The international clinical trial published in The New England Journal of Medicine found that cefazolin was noninferior to traditional antistaphylococcal penicillins (ASPs), such as cloxacillin and flucloxacillin, for treating methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia. Cefazolin was also associated with a lower incidence of acute kidney injury.

Clinical Context

S aureus bacteremia is the leading bacterial cause of infection-attributable mortality worldwide, with more than 1 in 4 affected patients dying within 90 days. Despite its serious clinical impact, the preferred beta-lactam antibiotic for methicillin-susceptible infections has remained uncertain. Endocarditis guidelines have traditionally favored ASPs, including flucloxacillin, cloxacillin, nafcillin, and oxacillin, partly because of concerns that cefazolin may be less effective when bacterial concentrations are high, a phenomenon known as the “inoculum effect.” Cefazolin can also be degraded by beta lactamases in vitro. However, a meta-analysis of observational studies suggested that cefazolin may be associated with lower 30-day mortality and fewer adverse effects.

International Trial

To address this uncertainty, the international SNAP trial conducted a randomized, open-label, noninferiority trial within an adaptive Bayesian platform at 91 centers in eight countries: Australia, Canada, Israel, Netherlands, New Zealand, Singapore, South Africa, and the UK.

From February 2022 through August 2024, researchers compared cefazolin with flucloxacillin or cloxacillin in adults hospitalized with methicillin-susceptible, penicillin-resistant S aureus bacteremia.

A total of 1341 patients were randomly assigned to cefazolin (671 patients) or ASP (670 patients). The mean age of the patients was 66 years. Osteoarticular infection was the most common source of bacteremia (32%), followed by skin and soft tissue infection and catheter-related bacteremia.

The primary outcome was all-cause mortality at 90 days, assessed using a hierarchical Bayesian model. The prespecified adjusted odds ratio threshold was < 1.2 for noninferiority and < 1.0 for superiority.

Noninferior, Less Toxic

Among the patients included in the analysis, the 90-day mortality was 15.0%, with 97 of 645 patients dying in the cefazolin group compared with 17.0%, or 109 of 642 patients, in the ASP group. The probability of cefazolin being noninferior to ASP was 99.2%, while the probability of superiority was 89.8%. The results met the prespecified criterion for noninferiority, prompting the Data and Safety Monitoring Committee to recommend closing enrollment in this treatment group.

Cefazolin was also associated with a significantly lower incidence of acute kidney injury, occurring in 13.9% of patients, or 92 of 660, than in the ASP group, occurring in 19.6%, or 127 of 648. The adjusted odds ratio was 0.67. Serious adverse reactions occurred in 1.8% vs 4.9% of patients receiving cefazolin vs those receiving ASP. Treatment discontinuation due to adverse effects was also less common with cefazolin vs ASP, at 1.6% vs 9.1%.

An interim analysis in June 2024 identified a safety signal involving kidney injury that led to a temporary pause in enrollment. Subsequent analysis found that the signal favored cefazolin over the ASPs. After the noninferiority criterion was met, the committee recommended closing enrollment in this trial arm.

Speaking with Univadis Spain, part of the Medscape Professional Network, Diego García Martínez de Artola, clinical microbiologist at Hospital Universitario Nuestra Señora de Candelaria in Santa Cruz de Tenerife, Spain, Antimicrobial Resistance and Mechanisms of Action Study Group and Study Group on Healthcare-associated Infections, scientific working group of the Spanish Society of Infectious Diseases and Clinical Microbiology, Madrid, Spain, said that “severe infections are highly complex and that even when appropriate treatment is given, some patients do not respond favorably.” “For this reason, we are constantly seeking to improve this area, which would represent a significant clinical advantage. The problem lies in the fact that treatments such as cloxacillin or flucloxacillin, depending on the country, have well-documented drawbacks: They require high doses and a very frequent and demanding dosing regimen, which can lead to complications such as phlebitis and renal toxicity. For this reason, the use of cefazolin to prevent these types of adverse effects has increased in recent years.”

“Although randomized clinical trials were lacking, we now have evidence from studies such as the SNAP Trial and the CloCeBa trial.” All pointed in the same direction. Therefore, when clinical guidelines are updated, it is likely that cefazolin will be ranked higher than cloxacillin.

Clinical Implications

The inoculum effect is of particular concern in patients with endocarditis. In this subgroup, 90-day mortality was also numerically lower with cefazolin vs ASP, at 15.7% vs 24.5%, although the number of patients was limited. The authors noted that this finding, together with the narrow overall noninferiority margin, should help reduce clinical concerns regarding the inoculum effect. A specific analysis using microbiological isolates from the trial is still pending to determine whether the “inoculum effect” showed any changes in outcomes.

“The inoculum effect has been widely discussed in vitro and in recent publications, including a multicenter retrospective analysis. The study found poorer microbiological outcomes, with greater difficulty in eradicating the bacteria, although the final clinical outcomes did not differ. This may reflect substantial differences in the laboratory methods used to detect the inoculum effect, making the findings difficult to standardize and limiting their ability to draw firm conclusions.”

“As more evidence becomes available and these methods are standardized, cefazolin is very likely to become firmly established in clinical practice guidelines. In fact, it is already routinely used in many centers, regardless of whether the infection involves a high or low inoculum. Given that clinical trials have shown similar clinical outcomes with fewer adverse effects, this shift is logical. It remains to be determined whether a specific subgroup may continue to benefit from cloxacillin. This question remains unresolved because the methods used to quantify the inoculum effect are currently heterogeneous,” García Martínez de Artola said.

The researchers identified several limitations, including the open-label design. However, the primary outcome, death, is an objective measure that is unlikely to be affected by observer bias. The study also had a limited ability to control clinical decisions after randomization, including changes in antibiotic therapy and management of the source of infection.

The authors concluded that in adults with MSSA bacteremia, cefazolin was noninferior to flucloxacillin or cloxacillin with respect to 90-day mortality and was associated with a lower incidence of acute kidney injury and a simpler dosing regimen.

These findings from a large, pragmatic, randomized trial provide robust evidence to guide the choice of beta-lactam antibiotics for this common and potentially life-threatening infection.

The authors of the study and García Martínez de Artola reported having any relevant financial conflicts of interest.

This story was translated from Univadis Spain.