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

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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%.

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Data Availability

All data generated or analysed during this study are included in this published article.

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Acknowledgements

We are grateful to Meiji Seika Pharma Co., Ltd., Japan, for supplying nacubactam hydrate and clinical isolates used in this study. We would like to thank Editage (www.editage.com) for English language editing.

Funding

This study was supported by the Japan Agency for Medical Research and Development (grant number: JP18pc0101028) and the Keio University Doctorate Student Grant-in-Aid Program of the Ushioda Memorial Fund and Meiji Seika Pharma Co., Ltd., Japan.

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Authors and Affiliations

  1. Division of Pharmacodynamics, Keio University Faculty of Pharmacy, 1-5-30 Shibakoen, Minato-Ku, Tokyo, 105-8512, Japan

    Yuki Igarashi, Wataru Takemura, Xiaoxi Liu, Nana Kojima, Takumi Morita, Yuki Enoki, Kazuaki Taguchi & Kazuaki Matsumoto

  2. Discipline of Pharmacy, Curtin Medical School, Faculty of Health Sciences, Curtin University, GPO Box U1987, Perth, Western Australia, 6845, Australia

    Victor Tuan Giam Chuang

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  1. Yuki Igarashi
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  2. Wataru Takemura
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  8. Kazuaki Taguchi
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  9. Kazuaki Matsumoto
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Contributions

Yuki Igarashi contributed to the conception and design of the study. In vitro PD experiments were performed by Yuki Igarashi. In vivo PD experiments were performed by Yuki Igarashi, Wataru Takemura, Xiaoxi Liu, Nana Kojima, and Takumi Morita. Yuki Igarashi, Yuki Enoki, Kazuaki Taguchi, and Kazuaki Matsumoto performed analysis and interpretation of data. Yuki Igarashi wrote the first draft of the manuscript. Victor Tuan Giam Chuang, Kazuaki Taguchi, and Kazuaki Matsumoto edited the manuscript. All authors have read and approved the final manuscript.

Corresponding author

Correspondence to Kazuaki Taguchi.

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Conflict of Interest

K. Matsumoto received grant support from Meiji Seika Pharma Co., Ltd. and Sumitomo Pharma Co., Ltd. as well as speaker honoraria from Meiji Seika Pharma Co., Ltd.

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Igarashi, Y., Takemura, W., Liu, X. et al. In vivo Pharmacokinetic/Pharmacodynamic Analysis of the Efficacy of the Cefepime/Nacubactam Combination Against β-Lactamase-Producing Enterobacterales based on the Instantaneous MIC Concept. Pharm Res 40, 2423–2431 (2023). https://doi.org/10.1007/s11095-023-03608-8

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