The dual threat of hypervirulent and multidrug-resistant Klebsiella pneumoniae: pathogenesis and prospects for intervention.

Klebsiella pneumoniae (Kp) has emerged as a major public health concern and is listed by the World Health Organization (WHO) as a critical-priority pathogen. Its clinical relevance is amplified by the rise of hypervirulent Klebsiella pneumoniae (hvKp), which combines enhanced pathogenicity with an alarming potential to acquire multidrug resistance (MDR). Unlike classical K. pneumoniae (cKp), hvKp causes severe community-acquired infections, including pyogenic liver abscess, meningitis, septic endophthalmitis, and necrotising fasciitis, leading to significant morbidity and mortality. Since the first reports from Taiwan in the 1980s, hvKp has spread globally, with convergent MDR-hvKp strains increasingly documented in Asia, North America, and Europe, posing urgent therapeutic challenges. The virulence of hvKp is largely driven by plasmid-encoded factors, including hypermucoid regulators (rmpA/rmpA2), siderophores such as aerobactin and salmochelin, and heavy-metal resistance genes. While phenotypic assays like the string test have historically been used, they lack specificity, and molecular biomarkers such as rmpA, rmpA2, iroB, iucA, and peg-344 remain inconsistently distributed across isolates. This complicates accurate differentiation of hvKp from cKp and underscores the pressing need for robust, standardized biomarker panels. This article reviews current knowledge on hvKp pathogenesis with a focus on gut colonization, immune evasion, and niche-specific regulation of virulence factors. We also examine the role of quorum sensing in fine-tuning hvKp virulence and highlight emerging anti-virulence strategies as promising alternatives to traditional antibiotics. By bridging mechanistic insights with translational approaches, this review aims to inform the development of effective diagnostic and therapeutic strategies against hvKp.