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

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, 104 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. AUC0–8 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 AUC0–8 [29.7 ± 6.3, 49.1 ± 19.1 and 67.6 ± 8.9 mg•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 AUCCSF(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•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.