Benzylpenicillin should be preferred over flucloxacillin or cloxacillin for the treatment of penicillin-susceptible Staphylococcus aureus (PSSA) bacteraemia, Australian and international research has found.

The study, conducted within the PSSA silo of the ongoing S. aureus Network Adaptive Platform (SNAP) trial [link here], found that benzylpenicillin delivered improved effectiveness and a better safety profile than the penicillinase-resistant penicillins.

The study recruited 281 adult patients with S. aureus bacteraemia admitted to 67 hospitals in Australia, New Zealand, Canada, Israel, the Netherlands, the UK, Singapore, and South Africa between February 2022 and June 2024.

Minimum duration of allocated IV antibiotic treatment was 14 days for uncomplicated bacteraemia and 28–42 days for complicated bacteraemia.

The study found 14% of the benzylpenicillin group and 21% of the flucloxacillin or cloxacillin group met the primary endpoint of all-cause mortality at 90 days (aOR 0.67), “…corresponding to a posterior probability of benzylpenicillin non-inferiority of 96·1% and of benzylpenicillin superiority of 88·9%.”

In a key secondary outcome, 11% of the benzylpenicillin group and 22% of the flucloxacillin or cloxacillin group developed acute kidney injury (AKI), (aOR 0·50, 95% CrI 0·26–0·94), “…corresponding to a posterior probability of non-inferiority of benzylpenicillin of 99·8% and superiority of benzylpenicillin of 98·4%.”

Most AKI was mild but renal replacement therapy was required in 2% of the benzylpenicillin group and 4% of the flucloxacillin or cloxacillin group. No ongoing renal replacement therapy was reported in either group.

The study, published in The Lancet [link here] found treatment failure occurred in 22% of the benzylpenicillin group versus 28% of the flucloxacillin or cloxacillin group (aOR 0·75, 95% CrI 0·42 to 1·33).

Other secondary outcomes included diagnosis of new foci of infection (5% v 5%), change of antibiotic due to any adverse event (5% v 8%) and any serious adverse reaction related to study drug (4% v 7%).

An accompanying comment article in the journal [link here] said the results also support the use of a combination of automated screening and confirmatory modern phenotypic penicillin-susceptibility testing to guide treatment decisions involving benzylpenicillin.

However it noted the study did not “…answer the most relevant question of benzylpenicillin versus cefazolin for PSSA.”

Cefazolin

Prof Steven Tong and Prof Joshua Davis

Meanwhile, another SNAP study found cefazolin was non-inferior to flucloxacillin or cloxacillin with respect to 90-day mortality and was associated with a lower incidence of AKI in hospitalised patients with methicillin-susceptible S. aureus bacteraemia.

Senior investigators on both studies are infectious diseases physicians Professor Steven Tong from the Victorian Infectious Diseases Service, Doherty Institute and University of Melbourne and Professor Joshua Davis from the John Hunter Hospital, Hunter Medical Research Institute and University of Newcastle.

The study, published in the NEJM [link here], randomised 1,341 patients from 91 sites across the eight countries to either cefazolin or flucloxacillin / cloxacillin.

Death from any cause within 90 days occurred in 15.0% of the cefazolin group and 17.0% of the flucloxacillin / cloxacillin group (aOR 0.81; 95% credible interval, 0.59 to 1.12; probability of noninferiority, 99.2%; probability of superiority, 89.8%).

AKI occurred in 13.9% of the cefazolin group versus 19.6% of the flucloxacillin / cloxacillin group (aOR 0.67; 95% credible interval, 0.50 to 0.89; probability of superiority, 99.7%).

Cefazolin was also associated with a lower risk of initiation of renal replacement therapy and a lower risk of treatment discontinuation due to adverse events.

The investigators said cefazolin has some potential disadvantages including higher drug-acquisition costs in some markets and a potentially broader antimicrobial spectrum.

“However, these concerns are balanced by its longer half-life, more favourable side-effect profile, and possible superiority to flucloxacillin or cloxacillin,” they said.

Paediatric trials for both studies are ongoing and will be subsequently reported.