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), in experimental pneumococcal meningitis. The penetration of gatifloxacin into CSF, calculated as the percentage of the area under the concentration-time curve (AUC) in CSF over the AUC in blood, was 46 to 56%. Gatifloxacin showed linear pharmacokinetics in CSF, and 1 h after intravenous dosages of 7.5, 15, or 30 mg/kg of body weight, peak CSF concentrations were 0.46 +/- 0.08 (mean +/- standard deviation), 0.94 +/- 0.16, and 1.84 +/- 0.5 microg/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 interrelationship among the highest measured values of gatifloxacin in blood and CSF/minimal bactericidal concentration (Cpeak/MBC), the time antibiotic concentrations exceeded the MBC (T > MBC), and AUC/MBC (r = 0.94); in single-dose experiments, each correlated significantly with the bacterial killing rate. Divided-dose regimens, resulting in greater T > MBC values but lower Cpeak/MBC ratios, were more effective in terms of bacterial clearance compared with corresponding single-dose regimens. Gatifloxacin therapy was as effective as currently recommended regimens (e.g., a combination of ceftriaxone and vancomycin) against this highly cephalosporin-resistant 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 entire dosing interval.
The University of Texas Southwestern Medical Center, Dallas, Texas 75235-9063, USA. GMCCRA@mednet.swmed.edu
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Friedland
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McCracken
D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000134:cerebrospinal fluid* / Q000494:pharmacology; D004352:Drug Resistance, Microbial; D024841:Fluoroquinolones; D000077734:Gatifloxacin; D008297:Male; D008586:Meningitis, Pneumococcal / Q000134:cerebrospinal fluid / Q000188:drug therapy*; D008826:Microbial Sensitivity Tests; D011817:Rabbits; D013296:Streptococcus pneumoniae / Q000187:drug effects
D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D000077734:Gatifloxacin