Innovative β-lactams and β-lactam/β-lactamase inhibitor combinations against carbapenemase-producing Enterobacterales

SUMMARYThe global dissemination of carbapenemase-producing Enterobacterales (CPE) represents one of the most pressing threats to modern antimicrobial therapy. The rapid worldwide expansion of these organisms has been driven by the emergence and successful dissemination of diverse carbapenemases belonging to Ambler classes A, B, and D, including KPC, OXA-48-like, and metallo-β-lactamases, such as NDM, VIM, and IMP. These enzymes severely compromise the activity of carbapenems, historically considered the cornerstone for treatment of severe infections caused by multidrug-resistant Gram-negative bacteria. In response to this growing challenge, substantial efforts in antibiotic discovery have led to the development of several novel β-lactams and β-lactam/β-lactamase inhibitor combinations specifically designed to restore activity against carbapenem-resistant Enterobacterales (CRE). This review provides a comprehensive microbiological overview of recently approved and investigational agents targeting CPE. We examine the structural and mechanistic features of key therapeutic options, including cefiderocol and multiple β-lactam/β-lactamase inhibitor combinations incorporating classical penicillin-based sulfone derivatives, diazabicyclooctanes, and cyclic boronates. Particular attention is given to the biochemical properties and inhibitory spectra of β-lactamase inhibitors, as well as the antimicrobial activity of novel β-lactams and β-lactam/β-lactamase inhibitor combinations against both isogenic strains and large collections of clinical Enterobacterales isolates. In addition, we discuss the emerging resistance mechanisms that may compromise the clinical effectiveness of these agents. Understanding the mechanistic basis of both activity and resistance is essential to guide their optimal therapeutic positioning and to inform the next generation of antimicrobial development aimed at combating the ongoing threat of CRE.