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...

Detailed studies of pharmacodynamic principles relevant to the therapy of bacterial meningitis are difficult to perform in man, while the rabbit model of bacterial meningitis has proved to be extremely valuable and has led to insights that appear relevant for the treatment of humans. Most importantly in the light of the restricted penetration of antibiotics into the CSF, animal studies have shown that in meningitis there is a dose-response curve between the CSF concentrations achieved by antibiotics and their bactericidal activity. This appears to be true for all classes of antibiotics thus far examined, including the beta-lactams, which do not show such a dose-response behaviour in other infections. Only CSF concentrations that exceed the MBC of the infecting organism by at least 10-30-fold achieve consistent and rapid bactericidal activity. Such rapid bactericidal activity is a requirement for successful therapy with beta-lactams and can be impaired with certain antibiotics by the specific conditions in infected CSF (protein content; acidic pH; slow-growing bacteria). However, rapid antibiotic killing of the infecting organisms may not be without adverse effects either. Some antibiotics, particularly beta-lactams lead to the brisk liberation of bacterial cell wall components (e.g. endotoxin, in the case of Gram-negative organisms) which have an inflammatory effect on the host and can lead to a temporary deterioration of the disease. Dexamethasone, when administered with the antibiotic, can prevent some of the adverse effects of rapid bacterial lysis.

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DNA polymerases of Candida albicans were purified to near homogeneity. Three well distinguished peaks of DNA polymerase activity (Enzyme I, II and III respectively) were obtained by DEAE-Sephacel chromatography. This purification step was followed by column chromatographies on Sepharose 6B and denatured DNA-cellulose. The enzymes' molecular mass and biochemical properties, including their inhibition by aphidicolin, were studied. Molecular mass was determined by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate and was found to be 110 kDa for Enzyme I, 80 kDa for Enzyme II and 50 kDa for Enzyme III.