Genomic epidemiology of ceftazidime-avibactam-resistant, carbapenem-resistant Klebsiella pneumoniae in Henan Province, China

Background Ceftazidime-avibactam (CZA) is a key treatment for carbapenem-resistant Klebsiella pneumoniae (CRKP), but resistance is emerging rapidly in China. Henan is a CRKP epicenter, yet the genomic drivers of CZA resistance remain unclear. Methods We conducted a multicenter genomic epidemiology study of 109 non-duplicate CZA-R-CRKP isolates collected from 12 hospitals in Henan between October 2020 and April 2025. Whole-genome sequencing (WGS) was used to resolve population structure, carbapenemase genotypes, predicted plasmid contexts, hypervirulence-associated markers, porin variants, and genomic clusters suggestive of possible transmission. Results ST11 predominated among the CZA-R-CRKP isolates (66.1%, 72/109) and accounted for nearly all isolates carrying bla KPC alone or with bla NDM (95.9%, 71/74), including most KPC + NDM co-producers. The proportions of carbapenemase genotypes differed across the sampled collection periods, with a higher proportion of KPC-containing genotypes in later periods; this descriptive pattern is not a population-level temporal trend. Phylogenomic analysis identified genomic clusters suggestive of possible transmission, including a neonatal-ward cluster of ST20-KL38- bla NDM-1 isolates. Seventy-two isolates carried at least one of five hypervirulence-associated markers, and this marker carriage was more frequent in bla KPC -containing groups than in the bla NDM -only group. Plasmid profiling showed that bla KPC was mainly associated with MOB-suite-predicted AA032-type plasmid clusters, whereas bla NDM was assigned to more heterogeneous predicted backbones. We identified a KPC variant, KPC-291, harboring dual catalytic-loop alterations (D179Y and G239_V240del), and an OmpK35 deletion variant frequently observed among bla KPC-2 -only isolates; these co-occurrence patterns were descriptive and not evidence of a functional interaction. Conclusions In this hospital-based collection, CZA-R-CRKP was dominated by ST11 lineages carrying bla KPC and hypervirulence-associated markers. The findings also show carbapenemase diversification, recurrent OmpK35 remodeling, and diverse predicted plasmid profiles; the genomic clusters and KPC-291 require further epidemiological and functional validation.