A Novel Subclone of Carbapenem-Resistant Klebsiella Pneumoniae St11 Emerges with Enhanced Transmissibility and Mortality

Abstract

Background: Carbapenem-resistant KPC-positive Klebsiella pneumoniae (CRKP) ST11 expands globally, becoming an urgent public health concern. Capsular switch occurs frequently in the epidemic clone. In this study, we aimed to understand the epidemiological and clinical significance of these events. Methods: CRKP causing bloodstream infections (BSI-CRKP) were identified among 10,134 K. pneumoniae isolates collected during 2013-2017 in a tertiary hospital in eastern China. Antimicrobial susceptibility profiles were evaluated by an automated system and genomic characterization was performed. Biofilm formation, a human neutrophil assay and Galleria mellonella model were used to determine the pathogenicity phenotypes. Findings: ST11 was dominant in BSI-CRKP isolates (177/218), composed of two major capsular types (KL), KL47 (76/177) and KL64 (95/177). ST11-KL47 was dominant in 2013-2014 (71.4%-90%), and ST11-KL64 has been prevalent since 2016 (71.8%-88.6%). ST11-KL64-infected patients had a significantly higher 30-day mortality (p=0.005), whereby KL64 was identified as one of the independent risk factors. In vitro ST11-KL64 produced significantly more biofilm, was more resistant to neutrophil killing, and decreased survival in the G. mellonella larvae infection model. Phylogenetic reconstruction demonstrates that ST11-KL64 is derived from an ST11-KL47-like ancestor via recombination. Acquisition of a pLVPK-like virulence plasmid did not alter the virulence in either subclone, although the rmpA gene, only identified in ST11-KL64 after 2015, substantially increases the tenacity of this subclone by enhancing environmental survival. Clonal expansion of the newly emerged ST11-KL64 subclone resulted in a progressive replacement of ST11-KL47. The convergence of KL64 and plasmid-mediated rmpA remains rare in specimens collected across China. Interpretation: A high-risk subclone of CRKP-ST11 emerged via frequent recombination and rapid acquisitions of genetic factors, resulting in enhanced pathogenicity and transmissibility. The newly emerging descendant poses a substantial threat to populations and health-care networks, suggesting the urgent need of tailor-made surveillance to prevent further dissemination. Funding: National Key Research and Development Program of China, the National Basic Research Program of China, the National Natural Science Foundation of China, and the Key Project of Science and Technology & Social Development of Zhejiang Province. Declaration of Interest: We declare no competing interests. Ethical Approval: This study was approved by the Institutional Review Board of the first affiliated hospital of Zhejiang university in China.