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Publications

Journal Article Randomized Controlled Trial Equivalence Trial Multicenter Study Comparative Study Ppublish 14 citations

PubMed: 42308484 DOI: 10.1056/NEJMoa2506905

Cefazolin for Methicillin-Susceptible Staphylococcus aureus Bacteremia.

N Engl J Med 394(23):2329-2339

Authors: Todd C Lee, Lauren A Barina, Genevieve Walls, Anna L Goodman, Dafna Yahav, Matthew P Cheng, Marc Bonten, Asha C Bowen, Tom Boyles, Nick Daneman, Miquel B Ekkelenkamp, Nesrin Ghanem-Zoubi, Marjolein P M Hensgens, Nynke G L Jager, Achim J Kaasch, Ilse J E Kouijzer, Roger J Lewis, Thomas Lumley, David C Lye, Emily G McDonald, Genevieve McKew, Alistair R D McLean, Brendan J McMullan, Zoe K McQuilten, Susan C Morpeth, David L Paterson, Jason A Roberts, J Owen Robinson, Hiroki Saito, Matthew Scarborough, Jaap Ten Oever, Rebecca M Turner, Jonas Tverring, Sebastiaan J van Hal, Steve A Webb, Lynda M Whiteway, Cesar A Arias, Andrew Henderson, George S Heriot, Tom L Snelling, Kevin Afra, Shabinah S Ali, Sharon Amit, Nicholas A Anagnostou, Sophia Archuleta, Stephen J Aston, Eugene Athan, Nadav Baharav, Anthony D Bai, Bridget E Barber … and 188 other authors

Affiliations

  • Department of Medicine, Division of Infectious Diseases, McGill University, Montreal.
  • Department of Infectious Diseases, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.
  • Department of Infectious Diseases, Division of Medicine, Middlemore Hospital, Auckland, New Zealand.
  • University College London Innovative Clinical Trials Unit, Institute of Clinical Trials and Methodology, University College London, London.
  • Department of Infection, Guy's and St. Thomas' National Health Service (NHS) Foundation Trust and King's College London, London.
  • Infectious Diseases Unit, Sheba Medical Center, Ramat Gan, Israel.
  • Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel.
  • Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center (UMC) Utrecht, Utrecht University, Utrecht, the Netherlands.
  • European Clinical Research Alliance on Infectious Diseases (Ecraid), Utrecht, the Netherlands.
  • Wesfarmers Centre of Vaccines and Infectious Diseases, Kids Research Institute Australia, Nedlands, WA, Australia.
  • Department of Infectious Diseases, Perth Children's Hospital, Nedlands, WA, Australia.
  • Clinical HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg.
  • Department of Medicine, Division of Infectious Diseases, Sunnybrook Health Sciences Centre, University of Toronto, Toronto.
  • Department of Medical Microbiology, Division of Laboratories, Pharmacy, and Biomedical Genetics, UMC Utrecht, Utrecht, the Netherlands.
  • Infectious Diseases Institute, Rambam Health Care Campus, Haifa, Israel.
  • Ruth and Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel.
  • Department of Infectious Diseases, UMC Utrecht, Utrecht University, Utrecht, the Netherlands.
  • Julius Center for Health Sciences and Primary Care, UMC Utrecht, Utrecht University, Utrecht, the Netherlands.
  • Department of Pharmacy, Pharmacology, and Toxicology, Radboud University Medical Center, Nijmegen, the Netherlands.
  • Medical Faculty of the Otto von Guericke University Magdeburg, Institute of Medical Microbiology and Hospital Hygiene, Magdeburg, Germany.
  • Health Campus Immunology, Infection, and Inflammation, Otto von Guericke University Magdeburg, Magdeburg, Germany.
  • Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
  • Berry Consultants, Austin, TX.
  • Department of Emergency Medicine, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles.
  • Department of Statistics, University of Auckland, Auckland, New Zealand.
  • National Centre for Infectious Diseases, Tan Tock Seng Hospital, Singapore.
  • Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
  • Department of Medicine, Division of General Internal Medicine, Research Institute of the McGill University Health Centre, Montreal.
  • Department of Microbiology and Infectious Diseases, Concord Repatriation and General Hospital, New South Wales Health Pathology, Concord, NSW, Australia.
  • Concord Clinical School, Faculty of Medicine and Health, University of Sydney, Concord, NSW, Australia.
  • Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, VIC, Australia.
  • Methods and Implementation Support for Clinical and Health Research Hub, Faculty of Medicine, Dentistry, and Health Sciences, University of Melbourne, Melbourne, VIC, Australia.
  • Faculty of Medicine and Health, University of New South Wales, Sydney.
  • Department of Infectious Diseases, Sydney Children's Hospital, Randwick, Sydney.
  • School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia.
  • Haematology, Alfred Hospital, Melbourne, VIC, Australia.
  • Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
  • Advancing Clinical Evidence in Infectious Diseases (ADVANCE-ID), Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
  • Infectious Diseases Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
  • University of Queensland Centre for Clinical Research, Faculty of Health, Medicine, and Behavioural Sciences, University of Queensland, Brisbane, Australia.
  • Herston Infectious Diseases Institute, Metro North Health, Brisbane, QLD, Australia.
  • Department of Infectious Diseases, Royal Perth Hospital, Perth, WA, Australia.
  • Department of Infectious Diseases, Fiona Stanley Hospital, Murdoch, WA, Australia.
  • Department of Emergency and Critical Care Medicine, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.
  • Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto.
  • Department of Infectious Diseases, Medical Research Council, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom.
  • Radboud University Medical Center Community for Infectious Diseases, Nijmegen, the Netherlands.
  • Department of Clinical Sciences Lund-Clinical Sciences Helsingborg, Faculty of Medicine, Infection Medicine, Lund University, Helsingborg, Sweden.
  • Department of Infectious Diseases, Helsingborg Hospital, Helsingborg, Sweden.
  • Department of Infectious Diseases and Microbiology, New South Wales Health Pathology, Royal Prince Alfred Hospital, Sydney.
  • Central Clinical School, University of Sydney, Sydney.
  • Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, VIC, Australia.
  • St. John of God Health Care, Perth, WA, Australia.
  • Internal Medicine, Infectious Diseases, Houston Methodist and Weill Cornell Medical College, Houston.
  • Department of Medicine, Weill Cornell Medical College, New York.
  • Infection Management Services, Princess Alexandra Hospital, Brisbane, QLD, Australia.
  • Department of Infectious Diseases, Melbourne Medical School, University of Melbourne, Parkville, VIC, Australia.
  • School of Public Health, University of Sydney, Camperdown, NSW, Australia.
  • Department of Infectious Diseases and Microbiology, Children's Hospital at Westmead, Westmead, NSW, Australia.
  • Department of Medicine, Division of Infectious Diseases, Fraser Health, Surrey, BC, Canada.
  • Microbiology Laboratory, Sheba Medical Center, Ramat Gan, Israel.
  • Microbiology and Infectious Diseases, Medicine, Cardiac and Critical Care, Southern Adelaide Local Health Network, Bedford Park, SA, Australia.
  • Department of Medicine, Division of Infectious Diseases, National University Hospital, Singapore.
  • Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
  • Tropical and Infectious Diseases Unit, University Hospitals of Liverpool Group, Liverpool, United Kingdom.
  • Department of Pharmacology and Therapeutics, Institute of Systems, Molecular, and Integrative Biology, University of Liverpool, Liverpool, United Kingdom.
  • Department of Infectious Diseases, School of Medicine, Centre for Innovation in Infectious Disease and Immunology Research, Deakin University, Geelong, VIC, Australia.
  • Department of Medicine, Division of Infectious Diseases, Queen's University, Kingston, ON, Canada.
  • Department of Infectious Diseases, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.
  • QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.

