Carbapenem-Resistant Gram-Negative Bacteria: Mechanisms, Pathogen-Specific Strategies

Carbapenem-resistant Gram-negative bacteria (CRGNB)-including carbapenem-resistant Enterobacteriaceae (CRE), carbapenem-resistant Pseudomonas aeruginosa (CRPA), and carbapenem-resistant Acinetobacter baumannii (CRAB)-pose a critical threat to public health due to their high associated morbidity and mortality. Key resistance mechanisms involve carbapenemase production, porin mutations, efflux pump overexpression, penicillin-binding proteins (PBPs) alterations, and biofilm formation, with prevalence varying geographically and by species. Effective management requires identifying the infection site, assessing disease severity, and determining the pathogen and its resistance profile to guide antimicrobial selection. Recommended agents include ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam, aztreonam-avibactam, ceftolozane-tazobactam, sulbactam-durlobactam, colistin, and tigecycline. For CRE, treatment depends on the carbapenemase type: KPC-producing strains are managed with novel β-lactam/β-lactamase inhibitor combinations (ceftazidime-avibactam, imipenem-relebactam, meropenem-vaborbactam); MBL-producing strains with ceftazidime-avibactam plus aztreonam or aztreonam-avibactam; and OXA-48-type-producing strains with ceftazidime-avibactam alone. For CRPA, ceftolozane-tazobactam is the primary option, while CRAB is treated with sulbactam-durlobactam-based combination therapy. However, disparities in treatment access persist; while these novel agents are recommended, alternative salvage strategies are often required in resource-limited settings. This review details the epidemiology of CRGNB, outlines pathogen-specific resistance mechanisms and corresponding therapies, highlights knowledge gaps, and suggests future directions to inform prevention and treatment efforts.