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

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- beta-lactam diazabicyclooctane beta-lactamase inhibitor with in vitro activity against some Enterobacterales expressing classes of beta-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 beta-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 beta-lactams and NAC administered in the murine thigh-infection model showed greater efficacy against CRE + /CPE + , CRE + /CPE-, and CRE/CPE + isolates harboring various beta-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 beta-lactams and NAC are potential candidates for the treatment of CRE and/or CPE infections. (c) 2021 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.

Automated summary

The study demonstrated that the combination of meropenem, cefepime, or aztreonam with Nacubactam exhibited potent in vivo antimicrobial activity in a murine thigh-infection model against Klebsiella pneumoniae and Escherichia coli, including carbapenem-resistant Enterobacterales and carbapenemase-producing Enterobacterales isolates. These findings suggest that these combinations are potential candidates for the treatment of CRE and/or CPE infections.