Global transmission architecture of VIM carbapenemases reveals host-specific dissemination strategies

Carbapenemase-producing Gram-negative bacteria carrying Verona integron-encoded metallo-{beta}-lactamase (VIM) pose a persistent global threat, yet the mechanisms driving their worldwide dissemination remain poorly resolved. We analysed 5,617 blaVIM-positive genomes collected from 73 countries or regions across six continents between 1999 and 2025 to reconstruct the global epidemiology and transmission architecture of VIM carbapenemases. Forty VIM variants were identified across 16 bacterial genera, revealing marked host preferences and temporal shifts. VIM-2 dominated global circulation, whereas VIM-1 and VIM-4 remained prominent among Enterobacterales. Strikingly, VIM spread followed distinct host-specific evolutionary strategies. In Pseudomonas aeruginosa, dissemination was largely clone-driven, with high-risk lineages ST111 and ST235 supporting long-term persistence through lineage expansion and stable inheritance. By contrast, Enterobacterales were dominated by horizontal transmission through broad-host-range IncHI2A, IncA, and IncC plasmids, although only a limited subset of plasmid-VIM combinations achieved intercontinental spread. Among 2,828 loci with sufficient flanking sequence, 96.2% were embedded within integrative genetic elements, frequently nested with insertion sequences and phage-related elements, revealing a multilayered mobile-element network underlying VIM persistence. Structural analyses showed a highly conserved metallo-{beta}-lactamase scaffold but recurrent diversification near substrate-interacting residues, particularly positions 224 and 228. Shared genetic clusters between human-associated and environmental isolates further suggested cross-niche circulation. Together, these findings establish a hierarchical, host-dependent framework for global VIM dissemination, integrating clonal expansion, plasmid transfer, and nested mobile genetic elements. ImportanceBy analysing 5,617 blaVIM-positive genomes worldwide, this study reveals a host-dependent transmission architecture of VIM carbapenemases. In P. aeruginosa, VIM dissemination is mainly driven by expansion of successful high-risk clones, particularly ST111 and ST235, whereas in Enterobacterales it is primarily mediated by broad-host-range plasmids enabling cross-species transfer. Global VIM spread is not driven by a single dominant pathway but by a limited number of successful clone-plasmid-mobile element combinations, while most genetic backgrounds remain regionally restricted. These findings define a hierarchical transmission model of VIM evolution and provide insights for genomic surveillance and targeted control of metallo-{beta}-lactamase-mediated antimicrobial resistance.