In Vitro Effectiveness of Meropenem and Cefmetazole Combination Treatment Against KPC-2-Producing Enterobacteriaceae

Hideharu Hagiya, Kotaro Aoki, Yukihiro Akeda, Norihisa Yamamoto, Rathina Kumar Shanmugakani, Yoshikazu Ishii, Kazunori Tomono

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)


Purpose: Optimal treatment regimens are yet to be established for carbapenemase-producing Enterobacteriaceae (CPE). We assessed the in vitro efficacy of meropenem (MEM) and cefmetazole (CMZ) combination treatment against blaKPC-2-positive Enterobacteriaceae, in comparison with that of double-carbapenem therapy using ertapenem (ERT). Materials and Methods: We performed checkerboard assay for 10 blaKPC-2-positive clinical isolates and Klebsiella pneumoniae BAA-1705 (possessing blaKPC-2), with synergistic effect being defined by a fractional inhibitory concentration index of ≤0.5. Subsequently, we conducted time-kill assays using K. pneumoniae BAA-1705 with an initial inoculum of 104-107 colony forming unit (CFU)/mL. Bactericidal effect was defined as the reduction of initial bacterial count by ≥103 CFU/mL in 24 hr. Finally, we applied scanning electron microscopy to observe morphological changes induced by the combination of MEM and CMZ. Results: Checkerboard assays revealed a synergistic effect in 7 out of 11 blaKPC-2 -positive Enterobacteriaceae when the MEM and CMZ combination was used, and no effect when the MEM and ERT combination was used. The minimum inhibitory concentration of MEM decreased 4-8-fold when combined with CMZ. Time-kill assays with an initial inoculum of 5 × 105 CFU/mL revealed regrowth under the combination of MEM and ERT (0.25 × minimum inhibitory concentration [MIC] each), whereas the combination of 0.25 × MIC each of MEM and CMZ exhibited bactericidal effect. Scanning electron microscopy results demonstrated that the combination of 0.5 × MIC MEM and 0.5 × MIC CMZ facilitated bacterial cell lysis compared with each antibiotic alone. Conclusion: The combination therapy using MEM and CMZ potentially has bactericidal effect against KPC-producing Enterobacteriaceae.

Original languageEnglish
Pages (from-to)839-845
Number of pages7
JournalMicrobial Drug Resistance
Issue number6
Publication statusPublished - Jul 1 2019
Externally publishedYes


  • carbapenemase-producing Enterobacteriaceae, cefmetazole
  • cephamycin
  • double-carbapenem therapy

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Pharmacology
  • Microbiology (medical)


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