Clinical Impact of the Cefazolin Inoculum Effect - ABSTRACT Methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia remains a major cause of morbidity, mortality, in the United States. Anti-staphylococcal penicillins have been the standard treatment for severe MSSA infections. However, accumulating evidence indicates that cefazolin provides comparable efficacy with fewer adverse events, lower toxicity, and reduced treatment costs. Consequently, cefazolin is now considered first-line therapy for severe MSSA infections. A major concern accompanying this therapeutic shift is the cefazolin inoculum effect (CzIE), defined as a cefazolin minimum inhibitory concentration >16 ìg/mL when tested at a high bacterial inoculum (107 CFU/mL). The CzIE has been associated with treatment failures and with production of specific staphylococcal â-lactamases, yet its true clinical impact and epidemiology remain poorly understood. Furthermore, current laboratory methods for detecting the CzIE are labor-intensive, costly, and impractical for routine clinical use. We developed a rapid nitrocefin-based colorimetric assay capable of detecting the CzIE within hours, making implementation in routine clinical microbiology laboratories feasible. We postulate that (i) the CzIE adversely affects outcomes in patients with MSSA bacteremia, and (ii) rapid detection of the CzIE can identify patients at increased risk of poor outcomes and guide optimal antimicrobial therapy. The proposed work includes a critical international component through collaboration with the Australian-led S. aureus Network Adaptive Platform (SNAP; Drs. Tong, Davis, and Howden), a large multicenter clinical trial expected to enroll 7,000 patients with S. aureus bacteremia across nearly 100 sites worldwide, including in the United States. SNAP is one of only two randomized clinical trials evaluating anti-staphylococcal penicillins vs. cefazolin for S. aureus bacteremia. Through SNAP, we will gain access to a globally representative collection of randomized clinical data and bacterial isolates, enabling rigorous assessment of the clinical impact of the CzIE. Conducting part of this research in foreign countries is scientifically essential because the prevalence of the CzIE varies substantially by geographic region. While approximately 25% of MSSA bloodstream isolates in the United States exhibit the CzIE, prevalence is significantly higher in South America (~40%). Inclusion of Chilean sites (Dr. Munita) will enrich the number of CzIE-positive cases and enable validation of our rapid diagnostic assay across, healthcare systems. Access to geographically distinct MSSA strains will also facilitate a more comprehensive evaluation of strain-specific determinants of the CzIE. The benefits to the US are direct and substantial by generating evidence to optimize antibiotic selection, improve patient outcomes, reduce treatment-related toxicity and healthcare costs, strengthen antimicrobial stewardship efforts, and provide a deployable diagnostic tool for U.S. clinical microbiology laboratories. By leveraging unique international epidemiologic, clinical, and microbiologic resources unavailable within the United States alone, this study will accelerate advances in the management of severe MSSA infections and improve care for thousands of Americans each year.
