Research Summary

Cefazolin Noninferior to Flucloxacillin/Cloxacillin for 90-Day Mortality in Adult MSSA Bacteremia

Anthony Calabro, MA

Key Highlights

  • Cefazolin met the prespecified criterion for noninferiority vs flucloxacillin or cloxacillin for 90-day all-cause mortality in adults with penicillin-resistant, methicillin-susceptible Staphylococcus aureus bacteremia.
  • Mortality at 90 days was 15% with cefazolin and 17% with antistaphylococcal penicillin therapy.
  • Acute kidney injury occurred in 13.9% of patients treated with cefazolin vs 19.6% of those treated with flucloxacillin or cloxacillin.
  • The open-label trial was conducted at 91 sites in 8 countries within the Staphylococcus aureus Network Adaptive Platform trial.

Cefazolin was noninferior to flucloxacillin or cloxacillin for 90-day all-cause mortality among adults with methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia and was associated with fewer kidney-related adverse outcomes, according to findings published in The New England Journal of Medicine.

The study addressed uncertainty about the preferred antibiotic backbone for penicillin-resistant MSSA bacteremia. The investigators noted that S aureus bacteremia is associated with high mortality and that, despite established management practices, the optimal antibiotic choice for MSSA bacteremia remains unclear.

Researchers conducted a pragmatic, open-label, randomized, non-inferiority comparison within the ongoing international Bayesian adaptive SNAP trial. The analysis included hospitalized adults aged 18 years or older with penicillin-resistant MSSA bacteremia who were enrolled within 72 hours of index blood culture collection.

Patients were randomly assigned 1:1 to cefazolin or an antistaphylococcal penicillin, defined as flucloxacillin or cloxacillin, depending on the country. The primary outcome was death from any cause within 90 days after platform entry. Secondary safety outcomes included acute kidney injury within 14 days, initiation of renal-replacement therapy, acute liver injury, serious adverse reactions, and treatment discontinuation due to adverse events.

Study Findings

Between February 17, 2022, and June 21, 2024, 1,341 adults underwent randomization in the methicillin-susceptible S aureus silo; 671 were assigned to cefazolin and 670 to flucloxacillin or cloxacillin. After loss to follow-up or withdrawal, 1,287 patients were included in the primary outcome analysis. The median patient age was 66 years, 31.4% were women, and the most common infection site was osteoarticular.

At 90 days, 97 of 645 evaluable patients in the cefazolin group died compared with 109 of 642 patients in the antistaphylococcal-penicillin group, corresponding to mortality rates of 15% and 17%, respectively. The adjusted odds ratio was 0.81, with a 95% credible interval of 0.59 to 1.12. The posterior probability of noninferiority was 99.2%, and the probability of superiority was 89.8%.

Acute kidney injury occurred in 92 of 660 patients receiving cefazolin and 127 of 648 receiving flucloxacillin or cloxacillin, corresponding to rates of 13.9% and 19.6%, respectively. The adjusted odds ratio was 0.67, with a 95% credible interval of 0.50 to 0.89, and the probability of superiority was 99.7%. Cefazolin was also associated with lower odds of reporting a serious adverse reaction and of treatment discontinuation due to an adverse event.

Clinical Implications

According to the study authors, the findings suggest that cefazolin was noninferior to flucloxacillin or cloxacillin for 90-day mortality in adult patients with MSSA bacteremia and was associated with fewer serious adverse events, particularly acute kidney injury.

The authors noted several limitations, including the open-label design, limited control over post-randomization physician decisions, and practice variability across sites. They also reported that isolates had not yet been tested for the cefazolin inoculum effect, although a microbiologic subgroup report was planned after central testing.

Expert Commentary

“In this pragmatic, international, open-label trial, treatment with cefazolin was noninferior to treatment with flucloxacillin or cloxacillin,” the researchers concluded.

Reference
Staphylococcus aureus Network Adaptive Platform (SNAP) Trial Group. Cefazolin for methicillin-susceptible Staphylococcus aureus bacteremia. N Engl J Med. 2026;394(23):2329-2339. doi:10.1056/NEJMoa2506905