In vivo Pharmacokinetic/Pharmacodynamic Analysis of the Efficacy of the Cefepime/Nacubactam Combination Against β-Lactamase-Producing Enterobacterales based on the Instantaneous MIC Concept.

PURPOSE

Nacubactam (NAC) is a novel diazabicyclooctane β-lactamase inhibitor used in combination with cefepime (CFPM). In this study, we aimed to determine the target pharmacokinetics (PK) and pharmacodynamics (PD) values of CFPM/NAC in mice infected with β-lactamase-producing Enterobacterales, such as the carbapenemase-producing Enterobacterales.

METHODS

Three strains of β-lactamase-producing Enterobacterales, Klebsiella pneumoniae MSC 21444, Escherichia coli MSC 20662, and K. pneumoniae ATCC BAA-1898, were used for checkerboard assays and fractionation studies and dose-range studies. A PK study was performed in neutropenic mice. Additionally, PK/PD analysis was performed based on the instantaneous minimum inhibitory concentration (MIC) concept.

RESULTS

Checkerboard measurements revealed that higher NAC concentrations decreased the CFPM MIC in a concentration-dependent manner. In all tested strains, fT > MIC calculated from the PK experiments showed a high correlation with the mean change in the bacterial count of thigh-infected mice in the in vivo PD study, suggesting that fT > MIC is an optimal PK/PD parameter for monitoring the CFPM/NAC combination. The target fT > MIC values for CFPM/NAC to achieve a bacteriostatic effect, 1-log-kill, and 2-log-kill values were 30, 49, and 94%, respectively.

CONCLUSIONS

Our results indicate that fT > MIC is a PK/PD parameter is suitable for monitoring the CFPM/NAC combination. The minimum target value for achieving a static effect against β-lactamase-producing Enterobacterales is 30%.