We used two strains of ampicillin-susceptible Escherichia coli to produce meningitis in rabbits and utilized these models (i) to compare the killing effects of parenteral trimethoprim-sulfamethoxazole (TMP-SMZ) and ampicillin on E. coli in cerebrospinal fluid after 8 h of treatment and (ii) to measure the penetration of TMP-SMZ and ampicillin into cerebrospinal fluid and the brain. At 16 h after intracisternal inoculation with a test strain, rabbits were treated with TMP (6 mg/kg per h) and SMZ (30 mg/kg per h), ampicillin (40 mg/kg per h), or saline intravenously for 8 h. TMP-SMZ levels were measured by high-pressure liquid chromatography, and ampicillin levels were measured by microbiological assay. Mean +/- standard deviation concentrations of TMP, SMZ, and ampicillin in cerebrospinal fluid (mean percent penetration) at the completion of 8 h of therapy were 0.80 +/- 0.41 (18%), 15.7 +/- 21.1 (27.2%), and 2.6 +/- 1.7 (8.9%) microgram/ml, respectively. TMP, SMZ, and ampicillin levels in brain homogenate after 8 h of therapy were 0.23 +/- 0.07 (6.6%), 3.31 +/- 3.3 (5.5%), and 0.6 +/- 4.53 (1.9%) microgram/g, respectively. TMP-SMZ infusion for 8 h produced a significant reduction in mean bacterial counts in cerebrospinal fluid in both models of meningitis compared with saline controls. The decrease in mean bacterial counts with TMP-SMZ therapy was equivalent to that produced by ampicillin.