underwent five separate courses of intravenous (IV) phage therapy with concomitant antibiotic for treatment of endovascular Pseudomonas aeruginosa LVAD infection. We assessed phage susceptibility, bacterial strain sequencing, serum neutralization, biofilm activity, and shelf-life of phage preparations. Five treatments of one to four wild-type virulent phage(s) were administered for 14-51 days after informed consent and regulatory approval. There was no successful outcome. Breakthrough bacteremia occurred in four of five treatments. Two patients died from the underlying infection. We noted a variable decline in phage susceptibility following three of five treatments, four of four tested developed serum neutralization, and prophage presence was confirmed in isolates of two tested patients. Two phage preparations showed an initial titer drop. Phage biofilm activity was confirmed in two. Phage susceptibility alone was not predictive of clinical efficacy in P. aeruginosa endovascular LVAD infection. IV phage was associated with serum neutralization in most cases though lack of clinical effect may be multifactorial including presence of multiple bacterial isolates with varying phage susceptibility, presence of prophages, decline in phage titers, and possible lack of biofilm activity. Breakthrough bacteremia occurred frequently (while the organism remained susceptible to administered phage) and is an important safety consideration.

Background Staphylococcus aureus bloodstream infection (bacteremia) is traditionally treated with at least 2 weeks of intravenous (IV) antibiotics in adults, 3–7 days in children, and often longer for those with complicated disease. The current practice of treating S. aureus bacteremia (SAB) with prolonged IV antibiotics (rather than oral antibiotics) is based on historical observational research and expert opinion. Prolonged IV antibiotic therapy has significant disadvantages for patients and healthcare systems, and there is growing interest in whether a switch to oral antibiotics following an initial period of IV therapy is a safe alternative for clinically stable patients. Protocol The early oral switch (EOS) domain of the S. aureus Network Adaptive Platform (SNAP) trial will assess early switch to oral antibiotics compared with continued IV treatment in clinically stable patients with SAB. The primary endpoint is 90-day all-cause mortality. Hospitalised SAB patients are assessed at platform day 7 ±2 (uncomplicated SAB) and day 14 ±2 (complicated SAB) to determine their eligibility for randomization to EOS (intervention) or continued IV treatment (current standard of care). Discussion Recruitment is occurring in the EOS domain of the SNAP trial. As of August 2023, 21% of all SNAP participants had been randomized to the EOS domain, a total of 264 participants across 77 centers, with an aim to recruit at least 1000 participants. We describe challenges and facilitators to enrolment in this domain to aid those planning similar trials. [ABSTRACT FROM AUTHOR]

Background: Prophylaxis with fluoroquinolones (FQ) is commonly used in patients with acute leukemia (AL) during neutropenia. This practice is supported by an older meta-analysis reporting reduced mortality using FQ prophylaxis. Later meta-analyses have failed to reproduce this finding, presumably due to higher background FQ resistance rates limiting their effectiveness. Summary: This article reviews the pros and cons of FQ prophylaxis mainly in patients with AL. Most current guidelines do not support universal prophylaxis but rather recommend a selective approach, weighing the benefits against the risks. This recommendation is based on the lack of mortality benefit reported in more recent meta-analyses. FQ prophylaxis was demonstrated to reduce bacteremia and febrile neutropenia episodes, although mostly in trials performed in low-resistance settings (<20%), whereas current FQ resistance rates may reach 30–60%. Other disadvantages of FQ include potential adverse events, antibiotic resistance development, cost, increase in Gram-positive infections and resistant Gram-negative infections following prophylaxis, Clostridioides difficile infection, and an effect on gut microbiota. Key Messages: Taking the above into consideration, alternative approaches other than universal FQ prophylaxis should be considered. Centers with high FQ resistance rates may consider either withholding prophylaxis or providing selective prophylaxis for high-risk patients screened negative for FQ-resistant bacteria. [ABSTRACT FROM AUTHOR]

