An update on beta-lactam-beta-lactamase inhibitor combinations for the treatment of carbapenem-resistant gram-negative pathogens

INTRODUCTION: Carbapenem-resistant Gram-negative bacteria represent a major global health threat driven by diverse β-lactamase enzymes, particularly KPC, metallo-β-lactamases, and OXA-type carbapenemases, leading to limited treatment options and high mortality. The development of novel β-lactam/β-lactamase inhibitor (BLBLI) combinations has significantly improved outcomes in resistant infections by restoring β-lactam activity against key resistance mechanisms, primarily among Enterobacterales. AREAS COVERED: This expert review summarizes the pharmacology, clinical efficacy, and safety of approved and emerging BLBLIs, including ceftolozane - tazobactam, cefepime - enmetazobactam, ceftazidime - avibactam, meropenem - vaborbactam, imipenem - relebactam, aztreonam - avibactam, and sulbactam - durlobactam. Emphasis is placed on activity against carbapenem-resistant Enterobacterales, difficult-to-treat Pseudomonas aeruginosa, and carbapenem-resistant Acinetobacter baumannii. Evidence derives from clinical trials, real-world studies, and pharmacokinetic/pharmacodynamic (PK/PD) analyses from major databases (PubMed, Scopus, Web of Science) from inception through January 2026, focusing on dosing optimization and outcomes. EXPERT OPINION: BLBLIs have transformed the management of KPC-producing infections, markedly reducing mortality compared with legacy therapies. However, their impact is threatened by the rising prevalence of metallo-β-lactamases and the persistent therapeutic gap in carbapenem-resistant A. baumannii. Future success will depend on next-generation inhibitors with broader enzyme coverage, optimized dosing strategies guided by PK/PD principles, and robust antimicrobial stewardship to preserve long-term efficacy.