Tracking international and regional dissemination of the KPC/NDM co-producing Klebsiella pneumoniae

Abstract

KPC and NDM co-producing carbapenem-resistant Klebsiella pneumoniae (KN-CRKP) showed an upward trend; nevertheless, global systematic and comprehensive analyses profiling remain lacking. 968 local CRKP were collected from 6 provinces in China, and 64,354 genomes were retrieved from GenBank. All 413 genomes of KN-CRKP were obtained from 32 countries, including 16 subtypes of KN-CRKP. The top three CRKP subtypes, K2N1-CRKP, K2N5-CRKP and K3N1-CRKP, exhibited distinct geographic distributions, with K2N1-CRKP and K2N5-CRKP primarily circulating in China while K3N1-CRKP showed predominant prevalence in USA. Meanwhile, ST11-KL64, ST11-KL47, and ST258-KL107, were the three most prevalent ST and KL, and 64.3% of ST11-KL64 KN-CRKP belonged to hypervirulent strains. Genomes revealed Clone Group 1, accounting for 55.0% of KN-CRKP, shifting from KL47 to KL64 and carrying more hypervirulence genes, has a significant advantage in adhesion, invasion, and proliferation, and its dispersal was the primary driver contributing to the worldwide spread of KN-CRKP. Furthermore, ST11 KN-CRKP was generally formed by KPC-producing CRKP acquiring bla_NDM-carrying plasmid and novel hybrid plasmids co-encoding KPC and NDM have occurred. Aztreonam/avibactam and cefiderocol were promising antimicrobial agents against KN-CRKP. The global KN-CRKP research, spanning from 2005 to 2024, provides valuable insights into the global transmission, dynamics, and treatment of KN-CRKP.

Fig. 1. Distribution and carbapenemase genes of worldwide and local KN-CRKP.

A Distribution of 388 KN-CRKP strains globally between 2005 and 2024. The pie charts show the top five countries (left) and provinces (right, in China) with the most separation B Percentage variations of carbapenemase genes from 2005 to 2024 in 167 strains KN-CRKP from China on Genbank. Source data are provided as a Source Data file. C Carbapenemase genes and their proportion of 388 strains KN-CRKP worldwide. D Number of global and China’s KN-CRKP strains between 2005 and 2024. Source data are provided as a Source Data file. E Carbapenemase genes and number of local KN-CRKP. Abbreviations: KN-CRKP, KPC and NDM co-producing carbapenem-resistant Klebsiella pneumoniae.

Fig. 2. Distribution of carbapenemase genes, country, hypervirulent genes and Clone group by ST and KL.

Data shown presented the distribution of carbapenemase genes (A), country (B), hypervirulent genes (C) and Clone group (D) by ST and KL. Each circle represented a genome colored based on the different types of the four classes. Barplots summarize the number of genomes from each KL (top) and ST (right) and are colored based on the different types of the four classes. Gray means absence. Source data are provided as a Source Data file. Abbreviations: CG Clone Group, MLST Multi-locus sequence type, KL K loci.

Fig. 3. Phylogenetic analysis and characteristics of 413 KN-CRKP globally and locally (2005–2024).

The phylogenetic tree was annotated by clade, Clone group, carbapenemase types, ST, serotype, virulence genes, sample, year, and country from inner to outer, separately. Different colors of branches denote different Clone groups. Abbreviations: CG Clone Group, MLST Multi-locus sequence type, KN-CRKP KPC and NDM co-producing carbapenem-resistant Klebsiella pneumoniae.

Fig. 4. Dated phylogeny and phylogeography analyses of 227 CG1 strains.

A Dated phylogeny of CG1 strains was illustrated and blue bars along branches denoted 95% highest posterior probabilities. The color of the tipnode and tiplab represented different countries and serotypes, respectively. B Regression of root-to-tip distance against sampling time showing temporal signal in CG1. Source data are provided as a Source Data file. C. Effective population size of CG1 strains based on the population structure. Shaded areas showed 95% highest posterior probabilities. D Phylogeography analyses of CG1 strains. Arrows showed the direction and dates of transmission. KN-CRKP isolate originated in Brazil, and then spread to the rest of the world. The radius of the blue circles, which indicate the main outbreak zones, corresponds to the total number of strains examined in each country. Abbreviations: CG Clone Group, KN-CRKP KPC and NDM co-producing carbapenem-resistant Klebsiella pneumoniae.

Fig. 5. Pan-genome and functional annotation of 413 KN-CRKP strains.

A Pan-genome analysis of 413 KN-CRKP by roary. The cells with blue color represent the presence of genes. The red box and Venn diagram indicated the difference in core genes between CG1 (n = 227) and non-CG1 (n = 186). Source data are provided as a Source Data file. As the number of genomes increased, the number of gene clusters was displayed at the top right. Means and standard errors (vertical line) were obtained by repeating 100 times random input orders of the genomes. The continuous curves were generated by the least-squares fit. B Differential gene function annotation of the top 30 listed in Clone group 1. Level 2 pathways were annotated with different colors, and the number of level 3 pathways was shown by step height. Abbreviations: CG Clone Group, KN-CRKP KPC and NDM co-producing carbapenem-resistant Klebsiella pneumoniae.

Fig. 6. bla_KPC- or bla_NDM-carrying plasmids analyses and formation mechanism of KN-CRKP.

A Networks of local KN-CRKP strains and their homologous strains B Networks of bla_KPC- and bla_NDM-carrying plasmids. C Phylogenetic analysis of bla_KPC- or bla_NDM-carrying plasmids harboured by KN-CRKP. Plasmids of the phylogenetic trees from left to right were bla_KPC-carrying plasmids and bla_NDM-carrying plasmids, respectively. The blue lines on the tree indicated tree scale, and the shades of tiplab were the plasmids co-carrying bla_KPC and bla_NDM. Connections of the two trees denoted the two separated plasmids located on the same genomes of KN-CRKP. D Formation mode of ST11 KN-CRKP. Created in BioRender. Mato, F. (2025) https://BioRender.com/dc61lmf. Abbreviations: CG Clone Group, MLST Multi-locus sequence type, KN-CRKP KPC and NDM co-producing carbapenem-resistant Klebsiella pneumoniae; KPC-CRKP, bla_KPC-carrying CRKP.