Carbapenem-resistant Escherichia coli (CREC) represent a major clinical threat because of limited treatment options and frequent multidrug resistance. While rapid molecular diagnostics improve treatment outcomes, the detection of carbapenemase genes, such as blaOXA-48-like, does not always correspond to phenotypic resistance, complicating management of bloodstream infections. We investigated 20 bloodstream E. coli isolates, from pediatric cancer patients at Children’s Cancer Hospital Egypt 57357, that harbored blaOXA-48-like genes yet were phenotypically susceptible to meropenem. Whole-genome sequencing was performed to characterize resistomes, virulomes, plasmid content, and the genetic context of OXA-48–like variants. The isolates belonged to 12 sequence types (STs), with ST405 and ST410 being the most frequent. blaOXA-244 predominated and was primarily chromosomal, whereas blaOXA-181 and blaOXA-484 were plasmid-borne, often co-localized with qnrS1. Resistome and virulome profiles were broadly conserved across meropenem-susceptible and resistant isolates. Structural modeling and protein–ligand interaction analyses of OXA-48, OXA-244, OXA-181, and OXA-484 illustrate how the substitutions Arg214Gly and Thr104Ala are consistent with localized alterations in active site geometry, despite preservation of key ligand interactions. These observations help explain the observed discordance between genotype and phenotype and highlight the limitations of relying solely on rapid gene detection for treatment decisions. Collectively, these findings highlight the need to interpret rapid PCR-based carbapenemase detection in conjunction with phenotypic susceptibility testing and genomic context, supporting balanced antimicrobial decision-making that preserves carbapenem use when appropriate while maintaining vigilance against the silent spread of carbapenemase-producing strains.