Benzylpenicillin versus flucloxacillin or cloxacillin for the treatment of penicillin-susceptible Staphylococcus aureus bacteraemia (SNAP): an international, multicentre, open-label, non-inferiority randomised controlled trial.

Summary

In adults with PSSA bacteraemia, benzylpenicillin had a high posterior probability of non-inferiority for 90-day mortality versus flucloxacillin/cloxacillin (adjusted OR 0.67; 95% CrI 0.35–1.28), and significantly reduced acute kidney injury (AKI) risk (adjusted OR 0.50). Recruitment was stopped early due to excess AKI in the anti-staphylococcal penicillin arm.

Key Findings

• 90-day mortality: 14% with benzylpenicillin vs 22% with flucloxacillin/cloxacillin (adjusted OR 0.67; 95% CrI 0.35–1.28).
• AKI occurred in 11% (benzylpenicillin) vs 22% (anti-staphylococcal penicillins); adjusted OR 0.50; high probability of superiority.
• Recruitment ceased early due to increased AKI in the flucloxacillin/cloxacillin group; formal non-inferiority criterion was not met as the CrI exceeded the NI margin.

Clinical Implications

When PSSA is confirmed, benzylpenicillin should be preferred over flucloxacillin/cloxacillin, given comparable mortality and lower AKI risk. Robust susceptibility testing workflows are essential to enable timely agent selection.

Limitations

• Open-label design with potential performance bias.
• Early termination and credible interval crossing the NI margin limit definitive non-inferiority conclusions.

Future Directions

Prospective implementation studies assessing outcomes and AKI with benzylpenicillin-first strategies, and optimization of rapid diagnostics to confidently identify PSSA at the bedside.