The etiology of urinary tract infections (UTIs) that require hospitalization, whether they originate in the hospital or in the community, is changing, with increasing findings of gram-positive organisms. The Council for Appropriate and Rational Antibiotic Therapy (CARAT) criteria recommend evaluating treatment choices on the basis of sound clinical evidence, potential for therapeutic benefits, safety, optimal duration of treatment, and cost-efficacy in order to improve antibiotic treatment. Evidence-based guidelines recommend fluoroquinolones for the treatment of patients with cases of pyelonephritis or bacterial prostatitis severe enough to warrant hospitalization. For other serious UTIs, fluoroquinolones are usually recommended either when traditional agents have failed or when resistance to traditional agents is high. Even in the context of rapidly changing antimicrobial resistance patterns, the fluoroquinolones have maintained consistent, well-tolerated efficacy against many of the principal organisms responsible for UTIs, and are generally considered safe for most patients. To increase the likelihood of treatment success with first-line therapy, an antimicrobial agent must attain sufficient concentrations in the target tissue or in the urine for an appropriate amount of time. Both levofloxacin and gatifloxacin are excreted unchanged in the urine in concentrations that far exceed the minimum inhibitory concentration of most uropathogens. Factors that affect cost-effectiveness that should be considered include acquisition costs as well as treatment success and ease of use for hospital staff.