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

Wataru Takemura; Sho Tashiro; Marina Hayashi; Yuki Igarashi; Xiaoxi Liu; Yuki Mizukami; Nana Kojima; Takumi Morita; Yuki Enoki; Kazuaki Taguchi; Yuta Yokoyama; Tomonori Nakamura; Kazuaki Matsumoto

doi:10.1007/s11095-021-03140-7

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

Wataru Takemura, Sho Tashiro, Marina Hayashi, Yuki Igarashi, Xiaoxi Liu, Yuki Mizukami, Nana Kojima, Takumi Morita, Yuki Enoki, Kazuaki Taguchi, Yuta Yokoyama, Tomonori Nakamura, Kazuaki Matsumoto

School of Pharmacy

Research output: Contribution to journal › Article › peer-review

6 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1839-1846
Number of pages	8
Journal	Pharmaceutical research
Volume	38
Issue number	11
DOIs	https://doi.org/10.1007/s11095-021-03140-7
Publication status	Published - 2021 Nov

Keywords

Beta-lactamase
Cefmetazole
Escherichia coli
Murine thigh infection model
Pharmacokinetics/pharmacodynamics

ASJC Scopus subject areas

Biotechnology
Molecular Medicine
Pharmacology
Pharmaceutical Science
Organic Chemistry
Pharmacology (medical)

Access to Document

10.1007/s11095-021-03140-7

Cite this

Takemura, W., Tashiro, S., Hayashi, M., Igarashi, Y., Liu, X., Mizukami, Y., Kojima, N., Morita, T., Enoki, Y., Taguchi, K., Yokoyama, Y., Nakamura, T., & Matsumoto, K. (2021). 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. Pharmaceutical research, 38(11), 1839-1846. https://doi.org/10.1007/s11095-021-03140-7

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. / Takemura, Wataru; Tashiro, Sho; Hayashi, Marina et al.

In: Pharmaceutical research, Vol. 38, No. 11, 11.2021, p. 1839-1846.

Research output: Contribution to journal › Article › peer-review

Takemura, W, Tashiro, S, Hayashi, M, Igarashi, Y, Liu, X, Mizukami, Y, Kojima, N, Morita, T, Enoki, Y , Taguchi, K , Yokoyama, Y , Nakamura, T & Matsumoto, K 2021, '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', Pharmaceutical research, vol. 38, no. 11, pp. 1839-1846. https://doi.org/10.1007/s11095-021-03140-7

@article{e5ba92c37c72461eb320ba38bcfa6422,

title = "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",

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.",

keywords = "Beta-lactamase, Cefmetazole, Escherichia coli, Murine thigh infection model, Pharmacokinetics/pharmacodynamics",

author = "Wataru Takemura and Sho Tashiro and Marina Hayashi and Yuki Igarashi and Xiaoxi Liu and Yuki Mizukami and Nana Kojima and Takumi Morita and Yuki Enoki and Kazuaki Taguchi and Yuta Yokoyama and Tomonori Nakamura and Kazuaki Matsumoto",

note = "Funding Information: 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. Funding Information: 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. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.",

year = "2021",

month = nov,

doi = "10.1007/s11095-021-03140-7",

language = "English",

volume = "38",

pages = "1839--1846",

journal = "Pharmaceutical Research",

issn = "0724-8741",

publisher = "Springer New York",

number = "11",

}

TY - JOUR

T1 - 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

AU - Takemura, Wataru

AU - Tashiro, Sho

AU - Hayashi, Marina

AU - Igarashi, Yuki

AU - Liu, Xiaoxi

AU - Mizukami, Yuki

AU - Kojima, Nana

AU - Morita, Takumi

AU - Enoki, Yuki

AU - Taguchi, Kazuaki

AU - Yokoyama, Yuta

AU - Nakamura, Tomonori

AU - Matsumoto, Kazuaki

N1 - Funding Information: 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. Funding Information: 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. Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

PY - 2021/11

Y1 - 2021/11

N2 - 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.

AB - 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.

KW - Beta-lactamase

KW - Cefmetazole

KW - Escherichia coli

KW - Murine thigh infection model

KW - Pharmacokinetics/pharmacodynamics

UR - http://www.scopus.com/inward/record.url?scp=85120326407&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85120326407&partnerID=8YFLogxK

U2 - 10.1007/s11095-021-03140-7

DO - 10.1007/s11095-021-03140-7

M3 - Article

C2 - 34853981

AN - SCOPUS:85120326407

SN - 0724-8741

VL - 38

SP - 1839

EP - 1846

JO - Pharmaceutical Research

JF - Pharmaceutical Research

IS - 11

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this