The CTX-M family of extended-spectrum β-lactamases (ESBLs) is a significant global public health threat. The prevalence of specific bla (CTX-M) genes varies geographically, but bla (CTX-M-15) and bla (CTX-M-14) dominate in most countries. We applied the latest Clinical Laboratory Standards Institute (CLSI) interpretive criteria (M100-S20) to a diverse collection of ESBL-producing Escherichia coli strains obtained from clinical specimens in our laboratory. Whereas under previous CLSI recommendations all isolates in this strain collection would have been reported as ceftazidime-resistant, under the new recommendations, approximately 11% of CTX-M-15-producing E. coli and 93% of CTX-M-14-producing E. coli respectively tested as ceftazidime-susceptible. We also found that, whilst many CTX-M-14-producers had minimum inhibitory concentrations (MICs) less than the breakpoint of 4 mg/L, the MIC distribution for these strains was higher than that of wild-type E. coli, with one CTX-M-14-producing isolate having an MIC of >64 mg/L. Although the new CLSI recommendations imply that ceftazidime can be safely used to treat serious infections due to CTX-M-producing E. coli, clinical outcome data are lacking. Consequently, the widespread use of ceftazidime in this setting could have profound clinical implications.