Global clinical trial reveals safest, most effective antibiotics for staphylococcal bloodstream infections

Results from the world’s largest study ever undertaken to improve treatment for Staphylococcus aureus infections—co-led by researchers at the Research Institute of the McGill University Health Centre—are simultaneously published in the New England Journal of Medicine and The Lancet.
 

A landmark international clinical trial has identified the optimal antibiotics for staphylococcal bloodstream infections, a breakthrough that is set to reshape treatment for the life-threatening condition. The SNAP Trial found that the standard antibiotic, cloxacillin (called flucloxacillin in many countries), should no longer be the drug of choice to treat the infection, revealing that cefazolin and benzylpenicillin offer safer and equally effective alternatives to patients.

The Staphylococcus aureus Network Adaptive Platform Trial (SNAP Trial), led by researchers at the Peter Doherty Institute for Infection and Immunity (Doherty Institute) and the University of Newcastle in Australia, is the largest international clinical trial ever conducted for Staphylococcus aureus infections involving more than 150 hospitals across more than 14 countries. The multi-centre trial rapidly evaluates different antibiotics and treatment strategies to reduce mortality and improve patient outcomes. In Canada, the Research Institute of the McGill University Health Centre (The Institute) coordinated the trial across six provinces and 32 hospitals.

Staphylococcal infections cause over one million deaths per year. The most serious form of infection is when it enters the bloodstream, with a mortality rate of 15 to 25 per cent. While there are effective antibiotics to treat the bloodstream infections, uncertainty has remained over which treatments lead to the best patient outcomes. 

Findings from the SNAP Trial, published simultaneously on June 17 in the New England Journal of Medicine (NEJM) and The Lancet, challenge the long-held assumption that cloxacillin should remain the default treatment and provide important new evidence to guide treatment strategy.

“For decades, we have not known the best way to treat this serious infection which affects hundreds of thousands of patients worldwide. We were taught that cloxacillin was better based on expert opinion and in vitro data. So it is critical that we now have randomized data that teaches us this thinking was not correct,” says Dr. Todd Lee, co-lead investigator on both papers, a scientist in The Institute’s Infectious Diseases and Immunity in Global Health (IDIGH) Program, infectious diseases and internal medicine physician at the McGill University Health Centre and Professor at McGill University. “International trials like SNAP help ensure that the results are reliable, broadly applicable and capable of changing care on a global scale.”

The NEJM study—Comparing cefazolin and cloxacillin

In the study published in the NEJM, researchers compared antibiotics used to treat methicillin-susceptible Staphylococcus aureus (MSSA) infections. They found that cefazolin is at least as effective as cloxacillin, but associated with fewer side effects and a lower risk of kidney injury.

The Royal Melbourne Hospital’s Professor Steven Tong, an infectious diseases physician at the Doherty Institute and global co-lead investigator of the SNAP Trial, says the results provide clear evidence that cefazolin should be considered the first-line option to treat MSSA bloodstream infections.

“In the treatment of MSSA infections, there is an 89 per cent probability that cefazolin is associated with lower mortality,” says Prof. Tong.“Patients treated with cefazolin fare better, with fewer deaths within 90 days (15 per cent compared to 17 per cent for those who received flucloxacillin. Cefazolin was also associated with fewer cases of acute kidney injury, at 14 per cent, compared to 20 per cent with flucloxacillin.”

“The results are sufficiently compelling that I immediately made the switch in my own clinical practice,” he adds.

The Lancet study—Comparing benzylpenicillin and cloxacillin

In the paper published in The Lancet, the study evaluated whether benzylpenicillin could be used to treat penicillin-susceptible Staphylococcus aureus (PSSA) infections where laboratory testing confirmed the susceptibility to penicillin.

Dr. Lee, first author of the NEJM study and senior author of The Lancet study, who led the recruitment of hundreds of patients across Canada, says benzylpenicillin was as effective as cloxacillin and likely safer.

“Patients treated with benzylpenicillin experienced less kidney damage, and mortality was also lower at 14 per cent compared with 22 per cent in the cloxacillin group,” says Dr. Lee.

A shift away from cloxacillin

Researchers said these results mark a turning point in the treatment of MSSA and PSSA bloodstream infections, signalling a shift in clinical practice.

