Convergence of carbapenem resistance and hypervirulence in a highly-transmissible ST11 clone of K. pneumoniae: An epidemiological, genomic and functional study

Co-occurrence of hypervirulence and KPC-2 carbapenem resistant phenotypes in a highly-transmissible ST11 clone ofKlebsiella pneumoniae has elicited deep concerns from public health stand point. To address this puzzle, we conducted a large-scale epidemiological, clinical and genomic study of K. pneumonia ST11 clones with both hypervirulence and carbapenem resistance in two tertiary hospitals in Zhejiang province. Most of the patients (15/23) were diagnosed with exclusively carbapenem-resistant K. pneumoniae (CRKP) infections. Ten death cases were reported, some of which are due to the failure of antibiotic therapies. As a result, we identified one new rare sequence types (ST449) to KPC-2-producing CRKP, in addition to the dominant ST11. These clinical isolates of K. pneumoniae are multi-drug resistant and possess a number of virulence factors. Experimental infections of wax moth larvae revealed the presence of hypervirulence at varied level, suggesting the complexity in bacterial virulence factors. However, plasmid curing assays further suggested that the rmpA2-virulence plasmid is associated with, but not sufficient for neither phenotypic hypermucoviscosity nor virulence of K. pneumoniae. Intriguingly, all the rmpA2 genes were found to be inactive due to genetic deletion. In total, we reported 21 complete plasmid sequences comprising 13 rmpA2-positive virulence plasmids and 8 bla(KPC-2)-harboring resistance plasmids. In addition to the prevalent pLVKP-like virulence plasmid variants (similar to 178kb), we found an unexpected diversity among KPC-2-producing plasmids whose dominant form is IncFII-IncR type (similar to 120kb), rather than the previously anticipated version of similar to 170kb. These findings provide an updated snapshot of convergence of hypervirulence and carbapenem resistance in ST11 K. pneumoniae.

Automated summary

The study identified a highly-transmissible ST11 clone of Klebsiella pneumoniae in two tertiary hospitals in Zhejiang province, which exhibited both hypervirulence and carbapenem resistance, raising public health concerns. Clinical isolates of this clone were multi-drug resistant and possessed multiple virulence factors, with varied levels of hypervirulence observed in experimental infections. Plasmid curing assays suggested a complex relationship between the virulence plasmid and phenotypic hypermucoviscosity or virulence of K. pneumoniae, with all rmpA2 genes found to be inactive due to genetic deletion.