Drug-resistant Klebsiella pneumoniae and related Enterobacterales represent an escalating global public health threat, increasingly limiting therapeutic options in both healthcare- and community-associated infections. This review summarizes how resistance in K. pneumoniae emerges from the synergy of intrinsic barriers and acquired determinants. Key molecular mechanisms include reduced permeability via porin remodeling (notably OmpK35/OmpK36), multidrug efflux (e.g., AcrAB-TolC and OqxAB), and enzymatic drug inactivation driven by extended-spectrum beta-lactamases and carbapenemases (e.g., KPC, OXA-48-like enzymes, and metallo-beta-lactamases). We also highlight clinically meaningful pathways underlying polymyxin/colistin resistance, including mgrB inactivation and PhoPQ/PmrAB-mediated lipid A modification. In addition to stable genetic resistance, adaptive programs can shape transient tolerance and persistence, including stress responses that modulate gene expression under antibiotic and host-imposed pressures. The ability of these organisms to form biofilms, particularly on medical devices, further complicates treatment and eradication. Finally, we discuss therapeutic implications and current options and limitations-including novel beta-lactam/beta-lactamase inhibitor combinations and siderophore cephalosporins-and emphasize the importance of aligning therapy and surveillance with the underlying resistance mechanisms and circulating high-risk lineages.

Department of Medicine and Technological Innovation University of Insubria 21100 Varese Italy

Department of Microbiology Faculty of Medicine and Dentistry Palacky University Olomouc Hnevotinska 3 77515 Olomouc Czech Republic

Laboratory of Medical Microbiology and Virology University Hospital of Varese 21100 Varese Italy

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