Abstract
BackgroundCarbapenemases confer resistance against a broad range of beta-lactams with a prevalence of 40-60% among CRE (carbapenem-resistant Enterobacteriaceae). CAZ-AVI is commonly used to treat infections due to CPE (carbapenemase-producing Enterobacteriaceae), typically guided by susceptibility testing with a single AVI concentration. This methodology does not take into consideration varying AVI concentration observed in vivo, and may not reliably predict positive clinical outcomes. Our objective was to investigate a novel susceptibility testing method to guide CAZ-AVI therapy.MethodsTwo bloodstream K. pneumoniae isolates (CAZ/AVI susceptible) from an abdominal source were recovered from 2 unrelated patients. Both patients were treated with CAZ/AVI, but had discordant outcomes: KP118 (eradication within 24h) and KP286 (persistent bacteremia for over 30 days). Carbapenemase production in the 2 isolates was confirmed via Carba NP test, and CAZ susceptibility was determined in a clinically relevant range of AVI concentration (0 - 16 mg/L). The concentration-response was characterized by the sigmoid inhibitory maximum effect (Emax) model. The best-fit parameter values were used to predict %T > MICi associated with CAZ/AVI exposures expected in peritoneal fluid after standard dosing (2.5g q8h). These CAZ/AVI exposures were simulated in the hollow-fiber infection model (HFIM), and the bacterial responses were correlated to observed clinical outcomes.ResultsThe AVI-dependent reduction in CAZ MIC was well characterized in both strains (R2 > 0.98). In HFIM, sustained suppression of KP118 (T > MICi = 100%) was observed over 5 days, but not with KP286 (T > MICi < 100%). These observations are consistent with the clinical courses of the patients.ConclusionThe discordant patient outcomes could be explained by MIC profiling of CAZ/AVI. This method appears to be more robust than conventional susceptibility testing, and the clinical utility of this approach should be further investigated.Disclosures All Authors: No reported disclosures
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