Clinical Impact of the Cefazolin Inoculum Effect

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ABSTRACT Staphylococcus aureus is a major human pathogen responsible for a wide range of life-threatening infections. Many of these infections are caused by methicillin-susceptible S. aureus (MSSA). MSSA represent a major burden among S. aureus infections and are important contributors to mortality. For decades, the first line of therapy for severe MSSA infections have been the isoxazolyl-penicillins (ISP, e.g., nafcillin). However, recent data suggest that clinical outcomes in MSSA bacteremia are similar in patients treated with cefazolin (vs nafcillin), a cephalosporin with activity against MSSA that appears to be less toxic. Indeed, treatment with nafcillin seems to be associated with increased costs, more drug reactions (including hepatotoxicity, interstitial nephritis and neutropenia) and, possibly, higher mortality. Due to these concerns, an important shift in the treatment of MSSA is occurring whereby clinicians are now using cefazolin as first line of therapy for severe MSSA infections. An important concern of using cefazolin and other cephalosporins as primary therapy for these serious infections is the cefazolin inoculum effect (CzIE), defined as a cefazolin minimal inhibitory concentration of > 16 µg/ml when a high inoculum (107 CFU/ml) is used. The CzIE has been associated with failures in the treatment of deep-seated MSSA infections and with the production of certain isotypes of the staphylococcal β-lactamase. However, the characterization of the clinical impact of this phenomenon in deep-seated MSSA infections is limited. In addition, it is currently not possible to detect the CzIE in a standard clinical microbiology laboratory given the cumbersome and expensive nature of the gold standard test for its detection. Our published and preliminary clinical data suggest that the CzIE is an important contributor to worse clinical outcomes of severe MSSA infections. Furthermore, we have developed and published a novel colorimetric nitrocefin-based rapid test (~3 h) that detects the CzIE with high sensitivity and specificity that can be incorporated in the routine clinical microbiology laboratory. We postulate that, i) the CzIE negatively impacts clinical outcomes in MSSA bacteremia treated with cefazolin and, ii) a rapid test can be readily implemented for the identification of the CzIE in S. aureus bacteremia and can detect patients at higher risk of poor outcomes. In order to address these hypotheses, we will take advantage of the Staphylococcus aureus Network Adaptive Platform (SNAP) trial, a multicenter, pragmatic, multi-arm, open-label adaptive platform trial addressing multiple therapeutic questions in patients with S. aureus bacteremia. We will focus in the MSSA “domain” that evaluates the effectiveness and safety of cefazolin vs ISP in a randomized fashion, currently enrolling in Australia, Singapore, Canada, Israel, New Zealand, United Kingdom, United States, Colombia and Chile. The specific aims of our proposal are: i) to define the clinical impact of the CzIE in MSSA bacteremia and, ii) to determine the clinical value and feasibility of a rapid test to detect the CzIE. Our findings are likely to transform the treatment approach for MSSA infections and will provide the basis to develop novel diagnostic tools to the management of MSSA infections.