Carbapenemases in Gram-Negative Bacilli: Classification, Detection, Therapeutic Options, and Resistance to Novel Antimicrobials

Carbapenem-resistant Gram-negative bacilli (CR-GNB), particularly Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii, remain a major clinical challenge and serious threat to modern medicine, with carbapenemase production representing a particular clinical and epidemiological concern. This structured narrative review integrates three clinically linked areas: the evolution and classification of clinically important carbapenemases; phenotypic and molecular methods for their detection and characterization; and the organism- and enzyme-specific activity of recently introduced antimicrobial agents and β-lactam–β-lactamase inhibitor combinations, including ceftolozane–tazobactam, ceftazidime–avibactam, meropenem–vaborbactam, imipenem–cilastatin–relebactam, cefiderocol, plazomicin, eravacycline, cefepime–enmetazobactam, sulbactam–durlobactam (FDA 2023), aztreonam–avibactam (EMA 2024; FDA 2025), and cefepime–zidebactam (FDA 2026). Particular emphasis is placed on baseline, experimentally selected and treatment-emergent resistance mechanisms and their clinical implications. Although these agents have substantially expanded the therapeutic armamentarium against CR-GNB, important gaps persist, particularly for metallo-β-lactamase-producing organisms, carbapenem-resistant A. baumannii, and metallo-β-lactamase-producing P. aeruginosa. Their activity may be compromised by pre-existing resistance determinants, target alterations, permeability defects, efflux-pump overexpression, β-lactamase evolution or overproduction, and combinations of these mechanisms, while treatment-emergent resistance threatens long-term effectiveness. By linking laboratory carbapenemase detection with a comparative, mechanism-based assessment of antimicrobial activity, resistance determinants, and clinical limitations, this review provides a practical framework for mechanism-directed therapy and antimicrobial stewardship and identifies priorities for future research, including improved direct inhibition of metallo-β-lactamases, more reliable therapeutic options for CR-GNB, prospective studies stratified by resistance mechanisms, strengthened epidemiological surveillance and infection-prevention strategies, and continued therapeutic innovation.