Pharmacodynamics of gatifloxacin in cerebrospinal fluid in experimental cephalosporin-resistant pneumococcal meningitis

Antimicrob Agents Chemother. 1998 Oct;42(10):2650-5. doi: 10.1128/AAC.42.10.2650.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Infective Agents / administration & dosage
  • Anti-Infective Agents / cerebrospinal fluid*
  • Anti-Infective Agents / pharmacology
  • Drug Resistance, Microbial
  • Fluoroquinolones*
  • Gatifloxacin
  • Male
  • Meningitis, Pneumococcal / cerebrospinal fluid
  • Meningitis, Pneumococcal / drug therapy*
  • Microbial Sensitivity Tests
  • Rabbits
  • Streptococcus pneumoniae / drug effects

Substances

  • Anti-Infective Agents
  • Fluoroquinolones
  • Gatifloxacin