PHARMACODYNAMICS OF GATIFLOXACIN IN CEREBROSPINAL-FLUID IN EXPERIMENTAL CEPHALOSPORIN-RESISTANT PNEUMOCOCCAL MENINGITIS

The purpose of this study was to evaluate the cerebrospinal fluid (CSF ) pharmacodynamics of a new fluoroquinolone, gatifloxacin (AM-1155), i n experimental pneumococcal meningitis, The penetration of gatifloxaci n into CSF, calculated as the percentage of the area under the concent ration-time curve (AUC) in CSF over the AUC in blood, was 46 to 56%. G atifloxacin showed linear pharmacokinetics in CSF, and 1 h after intra venous dosages of 7.5, 15, or 30 mg/kg of body weight, peak CSF concen trations were 0.46 +/- 0.08 (mean +/- standard deviation), 0.94 +/- 0. 16, and 1.84 +/- 0.5 mu g/ml, respectively. The elimination half-life of gatifloxacin in CSF was 3.8 to 5.6 h (compared with 2.7 to 3.2 h in blood), There was a significant inter relationship among the highest measured values of gatifloxacin in blood and CSF/minimal bactericidal concentration (C-peak/MBC). the time antibiotic concentrations exceede d the MBC (T > MBC), and AUC/MBC (r = 0.94); in single-dose experiment s, each correlated significantly with the bacterial killing rate, Divi ded-dose regimens, resulting in greater T > MBC values but lower C-pea k/MBC ratios, were more effective in terms of bacterial clearance comp ared with corresponding single-dose regimens, Gatifloxacin therapy,vas as effective as currently recommended regimens (e.g., a combination o f ceftriaxone and vancomycin) against this highly cephalosporin-resist ant pneumococcal strain. The bactericidal activity of gatifloxacin in CSF was closely related to the AUC/MBC ratio, but maximal activity was achieved only when drug concentrations exceeded the MBC for the entir e dosing interval.