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

• Published in: Pharmaceutical research 2021-11, Vol.38 (11), p.1839-1846
• Main Authors: Takemura, Wataru, Tashiro, Sho, Hayashi, Marina, Igarashi, Yuki, Liu, Xiaoxi, Mizukami, Yuki, Kojima, Nana, Morita, Takumi, Enoki, Yuki, Taguchi, Kazuaki, Yokoyama, Yuta, Nakamura, Tomonori, Matsumoto, Kazuaki
• Format: Article
• Language: English
• Subjects: Analysis; Animal models; Animals; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Antibacterial activity; Antibacterial agents; Antibiotics; Beta lactamases; beta-Lactam Resistance; beta-Lactamases - metabolism; Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Carbapenems; Carbapenems - pharmacology; Carbapenems - therapeutic use; Cefmetazole; Cefmetazole - pharmacology; Cefmetazole - therapeutic use; Disease Models, Animal; E coli; Escherichia coli; Escherichia coli - drug effects; Escherichia coli - enzymology; Escherichia coli Infections - drug therapy; Escherichia coli Infections - microbiology; Escherichia coli Proteins - metabolism; Female; Health aspects; Humans; Infection; Infections; Medical Law; Medical research; Medicine, Experimental; Mice; Microbial Sensitivity Tests; Minimum inhibitory concentration; Neutropenia; Neutropenia - drug therapy; Neutropenia - microbiology; Pharmacodynamics; Pharmacokinetics; Pharmacology/Toxicology; Pharmacy; Research Paper; β Lactamase
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-021-03140-7

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 (f T>MIC), with the target values for a static effect and 1 log 10 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 “ f T>MIC” ≥ 69.6% for the treatment of ESBL-EC infections.