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

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 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.

Use of modeling techniques to aid in antibiotic selection

“…For example, in a study of rats treated with lomefloxacin for pseudomonal sepsis, no differences were reported among C max /MIC, AUC/MIC and T eff , as predictors of survivorship; the coefficients of determination (r 2 ) were 0.99, 0.99, and 0.98, respectively [35]. Similar predictive potentials of the MBC analogues of these predictors were reported in rabbits with pneumococcal meningitis that were treated with gatifloxacin (r 2 s of 0.74, 0.69, and 0.68, respectively) [39]. Also, no significant differences were observed between the predictive forces of log C max /MIC and T eff of gemifloxacin [40] in murine models of thigh or lung infections caused by Streptococcus pneumoniae (r 2 of 0.53 and 0.48, respectively) and Klebsiella pneumoniae (r 2 of 0.72 and 0.59 to 0.85, respectively).…”

Plasma Concentrations, Pharmacokinetics and Urinary Excretion of Gatifloxacin after Single Intravenous Injection in Buffalo Calves

“…If a drug is to be used effectively, it is important to investigate its pharmacokinetics in each animal species and the climate in which the drug is to be used clinically (Nawaz et al, 1980). Accordingly, pharmacokinetic studies of gatifloxacin have been conducted in humans (Nakashima et al, 1995), rabbits (Lutsar et al, 1998) and mice (Andes and Craig, 2002). However, there is no information available on the pharmacokinetics of gatifloxacin in buffalo species.…”

Fluoroquinolones in the treatment of meningitis

“…Several studies in pneumococcal meningitis have also shown that a maximal bactericidal efficacy is obtained when the concentration of the fluoroquinolones in CSF exceed the MBC (or MIC) during the entire dosing interval [50]. This feature is probably due to the short sub-MIC effect (postantibiotic effect) of quinolones against pneumococci [49,50]. In an in vitro pharmacodynamic model, the importance of T > MBC has also been demonstrated for quinolone therapy against gram-negative pathogens [51].…”