Cerebrospinal fluid penetration and pharmacokinetics of levofloxacin in an experimental rabbit meningitis model.

Abstract

This study was designed to investigate the penetration across the blood-brain barrier of three doses of levofloxacin using a microdialysis probe implanted into the cerebrospinal fluid (CSF) of a rabbit pneumococcal meningitis model. The microdialysis guide cannula was implanted into rabbit subarachnoid space using a stereotaxic frame. After 3 days, 10(4) cfu Streptococcus pneumoniae serotype 3 in 0.3 mL saline was injected via intracisternal puncture and animals were allowed to incubate the organisms for 16-18 h. Groups of animals (n = 5) then received 7, 10.5 or 14 mg/kg iv of the drug over 10 min. Plasma samples were obtained via an ear vein 0, 0.25, 0.5, 0.75, 1, 2, 4, 6 and 8 h after the antibiotic infusion. CSF microdialysis effluent samples were collected every 0.5 h for the entire experiment. Plasma and microdialysis effluent samples were analysed by HPLC. AUC(0-8) in plasma and CSF were computed using the trapezoid rule. The elimination half-life in plasma and CSF was calculated using non-linear regression analysis. The unbound peak plasma concentrations for the three doses studied were 3.9, 6.4 and 10.3 mg/L, respectively. There was a significant increase in the plasma AUC(0-8) [29.7 +/- 6.3, 49.1 +/- 19.1 and 67.6 +/- 8.9 mg x h/L (P < 0.005)]. The unbound peak CSF concentrations were 3.8, 5.7 and 8.6 mg/L and occurred at 0-0.5 h after the administration of the dose. The AUC(CSF(0-8)) was significantly higher as the dose was increased (7 mg/kg, 15.8 +/- 6.6; 10.5 mg/kg, 37.3 +/- 7.8; and 14 mg/kg, 46.4 +/- 20.9 mg x h/L; P < 0.03). The penetration of levofloxacin averaged 53% for the 7 mg/kg dosage group, 76% for the 10.5 mg/kg group and 68% for the 14 mg/kg group. Our results demonstrate that levofloxacin penetration into the CSF averages 66% for the doses that would be used in clinical practice.