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Cefmetazole as an Alternative to Carbapenems Against Extended-Spectrum Beta-Lactamase-Producing Escherichia coli Infections Based on In Vitro and In Vivo Pharmacokinetics/Pharmacodynamics Experiments

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Abstract

Purpose

Cefmetazole (CMZ) has received attention as a pharmaceutical intervention for extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-EC) infections. This study aimed to investigate the pharmacokinetics/pharmacodynamics (PK/PD) characteristics of CMZ against ESBL-EC.

Methods

The susceptibility and time-killing activity of CMZ against clinically isolated ESBL-EC (EC9 and EC19) were determined in vitro. The optimal PK/PD index and its target value were calculated based on the results of a PK study in healthy mice and PD study in neutropenic murine thigh infection model mice.

Results

The minimum inhibitory concentrations (MICs) of CMZ against EC9 and EC19 were 2.0 and 1.0 µg/mL, respectively. Time–kill studies showed that colony-forming units decreased in a time-dependent manner at CMZ concentrations in the range of 4–64 × MIC. In in vivo PK/PD studies, the antibacterial effect of CMZ showed the better correlation with the time that the free drug concentration remaining above the MIC (fT>MIC), with the target values for a static effect and 1 log10 kill reduction calculated as 57.6% and 69.6%, respectively.

Conclusion

CMZ possesses time-dependent bactericidal activities against ESBL-EC and is required to achieve “fT>MIC” ≥ 69.6% for the treatment of ESBL-EC infections.

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Data Availability

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

Abbreviations

CFU:

Colony-forming units

CIV:

Continuous intravenous infusion

CLSI:

Clinical and Laboratory Standards Institute

CMZ:

Cefmetazole

ESBL:

Extended-spectrum beta-lactamase

ESBL-EC:

Extended-spectrum beta-lactamase-producing Escherichia coli

fAUC24/MIC:

Ratio of the area under the free drug concentration–time curve for a 24 h period to the minimum inhibitory concentration

fCmax/MIC:

Ratio of the maximum free drug concentration to the minimum inhibitory concentration

fT>MIC:

Time that the free drug concentration remaining above the minimum inhibitory concentration

HPLC:

High-performance liquid chromatography

MIC:

Minimum inhibitory concentration

PK/PD:

Pharmacokinetics/pharmacodynamics

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ACKNOWLEDGMENTS AND DISCLOSURES

This work was supported by JSPS KAKENHI (Grant Number JP18K06795). Sho Tashiro wishes to thank the Nagai Memorial Research Scholarship from the Pharmaceutical Society of Japan. We would like to thank Editage (www.editage.com) for English language editing. All authors meet the ICMJE authorship criteria. The authors declare no potential conflicts of interest.

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Author notes

  1. Wataru Takemura and Sho Tashiro contributed equally to this manuscript.

Authors and Affiliations

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

    Wataru Takemura, Sho Tashiro, Marina Hayashi, Yuki Igarashi, **aoxi Liu, Yuki Mizukami, Nana Kojima, Takumi Morita, Yuki Enoki, Kazuaki Taguchi & Kazuaki Matsumoto

  2. Division of Pharmaceutical Care Sciences, Center for Social Pharmacy and Pharmaceutical Care Sciences, Keio University Faculty of Pharmacy, Tokyo, Japan

    Yuta Yokoyama & Tomonori Nakamura

Authors
  1. Wataru Takemura
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Contributions

Wataru Takemura, Sho Tashiro, Yuta Yokoyama, Kazuaki Matsumoto contributed to the study conception and design. Data collection were performed by Wataru Takemura, Sho Tashiro, Marina Hayashi, Yuki Igarashi, **aoxi Liu, Yuki Mizukami, Nana Kojima, Takumi Morita. Analysis and interpretation of data were performed by Wataru Takemura, Sho Tashiro, Yuki Enoki, Kazuaki Taguchi, Yuta Yokoyama, Tomonori Nakamura, Kazuaki Matsumoto. The first draft of the manuscript was written by Wataru Takemura and Sho Tashiro and was revised critically by Kazuaki Taguchi and Kazuaki Matsumoto. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Kazuaki Taguchi.

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Takemura, W., Tashiro, S., Hayashi, M. et al. Cefmetazole as an Alternative to Carbapenems Against Extended-Spectrum Beta-Lactamase-Producing Escherichia coli Infections Based on In Vitro and In Vivo Pharmacokinetics/Pharmacodynamics Experiments. Pharm Res 38, 1839–1846 (2021). https://doi.org/10.1007/s11095-021-03140-7

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