Clinical efficacy, safety and pharmacokinetics of novel β-lactam/β-lactamase inhibitor combinations: a systematic review.

Background: Antimicrobial resistance is a global public health threat that requires urgent solutions. One strategy to decrease resistance of Gram-negative bacteria (GNB) to β-lactam antibiotics (BL) is their combination with β-lactamase inhibitors (BLI). Objectives: This systematic review analyses the outcomes, safety and pharmacokinetics (PK) of recently approved or under clinical development BLI and BL/BLI combinations. Methods: The systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. PubMed, Embase, and Cochrane electronic databases were used to search for articles from January 2010 to November 2024. The studies were retrieved and screened on the basis of predefined exclusion and inclusion criteria. A quality assessment of the included studies was conducted following the New Castle-Ottawa Scale. Results: A total of 191 articles addressing clinical research regarding the efficacy, safety, tolerability, and PK of new BL/BLI combinations with avibactam, durlobactam, enmetazobactam, nacubactam, relebactam, taniborbactam, tazobactam, vaborbactam and zidebactam were included. According to the published literature, clinical research supports the novel BL/BLI combinations for the treatment of complicated urinary tract infections, complicated intra-abdominal infections, and hospital-acquired and ventilator-associated pneumonia (HAP/VAP) caused by GNB. In spite of that, the development of new BLI effective for class B metallo-β-lactamases (MBL) is still challenging, being aztreonam/avibactam the only approved combination active against MBL-producing bacteria. Conclusions: Although there has been extensive research to develop new BLI and BL/BLI combinations, only a few have reached the market. More evidence of its usefulness in the real world is still needed.