Benzylpenicillin is as effective as, and safer than the "antistaphlococcal" penicillins cloxacillin or flucloxacillin in treating penicillin-susceptible Staphylococcus auerus (PSSA), according to findings of the global Staphylococcus aureus Network Adaptive Platform Trial (SNAP).1
Although the rise of penicillinase-producing S auerus prompted development and widespread use of the antistaphyloccoccal semi-synthetic penicillins, the investigators point out that PSSA is re-emerging internationally—responsible for up to 25% of all clinical S aureus isolates in some areas—and that treatment with penicillin has fewer associated adverse effects such as phlebitis, hepato- and nephrotoxicity.
"Although antistaphylococcal penicillins should no longer be considered the standard of care for adult with PSSA bacteremia, whether benzylpenicillin or cefazolin should be preferred is a question that remains unanswered," the investigators indicated.
To ascertain whether benzylpenicillin is non-inferior to flucloxacillin or cloxacillin for S aureus bacteremia that is laboratory confirmed penicillin-susceptible, they followed 90-day outcomes of 493 patients with PSSA bacteremia in the platform trial of over 2,600 adult patients assigned to siloed groups based on antibiotic susceptibility of their PSSA, MSSA, or methicillin-resistant (MRSA) isolates.
The primary outcome was all-cause mortality at 90 days. Determining a 90-day mortality rate of 15% in the control group, a non-inferiority margin of adjusted OR less than 1.20 translated to an absolute difference of 2.5% in 90-day mortality.Superiority was defined as an adjusted OR of less than 1.0.
The recommended standard dosing of benzylpenicillin was 1.8gm (3 million units) intravenously every 4 hours or 2.4 gm (4 million units) every 6 hours, at the discretion of the treating clinician.The semi-synthetic penicillin regimens were flucloxacillin 2gm intravenously every 6 hours or cloxacillin 2.0gm every 4 hours; each adjusted for renal dysfunction, critical illness, and for continuous infusion. Duration of treatment was a minimum of 14 days for uncomplicated bacteremia and between 28 to 42 days for complicated bacteremia.
The SNAP investigators reported that 21 of 152 (14%) in the benzylpenicillin group and 26 of 121 (22%) in the flucloxacillin or cloxacillin group met the primary outcome of death at 90 days (adjusted OR 0.67, 95% CI 0.35-1.28; with posterior probability of benzylpenicillin non-inferiority of 96.1% and superiority of 88.9%).
What You Need to Know
In patients with penicillin-susceptible Staphylococcus aureus (PSSA) bacteremia, 90-day mortality was 14% with benzylpenicillin vs 22% with cloxacillin/flucloxacillin, meeting the trial’s non-inferiority criteria and suggesting comparable effectiveness.
Benzylpenicillin demonstrated a better safety profile. Acute kidney injury occurred in 11% of patients receiving benzylpenicillin compared with 22% receiving cloxacillin/flucloxacillin, prompting early discontinuation of this trial comparison because of the safety signal.
.The findings challenge the traditional standard of care for PSSA: As PSSA is re-emerging globally and may account for up to 25% of S aureus isolates in some region
The issue of safety was prominent in this assessment, with acute renal injury occurring in 17 of 153 (11%) in the benzylpenicillin group, compared to 27 of 124 patients (22%) receiving flucloxacillin or cloxacillin. This portion of the platform trial, as well as the comparison of cefazolin to semi-synthetic penicillins for MSSA, was discontinued early in response to that safety signal.
In accompanying commentary, Annette Westgeest, PhD, Leiden University Center of Infectious Diseases, Netherlands, and Vance Fowler, Jr., MD, MHS, Division of Infectious Diseases, Department of Medicine, Duke University School of Medicine, Durham, NC, welcomed these first published results from the SNAP trial to be published, characterizing them as key contributions to the field.2
"First, it shows that benzylpenicillin is likely to be at least non-inferior to flucloxacillin or cloxacillin in terms of 90-day mortality and is probably less nephrotoxic.Second, the results support the use of a combination of automated screening and confirmatory modern phenotypic penicillin-susceptibility testing to guide treatment decisions involving benzylpenicillin," Westgeest and Fowler indicated.2
References
1. SNAP Trial Group. Benzylpenicillin versus flucloxacillin or cloxacillin for the treatment of penicillin-susceptible Staphylococcus aureus bacteremia (SNAP): an international, multicentre, open-label, non-inferiority randomised controlled trial. The Lancet. 2026, published online June 17. https://doi.org/10.1016/S0140-6736(26)00761-0. Accessed July 3, 2026.
2. Westgeest AC, Fowler VG. Treating penicillin-susceptible Staphylococcus aureus bacteraemia: confusing the issue with facts. The Lancet. 2026, published online June 17. https://doi.org/10.1016/S0140-6736(26)00857-3. Accessed July 3, 2026.
