Cefazolin Proves Its Mettle for Methicillin-Susceptible Staph Infections

Cefazolin was effective for the treatment of bacteremia caused by methicillin-susceptible Staphylococcus aureus (MSSA), findings of an international open-label platform trial showed.

Among patients hospitalized with penicillin-resistant MSSA bacteremia, the 90-day mortality rate was 15% among those randomized to cefazolin versus 17% for those receiving either cloxacillin or flucloxacillin (adjusted OR 0.81, 95% credible interval [CrI] 0.59-1.12).

By Bayesian analysis, cefazolin’s probability of noninferiority to the antistaphylococcal penicillins was 99.2% and its probability of superiority 89.8% in the study of nearly 1,300 individuals, as reported by Stephen Tong, MBBS, PhD, and fellow collaborators of the Staphylococcus aureus Network Adaptive Platform (SNAP) Trial Group.

Cefazolin patients also had a lower incidence of acute kidney injury within 14 days than those taking the penicillins, 13.9% vs 19.6% (adjusted OR 0.67, 95% CrI 0.50-0.89), with cefazolin showing a 99.7% probability of superiority, the researchers detailed in the New England Journal of Medicine.

These results should allay theoretical concerns about the cefazolin inoculum effect (CIE) when considering this first-generation cephalosporin in MSSA bacteremia, said Tong, of the Peter Doherty Institute for Infection and Immunity in Melbourne, Australia. The CIE relates to findings from the laboratory, where some MSSA strains produce a beta-lactamase that breaks down cefazolin. Additionally, case reports had suggested that cefazolin treatment may fail when infections are caused by bacteria that can cause CIE.

SNAP shows that cefazolin’s effectiveness was not hindered by CIE after all: “For such a large group of patients, including the subgroup with endocarditis, cefazolin was as effective and probably more effective than ASPs [antistaphylococcal penicillins],” Tong told MedPage Today.

Even so, the researchers plan to take a closer look at the CIE’s potential role by phenotyping and genotyping the study’s S. aureus isolates, he noted.

The bottom line for clinicians treating MSSA bacteremia: “Cefazolin should be the preferred antibiotic,” Tong said. “In my practice, the only time I am using ASPs is where there has been a relapse of invasive MSSA following an appropriate treatment course with cefazolin.”

A leading cause of bacteria-related death, S. aureus bacteremia can lead to mortality rates reaching 10% at 7 days and 30% at 1 year. While methicillin-resistant S. aureus (MRSA) is better known to the public, MSSA can also cause serious or fatal outcomes. Both are typically treated with IV antibiotics over several weeks — though a two-dose infusion of dalbavancin (Dalvance) has also been found to be effective.

The ongoing SNAP trial has multiple arms comparing interventions to manage S. aureus bacteremia, including standard therapies vancomycin and daptomycin versus cefazolin in MRSA; benzylpenicillin versus flucloxacillin or cloxacillin in penicillin-susceptible S. aureus (PSSA); and adjunctive clindamycin in MRSA, MSSA, or PSSA.

The present MSSA analysis included 1,287 adults hospitalized from February 2022 to June 2024 across eight countries and 91 sites. Median patient age was 66 years, 31% were women, and the most common infections were osteoarticular (32% of patients).

The SNAP researchers randomized patients 1:1 to either 2 g of IV cefazolin every 8 hours, or to one of the two antistaphylococcal penicillins, depending on country: 2 g of IV flucloxacillin every 6 hours, or 2 g of cloxacillin every 4 hours. Minimum antibiotic treatment was 14 days for uncomplicated bacteremia and 28 to 42 days for complicated bacteremia. Clinical management was left to treating clinicians’ discretion.

The primary outcome was death from any cause within 90 days. The probability of noninferiority was based on an adjusted OR <1.2, and the probability of superiority was set for adjusted OR <1.0.

Safety outcomes included acute kidney injury, renal replacement therapy, and acute liver injury.

Rates of acute liver injury within 14 days were 13.1% in the cefazolin group and 13.9% in the penicillin group, with a 90% probability of noninferiority for cefazolin. A total of 2.5% of cefazolin patients and 4.1% of penicillin patients started renal replacement therapy within 90 days, with 0.6% and 0.5%, respectively, still needing that therapy at 90 days.

The rate of drug-related serious adverse reactions was 1.8% among those on cefazolin and 4.9% among the penicillin patients, with a 99.9% noninferiority probability and a 99.8% superiority probability for cefazolin. A total of 1.6% of cefazolin patients changed antibiotic because of an adverse event, compared with 9.1% of those in the penicillin group.

Study limitations included its open-label design and the limited control over clinician decisions after patients were randomized to treatment. Practice variability across sites could have introduced heterogeneity in results.