In Vitro Efficacy of Meropenem-Cefmetazole Combination Therapy against New Delhi Metallo-β-lactamase-producing Enterobacteriaceae

Hideharu Hagiya, Yo Sugawara, Yuko Tsutsumi, Yukihiro Akeda, Norihisa Yamamoto, Noriko Sakamoto, Rathina Kumar Shanmugakani, Ryuichiro Abe, Dan Takeuchi, Isao Nishi, Yoshikazu Ishii, Shigeyuki Hamada, Kazunori Tomono

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Limited treatment options complicate management of infections with New Delhi metallo-β-lactamase (NDM)-producing organisms. The efficacy of combination therapy with meropenem (MEM) and cefmetazole (CMZ) was assessed against NDM-producing Enterobacteriaceae. Materials and Methods: Twelve Escherichia coli clinical isolates harbouring blaNDM-1 and a positive control E. coli BAA-2469 harbouring blaNDM-1 were studied. Minimum inhibitory concentrations (MICs) of MEM, ertapenem (ERT) and CMZ were determined by broth microdilution. Checkerboard and time-kill assays were performed to confirm the in vitro efficacy of the MEM/CMZ combination. Scanning electron microscopy, kinetic studies and whole-genome sequence analysis were used to determine the antimicrobial resistance mechanisms. Results: MICs of MEM, ERT and CMZ in monotherapy ranged from 8 to 32, 16 to 128, and 32 to 512 µg/mL, respectively. In the checkerboard assay, MEM/ERT resulted in no synergy, whereas MEM/CMZ showed a synergistic effect in all the tested isolates. Furthermore, the MIC of MEM in combination decreased by 2- to 8-fold compared with that of MEM alone. The time-kill study revealed a bactericidal effect in 4 of 13 isolates at 24 h. Scanning electron microscopy showed spheroidisation of the bacterial cell in the MEM/CMZ combination; this was not observed in single antibiotic conditions. Kinetic studies indicated CMZ was a better antagonist for NDM-1 than ERT. Whole-genome sequence analysis did not reveal any explainable differences between isolates susceptible and those non-susceptible to combination therapy. Conclusion: In vitro studies showed the potential effectiveness of MEM/CMZ combination therapy against NDM-producing organisms.

Original languageEnglish
Article number105905
JournalInternational Journal of Antimicrobial Agents
Volume55
Issue number3
DOIs
Publication statusPublished - Mar 2020

Keywords

  • carbapenem-resistant Enterobacteriaceae
  • carbapenemase-producing Enterobacteriaceae
  • cefmetazole
  • cephamycin
  • combination therapy

ASJC Scopus subject areas

  • Microbiology (medical)
  • Infectious Diseases
  • Pharmacology (medical)

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