Using a rabbit model of pneumococcal meningitis, we compared the pharmacokinetics and bactericidal activities in cerebrospinal fluid (CSF) of older (ciprofloxacin, ofloxacin) and newer (levofloxacin, temafloxacin, CP-116,517, and Win 57273) quinolones with those of the -lactam ceftriaxone. All quinolones penetrated into the inflamed CSF better than ceftriaxone, and the speed of entry into CSF was closely related to their degrees of lipophilicity. At a dose of 10 mg/kg ⅐ h, which in the case of the quinolones already in use in clinical practice produced concentrations attainable in the sera and CSF of humans, ciprofloxacin had no antipneumococcal activity (⌬log 10 CFU/ml ⅐ h, ؉0.20 ؎ 0.14). Ofloxacin (⌬log 10 CFU/ml ⅐ h, ؊0.13 ؎ 0.12), temafloxacin (⌬log 10 CFU/ml ⅐ h, ؊0.19 ؎ 0.18), and levofloxacin (⌬log 10 CFU/ml ⅐ h, ؊0.24 ؎ 0.16) showed slow bactericidal activity (not significantly different from each other), while CP-116,517 (⌬log 10 CFU/ml ⅐ h, ؊0.59 ؎ 0.21) and Win 57273 (⌬log 10 CFU/ml ⅐ h, ؊0.72 ؎ 0.20) showed increased bactericidal activities in CSF that was comparable to that of ceftriaxone at 10 mg/kg ⅐ h (⌬log 10 CFU/ml ⅐ h, ؊0.80 ؎ 0.17). These improved in vivo activities of the newer quinolones reflected their increased in vitro activities. All quinolones and ceftriaxone showed positive correlations between bactericidal rates in CSF and concentrations in CSF relative to their MBCs. Only when this ratio exceeded 10 did the antibiotics exhibit rapid bactericidal activities in CSF. In conclusion, in experimental pneumococcal meningitis the activities of new quinolones with improved antipneumococcal activities were comparable to that of ceftriaxone.Pneumococci resistant to several antibiotics are becoming a worldwide challenge. In many areas at least 10% of pneumococcal isolates, including those isolated from cerebrospinal fluid (CSF), show reduced susceptibility to penicillin (15,17,34). Penicillin resistance in pneumococci is often associated with an increase in the MICs of other -lactam antibiotics, and the failure of cefotaxime and ceftriaxone in the treatment of meningitis caused by penicillin-resistant Streptococcus pneumoniae has been observed (1, 7).Quinolones are rapidly bactericidal in vitro and in vivo for susceptible organisms in a highly concentration-dependent way (4, 5). Because of their lipophilicity, quinolones enter the CSF better than other classes of antimicrobial agents (3, 26). However, quinolones have infrequently been used in the past for the therapy of meningitis. They are relatively contraindicated in children, the age group most susceptible to the development of meningitis, and the currently approved quinolones possess only marginal activities against important meningeal pathogens such as S. pneumoniae, other streptococci, and Listeria monocytogenes (26).In recent years, new quinolones with improved activities against gram-positive pathogens, including S. pneumoniae, have been developed (9,11,29,30). These quinolones remain active against -lactam-resistant pneumococci and...