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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.)

Staphylococcus aureus bloodstream (SAB) infection is a common and severe infectious disease, with a 90-day mortality of 15%-30%. Despite this, <3000 people have been randomized into clinical trials of treatments for SAB infection. The limited evidence base partly results from clinical trials for SAB infections being difficult to complete at scale using traditional clinical trial methods. Here we provide the rationale and framework for an adaptive platform trial applied to SAB infections. We detail the design features of the Staphylococcus aureus Network Adaptive Platform (SNAP) trial that will enable multiple questions to be answered as efficiently as possible. The SNAP trial commenced enrolling patients across multiple countries in 2022 with an estimated target sample size of 7000 participants. This approach may serve as an exemplar to increase efficiency of clinical trials for other infectious disease syndromes., Competing Interests: Potential conflicts of interest. A. M. is an employee of Berry Consultants LLC, in which capacity she is contracted as a consultant to numerous pharmaceutical and device companies on topics of statistical modeling and trial design, and reports grants and contracts unrelated to this work and consulting fees from Berry Consultants LLC. A. C. B. reports participation as a member of the CAMERA-2 data and safety monitoring board (DSMB) and as chair of the Skin Trial DSMB; a role as Vice President of the World Society of Pediatric Infectious Diseases and as Co-Chair, Australian and New Zealand Paediatric Infectious Diseases group of the Australasian Society of Infectious Diseases (ASID). D. L. P. 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. R. reports contracts or grants paid to institution and unrelated to this work from the British Society of Antimicrobial Chemotherapy, bioMérieux, Pfizer, and QPEX; consulting fees paid to author from Gilead, Pfizer, Sandoz, Wolters Kluwer, Summit Pharma, and MSD; payment to author for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events from MSD, Pfizer, and Cipla; an unpaid leadership or fiduciary role with Sepsis Clinical Care Standard, Australian Commission on Safety and Quality in Health Care, Consensus Guidelines on Prolonged Infusion of Beta-Lactam Antibiotics, American College of Clinical Pharmacy, Disease Modifying Treatment and Chemoprophylaxis, Australian National COVID-19 Clinical Evidence Taskforce, and Surviving Sepsis Guidelines. M. P. C. reports research support from the McGill Interdisciplinary Initiative in Infection and Immunity; research contracts from Cidara Therapeutics, Scynexis, and Amplyx; consulting fees as a scientific consultant for AstraZeneca; 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. L. 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. Y. C. T. 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. T. C. L. 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. S. C. M. reports grants or contracts unrelated to this work from the HRC, and a nonremunerated role as the Chair of the New Zealand Microbiology Network. 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) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Introduction: This study aims to assess the association of piperacillin/tazobactam and meropenem minimum inhibitory concentration (MIC) and beta-lactam resistance genes with mortality in the MERINO trial., Methods: Blood culture isolates from enrolled patients were tested by broth microdilution and whole genome sequencing at a central laboratory. Multivariate logistic regression was performed to account for confounders. Absolute risk increase for 30-day mortality between treatment groups was calculated for the primary analysis (PA) and the microbiologic assessable (MA) populations., Results: In total, 320 isolates from 379 enrolled patients were available with susceptibility to piperacillin/tazobactam 94% and meropenem 100%. The piperacillin/tazobactam nonsusceptible breakpoint (MIC >16 mg/L) best predicted 30-day mortality after accounting for confounders (odds ratio 14.9, 95% confidence interval [CI] 2.8-87.2). The absolute risk increase for 30-day mortality for patients treated with piperacillin/tazobactam compared with meropenem was 9% (95% CI 3%-15%) and 8% (95% CI 2%-15%) for the original PA population and the post hoc MA populations, which reduced to 5% (95% CI -1% to 10%) after excluding strains with piperacillin/tazobactam MIC values >16 mg/L. Isolates coharboring extended spectrum β-lactamase (ESBL) and OXA-1 genes were associated with elevated piperacillin/tazobactam MICs and the highest risk increase in 30-day mortality of 14% (95% CI 2%-28%)., Conclusions: After excluding nonsusceptible strains, the 30-day mortality difference from the MERINO trial was less pronounced for piperacillin/tazobactam. Poor reliability in susceptibility testing performance for piperacillin/tazobactam and the high prevalence of OXA coharboring ESBLs suggests that meropenem remains the preferred choice for definitive treatment of ceftriaxone nonsusceptible Escherichia coli and Klebsiella., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)