Penicillin was once widely used to treat Staphylococcus aureus, but antibiotic resistance led clinicians to adopt cloxacillin as the standard treatment for MSSA and PSSA infections. In recent years, researchers like Dr. Matthew Cheng at The Institute have described the reemergence of penicillin susceptibility.

The findings support moving away from cloxacillin as the default treatment for MSSA and PSSA infections, given safer and equally effective alternatives are available.

Professor Joshua Davis, an infectious diseases physician at the University of Newcastle and the Hunter Medical Research Institute, and global co-lead investigator of the SNAP Trial, says some strains are once again susceptible to penicillin, renewing interest in carefully reintroducing older antibiotics.

“These findings show clinicians can confidently use penicillin susceptibility results to guide treatment where laboratory testing is available,” says Prof. Davis.

Lyn Whiteway, a sepsis survivor and patient partner on both trials, welcome the findings.

“The SNAP Trial shows what is possible when patients are truly at the centre of research. These findings will save lives and spare people from unnecessary harm,” says Ms. Whiteway.

“We are profoundly grateful to the Canadian patients who participated in SNAP. Clinical trials are only possible because individuals are willing to contribute to research at a vulnerable moment in their lives. Their participation has generated evidence that will improve care for patients with serious Staph aureus infections today and for many years to come,” says Dr. Emily McDonald, a scientist in The Institute’s IDIGH Program and co-principal investigator of the studies.

The next challenge: translating the findings

Researchers say the next challenge will be translating the findings into routine clinical practice.

While cefazolin availability may need to increase in some countries, researchers say implementation will ultimately depend on hospitals, laboratories and guideline groups incorporating the findings into clinical care.

“By bringing together patients, researchers and hospitals from around the world, we can answer important questions more quickly and with greater confidence than any single centre could on its own,” says Dr. Lee. “Trials generate the evidence, but the next step is making sure that evidence changes practice.” 


About the SNAP Trial

• The SNAP Trial is a major Australia-led global clinical study investigating the most effective treatments for Staphylococcus aureus bloodstream infections across all age groups.
• This trial is the world’s largest study ever undertaken to improve treatment for Staphylococcus aureus infections. 
• So far in the overarching SNAP Trial, participants have been enrolled in Australia, Canada, France, Germany, Israel, Japan, Malaysia, the Netherlands, New Zealand, Singapore, South Africa, Sweden, the United Kingdom and the United States. The trial will continue testing new approaches to improve outcomes for patients facing this serious infection.

About the studies

Peer-reviewed paper: The Staphylococcus aureus Network Adaptive Platform (SNAP) Trial Group. Cefazolin for Methicillin-Susceptible Staphylococcus aureus bacteremia. The New England Journal of Medicine (NEJM) (2026). DOI: http://doi.org/10.1056/NEJMoa2506905

Peer-reviewed paper: The Staphylococcus aureus Network Adaptive Platform (SNAP) Trial Group. 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. The Lancet 2026; published online June 17. https://doi.org/S0140-6736(26)00761-0

Funding: This study was supported by the National Health and Medical Research Council (NHMRC) and Medical Research Future Fund (MRFF) in Australia; the Canadian Institutes of Health Research (CIHR) and the Accelerating Clinical Trials Consortium Canada (ACTAEC); the University Medical Center (UMC) Utrecht and ZonMW in the Netherlands; the Health Research Council of New Zealand (HRC) and the Starship Foundation in New Zealand; the National Healthcare Group Fund and National Medical Research Council (NMRC) in Singapore; the National Institute for Health and Care Research (NIHR) in the UK and the Paterson Family Foundation supported activities in South Africa.

Collaboration: This study was led by researchers at the Doherty Institute (a joint venture between the University of Melbourne and the Royal Melbourne Hospital) and the University of Newcastle through the SNAP Trial. It is the result of an international consortium with the Doherty Institute (Australia), Aotearoa Clinical Trials (New Zealand), the European Clinical Research Alliance on Infectious Diseases (ECRAID Netherlands), the Research Institute of the McGill University Health Centre (The Institute, Canada), University College London Innovative Clinical Trials Unit (UK), The University Medical Center Utrecht (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).


Media contact
Fabienne Landry
Communications coordinator, Research, MUHC
[email protected]