Clinically Significant Carbapenemases in Gram-Negative Pathogens: Molecular Diversity and Advances in β-Lactamase Inhibitor Therapy.

Carbapenems comprise a class of β-lactam antibiotics with broad-spectrum hydrolytic activity and are often reserved as last-line agents for the treatment of serious multidrug-resistant (MDR) bacterial infections. Clinically important nosocomial MDR Gram-negative bacteria (GNB) include Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. Carbapenem resistance among these organisms is predominantly mediated by the production of β-lactamases called carbapenemases, such as K. pneumoniae carbapenemase (KPC), New Delhi metallo-β-lactamase (NDM), imipenemase (IMP), Verona integron-encoded metallo-β-lactamase (VIM), and selected oxacillinase (OXA)-type carbapenemases. These enzymes degrade carbapenems, significantly compromising their clinical efficacy. To address escalating antimicrobial resistance, novel next-generation β-lactamase inhibitors (BLIs), partnered with established β-lactams (BLs), have been approved or are currently under development to inhibit carbapenemase activity. The present narrative review aims to synthesize the most current information on the major carbapenemases and discusses recently approved and investigational BL/BLI combination therapies in terms of their mechanisms of action, spectrum of activity, gaps in coverage, and available clinical and in vitro evidence. Development of resistance to novel BL/BLI combinations is also examined. Comparative analysis of inhibitory spectra and microbiological coverage indicates a continued need for metallo-β-lactamase inhibitors with direct pan-inhibitory activity, pathogen-specific BL/BLI regimens for carbapenem-resistant A. baumannii, and carbapenemase-targeted agents effective in the context of non-enzymatic resistance mechanisms. Treatment-emergent resistance to novel BL/BLIs and limitations in activity profiles underscore the critical need for continued innovation in pipeline development, vigilant global and local surveillance of carbapenemase epidemiology, and robust antimicrobial stewardship strategies to aid in preserving the efficacy of the antibacterial drug armamentarium.