LAUSR

OBJECTIVE To correlate results of a modified susceptibility testing method to outcomes of ceftazidime-avibactam (CAZ/AVI) therapy. METHODS Two bloodstreamK. 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 24 h) and KP286 (persistent bacteremia for over 30 days). Carbapenemase production in the two isolates was confirmed via Carba NP test. CAZ minimum inhibitory concentration (MIC) was determined with escalating avibactam concentration (0 - 16 mg/L). The concentration-response was characterized by the sigmoid inhibitory maximum effect model. The best-fit parameter values were used to predict %T > MICi associated with CAZ/AVI exposures expected in peritoneal fluid after standard dosing (2.5 g every 8 h). These CAZ/AVI exposures were simulated in the hollow-fiber infection model (HFIM), and the bacterial responses were correlated to observed clinical outcomes. RESULTS The AVI-dependent reduction in CAZ MIC was well characterized in both bacterial isolates (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. CONCLUSIONS The discordant patient outcomes could be potentially explained by MIC profiling of CAZ/AVI. This method appears to be more robust than conventional susceptibility testing in predicting positive clinical outcome of CAZ/AVI therapy, and the clinical utility of this approach should be further investigated.