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Antimicrobial Agents and Chemotherapy, October 1998, p. 2650-2655, Vol. 42, No. 10
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Pharmacodynamics of Gatifloxacin in Cerebrospinal Fluid in Experimental Cephalosporin-Resistant Pneumococcal Meningitis

Irja Lutsar,* Ian R. Friedland, Loretta Wubbel, Cynthia C. McCoig, Hasan S. Jafri, Winston Ng, Faryal Ghaffar, and George H. McCracken Jr.

The University of Texas Southwestern Medical Center, Dallas, Texas

Received 9 February 1998/Returned for modification 31 May 1998/Accepted 20 July 1998

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 µg/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.

* Corresponding author. Mailing address: Department of Pediatrics, Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75235-9063. Phone: (214) 648-3082. Fax: (214) 648-2961. E-mail: GMCCRA{at}mednet.swmed.edu.

Antimicrobial Agents and Chemotherapy, October 1998, p. 2650-2655, Vol. 42, No. 10
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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