Carbapenem-Resistant Klebsiella pneumoniae: Clinical Epidemiology, Resistant Mechanisms, and Therapeutic Challenges

Abstract

Carbapenem-resistant Klebsiella pneumoniae (CRKP) represents a critical global health threat, ranked by the WHO as the top priority pathogen requiring urgent new therapeutics. As a leading member of the ESKAPE group, K. pneumoniae has evolved from a commensal organism to an extensively drug-resistant (XDR) pathogen capable of causing severe nosocomial infections with high mortality. This review examines the clinical epidemiology, molecular resistance mechanisms, and therapeutic challenges of CRKP. Geographic heterogeneity is evident, with KPC-2 dominating in China and North America, NDM-1 rising in South America, and OXA-48 prevalent in Europe. High-risk clones such as ST11 and ST258 are associated with increased all-cause mortality (pooled OR up to 3.57) and prolonged hospital stays. Resistance arises primarily from carbapenemase production (Class A KPC, Class B MBLs, Class D OXA-48-like) combined with non-enzymatic mechanisms including porin loss (OmpK35/36) and efflux pump overexpression (AcrAB-TolC, OqxAB). Alarmingly, convergence of hypervirulence and resistance in strains carrying siderophores (aerobactin, yersiniabactin) and hypercapsulation is increasing, particularly in Asia. Diagnostic strategies range from phenotypic assays (mCIM, CARBA 5) to whole-genome sequencing. Treatment remains challenging; older agents like colistin and tigecycline show limited efficacy and toxicity, while newer options ceftazidime-avibactam, meropenem-vaborbactam, cefiderocol, and aztreonam-avibactam offer improved outcomes but face emerging resistance through blaKPC mutations and siderophore receptor alterations. Future directions include phage therapy and monoclonal antibodies. Comprehensive infection control, antimicrobial stewardship, and innovative non-antibiotic approaches are essential to curb the escalating burden of CRKP.