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Infections caused by metallo-beta-lactamase-producing organisms (MBLs) are a global health threat. Our understanding of transmission dynamics and how MBLs establish endemicity remains limited. We analysed two decades of bla_IMP-4 evolution in a hospital using sequence data from 270 clinical and environmental isolates (including 169 completed genomes) and identified extreme gene promiscuity across 7 Gram-negative genera, 68 bacterial strains and 7 distinct plasmid types. An initial multi-species outbreak of conserved IncC plasmids (95 genomes across 37 strains) allowed endemicity to be established through the ability of bla_IMP-4 to disseminate in successful strain-genetic setting pairs we termed ‘propagators’, in particular Serratia marcescens and Enterobacter hormaechei. From this reservoir, bla_IMP-4 persisted through diversification of genetic settings that resulted from transfer of bla_IMP-4 plasmids between bacterial hosts and of the integron carrying bla_IMP-4 between plasmids. Our findings provide a framework for understanding endemicity and spread of MBLs and may have broader applicability to other carbapenemase-producing organisms.