Extended-spectrum cephalosporins and the inoculum effect in tests with CTX-M-type extended-spectrum β-lactamase-producing Escherichia coli: Potential clinical implications of the revised CLSI interpretive criteria

Based on the new recommendations of the Clinical and Laboratory Standards Institute (CLSI), the revised cephalosporin breakpoints may result in many CTX-M-producing Escherichia coli being reported as susceptible to ceftazidime. We determined the activity of ceftazidime and other parenteral β-lactam agents in standard- and high-inoculum minimum inhibitory concentration (MIC) tests against CTX-M-producing E. coli isolates. Antimicrobial susceptibility was determined using a broth microdilution MIC method with inocula that differed 100-fold in density. An inoculum effect was defined as an eight-fold or greater increase in MIC on testing with the higher inoculum. When the revised CLSI ceftazidime breakpoint of 4 μg/mL was applied, 34 (34.3%) of the 99 CTX-M-producers tested were susceptible. More specifically, for 42 CTX-M-14-producing E. coli isolates, 32 (76.2%) were susceptible at 4 μg/mL. Cefotaxime, ceftazidime, cefepime and piperacillin/tazobactam were found to be associated with inoculum effects in 100% of the evaluable tests for extended-spectrum β-lactamase-producing E. coli isolates. The MIC50 (MIC required to inhibit 50% of isolates) of ceftazidime was 16 μg/mL in the standard-inoculum tests and >512 μg/mL in the high-inoculum tests. In the high-inoculum tests including isolates encoding CTX-M-14, ceftazidime was dramatically affected, with susceptibility decreasing from 82.1% of isolates inhibited at 4 μg/mL in the standard-inoculum tests to 0% at high inoculum. Although further studies may demonstrate that ceftazidime has a role in the treatment of infections caused by these organisms, we suggest that until more data become available, clinicians should be cautious about treating serious CTX-M-producing E. coli infections with ceftazidime or cefepime.