Researchers from Wits University have contributed to a landmark global antibiotics trial for life-threatening golden staph bloodstream infections, with the findings being published this month in both The New England Journal of Medicine as well as The Lancet.
The results are expected to influence treatment decisions in South Africa as well as internationally.
The Clinical Health Research Unit (CHRU) at Wits was the only low- and middle-income country site in the study, recruiting patients from Helen Joseph Hospital in Johannesburg for the research.
The findings showed that flucloxacillin should no longer be the default treatment for these infections, with cefazolin and benzylpenicillin emerging as safer, equally effective alternatives depending on the type of infection, said the teams. The breakthrough is anticipated to reshape treatment for the life-threatening condition.
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, is the largest international clinical trial ever conducted for golden staph (Staphylococcus aureus) infections.
Disproportionate disease burden in LMICs
It involved more than 150 hospitals across more than 14 countries, including South Africa (the only low- and middle-income country site participating in this research).
Dr Tom Boyles, Senior Researcher at CHRU, said the inclusion of a South African site was crucial for ensuring the findings apply to patients across different healthcare settings globally.
“Our participation demonstrates that high-quality clinical trial research can be conducted in resource-constrained settings,” he said. “Between August 2023 and May 2025, we successfully enrolled 28 participants with 100% follow-up completion, proving that LMIC sites can contribute valuable data to global research efforts.”
Golden staph infections cause more than a million deaths annually. The most serious form is when it enters the bloodstream, with a mortality rate of 15% to 25%.
The burden is disproportionately higher in low- and middle-income countries like South Africa.
Boyles emphasised the importance of including diverse populations in clinical research: “The high disease burden we see in our setting, combined with our cost-effective operations, reinforces why LMIC participation is both strategically important and ethically imperative.
“These findings will directly benefit South African patients and healthcare systems.”
Challenging assumptions, guiding treatment strategies
While there are effective antibiotics to treat bloodstream infections, uncertainty has remained over which treatments lead to the best patient outcomes.
Findings from the SNAP Trial challenge the long-held assumption that flucloxacillin should remain the default treatment, and provide important new evidence to guide treatment strategy.
The NEJM study – Comparing cefazolin and flucloxacillin
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 flucloxacillin, 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 in Australia and global co-lead investigator of the trial, said the results provide clear evidence that cefazolin should be considered the first-line option to treat MSSA bloodstream infections.
“In the treatment of MSSA bloodstream infections, there is an 89% probability that cefazolin is associated with lower mortality,” he said. “Patients treated with cefazolin fare better, with fewer deaths within 90 days (15% compared with 17% for those who received flucloxacillin). Cefazolin was also associated with fewer cases of acute kidney injury, at 14%, compared with 20% with flucloxacillin.”
The Lancet study – Comparing benzylpenicillin and flucloxacillin
In the Lancet paper, the study evaluated whether benzylpenicillin could be used to treat penicillin-susceptible Staphylococcus aureus (PSSA) infections where laboratory testing confirmed the susceptibility to penicillin.
Professor Todd Lee, a scientist at the Research Institute of the McGill University Health Centre and Infectious Diseases and Internal Medicine Physician at the McGill University Health Centre in Canada and co-lead investigator of both studies, said benzylpenicillin was as effective as flucloxacillin and probably safer.
“Patients treated with benzylpenicillin experienced less kidney damage, with mortality also lower at 14% compared with 22% in the flucloxacillin group,” he said.
A shift away from flucloxacillin
The 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 of golden staph led clinicians to adopt flucloxacillin as the standard treatment for MSSA and PSSA infections.
The findings support moving away from flucloxacillin as the default treatment for both, 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 in Australia, and global co-lead investigator of the SNAP Trial, said 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,” he noted.
Lyn Whiteway, a sepsis survivor and consumer representative on both trials, welcomed the findings.
“The 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,” she said.
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.
“This is the largest trial ever conducted on staphylococcal bloodstream infections. It brought together countries from all over the world to answer important questions and improve care for millions of people,” added Lee.
“Trials generate the evidence, but the next step is making sure that evidence changes practice.”
See more from MedicalBrief archives:
Second antibiotic no advantage for treating super-bug Golden Staph
New CDC guidelines for S aureus prevention and control in NICUs
Superbugs ‘could kill 39m people by 2050’ – worldwide analysis