Cefazolin matches standard therapy—and may be safer—for MSSA bacteremia

Clinical Takeaway: For adults with penicillin-resistant, methicillin-susceptible S. aureus bacteremia, cefazolin can be considered a preferred IV backbone therapy when clinically appropriate, with similar survival and less nephrotoxicity than flucloxacillin or cloxacillin.

Clinicians have long debated whether cefazolin’s ease of use and tolerability outweigh concerns about the cefazolin inoculum effect in high-burden MSSA infections. This trial provides randomized evidence supporting cefazolin as a strong first-line option.

In this pragmatic, open-label, international Bayesian adaptive platform trial, 1341 adults with MSSA bacteremia were randomized at 91 sites in 8 countries to cefazolin or an antistaphylococcal penicillin. The primary outcome was all-cause mortality within 90 days.

Among evaluable patients, 90-day mortality was 15.0% with cefazolin vs 17.0% with flucloxacillin or cloxacillin (adjusted odds ratio [aOR], 0.81; 95% credible interval, 0.59–1.12). Cefazolin met the prespecified noninferiority threshold with 99.2% posterior probability; the probability of superiority was 89.8%. Mortality also numerically favored cefazolin at day 14 (3.7% vs 5.6%), day 28 (7.1% vs 10.5%), and day 42 (9.5% vs 13.0%).

Safety findings were more clearly favorable for cefazolin. Acute kidney injury within 14 days occurred in 13.9% vs 19.6% of patients (aOR, 0.67; 95% credible interval, 0.50–0.89; 99.7% probability of superiority). Serious adverse reactions related to trial drug were reported in 1.8% vs 4.9%, and antibiotic changes due to adverse events occurred in 1.6% vs 9.1%.

The authors wrote that concerns about the cefazolin inoculum effect “should be substantially allayed” by the trial’s narrow noninferiority margin and similar estimated treatment effect among patients with infective endocarditis.

Source: The Staphylococcus aureus Network Adaptive Platform (SNAP) Trial Group. (2026, June 17). N Engl J Med. Cefazolin for Methicillin-Susceptible Staphylococcus aureus Bacteremia