Emergence of Tigecycline Nonsusceptible and IMP-4 Carbapenemase-Producing K2-ST65 Hypervirulent Klebsiella pneumoniae in China

ABSTRACT

Carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKP) poses a significant public health challenge worldwide, but research on IMP-producing CR-hvKP and its tigecycline resistance is extremely scarce. We report herein the recovery of two IMP-4–producing, capsular serotype K2, sequence type 65 (K2-ST65), hypervirulent K. pneumoniae isolates (C1672 and C2051), which caused severe and fatal infections in ICU patients, after retrospectively screening 3,285 carbapenem-resistant K. pneumoniae isolates from 26 provinces in China. Notably, C2051 also demonstrated tigecycline nonsusceptibility, mediated by a frameshift mutation in the TetR/AcrR family transcriptional regulator. Both strains harbored bla _IMP-4 and critical plasmid-borne virulence genes ( rmpA/ rmpA2, iucA, and iroN) and demonstrated high virulence in Galleria mellonella, indicating CR-hvKP. The bla _IMP-4 gene was located on the IncU- and IncN-type plasmids, which showed high stability in C1672 and C2051 after serial passage for 5 days, with retention rates of 87% and 93.7%, respectively. No significant differences in growth rates were observed among the parental strains and the corresponding resistance plasmid-cured mutants ( P = 0.5273), suggesting that strains carrying the bla _IMP and virulence plasmids have the potential to exist for a long time without compromising fitness. The genetic environments of the bla _IMP-4 gene in both strains were similar, and it has been inferred that the genetic regions of bla _IMP-4 were inserted into different backbones. Several conjugal transfer genes, such as traO, traE, traN, and traBCD, were identified in the bla _IMP-4-bearing plasmid of C2051, suggesting a higher ability for plasmid transmission. The convergence of IMP carbapenemase and tigecycline nonsusceptibility in a classic hypervirulent K. pneumoniae lineage highlights the need to enhance clinical awareness and epidemiologic surveillance.

IMPORTANCE To date, research on IMP-producing CR-hvKP is extremely scarce. Only one case of urinary tract infection caused by an IMP-6–producing K1-ST23 hypervirulent K. pneumoniae isolate in Japan was recorded, with a limited description of clinical information and genomic features. None of the published studies examined the virulence of the reported strains or the stability and fitness of resistance plasmids or presented a phylogenetic analysis. This dearth of data is notable because CR-hvKP infections are increasingly identified, but critical characteristics of the emerging resistance mediated by IMP carbapenemases in CR-hvKP remain unknown. Here, we report the emergence of two IMP-4 carbapenemase-producing K2-ST65 hypervirulent K. pneumoniae isolates that caused severe and fatal infections in clinical settings in China. Notably, one of them also demonstrated tigecycline nonsusceptibility. These strains carrying bla _IMP and virulence plasmids had the potential to exist for a long time without compromising their fitness, highlighting the urgent need to enhance clinical awareness and epidemiologic surveillance to prevent their dissemination.