Among 477 patients with susceptible Enterobacter spp., 49 subsequently harbored third-generation cephalosporin-resistant Enterobacter spp. Broad-spectrum cephalosporins were independent risk factors for resistance (relative risk [OR] ؍ 2.3, P ؍ 0.01); quinolone therapy was protective (OR ؍ 0.4, P ؍ 0.03). There were trends toward decreased risk for resistance among patients receiving broad-spectrum cephalosporins and either aminoglycosides or imipenem. Of the patients receiving broad-spectrum cephalosporins, 19% developed resistance.Enterobacter spp. are among the most common gram-negative pathogens associated with hospital infections, representing 6% of all nosocomial isolates recovered and 11% of pneumonia isolates (8).Resistance to -lactam antibiotics often complicates the treatment of Enterobacter infections (2, 6). In a recent report, 36% of Enterobacter spp. infections in intensive care units were resistant to broad-spectrum cephalosporins (9). Most commonly, resistance to third-generation cephalosporins in this organism is mediated by chromosomal AmpC cephalosporinase. Although isolates often appear susceptible in vitro, antibiotic pressure can facilitate the emergence of derepressed mutant Enterobacter cells which produce AmpC -lactamases at high levels constitutively (12; A. A. Medeiros, Editorial, Clin. Infect. Dis. 25:341-342, 1996). In addition, exposure to certain -lactam antibiotics results in increased synthesis of AmpC and induction of resistance to broad-spectrum cephalosporins.A landmark study by Chow et al. showed a strong correlation between previous broad-spectrum cephalosporin exposure and the isolation of Enterobacter spp. resistant to these agents (2). Although the study demonstrated emergence of resistance during therapy of Enterobacter bacteremia with broad-spectrum cephalosporins in 19% of patients, the prospective nature of this study precluded a large enough sample size on which conclusive analysis of risk factors for emergence of resistance could be performed (only six patients showed the emergence of a resistant strain). No study to date has had enough statistical power to study this question comprehensively. We applied here effective analytical methods to a large study cohort to measure the effects of antimicrobial agent exposures on the emergence of broad-spectrum cephalosporin resistance among Enterobacter spp. We analyzed antimicrobial risk factors as timedependent variables (7) so that risk estimates would account for the duration of time an individual was exposed to an antimicrobial agent only after therapy with the agent had commenced, thus decreasing the potential for bias.The study design was a retrospective cohort. All patients admitted to Beth Israel Deaconess Medical Center, West Campus, Boston, Mass., between October 1993 and September 1997 with cultures positive for Enterobacter spp. susceptible to broadspectrum cephalosporins were included in the study. Patients remained in the cohort until Enterobacter spp. resistant to broadspectrum cephalosporins were i...