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Background: The spread of transmissible plasmids with carbapenemase genes has contributed to a global increase in carbapenemase-producing Enterobacterales over the past two decades, with bla NDM and bla OXA among the most prevalent carbapenemase genes., Objectives: To characterize an Escherichia coli isolate co-carrying bla NDM-5 and bla OXA-181 (JBEHAAB-19-0176) that was isolated in the Japan Antimicrobial Resistant Bacterial Surveillance in 2019-20, and to evaluate the functional advantage of carrying both genes as opposed to only one., Methods: The whole-genome sequence of the isolate was determined using long- and short-read sequencing. Growth assay and co-culture experiments were performed for phenotypic characterization in the presence of different β-lactam antibiotics., Results: WGS analysis showed that bla NDM-5 and bla OXA-181 were carried by the same IncX3 plasmid, pJBEHAAB-19-0176_NDM-OXA. Genetic characterization of the plasmid suggested that the plasmid emerged through the formation of a co-integrate and resolution of two typical IncX3 plasmids harbouring bla NDM-5 and bla OXA-181 , which involved two recombination events at the IS 3000 and IS 26 sequences. When cultured in the presence of piperacillin or cefpodoxime, the growth rate of the transformant co-harbouring bla NDM-5 and bla OXA-181 was significantly higher than the transformant with only bla NDM-5 . Furthermore, in co-culture where the two bla NDM-5 -harbouring transformants were allowed to compete directly, the strain additionally harbouring bla OXA-181 showed a marked growth advantage., Conclusions: The additional carriage of bla OXA-181 confers a selective advantage to bacteria in the presence of piperacillin and cefpodoxime. These findings may explain the current epidemiology of carbapenemase-producing Enterobacterales, in which bacteria carrying both bla NDM-5 and bla OXA-48 -like genes have emerged independently worldwide., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)