Cefazolin non-inferior to penicillins for methicillin-susceptible Staphylococcus aureus bacteremia

1. In this international randomized controlled trial of adults with methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia, cefazolin was noninferior to antistaphylococcal penicillins for 90-day mortality.

2. Cefazolin was also associated with fewer adverse events, particularly lower rates of acute kidney injury and treatment discontinuation due to toxicity.

Evidence Rating Level:  1 (Excellent) 

Study Rundown: Methicillin-susceptible Staphylococcus aureus (MSSA) remains one of the most dangerous causes of bacteremia, with persistently high mortality despite modern antimicrobial therapy. Antistaphylococcal penicillins such as flucloxacillin, nafcillin, and cloxacillin have long been regarded as standard therapy, especially for complicated infections like endocarditis. However, cefazolin has increasingly been used in practice because of more convenient dosing and a more favorable side-effect profile, though concerns about the “cefazolin inoculum effect” have limited broader acceptance. This randomized controlled trial compared cefazolin with antistaphylococcal penicillins in adults with MSSA bacteremia across multiple countries. Cefazolin achieved noninferior survival outcomes at 90 days and demonstrated superior safety, particularly with respect to renal toxicity. Mortality trends also numerically favoured cefazolin at earlier follow-up intervals, though the trial was primarily designed to assess noninferiority rather than superiority. Strengths included pragmatic enrollment across diverse healthcare settings and use of a hard clinical endpoint. Limitations included the open-label design, potential heterogeneity in post-randomization management such as source control and additional imaging, and lack of microbiologic testing for the cefazolin inoculum effect at the time of publication. Overall, these findings support cefazolin as a strong first-line option for MSSA bacteremia, offering comparable efficacy and improved tolerability.

Click to read the study in NEJM

Relevant Reading: Contemporary use of cefazolin for MSSA infective endocarditis: analysis of a national prospective cohort

In-Depth [randomized controlled trial]: This open-label, randomized controlled trial enrolled 1,341 adults with penicillin-resistant MSSA bacteremia across 91 sites in 8 countries. Patients were randomized 1:1 to receive either cefazolin (n=671) or flucloxacillin/cloxacillin (n=670). The primary endpoint was all-cause mortality at 90 days using a Bayesian noninferiority framework. Among evaluable patients, 90-day mortality occurred in 15.0% (97 of 645) of the cefazolin group versus 17.0% (109 of 642) of the antistaphylococcal penicillin group (adjusted OR, 0.81; 95% credible interval [CrI], 0.59 to 1.12). This corresponded to a 99.2% probability of noninferiority and a 89.8% probability of superiority for cefazolin, though superiority criteria were not formally met. Acute kidney injury within 14 days occurred in 13.9% of cefazolin-treated patients versus 19.6% of those receiving flucloxacillin/cloxacillin (adjusted OR, 0.67; 95% CrI, 0.50 to 0.89). Serious drug-related adverse reactions were also lower with cefazolin (1.8% vs 4.9%; adjusted OR, 0.41; 95% CrI, 0.21 to 0.77). Antibiotic discontinuation due to adverse events occurred substantially less often with cefazolin (1.6% vs 9.1%). These findings suggest cefazolin offers similar efficacy with improved tolerability compared with traditional antistaphylococcal penicillins for MSSA bacteremia.

Image: PD

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