Novel β-lactam-β-lactamase inhibitor combinations: expectations for the treatment of carbapenem-resistant Gram-negative pathogens

Abstract

The burden of antimicrobial resistance among Gram-negative bacteria is increasing and growing into a major threat of public health. Treatment options for carbapenem-resistant Enterobacteriaceae are limited and resistance rates to existing compounds are mounting. The pipeline includes only a small number of novel anti-infective agents in development or in the market with promising results against multidrug-resistant (MDR) Gram-negative. Areas covered: Herein the authors present the modern available knowledge regarding novel β-lactam-β-lactamase inhibitors, i.e. mechanisms of action, in vitro activity, current PK/PDs, clinical trials and clinical efficacy against MDR and XDR Gram-negatives, as well as toxicity issues. Expert opinion: Ceftazidime-avibactam and meropenem-vaborbactam are promising therapeutic options as both are active against Enterobacteriaceae producing ESBL, AmpC, and KPC, whereas only avibactam inhibits certain class D β-lactamases, mainly OXA-48. New drugs active against Gram-negative MDR isolates including imipenem/cilastatin with relebactam and avibactam combined with aztreonam or ceftaroline are in different stages of development. However, the disadvantage to be seriously considered by the clinician is that β-lactam/β-lactamase inhibitors are ineffective against metallo-β-lactamases (with the exception of aztreonam-avibactam) as well as Acinetobacter baumannii.

Keywords: PK/PD; avibactam; carbapenem-resistant Enterobacteriaceae; drug development; multidrug resistant; relebactam; vaborbactam; Β-lactamase Inhibitors.