Global study identifies safer, equally effective antibiotic for bloodstream infections caused by Staphylococcus aureus

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 (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, two to three 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.

Cefazolin equally effective, but safer

The Staphylococcus aureus Network Adaptive Platform (SNAP) study compared cefazolin and flucloxacillin in 1,341 patients with S. aureus bloodstream infections across eight countries. Patients from the Radboudumc also participated in the study. 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.

Radboudumc coordinates Dutch research

Researchers at Radboudumc, including Nynke Jager, Roger Brüggemann, Ilse Kouijzer and Jaap ten Oever, received a ZonMw grant in 2022 that enabled Dutch participation in the SNAP study, and together with UMC Utrecht and Ecraid, they coordinate SNAP in the Netherlands.

In addition, Radboudumc is leading two Dutch sub-studies, coordinated by PhD candidate Fleur Sinkeler. These studies investigate exposure to cefazolin and flucloxacillin, their effectiveness, side effects, and differences in resistance between these antibiotics. Principal investigator and hospital pharmacist-clinical pharmacologist 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.'

Photo: Principal investigator and hospital pharmacist-clinical pharmacologist Nynke Jager.

A new standard of care  

Infectious disease specialist Marjolein Hensgens (UMC Utrecht): '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.' The study marks an important milestone in global infectious disease research and clinical collaboration. Medical microbiologist Marc Bonten (UMC Utrecht): '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.'

The SNAP study

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 recenlty 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. The SNAP component for which the current results have been reported, as well as the Dutch sub-studies, are funded by ZonMw (Good Use of Medicines programme) and UMC Utrecht. Ten hospitals in the Netherlands participate in the study.

About this publication

This article is published in New England Journal of Medicine: Cefazolin versus Cloxacillin or Flucloxacillin for Methicillin-Susceptible Staphylococcus aureus bacteremia: A Randomized Clinical Trial. Todd Lee, [...], Nynke Jager, Ilse Kouijzer, Jaap ten Oever, Fleur Sinkeler, [...], Steven Tong. DOI: 10.1056/NEJMoa2506905.

The articel about penicillin-susceptible S. aureus is published in The Lancet: Benzylpenicillin versus Cloxacillin or Flucloxacillin for the treatment of Penicillin2 Susceptible Staphylococcus aureus s bacteraemia: A Randomised Controlled Trial. Joshua Davis, [...], Nynke Jager, Ilse Kouijzer, Fleur Sinkeler, Jaap ten Oever, [...], Todd Lee. DOI: S0140-6736(26)00761-0.