Global trial shows safer antibiotic option for staph blood infection

The SNAP trial, funded in the UK by the National Institute for Health and Care Research (NIHR) found that a little used antibiotic, cefazolin, is as effective as and safer than the current UK standard therapy, flucloxacillin, for treating life-threatening staph blood infections.  More than half of staph blood infections lead to sepsis and 15% to 25% of those who get these infections die within three months.

The researchers also found that a commonly used antibiotic, penicillin, can be used when the staph is treatable with this in the laboratory. And that similarly this is probably as effective as flucloxacillin, and safer.

The findings from the SNAP trial, published 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.

Staph (Staphylococcus aureus) is a leading cause of deadly blood infection, associated with over 1 million deaths worldwide each year and affecting over 14,000 patients each year in the UK. While effective antibiotic treatments exist, there has been no clear agreement about which antibiotic leads to the best outcomes for patients.

The NEJM results – Comparing cefazolin and flucloxacillin
In the trial published in the NEJM, researchers compared antibiotics used to treat meticillin-susceptible Staphylococcus aureus (MSSA) infections (i.e. blood infections that are not resistant to the meticillin antibiotic). It found cefazolin is at least as good as flucloxacillin for helping people to survive this infection, and associated with fewer side effects and a lower risk of kidney injury. It compared cefazolin and flucloxacillin in 1,341 adults with staph blood infections across eight countries taking part in this part of the trial.

In patients who received cefazolin there were fewer cases of changes in how the kidneys are working (as measured by blood tests). Such kidney changes can cause long-term health problems and occurred in fewer of those given cefazolin compared to those given flucloxacillin.

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

This trial compared penicillin and flucloxacillin in 281 adults with staph blood infections. Penicillin was found to be likely to be at least as good for helping people to live with this infection as flucloxacillin.

In patients who received penicillin there were similarly fewer cases of changes in how the kidneys are working (as measured by blood tests). These occurred in 11% of those given penicillin compared to 22% of those given flucloxacillin. Mortality was also 14% in the penicillin group compared with 22% in the flucloxacillin group.

Professor Anna Goodman, UK lead of the SNAP trial at the UCL Innovative Clinical Trials, said: “This trial fills a major research gap. Our results strongly support cefazolin as the new first treatment for most adults with these infections. They also show a role for penicillin in some cases. It’s been helpful to deliver it in collaboration with researchers around the world and patients who have been affected by the condition, who we found via the UK Sepsis Trust.

“The results represent huge progress in the management of this disease with the first change in our approach to antibiotics in decades. Not only are cefazolin and penicillin as effective as flucloxacillin at treating penicillin- and meticillin-susceptible staph blood infection, but they also lead to significantly fewer abnormal blood tests.”

Staph infections are caused by bacteria called Staphylococcus aureus. They most often affect the skin and cause relatively minor problems. However, if the bacteria enter the bloodstream or other parts of the body, they can cause serious infections such as blood poisoning, blood infection or sepsis.

These more serious infections can affect anyone, but individuals at higher risk include people with catheters in their veins (as happens when people receive renal replacement therapy also called haemodialysis) or implanted devices (such as pacemakers), and people with diabetes. Those living with cancer and on immune suppressing medication, those who cannot get out of bed, and those who inject drugs are also more vulnerable to these infections.

Kim Smith, a sepsis survivor and a patient representative on the trial, said: “The SNAP study was extremely valuable for having real people taking part in the trials, for knowledge and people’s health. I believe this will help save lives, as well as save people from organ damage.”

Joanne Lloyd, a public contributor to the trial, who joined due to her experience caring for a loved one, said: “My son survived sepsis, and I was there caring for him through it all. I know how frightening and uncertain it can be. The SNAP trial gives real hope, it shows we can treat these serious infections more safely, without losing effectiveness. Research like this matters because it helps families like mine get better care. From a patient and carer perspective, it’s great that this trial involved so many countries and hospitals working together. It shows how important international collaboration is in answering long-standing questions about treatment.”

Professor Danny McAuley, Scientific Director of NIHR Programmes, said: “Staph blood infections are a common cause of sepsis, a potentially deadly condition. Landmark results from this international trial provide new evidence that cefazolin, is as effective and safer than the current UK treatment. This is a crucial finding in the mission to improve antimicrobial stewardship and ensure there are fewer lives lost to the biggest killers.

“For 20 years, we’ve funded and supported breakthrough research that has changed care and improved the lives of millions, nationally and internationally, focusing on questions that matter most to the public, patients and professionals.”

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 blood infections.

“In the treatment of MSSA blood infections, there is an 89% probability that cefazolin is associated with lower mortality,” said Professor Tong.

“Patients treated with cefazolin fare better, with fewer deaths within 90 days (15% compared to 17% for those who received flucloxacillin). Cefazolin was also associated with fewer cases of acute kidney injury, at 14%, compared to 20% with flucloxacillin.

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

Professor Todd Lee, a scientist based at the Research Institute of the McGill University Health Centreand Infectious Diseases and Internal Medicine physician at the McGill University Health Centre in Canada and co-lead investigator of both trials, emphasised the global scope of the work.

“This is the largest trial ever conducted on staphylococcal bloodstream infections. It brought together countries from all over the world to answer an important question and improve care for millions of people,” said Professor Lee.

A shift away from flucloxacillin
Researchers said these results mark a turning point in the treatment of MSSA and PSSA blood infections, signalling a shift in clinical practice.

Penicillin was once widely used to treat Staphylococcus aureus, but antibiotic resistance of staph led clinicians to adopt flucloxacillin as the standard treatment for MSSA and PSSA blood infections. The findings support moving away from flucloxacillin as the default treatment for MSSA and PSSA blood infections, given safer alternatives are available.

The new results mark the first major finding from the ongoing SNAP trial, which aims to improve treatment for Staphylococcus aureus infections around the world. These parts of the trial took place in Australia, Canada, Israel, the Netherlands, New Zealand, Singapore, South Africa and the UK – each supported by regional funders working together to form one global network.

Global leadership was provided by the University of Melbourne trial team led by Professor Steven Tong and Professor Josh Davis.

So far, over 6,000 participants have been enrolled in over 150 sites in those countries stated, and more recently in Germany and Sweden, Germany, Japan, Malaysia, and the United States.  The trial will continue testing new approaches to improve outcomes for patients facing this serious infection.

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. 

Professor Goodman said: “Sepsis and staph blood infections are devastating for those affected and those who care for them. We are grateful to all those who took part and supported these two trials which will change practice.  The platform trial continues as we ask further important questions in this area.”

Links

• The NEJM paper
• The Lancet paper
• Professor Anna Goodman’s academic profile
• UCL Innovative Clinical Trials Unit
• UCL Population Health Sciences

Image

• Credit: iStock / gorodenkoff

Media contact

Mark Greaves

m.greaves [at] ucl.ac.uk

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