Cefazolin is as effective and safer than the antistaphylococcal semisynthetic penicillins cloxacillin or flucloxacillin in treating methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia, according to findings from an international platform trial.1
The Staphylococcus aureus Network Adaptive Platform (SNAP) trial was conducted at 91 sites in 8 countries, assigning over 2600 adult patients presenting with S aureus bacteremia to treatment group silos based on susceptibility of their MSSA, penicillin-susceptible S aureus (PSSA), or methicillin-resistant S aureus isolates.
"This is the largest trial ever conducted on staphylococcal bloodstream infections," declared Todd Lee, MD, MPH, professor in the Division of Infectious Diseases in the Department of Medicine at McGill University in Montreal, Quebec, Canada, and co–lead investigator of the SNAP trial, in a statement released on publication of the study.2
"It brought together countries from all over the world to answer an important question and improve care for millions of people," Lee said.
The investigators compared 90-day outcomes, with all-cause mortality as the primary outcome, in 645 patients treated with cefazolin and 642 with an antistaphylococcal penicillin. Although the comparator penicillins are not used in the US, the investigators cite data that suggest the adverse events with antistaphylococcal penicillins are broadly similar.
"Therefore, the findings in this trial with regard to mortality and nephrotoxic effects may apply to antistaphylococcal penicillins other than flucloxacillin or cloxacillin," they indicate.
The criterion for noninferiority was prespecified as an adjusted OR (aOR) of less than 1.2, approximating an absolute difference in mortality of less than 2.5 percentage points with mortality of 15% in the antistaphylococcal-penicillin group. The probability of superiority corresponded to an aOR of less than 1.0.
Cefazolin was administered as 2 g intravenously every 8 hours or every 6 hours for critical illness or endocarditis. Flucloxacillin was dosed at 2 g intravenously every 6 hours or every 4 hours for critical illness or endocarditis, and cloxacillin was dosed at 2 g every 4 hours; each regimen was adjusted for renal function.
The investigators reported 90-day mortality in 15% of patients (97 of 654) among those receiving cefazolin and in 17% of patients (109 of 642) in the antistaphylococcal penicillin group (aOR, 0.81; 95% CI, 0.59-1.12; 99.2% probability of noninferiority and 89.8% probability of superiority).
The groups were also separated by serious adverse events, including acute kidney injury in 13.9% (92 of 660) in the cefazolin group compared with 19.6% (127 of 648) in the antistaphylococcal penicillin group (aOR, 0.67; 0.50-0.89; 99.7% probability of superiority). This portion of the platform trial, in addition to the comparison of penicillin to the semisynthetic antistaphylococcal penicillins for PSSA, was discontinued early in response to that safety signal.
What You Need to Know
In the international SNAP trial of more than 1200 patients with MSSA bacteremia, cefazolin was noninferior to antistaphylococcal penicillins for 90-day mortality (15% vs 17%), with an 89.8% probability of superiority.
Patients treated with cefazolin experienced significantly fewer cases of acute kidney injury than those receiving cloxacillin or flucloxacillin (13.9% vs 19.6%), prompting early discontinuation of that trial comparison because of the safety advantage.
As the largest randomized trial ever conducted in Staphylococcus aureus bacteremia, the SNAP study findings provide strong evidence that cefazolin offers comparable efficacy with improved tolerability, leading investigators to recommend it as a first-line treatment option for MSSA bacteremia.
Steven Tong, MBBS, PhD, of the Department of Infectious Diseases at the University of Melbourne in Australia and co–lead investigator of SNAP, finds the results are clear evidence that cefazolin should be considered as first-line treatment for MSSA bacteremia.2
"In the treatment of MSSA blood infections, there is an 89% probability that cefazolin is associated with lower mortality. Patients treated with cefazolin fare better, with fewer deaths within 90 days," Tong stated.
"The results are sufficiently compelling that I immediately made the switch in my own clinical practice," Tong added.
References
1. Lee TC, Barina LA, Walls G, et al; 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
