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

ABSTRACT

Introduction: 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:

• Β-lactamase Inhibitors
• carbapenem-resistant Enterobacteriaceae
• multidrug resistant
• avibactam
• vaborbactam
• relebactam
• drug development
• PK/PD

Article highlights

• The burden of antimicrobial resistance among Gram-negative bacteria is increasing. The most relevant mechanism of resistance in Gram-negative bacteria is the presence of β-lactamases.

• Several new anti-infective combinations with a β-lactamase inhibitor are in market i.e. ceftazidime/avibactam and meropenem/vaborbactam or different stages of clinical development i.e. imipenem/cilastatin/relebactam, aztreonam/avibactam, ceftaroline/avibactam, cefepime/zidebactam and meropenem/nacubactam.

• Ceftazidime/avibactam, the first β-lactam/β-lactamase inhibitor in market since 2015 has exhibited excellent in vitro activity against Enterobacteriaceae and P. aeruginosa producing ESBL, AmpC and KPC as well some class D enzymes. Approved for cUTI, IAI and HAP/VAP as well as Gram-negative infections with limited options.

• Meropenem/vaborbactam was approved by FDA in 2017 for cUTI with excellent in vitro activity against Enterobacteriaceae producing ESBL, AmpC and KPC. Inactive against metallo-β-lactamase as well as Acinetobacter baumannii (similar to ceftazidime/avibactam).

• Imipenem/cilastatin/relebactam is active against Enterobacteriaceae and P. aeruginosa producing ESBL, AmpC, KPC and porin mutations and is currently in a clinical development program for a variety of infections.

• The major advantage of aztreonam/avibactam is activity against Enterobacteriaceae producing metallo-β-lactamases.

• Zidebactam and nacubactam mechanism of actions are described as ‘tripartite’ displaying activity against Enterobacteriaceae via affinity for PBP2, inhibiting β-lactamases as well as a β-lactam enhancer.

• It will be important to ensure appropriate use of novel β-lactam-β-inhibitors for serious infections caused by MDR and XDR Gram-negative to minimize emergence of resistance.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.