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(See the Editorial Commentary by Perez and Bonomo, on pages 175–7.)Background. Extended-spectrum ß-lactamase–producing Escherichia coli (ESBL-EC) is an important cause of invasive infections. Alternatives to carbapenems—considered the drugs of choice—are needed because of the emergence of carbapenemase-producing enterobacteria. The efficacy of ß-lactam/ß-lactam inhibitors (BLBLI) in such infections is controversial.Methods. The authors performed a post hoc analysis of patients with bloodstream infections due to ESBL-EC from 6 published prospective cohorts. Mortality and length of hospital stay in patients treated with an active BLBLI (amoxicillin-clavulanic acid [AMC] and piperacillin-tazobactam [PTZ]) or carbapenem were compared in 2 cohorts: the empirical therapy cohort (ETC) and the definitive therapy cohort (DTC). Confounding was controlled by multivariate analysis; for patients in the ETC, a propensity score for receiving carbapenem was also used.Results. The ETC included 103 patients (BLBLI, 72; carbapenem, 31), and the DTC included 174 (BLBLI, 54; carbapenem, 120). Mortality rates at day 30 for those treated with BLBLI versus carbapenems were 9.7% versus 19.4% for the ETC and 9.3% versus 16.7% for the DTC, respectively (P > .2, log-rank test). After adjustment for confounders, no association was found between either empirical therapy with BLBLI (adjusted hazard ratio [HR], 1.14; 95% confidence interval [CI], .29–4.40; P = .84) or definitive therapy (adjusted HR, 0.76; 95% CI, .28–2.07; P = .5) and increased mortality. Furthermore, BLBLI therapy, with respect to carbapenem, was not found to influence length of hospital stay.Conclusions. These results suggest that AMC and PTZ are suitable alternatives to carbapenems for treating patients with bloodstream infections due to ESBL-EC if active in vitro and would be particularly useful as definitive therapy.