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- Title
In vivo Pharmacokinetic/Pharmacodynamic Analysis of the Efficacy of the Cefepime/Nacubactam Combination Against β-Lactamase-Producing Enterobacterales based on the Instantaneous MIC Concept.
- Authors
Igarashi, Yuki; Takemura, Wataru; Liu, Xiaoxi; Kojima, Nana; Morita, Takumi; Chuang, Victor Tuan Giam; Enoki, Yuki; Taguchi, Kazuaki; Matsumoto, Kazuaki
- Abstract
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 (MICi) concept. Results: Checkerboard measurements revealed that higher NAC concentrations decreased the CFPM MIC in a concentration-dependent manner. In all tested strains, fT > MICi 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 > MICi is an optimal PK/PD parameter for monitoring the CFPM/NAC combination. The target fT > MICi values for CFPM/NAC to achieve a bacteriostatic effect, 1-log10-kill, and 2-log10-kill values were 30, 49, and 94%, respectively. Conclusions: Our results indicate that fT > MICi 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%.
- Subjects
CEFEPIME; PHARMACOKINETICS; KLEBSIELLA pneumoniae; ESCHERICHIA coli; PHARMACODYNAMICS; FOSFOMYCIN; IN vivo studies
- Publication
Pharmaceutical Research, 2023, Vol 40, Issue 10, p2423
- ISSN
0724-8741
- Publication type
Article
- DOI
10.1007/s11095-023-03608-8