Pharmacodynamic evaluation of meropenem, cefepime, or aztreonam combined with a novel β-lactamase inhibitor, nacubactam, against carbapenem-resistant and/or carbapenemase-producing Klebsiella pneumoniae and Escherichia coli using a murine thigh-infection model.

Abstract

BACKGROUND:

Carbapenem-resistant Enterobacterales (CRE) and carbapenemase-producing Enterobacterales (CPE) are difficult to treat and are a serious public health threat. Nacubactam (NAC) is a novel non-β-lactam diazabicyclooctane β-lactamase inhibitor with in vitro activity against some Enterobacterales expressing classes of β-lactamases.

METHODS:

The antimicrobial efficacy of meropenem (MEM), cefepime (FEP), and aztreonam (ATM), each in combination with NAC, were assessed in vitro and in vivo against Klebsiella pneumoniae and Escherichia coli. Ten isolates, including CRE and/or CPE with β-lactamase genes, were used in this study. The relationship between phenotype and in vivo efficacy was assessed in a murine neutropenic thigh-infection model. Efficacy was determined by the change in bacterial quantity.

RESULTS:

The results of the in vitro study showed the minimum inhibitory concentrations of the combination of NAC with either MEM, FEP, or ATM in a 1:1 ratio were 2 to >128-fold lower than those of MEM, FEP, or ATM alone against CRE+ isolates. In addition, combinations of β-lactams and NAC administered in the murine thigh-infection model showed greater efficacy against CRE+/CPE+, CRE+/CPE-, and CRE-/CPE+ isolates harboring various β-lactamase genes (IMP-1, IMP-6, KPC, DHA-1, or OXA-48) compared with MEM, FEP, ATM, and NAC alone.

CONCLUSION:

MEM, FEP, or ATM in combination with NAC showed potent in vivo antimicrobial activity in a murine thigh-infection model caused by K. pneumoniae and E. coli, including CRE and/or CPE isolates. These findings indicate that these combinations of β-lactams and NAC are potential candidates for the treatment of CRE and/or CPE infections.

• Authors: Mao Hagihara, Hideo Kato, Toshie Sugano, Hayato Okade, Nobuo Sato, Yuichi Shibata, Daisuke Sakanashi, Nobuhiro Asai, Yusuke Koizumi, Hiroyuki Suematsu, Yuka Yamagishi, Hiroshige Mikamo
• Journal: International journal of antimicrobial agents (Int J Antimicrob Agents) Vol. 57 Issue 5 Pg. 106330 (May 2021) ISSN: 1872-7913 [Electronic] Netherlands
• PMID: 33789129 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier Ltd. All rights reserved.

Chemical References

• Anti-Bacterial Agents
• Azabicyclo Compounds
• Bacterial Proteins
• Lactams
• Cefepime
• nacubactam
• beta-Lactamases
• carbapenemase
• Meropenem
• Aztreonam

Topics

• Animals
• Anti-Bacterial Agents (pharmacology)
• Azabicyclo Compounds (pharmacology)
• Aztreonam (pharmacology)
• Bacterial Proteins (genetics, metabolism)
• Carbapenem-Resistant Enterobacteriaceae (drug effects)
• Cefepime (pharmacology)
• Dose-Response Relationship, Drug
• Drug Resistance, Bacterial
• Drug Therapy, Combination
• Enterobacteriaceae Infections (drug therapy, microbiology)
• Escherichia coli (drug effects)
• Humans
• Klebsiella pneumoniae (drug effects)
• Lactams (pharmacology)
• Meropenem (pharmacology)
• Mice
• Mice, Inbred ICR
• Microbial Sensitivity Tests
• Models, Animal
• Specific Pathogen-Free Organisms
• beta-Lactamases (genetics, metabolism)