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The purpose of this study was to assess treatment with a fluoroquinolone or trimethoprim-sulfamethoxazole versus cephalosporins for pyelonephritis in discharged patients from a community hospital setting.A retrospective chart review was completed for adult female patients who received a prescription for a cephalosporin, fluoroquinolone or trimethoprim-sulfamethoxazole for the treatment of pyelonephritis within the network of a large healthcare system. The primary endpoint evaluated the failure rate of each treatment group. The secondary endpoint evaluated the difference between rates of resistance on culture and sensitivity reports for treatment groups.A total of 55 patients in the cephalosporin group and 43 patients in the fluoroquinolone and trimethoprim-sulfamethoxazole group were reviewed. The primary endpoint occurred in 0% of the patients in the cephalosporin group and in 23% of the patients in the fluoroquinolone and trimethoprim-sulfamethoxazole group, p < 0.001. Of the 98 urine samples collected, 71 samples were positive for pathogen growth. Upon evaluation of these isolates, 6% were resistant to cephalexin, 1% was resistant to cefdinir, 3% were resistant to ciprofloxacin and 23% were resistant to trimethoprim-sulfamethoxazole. Trimethoprim-sulfamethoxazole showed statistical significance for more bacterial resistance compared to the other agents, p < 0.01.Failure of therapy for pyelonephritis occurred more often in the fluoroquinolone and trimethoprim-sulfamethoxazole group than in the cephalosporin group. The findings in this study are most applicable to patients who are treated on an outpatient basis. A prospective, randomized clinical trial is necessary to confirm these results.