Background: Staphylococcus aureus bloodstream infection (bacteremia) is traditionally treated with at least 2 weeks of intravenous (IV) antibiotics in adults, 3-7 days in children, and often longer for those with complicated disease. The current practice of treating S. aureus bacteremia (SAB) with prolonged IV antibiotics (rather than oral antibiotics) is based on historical observational research and expert opinion. Prolonged IV antibiotic therapy has significant disadvantages for patients and healthcare systems, and there is growing interest in whether a switch to oral antibiotics following an initial period of IV therapy is a safe alternative for clinically stable patients., Protocol: The early oral switch (EOS) domain of the S. aureus Network Adaptive Platform (SNAP) trial will assess early switch to oral antibiotics compared with continued IV treatment in clinically stable patients with SAB. The primary endpoint is 90-day all-cause mortality. Hospitalised SAB patients are assessed at platform day 7 ±2 (uncomplicated SAB) and day 14 ±2 (complicated SAB) to determine their eligibility for randomization to EOS (intervention) or continued IV treatment (current standard of care)., Discussion: Recruitment is occurring in the EOS domain of the SNAP trial. As of August 2023, 21% of all SNAP participants had been randomized to the EOS domain, a total of 264 participants across 77 centers, with an aim to recruit at least 1000 participants. We describe challenges and facilitators to enrolment in this domain to aid those planning similar trials., Competing Interests: Potential conflicts of interest. A. McGlothlin is an employee of Berry Consultants, LLC, a statistical consulting firm that specializes in the design of adaptive and platform clinical trials. Berry Consultants received compensation for work included in the content of the submission. A. C. Bowen reports participation as a member of the CAMERA-2 data and safety monitoring board (DSMB) and as chair of the Skin Trial DSMB; she also reports participation on Phage Trial DSMB and participation as Chair of FOSUTI DSMB; a role as Vice President of the World Society of Paediatric Infectious Diseases and as Co-Chair, Australian and New Zealand Pediatric Infectious Diseases group of the Australasian Society of Infectious Diseases (ASID). D. L. Paterson reports grants or contracts made to institution and unrelated to this work from Shionogi, Merck, and Pfizer; consulting fees to author from Antimicrobial Resistance Action Fund and Spero Therapeutics; payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events to author from Pfizer and Merck; support for attending meetings and/or travel to author from Pfizer; and an unpaid leadership or fiduciary role with ASID. J. A. Roberts reports contracts or grants paid to institution and unrelated to this work from Pfizer and QPEX and investigator grant (APP2009736) and Advancing Queensland Clinical Fellowship; consulting fees paid to author from QPEX, Advanz Pharma, Gilead, Pfizer, Sandoz, Summit Pharma, and MSD; payment to author for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from MSD, Gilead, Pfizer, and Cipla. J. Ten Oever reports grants or contracts unrelated to this work from Pfizer and MSD; support for attending meetings and/or travel to author from Pfizer; M. P. Cheng reports research support from the Canadian Institutes of Health Research and is supported by the Fonds de Recherche du Québec—Santé; research contracts from Cidara Therapeutics, Scynexis, and Amplyx Pharmaceuticals; consulting fees as a scientific consultant for AstraZeneca, Takeda, Merck, and Pfizer; 3 pending patents (Methods for detecting tissue damage, graft-versus-host disease, and infections using cell-free DNA profiling; Methods for assessing the severity and progression of SARS-CoV-2 infections using cell-free DNA; and rapid identification of antimicrobial resistance and other microbial phenotypes using highly multiplexed fluorescence in situ hybridization); stock options as a member of the scientific advisory board for GEn1E Lifesciences and Nomic Bio; and equity as co-founder of Kanvas Biosciences. R. J. Lewis is an employee of Berry Consultants, LLC, a statistical consulting firm that specializes in the design of adaptive and platform clinical trials. Berry Consultants received compensation for work included in the content of the submission. S. A. W. reports personal consulting fees from ClinicIQ pharma and Roche; an unpaid role as chair of Australian Clinical Trials Alliance; and stock and options with ClinicIQ. S. C. Morpeth reports grants or contracts unrelated to this work from the HRC, and a nonremunerated role as the Chair of the New Zealand Microbiology Network. S. Kalimuddin reports consulting fees from Gilead, Janssen, and Takeda (payments made to Singapore General Hospital) and grants or contracts unrelated to this work from National Medical Research Council, Singapore. S. Y. C. Tong reports a contract as a paid consultant for advice on clinical trial design, and consulting fees from Roivant Sciences as a paid consultant for advice on clinical trial design; and reports grants or contracts unrelated to this work from Australian National Health and Medical Research Council. T. C. Lee reports research salary support from Fonds de Recherche Quebec–Sante, operating funds for other studies including CATCO from the CIHR; and operating funds for other studies from the McGill Interdisciplinary Institute Infection and Immunity. Conflicts that the editors consider relevant to the content of the article have been disclosed. Collaborating authors have not been asked for their potential conflicts. A. Campbell reports National Health and Medical Research Council (grant 2014900) for SNAPPY and Perth Children's Hospital Foundation for site funding for SNAPPY