Carbapenem-resistant Gram-negative pathogens: molecular epidemiology, diagnostic advances, and emerging therapeutic strategies.

Carbapenem-resistant Gram-negative pathogens (CR-GNPs) have become an important global health problem, contributing significantly to healthcare-associated infections, extended hospital stays, high mortality rates, and higher healthcare costs. The dissemination of carbapenem resistance is mainly attributed to the spread of carbapenemase-encoding genes, such as the Klebsiella pneumoniae carbapenemase (KPC), the New Delhi metallo-β-lactamase (NDM), the Verona integron-encoded metallo-β-lactamase (VIM), the imipenemase (IMP), and the oxacillinase-48 (OXA-48)-like enzymes associated with clinically important Gram-negative pathogens, including Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii, and Pseudomonas aeruginosa. As well as carbapenemase production, resistance can also develop via alteration of porins, upregulation of efflux pumps, and the buildup of several resistance factors, generating highly adaptable and hard-to-treat microbes. Phenotypic resistance patterns may not predict the underlying mechanism and accurate laboratory detection remains challenging. The identification and monitoring of carbapenem-resistant organisms have undergone improvement in recent years thanks to molecular diagnostics, rapid phenotypic tests, whole-genome sequencing and metagenomics. At the same time, new drugs have been developed, such as ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam, cefiderocol and combinations of aztreonam, offering increased treatment options, but with emerging resistance an issue. This mini review covers the molecular epidemiology of CR-GNPs, the latest developments and challenges in diagnosing these infections, new therapeutic options, and future perspectives on genomic surveillance, antimicrobial stewardship, and precision medicine strategies to address the increasing threat of carbapenem resistance.