The recent increase of CTX-M-15-producing Escherichia coli isolates in our institution was caused by diverse clonal backgrounds, including mainly B2 sequence type 131 (ST131) clones presenting variable virulence profiles but also A(1) (ST617, ST410), B1, and D(1) (ST405) clones. Besides IncFII-pC15-1a, we detected multidrug-resistant IncA/C(2) and IncN plasmids carrying bla(CTX-M-15) and/or qnrS1. Our study highlights the diversification of highly transmissible resistant and virulent clones and the recombinogenic potential of broad-host plasmids contributing to the expansion of genetic regions coding for multidrug resistance to other bacterial lineages.