In vitro activity and resistance mechanisms of novel antimicrobial agents against metallo-β-lactamase producers

The carbapenemase-producing Gram-negative organisms represent an urgent clinical and public health concern, as they have been associated with increased mortality and high dissemination in healthcare settings. Although overall incidence rates of infections sustained by metallo-beta-lactamase (M beta L)-producers have remained lower than those sustained by other carbapenemase-producers, albeit with substantial geographic differences, a significant increase in the prevalence of M beta L-producers has been observed over the last decade. The recent development of new antimicrobials expanded the armamentarium to counter the challenge of metallo-beta-lactamase (M beta L)-producers. Cefiderocol and aztreonam/avibactam are already clinically available and recommended by international guidelines. In addition, two new classes of beta-lactam/ beta-lactamase combinations are under clinical evaluation: (i) combination of beta-lactam with novel boronic-derived inhibitors (e.g. taniborbactam and xeruborbactam), (ii) combination of beta-lactam with last generation diazabicyclooctane beta-lactamase inhibitors (e.g. zidebactam and nacubactam), active on most of serine-beta-lactamases but also showing strong intrinsic activity on PBP-2. This review aims to provide up-to-date data on the characteristics, activity and emerging resistance mechanisms of the armamentarium of clinically available or soon-to-be introduced drugs for the treatment of M beta L-producing Gram-negative organisms.