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In 2010, the Clinical and Laboratory Standards Institute (CLSI) revised and lowered the ceftriaxone minimum inhibitory concentration breakpoints for Enterobacteriaceae and removed the requisite extended spectrum β-lactamase phenotypic testing for organisms with elevated minimum inhibitory concentrations. The impact that these recommendations have on clinical outcomes of children have not been previously evaluated.We conducted a retrospective study to compare clinical outcomes between children treated with ceftriaxone and those treated with broader spectrum β-lactams for Enterobacteriaceae bacteremia with reduced susceptibility (minimum inhibitory concentrations 4–8 µg/mL) to ceftriaxone according to the new CLSI interpretive criteria. Mortality and microbiological relapse were evaluated using a multivariable logistic regression model.There were a total of 783 unique children with Enterobacteriaceae bacteremia during the study period. Using the CLSI breakpoints before 2010, 76 children would have had clinical isolates resistant to ceftriaxone. With the revised breakpoints, 229 Enterobacteriaceae isolates would no longer be susceptible to ceftriaxone (>300% increase). Of the 136 children who met eligibility criteria, 63 children received ceftriaxone and 73 children received broader spectrum β-lactams. There was no difference in 30-day mortality (odds ratio 0.81, 95% confidence interval: 0.31–2.59) or microbiological relapse (odds ratio 0.97, 95% confidence interval: 0.36–2.66) between the groups.Our findings do not support the proposed clinical benefit of more conservative CLSI breakpoints. The revised breakpoints promote increased broad-spectrum β-lactam use. The need for lowered ceftriaxone breakpoints against Enterobacteriaceae in children needs to be reevaluated in larger prospective studies.