Abstract
Carbapenem-resistant Klebsiella pneumoniae (CRKP), a WHO's critical priority pathogen, continuously evolves to generate health-threatening high-risk (sub)lineages. Here, we conducted a 10-year surveillance of nosocomial CRKP infections, collecting and whole-genome sequencing 1513 clinical isolates, accompanied by clinical data. We applied fine-scale genome analysis for 60,724 non-local public-available K. pneumoniae genomes. We identified a predominant ST11-KL64 sublineage widely-disseminated across China and internationally-distributed. Isolates of this sublineage were more frequently recovered during seasonal influenza peaks and harbored plasmids encoding 'hypervirulence' factors but caused no increase in patient mortality. Instead, they exhibited enhanced invasiveness and translocation capacity. Mechanistically, this suggested highly invasive CRKP (hiCRKP) sublineage showed elevated resistance to macrophage-mediated phagocytosis, partly due to the virulence-encoding plasmid and the loss of two chromosomal fimD gene copies. Additionally, hiCRKP isolates carried more antimicrobial resistance genes, resulting in enhanced resistance to clinically important quinolones and tetracyclines. To address the hiCRKP-imposed challenge, we constituted a phage cocktail, which significantly improved survival in a murine infection model. Our findings unveil a clinically-relevant high-risk sublineage resulted from the ongoing evolutionary diversification of CRKP. Importantly, the 'hypervirulent' CRKP is more potent to cause diseases rather than the thought-to-be more deaths, explaining its rapid emergence in healthcare settings.