Adequate concentrations of beta-lactam antibiotics in cerebrospinal fluid (CSF) are difficult to achieve for meningitis caused by drug-resistant Streptococcus pneumoniae. Ceftriaxone in dosages of 150 or 400 mg/kg of body weight per day, given in one or two doses, was used for the treatment of experimental highly cephalosporin-resistant (MIC and MBC, 4 microg/ml) pneumococcal meningitis. The bacterial killing rate (delta log10 CFU per milliliter per hour) and pharmacokinetic indices, including percentage of time the antibiotic concentration exceeded the MBC during a 24-h period (T>MBC), CSF peak concentration above the MBC, and area under the concentration-time curve from 0 to 24 h above MBC, were measured and correlated. By multiple stepwise regression, only T>MBC independently predicted the bacterial killing rate. There was a direct linear correlation between T>MBC in CSF and the bacterial killing rate during the first 24 h of therapy (r = 0.87; P = 0.004). Sterilization of CSF was achieved only when the T>MBC was 95 to 100%. In the first 24 h, the 200-mg/kg/12-h regimen, compared with the 400-mg/kg/24-h regimen, was associated with a greater T>MBC (87% +/- 10% versus 60% +/- 22%; P = 0.03) and greater bacterial killing rate (0.2 +/- 0.04 versus 0.13 +/- 0.07; P = 0.003), confirming that ceftriaxone exhibits time-dependent bactericidal activity. After 24 h, the T>MBC and the CSF sterilization rates were similar whether ceftriaxone was given once or twice daily.