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

A landmark international clinical trial has identified the optimal antibiotics for golden staph bloodstream infections, a breakthrough that is set to reshape treatment for the life-threatening condition. The SNAP Trial found that the standard antibiotic, flucloxacillin, 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, is the largest international clinical trial ever conducted for golden staph (Staphylococcus aureus) infections involving more than 150 hospitals across more than 14 countries including Singapore. The multi-centre trial rapidly evaluates different antibiotics and treatment strategies to reduce mortality and improve patient outcomes. Locally, the trial is coordinated by the Singapore Infectious Disease Clinical Research Network (SCRN), a division under Communicable Diseases Agency (CDA) that conducts multi-centre clinical studies. SCRN comprises a network of infectious disease doctors, microbiologists and clinical research professionals from all Singapore public acute care institutions, including the National Centre for Infectious Diseases (NCID). The division collaborates with primary care providers, academia, industry and international partners to conduct high-quality clinical research aimed at informing medical practice and policymaking.

Golden staph infections cause over one million deaths worldwide per year. The most serious form of golden staph infections is when it enters the bloodstream, with a mortality rate of 15 to 25 per cent. In Singapore, just within three public acute hospitals – Tan Tock Seng Hospital (TTSH), Singapore General Hospital (SGH) and National University Hospital (NUH) – there areapproximately 800 golden staph bloodstream infections encountered yearly. 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 today in the New England Journal of Medicine (NEJM) and The Lancet, 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 SNAP 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 per cent probability that cefazolin is associated with lower mortality,” said Professor 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.”

Professor David Lye, an Infectious Diseases Senior Consultant at TTSH and NCID, and Group Director, Research at CDA, and Singapore’s Principal Investigator of the SNAP trial, said, “The SNAP trial emerged out of the previously completed CAMERA2 trial published in JAMA in 2020, which TTSH, SGH and NUH contributed to. These three hospitals in Singapore proceeded to participate in the SNAP trial.” He added, “The infectious diseases team at TTSH is proud to be part of SNAP. S. aureus bacteraemia remains among the top three causes of bloodstream infection among patients in TTSH. The findings in this MSSA study are highly significant and will change local and international practice to guide doctors in choosing first-line antibiotics to treat this common, serious bloodstream infection. It also shows why patients and doctors should proactively be part of large and well-designed randomised controlled trials.”

The Lancet study – Comparing benzylpenicillin and flucloxacillin

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.

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 likely safer.

“Patients treated with benzylpenicillin experienced less kidney damage, with mortality also lower at 14 per cent compared with 22 per cent in the flucloxacillin group,” said Professor Lee.

A shift away from flucloxacillin

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 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 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,” said Professor Davis.

Dr Shirin Kalimuddin, Senior Consultant, Department of Infectious Diseases, SGH, and its Principal Investigator, said, “Bloodstream infections caused by S. aureus bacteria are challenging to treat. They are associated with significant healthcare burden, including a mortality risk of up to 20 per cent, longer hospital length of stay, higher hospitalisation costs, and overall poorer quality of life post-infection. We are proud that Singapore, involving three sites at SGH, TTSH and NUH, has contributed to this global platform trial to determine the best-practice treatment for S. aureus infections. This practice-changing clinical trial demonstrates the value of investigator-initiated collaborative research in generating evidence that directly impacts patient care. We hope the findings from this trial will inform clinical practice both locally and globally, and lead to better outcomes for our patients affected by this serious infection.”

Lyn Whiteway, a sepsis survivor and consumer representative on both trials, welcomed 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,” said Ms Whiteway.

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 Professor Lee.

“Trials generate the evidence, but the next step is making sure that evidence changes practice.”