Abstract Carbapenem-resistant Enterobacteriaceae are considered by WHO as “critical” priority pathogens for which novel antibiotics are urgently needed. The dissemination of carbapenemase-producing Escherichia coli (CP- Ec ) in the community is a major public health concern. However, the global molecular epidemiology of CP- Ec isolates, as well as the genetic bases for the emergence and global dissemination of specific lineages, remain largely unknown. Here, by combining a thorough genomic and evolutionary analysis of Ec ST410 isolates with a broad analysis of 12,584 E. coli and Shigella genomes, we showed that the fixation of carbapenemase genes depends largely on a combination of mutations in ftsI encoding the penicillin binding protein 3 and in the porin genes ompC and ompF . Mutated ftsI genes and a specific ompC allele inducing reduced susceptibility to diverse β-lactams spread across the species by recombination. The selection of CP- Ec lineages able to disseminate is more complex than the mere acquisition of carbapenemase genes.