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Background Infections due to extended-spectrum β-lactamase–producing Escherichia coli and Klebsiella species (ESBL-EK) have increased markedly in recent years. Risk factors for mortality among ESBL-EK infections have not been studied. Methods This retrospective cohort study was conducted in a 625-bed tertiary care medical center and a 344-bed urban community hospital to determine whether inadequate initial antimicrobial therapy (IIAT) (>48 hours between the time a culture was obtained and initiation of an agent to which the infecting organism was susceptible) is associated with mortality in ESBL-EK infections. All hospitalized patients with an ESBL-EK infection between June 1, 1997, and December 31, 2002, were eligible for inclusion. Subsequently, we conducted a nested case-control study to identify risk factors for IIAT. Results Of 187 subjects, 32 (17.1%) died while in the hospital. Clinical site of infection was a significant effect modifier in the association between IIAT and mortality. The presence of IIAT was an independent risk factor for mortality, but only for nonurinary ESBL-EK infections (adjusted odds ratio [95% confidence interval], 10.04 [1.90-52.96]). Independent risk factors for IIAT were (1) infection with a multidrug-resistant ESBL-EK (ie, resistant to sulfamethoxazole-trimethoprim, aminoglycosides, and quinolones) (14.58 [1.91-111.36]) and (2) health care–acquired ESBL-EK infection (4.32 [1.49-12.54]). Conclusions Inadequate initial antimicrobial therapy is an independent risk factor for mortality in ESBL-EK infections, but only among nonurinary infections. Multidrug resistance was a strong risk factor for IIAT. [ABSTRACT FROM AUTHOR]