MIC profiling of ceftazidime/avibactam against two carbapenemase-producing Klebsiella pneumoniae isolates

•Report of two bacteraemia cases due to carbapenemase-producing Klebsiella pneumoniae.•Both isolates were susceptible to ceftazidime/avibactam (CAZ/AVI) by conventional testing.•Discordant clinical outcomes were observed with CAZ/AVI therapy.•MIC profiling was used to predict %T > MICi exposures of CAZ/AVI.•MIC profiling appears robust in predicting positive clinical outcomes. The aim of this study was to correlate the results of a modified susceptibility testing method with outcomes of ceftazidime/avibactam (CAZ/AVI) therapy. Two bloodstream K. pneumoniae isolates (CAZ/AVI-susceptible) from an abdominal source were recovered from two unrelated patients. Both patients were treated with CAZ/AVI but had discordant outcomes: KP118 (eradication within 24 h) and KP286 (persistent bacteraemia for over 30 days). Carbapenemase production in the two isolates was confirmed by Carba NP test. The CAZ minimum inhibitory concentration (MIC) was determined with escalating AVI concentrations (0–16 mg/L). The concentration–response was characterised 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 a hollow-fibre infection model (HFIM), and the bacterial responses were correlated with observed clinical outcomes. The AVI-dependent reduction in CAZ MIC was well characterised in both bacterial isolates (r2 ≥ 0.98). In the HFIM, sustained suppression of KP118 (T > MICi = 100%) was observed over 5 days, but not with KP286 (T > MICi