Abstract

BACKGROUND

Staphylococcus aureus bacteremia is associated with high mortality. Whether cefazolin or an antistaphylococcal penicillin should be preferred for the treatment of methicillin-susceptible S. aureus bacteremia is unclear.

METHODS

In an ongoing international Bayesian adaptive platform trial, we conducted an open-label, randomized comparison of cefazolin with an antistaphylococcal penicillin (flucloxacillin or cloxacillin) in adult patients with penicillin-resistant, methicillin-susceptible S. aureus bacteremia. The primary outcome, which was evaluated with a hierarchical Bayesian logistic-regression model, was death from any cause within 90 days after enrollment in the platform. We assessed the posterior probability of the noninferiority of cefazolin to flucloxacillin or cloxacillin (with the criterion for noninferiority prespecified as an adjusted odds ratio of <1.2, which approximates an absolute difference in mortality of <2.5 percentage points if mortality in the antistaphylococcal-penicillin group is 15%), as well as the posterior probability of superiority (with the criterion of an adjusted odds ratio of <1.0). Secondary safety outcomes included the development of acute kidney injury within 14 days.

RESULTS

This domain of the ongoing trial was conducted between February 17, 2022, and August 7, 2024, by which time the criterion for noninferiority had been met. Mortality at 90 days among adults who could be evaluated was 15.0% (97 deaths among 645 patients) in the cefazolin group and 17.0% (109 deaths among 642 patients) in the antistaphylococcal-penicillin group (adjusted odds ratio, 0.81; 95% credible interval, 0.59 to 1.12; probability of noninferiority, 99.2%; probability of superiority, 89.8%). Acute kidney injury occurred in 92 of 660 patients (13.9%) in the cefazolin group, as compared with 127 of 648 (19.6%) in the antistaphylococcal-penicillin group (adjusted odds ratio, 0.67; 95% credible interval, 0.50 to 0.89; probability of superiority, 99.7%).

CONCLUSIONS

In patients with methicillin-susceptible S. aureus bacteremia, cefazolin was noninferior to flucloxacillin or cloxacillin with respect to 90-day mortality and was associated with a lower incidence of acute kidney injury. (Funded by the National Health and Medical Research Council and others; SNAP ClinicalTrials.gov number, NCT05137119.).

MeSH

Bacteremia, Staphylococcus, Mortality, Probability, Kidney, Floxacillin, Odds Ratio, Cefazolin, Staphylococcus Aureus, Acute Kidney Injury, Methicillin, Cloxacillin