2026/06/17 by Joshua S Davis, Owen Robinson, Genevieve Walls +97 · 1 voice
Medicine · #Antibiotics Pharmacokinetics and Efficacy #Antimicrobial Resistance in Staphylococcus #Drug-Induced Adverse Reactions
paper · doi:10.1016/s0140-6736(26)00761-0
openalex publication_date 2026/06/17 · openalex created_date 2026/06/18 · openalex updated_date 2026/07/12
BACKGROUND: Previously considered rare, penicillin-susceptible Staphylococcus aureus (PSSA) bacteraemia has re-emerged worldwide. Although benzylpenicillin might offer advantages in terms of pharmacokinetic and adverse effect profiles, anti-staphylococcal penicillins are recommended for serious infections because of concern over undetected penicillin resistance. We aimed to compare benzylpenicillin with anti-staphylococcal penicillins (cloxacillin or flucloxacillin) for the treatment of PSSA bacteraemia in adults. METHODS: This investigator-initiated, international, multicentre, open-label, non-inferiority, randomised controlled trial was conducted within the PSSA silo of the backbone domain of the ongoing S aureus Network Adaptive Platform (SNAP) trial. We enrolled patients of all ages who were admitted with S aureus bacteraemia at 67 hospitals across Australia, New Zealand, Canada, Israel, the Netherlands, the UK, Singapore, and South Africa. Herein, we report results for adult patients (aged ≥18 years). Participants were randomly allocated 1:1 to receive either benzylpenicillin, or flucloxacillin or cloxacillin. Trial staff, staff caring for participants, and participants were aware of the treatment allocated and received. Cloxacillin was used only where flucloxacillin was not available (ie, Canada, Israel, Singapore, and South Africa). Recommended standard dosing for benzylpenicillin was 1·8 g intravenously once every 4 h or 2·4 g once every 6 h; for flucloxacillin 2·0 g intravenously once every 6 h; and for cloxacillin 2·0 g intravenously once every 4 h. The primary outcome was all-cause mortality 90 days after platform entry, assessed in the intention-to-treat population, including all patients with available data. The primary outcome was analysed by use of a hierarchical Bayesian logistic regression model, with non-inferiority of benzylpenicillin defined as an adjusted odds ratio (OR) of less than 1·20. Analyses occurred after every 500 participants reached 90-day follow-up. The SNAP trial is registered with ClinicalTrials.gov (NCT05137119) and is ongoing. FINDINGS: Following the fourth interim analysis, the data and safety monitoring committee recommended ceasing recruitment before prespecified stopping thresholds were reached because of increased acute kidney injury (AKI) in participants receiving flucloxacillin or cloxacillin, and the PSSA silo was closed for recruitment on Aug 7, 2024. Between Feb 18, 2022, and June 21, 2024, of 493 adults with PSSA bacteraemia, 125 were randomly assigned to the flucloxacillin or cloxacillin group and 156 to the benzylpenicillin group. The median age was 67 years (IQR 56-77), 87 (31%) were female, and 194 (69%) were male. 21 (14%) of 152 in the benzylpenicillin group and 26 (22%) of 121 in the flucloxacillin or cloxacillin group met the primary outcome of death at 90 days (adjusted OR 0·67, 95% credible interval [CrI] 0·35-1·28), with a posterior probability of benzylpenicillin non-inferiority of 96·1% and of benzylpenicillin superiority of 88·9%. AKI occurred in 17 (11%) of 153 patients in the benzylpenicillin group and 27 (22%) of 124 patients in the flucloxacillin or cloxacillin group (adjusted OR 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%. Seven total serious adverse reactions were reported from six (4%) of 156 participants in the benzylpenicillin group and ten were reported from nine (7%) of 125 participants in the flucloxacillin or cloxacillin group. INTERPRETATION: Although the prespecified non-inferiority criterion for benzylpenicillin was not met, the probability of benzylpenicillin being non-inferior for mortality, along with a reduction in risk of AKI, indicates that benzylpenicillin should be preferred over flucloxacillin or cloxacillin for treatment of PSSA bacteraemia in adults. FUNDING: National Health and Medical Research Council, Medical Research Future Fund, Canadian Institutes of Health Research, Accelerating Clinical Trials Consortium, UMC Utrecht, ZonMW Good Use of Medicines programme, Health Research Council of New Zealand, Starship Foundation, National Healthcare Group Fund, National Medical Research Council, National Institute for Health and Care Research, Medical Research Council, and Paterson Family Foundation.