The Cefazolin Inoculum Effect: An Underappreciated Factor in MSSA Treatment Strategies.

Methicillin-susceptible Staphylococcus aureus (MSSA) remains a major cause of morbidity and mortality worldwide, particularly owing to its role in complicated infections including bloodstream infections, osteomyelitis, and infective endocarditis. In 2017, an estimated 119,247 cases of S. aureus bloodstream infections were reported in the USA, resulting in approximately 19,832 deaths. While the prevalence of MSSA varies by region and demographic factors, MSSA has been reported to be approximately two times more common than methicillin-resistant S. aureus (MRSA) in both total and complicated infections. Cefazolin, a first-generation cephalosporin, is widely used for MSSA treatment owing to its favorable safety profile, cost-effectiveness, and availability. However, its efficacy may be compromised by the cefazolin inoculum effect (CzIE)-a phenomenon where cefazolin activity diminishes at high bacterial densities, such as those found in endocardial vegetations or abscesses. Importantly, CzIE is not universally present across all MSSA isolates and geographical areas, with reported prevalence ranging from 0% to 55%. Initially considered a result of producing specific allotypes of the staphylococcal β-lactamase enzyme BlaZ (i.e., allotypes A and C), recent work sheds new light on different BlaZ allotypes associated with the effect while establishing that no single genetic determinant or allotype is uniquely and definitively responsible. When present, CzIE can lead to elevated cefazolin MICs at high inocula, potentially resulting in treatment failure, prolonged hospitalization, and increased mortality. Despite these concerns, clinical data remain inconclusive, and the true impact of CzIE on patient outcomes is still under investigation. This review critically evaluates the molecular basis, clinical relevance, and diagnostic challenges of CzIE, with the goal of informing antibiotic stewardship and optimizing treatment strategies for serious MSSA infections.