The effectiveness of gatifloxacin therapy (15 mg/kg every 5 h [q5h]) was compared with that of meropenem (75 mg/kg q5h) and cefotaxime (75 mg/kg q5h) therapy in experimental meningitis caused by a -lactamase-producing strain of Escherichia coli. Gatifloxacin therapy was more rapidly bactericidal than cefotaxime but similar to meropenem therapy (bacterial killing rates at 5 h, 0.83 ± 0.26, 0.46 ± 0.3, and 0.73 ± 0.17 CFU/ml/h, respectively; P = 0.03 for gatifloxacin versus cefotaxime). At 10 h, seven of eight animals treated with gatifloxacin had <10 CFU/ml in their cerebrospinal fluid, compared with one of seven treated with cefotaxime therapy (P = 0.01). Gatifloxacin was at least as effective as currently available antibiotics in this model of E. coli meningitis.