In a large clinical trial, an international team has found that the antibiotic cefazolin is as effective as, but safer than, flucloxacillin, the current standard treatment for bloodstream infections caused by Staphylococcus aureus. In the Netherlands, the study is coordinated by UMC Utrecht, Radboudumc and Ecraid.
Staphylococcus aureus
Staphylococcus aureus (S. aureus) is a major cause of life-threatening bloodstream infections (sepsis), which are responsible for approximately 300,000 deaths worldwide each year. In the Netherlands alone, despite the best possible care, 2–3 patients die every day as a result of such infections.
Although effective antibiotics are available to treat bloodstream infections, it has remained unclear which antibiotic provides the best outcomes. For decades, flucloxacillin has been the preferred treatment in the Netherlands, whereas cefazolin is the first-line choice in countries such as the United States. Until now, no large randomized trial had directly compared the two drugs. The SNAP study therefore compared flucloxacillin and cefazolin to determine whether both are equally effective against bloodstream infections caused by S. aureus. The safety profiles of the two antibiotics were also compared.
The Staphylococcus aureus Network Adaptive Platform (SNAP) study compared cefazolin and flucloxacillin in 1,341 patients with S. aureus bloodstream infections across eight countries. The results, now published in the New England Journal of Medicine, provide the clearest evidence to date. The study, the largest of its kind, demonstrated that cefazolin is at least as effective as flucloxacillin and is also safer for the treatment of S. aureus bloodstream infections.
Fifteen percent of patients who received cefazolin died within 90 days, compared with 17 percent of those who received flucloxacillin. In addition, cefazolin was associated with fewer cases of acute kidney injury than flucloxacillin. Acute kidney injury is a serious complication that can occur during sepsis or its treatment, and in this study the choice of antibiotic influenced the risk of developing it.
Dr. Marjolein Hensgens
Dr. Marjolein Hensgens, internist-infectious disease specialist at UMC Utrecht and principal investigator of the SNAP study in Europe, explains: “The results show that patients treated with cefazolin do just as well as—and possibly even better than—those treated with flucloxacillin. Moreover, treatment with cefazolin is associated with significantly fewer side effects.”
Radboudumc coordinates two Dutch sub-studies focusing, among other things, on optimizing the dosing of cefazolin and flucloxacillin. Principal investigator and hospital pharmacist-clinical pharmacologist Dr. Nynke Jager says: “Cefazolin is therefore safer and equally effective as flucloxacillin. To further optimize treatment, we are collecting information on drug exposure, effectiveness, and adverse effects. We are also investigating differences in resistance between flucloxacillin and cefazolin. With this information, we hope to provide even better, more personalized treatment in the future.”
According to Professor Marc Bonten, medical microbiologist and Professor of Molecular Epidemiology of Infectious Diseases at UMC Utrecht, the study marks an important milestone in global infectious disease research and clinical collaboration.
He says: “The SNAP study is a major step forward, not only because of what it teaches us about patient care, but also because it demonstrates the power of international collaboration in answering questions that have challenged us for decades. For the first time, we have randomized clinical trial evidence to guide the treatment of severe staphylococcal infections. These results support cefazolin becoming the new standard treatment for most adults with this type of infection.”
These findings are the first major results from the ongoing SNAP study, which aims to improve the treatment of S. aureus infections worldwide. Because SNAP is a platform trial, multiple treatment strategies can be evaluated simultaneously.
Within this framework, results have also been published in The Lancet on the best treatment for penicillin-susceptible S. aureus (a minority of S. aureus infections in the Netherlands). That study compared benzylpenicillin and flucloxacillin. Benzylpenicillin was associated with fewer kidney-related adverse events and was likely at least as effective as flucloxacillin. At present, only a limited number of Dutch hospitals use benzylpenicillin to treat S. aureus infections.
To date, more than 6,000 patients have participated in the study. Participants were enrolled at more than 130 hospitals in Australia, Canada, Germany, Israel, the Netherlands, New Zealand, Singapore, South Africa, Sweden, France, Spain, and the United Kingdom.
UMC Utrecht and Ecraid, led by Dr. Marjolein Hensgens and Dr. Lennie Derde, serve as the coordinating study center for Europe. Both are also members of the international SNAP steering committee. Coordination in the Netherlands takes place in collaboration with Radboudumc under the leadership of Dr. Nynke Jager.
The SNAP component for which the current results have been reported, as well as the Dutch sub-studies, are funded by ZonMw (Proper Use of Medicines programme) and UMC Utrecht. Ten hospitals in the Netherlands participate in the study. This research would not have been possible without the commitment and contribution of patients and their loved ones.
Cefazolin for Methicillin-Susceptible Staphylococcus aureus bacteremia by the Staphylococcus aureus Network Adaptive Platform (SNAP) Trial Group – The New England Journal of Medicine
Benzylpenicillin versus flucloxacillin or cloxacillin for the treatment of penicillin-susceptible Staphylococcus aureus bacteraemia (SNAP): an international, multicentre, open-label, non-inferiority randomised controlled trial by the Staphylococcus aureus Network Adaptive Platform (SNAP) Trial Group – The Lancet
The SNAP study is funded by UMC Utrecht and ZonMw (GGG 2022, 10140022110014) in the Netherlands; the National Health and Medical Research Council (NHMRC) and the Medical Research Future Fund (MRFF) in Australia; the Canadian Institutes of Health Research (CIHR) and the Accelerating Clinical Trials Consortium Canada (ACTAEC); the Health Research Council of New Zealand (HRC) and the Starship Foundation in New Zealand; the National Medical Research Council (NMRC) in Singapore; the National Institute for Health and Care Research in the United Kingdom; the Paterson Family Foundation in South Africa; and the National Institutes of Health in the United States.
The study was initiated by researchers from the Doherty Institute and the University of Newcastle and has since developed into an international collaboration involving the Doherty Institute (Australia), Aotearoa Clinical Trials (New Zealand), the European Clinical Research Alliance on Infectious Diseases (ECRAID, the Netherlands), the Research Institute of the McGill University Health Centre (RI-MUHC, Canada), University College London (United Kingdom), UMC Utrecht and Radboudumc (the Netherlands), the Clinical HIV Research Unit (CHRU, South Africa), Tan Tock Seng Hospital (TTSH, Singapore), and Rambam Health Corporation, the Sheba Fund for Health Services and Research, and Beilinson Hospital (Israel).