and Raine Clinician Fellowship; participation on Data safety monitoring board for the B part of the NT Meningococcal B study; a role as Co-chair Australian and New Zealand Pediatric Infectious Diseases Special Interest Group Committee. A. Legg reports payment to author for Australian Pharmacy Council—EVUSHELD module and webinar and SHPA webinar; support for attending meetings and/or travel from Therapeutic Guidelines group meeting. L. Whiteway reports being remunerated for time attending meetings, and review of patient facing materials as consumer/PPI representative on the SNAP global trial steering committee. M. Bonten reports grants or contracts (all payments to UMCU) from Janssen Vaccines, Merck, LimmaTech, CureVac, Spherecydes; consulting fees (all payments to UMCU) from Janssen Vaccines, AstraZeneca, Pfizer, Sperecydes, Shionogi, GSK; participation on Data Safety Monitoring Board or Advisory Board for Sanofi (payments to UMCU). S. A. Webb reports grant from National Health and Medical Research Council of Australia that supports SNAP; personal consultings fees from ClinicIQ pharma and Roche; no patents or participation on Data Safety Monitoring Boards or Advisory Boards relevant to this work; unpaid roles as Chair and Director of Australian Clinical Trials Alliance; stock or stock options with Reliis. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objective: To evaluate the risk of recurrent Clostridioides difficile infection (CDI) in solid-organ transplant (SOT) recipients., Methods: Retrospective multicenter study including SOT recipients with a first CDI episode in the year after transplantation (Jan 2017-June 2020). The primary outcome measure was recurrence, defined as a new CDI ≤56 days from the first episode. A competing risk analysis was performed using the sub-distribution hazard model multivariable analysis., Results: 191 SOT recipients were included: 101 (52.9%) were kidney, 66 (34.6%) liver, 11 (5.8%) lung, 8 (4.2%) simultaneous pancreas-kidney, 4 (2.1%) heart and 1 (0.5%) pancreas alone recipients. Treatment for the first CDI were: vancomycin (n = 114,59.7%), vancomycin+metronidazole (n = 39,20.4%), metronidazole (n = 26,13.6%), fidaxomicin (n = 9,4.7%), 3 patients did not receive any therapy. After the first CDI, 17/191 (8.9%) patients died within 56-day mortality without having a recurrence, while 23/191 (12%) patients had a recurrence. Among patients with recurrent CDI, 56-day mortality rate was 30.4% (7/23 patients). On multivariable analysis, severe CDI (sHR4.01, 95% CI 1.77-9.08, p < .001) and metronidazole monotherapy (sHR 3.65, 95% CI 1.64-8.14, p = .001) were factors independently associated with recurrence., Conclusions: Metronidazole monotherapy is associated with increased risk of recurrent CDI in SOT recipients. Therapeutic strategies aimed to reduce the risk of recurrence should be implemented in this setting., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: GT received honoraria for educational meetings by Shionogi and participated to scientific board for MSD. MF received unconditional grants from MSD, Gilead and speaker honoraria from Shionogi, Pfizer, Menarini, MSD, Gilead, GSK, MundiPharma and TermoFisher. Declared conflicts of interest are outside the submitted work and did not affect the scientific objectivity of this study. The other authors have none to declare., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Despite the burden of pyelonephritis after kidney transplantation, there is no consensus on initial empirical antibiotic management., Methods: We surveyed clinicians throughout the world on their practice and opinions about the initial empirical therapy of post-transplant pyelonephritis, using clinical vignettes. A panel of experts from 19 countries on six continents designed this survey, and invited 2145 clinicians to participate., Results: A total of 721 clinicians completed the survey (response rate: 34%). In the hypothetical case of a kidney transplant recipient admitted with pyelonephritis but not requiring intensive care, most respondents reported initiating either a 3rd-generation cephalosporin (37%) or piperacillin-tazobactam (21%) monotherapy. Several patient-level factors dictated the selection of broader-spectrum antibiotics, including having a recent urine culture showing growth of a resistant organism (85% for extended-spectrum ß-lactamase-producing organisms, 90% for carbapenemase-producing organisms, and 94% for Pseudomonas aeruginosa). Respondents attributed high importance to the appropriateness of empirical therapy, which 87% judged important to prevent mortality. Significant practice and opinion variations were observed between and within countries., Conclusion: High-quality studies are needed to guide the empirical management of post-transplant pyelonephritis. In particular, whether prior urine culture results should systematically be reviewed and considered remains to be determined. Studies are also needed to clarify the relationship between the appropriateness of initial empirical therapy and outcomes of post-transplant pyelonephritis., (© 2024 The Author(s). Transplant Infectious Disease published by Wiley Periodicals LLC.)