TOPLINE

In patients with methicillin-susceptible Staphylococcus aureus bacteremia, cefazolin proved noninferior to antistaphylococcal penicillins (flucloxacillin and cloxacillin) for 90-day mortality and was also associated with a lower risk for acute kidney injury.

METHODOLOGY

• Researchers conducted an international, Bayesian adaptive noninferiority trial across eight countries to evaluate the efficacy and safety of cefazolin to treat patients with methicillin-susceptible S aureus bacteremia.
• They enrolled 1341 adults (median age, 66 years; 31.4% women) within 72 hours of blood sample collection for the index blood culture, who were randomly assigned to receive cefazolin or an antistaphylococcal penicillin (flucloxacillin or cloxacillin).
• Patients received 2 g cefazolin intravenously (IV) every 8 or 6 hours, 2 g flucloxacillin IV every 6 or 4 hours, or 2 g cloxacillin IV every 4 hours. The primary outcome was death from any cause within 90 days after enrollment. The prespecified threshold for noninferiority was an odds ratio (OR) < 1.2 and for superiority an OR < 1.0.
• Secondary platform outcomes included death from any cause within 14, 28, and 42 days; microbiologic treatment failure and diagnosis of new foci of infection between days 15 and 90; and Clostridioides difficile infection within 90 days.
• Secondary safety outcomes included acute kidney injury (defined as an absolute increase ≥ 26.5 μmol/L in creatinine level within 5 days or a relative increase ≥ 50% from baseline within 14 days), the initiation of renal replacement therapy, and acute liver injury.

TAKEAWAY

• The mortality rate at 90 days was 15.0% in the cefazolin group compared with 17.0% in the antistaphylococcal penicillin group, meeting the prespecified criterion for noninferiority (adjusted OR [aOR], 0.81; 95% credible interval [CrI], 0.59-1.12; posterior probability of noninferiority, 99.2%; posterior probability of superiority, 89.8%).
• No significant differences were noted in death from any cause within 14, 28, and 42 days; microbiologic treatment failure and diagnosis of new foci of infection between days 15 and 90; and C difficile infection within 90 days.
• Acute kidney injury occurred less often among patients who received cefazolin than among those who received flucloxacillin or cloxacillin (13.9% vs 19.6%; aOR, 0.67; 95% CrI, 0.50-0.89; probability of superiority, 99.7%). The posterior probability of a lower risk of initiating renal replacement therapy within 90 days was 94.6% with cefazolin, and the rate of acute liver injury within 14 days was similar between groups (13.1% vs 13.9%; aOR, 0.96; 95% CrI, 0.68-1.35).
• Cefazolin was associated with lower odds of serious adverse reactions than flucloxacillin or cloxacillin (aOR, 0.41; 95% CrI, 0.21-0.77) and lower odds of treatment discontinuation due to adverse events (aOR, 0.21; 95% CrI, 0.11-0.38).

IN PRACTICE

“In this pragmatic, international, open-label trial, treatment with cefazolin was noninferior to treatment with flucloxacillin or cloxacillin with respect to 90-day all-cause mortality among adults with methicillin-susceptible S aureus bacteremia,” the authors concluded. “Cefazolin was associated with fewer serious adverse events, in particular, a lower incidence of acute kidney injury.”

SOURCE

The study was led by Todd C. Lee, MD, MPH, McGill University Health Centre, Montreal, Quebec, Canada. It was published online on June 17 in The New England Journal of Medicine.

LIMITATIONS

The open-label design could have introduced bias. Postrandomization care was not standardized or fully captured, and clinical practice varied across sites.

DISCLOSURES

This study received support from grants provided by the National Health and Medical Research Council and the Medical Research Future Fund in Australia; the Canadian Institutes of Health Research and the Accelerating Clinical Trials Consortium in Canada; the ZonMw Good Use of Medicines program and the University Medical Center Utrecht in the Netherlands; the Health Research Council of New Zealand and the Starship Foundation in New Zealand, and several other organizations. Several authors reported receiving research grants or speaker fees or having other ties with various sources. Full disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.