In Vitro Dynamic Model Evaluation of Meropenem Alone and in Combination with Avibactam Against Carbapenemase-Producing Klebsiella pneumoniae

<b>Background:</b> A potential strategy to maintain the efficacy of carbapenems against carbapenemase-producing <i>Klebsiella pneumoniae</i> (CPKP) is their combination with carbapenemase inhibitors. To address these issues, the effectiveness of a novel combination of meropenem with avibactam against CPKP was studied. Additionally, the applicability of a pharmacokinetically-based approach to antibiotic/inhibitor minimum inhibitory concentration (MIC) determinations to better predict efficacy was examined. <b>Methods:</b> CPKP strains were exposed to meropenem alone or in combination with avibactam in an in vitro hollow-fiber infection model. Treatment effects were correlated with simulated antibiotic and antibiotic/inhibitor combination ratios of the area under the concentration-time curve (AUC) to the MIC (AUC/MIC). All MICs were determined at standard and at high inocula; combination MICs were determined using the conventional approach with fixed avibactam concentration or using the pharmacokinetic (PK)-based approach with a fixed meropenem-to-avibactam concentration ratio, equal to the respective drug therapeutic AUC ratios. <b>Results:</b> Meropenem alone was not effective even against a "susceptible" CPKP strain. The addition of avibactam significantly improved both meropenem MICs and its effectiveness. The effects of meropenem alone and in combination with avibactam (merged data) correlated well with AUC/MIC ratios only when MICs were determined at high inocula and using the PK-based approach (<i>r</i>² 0.97); the correlation was worse with the conventional approach (<i>r</i>² 0.73). <b>Conclusions:</b> The effectiveness of meropenem/avibactam against CPKP is promising. A single "effect-AUC/MIC" relationship useful for predicting meropenem efficacy (alone or in combination with avibactam) was obtained using MICs at high inocula and combination MICs determined using a PK-based approach.