Pharmacodynamics and pharmacokinetics of A-80556 using microdialysis in a Streptococcus pneumoniae meningitis model

Using microdialysis in a rabbit model of Streptococcus pneumoniae meningitis, the pharmacokinetics and pharmacodynamics of a new fluoroquinolone, A-80556, were determined. A-80556 (10 mg/kg iv) was administered to four rabbits. Saline was given to four separate control animals. A microdialysis probe perfused the CSF (2 μL/min) and effluent was collected at 0-0.25, 0.25-1, 1-2, 2-4, and 4-6 h after injection of A-80556. Seven blood samples were collected and analyzed by HPLC. At 0, 2, 4, and 6 h 300 μL of CSF was withdrawn for pharmacodynamic measurements. Plasma A-80556 concentrations demonstrated AUC(0-∞), 2.40 ± 0.272 μg.h/mL; T( 1/4 β) 1.07 ± 0.011 h; V(d) 6.35 ± 0.50 L/kg; and Cl(t), 4.23 ± 0.48 L/h.kg. Penetration into the CSF was 18.21%. Pharmacodynamics using time-kill curves showed a 3-log reduction in bacterial counts in CSF at 2 h after administration continuing for the remaining four hours of the experiment. These results demonstrate that microdialysis can be used for determination of drug penetration and efficacy in experimental S. pneumoniae meningitis.