This international, open-label, non-inferiority RCT (SNAP trial, NCT05137119) compared benzylpenicillin vs. flucloxacillin or cloxacillin for treatment of PSSA bacteraemia in adults (≥18 years) across 67 hospitals in 8 countries, with a primary endpoint of 90-day all-cause mortality.
90-day mortality was 14% (21/152) with benzylpenicillin vs. 22% (26/121) with flucloxacillin/cloxacillin (adjusted OR 0.67, 95% CrI 0.35–1.28; posterior probability of non-inferiority 96.1%, superiority 88.9%). AKI occurred in 11% (17/153) vs. 22% (27/124), respectively (adjusted OR 0.50, 95% CrI 0.26–0.94; posterior probability of superiority 98.4%). The prespecified non-inferiority stopping threshold (>99% posterior probability) was not formally met before early closure.
- Trial closed early (n=281 vs. larger planned size) due to a safety signal, which may exaggerate treatment effect estimates and caused chance imbalance in group sizes. - Open-label design may have influenced clinician decisions (e.g., more antibiotic switches for perceived inefficacy in the benzylpenicillin arm: 7% vs. 1%). - Cloxacillin dosed at 12 g/day without renal adjustment per Canadian guidelines; AKI findings may not generalize to lower cloxacillin doses or to nafcillin/oxacillin used in the USA.
For adults with confirmed PSSA bacteraemia (verified by phenotypic disc diffusion or blaZ PCR), benzylpenicillin should be preferred over flucloxacillin or cloxacillin — it showed lower mortality and roughly half the rate of AKI. This switch requires reliable penicillin susceptibility testing beyond automated methods alone.
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