Pharmacodynamics and bactericidal activity of trovafloxacin (trova) in CSF in experimental cephalosporin-resistant pneumococcal meningitis

The antibacterial activity of quinolones in serum is concentration-dependent, but this has not been shown in cerebrospinal fluid (CSF). The aim of this study was to characterize the pharmacodynamic profile of trova in CSF in experimental cephalosporin-resistant (MBC ceftriaxone = 4 μg/ml; trova = 0.125 μg/ml) pneumococcal meningitis, to determine whether the activity is concentration- or time-dependent, and to suggest a treatment regimen for children with meningitis. Using the rabbit meningitis model we gave dosages of 10-20 mg/kg of trova in one or multiple IV doses. CSF was obtained to determine pharmacokinetic indices and bacterial concentrations for a period up to 24 h. Pharmacokinetic indices and bacterial killing in CSF after a single dose were as follows for 6 h: Dosage AUC Cpeak t1/2 (h) Bact. Killing Rate (mg/kg) (μg/ml · hr) (μg/ml) (Δlog CFU/ml/h) 10 1.93 plusmn; 0.14 0.60 plusmn; 0.12 1.33 plusmn; 0.21 0.38 15 2.60 plusmn; 0.06 0.68 plusmn; 0.04 1.79 plusmn; 0.07 0.55 20 3.92 plusmn; 0.05 1.18 plusmn; 0.07 1.41 plusmn; 0.04 0.73 During the first 6 h a concentration-dependent reduction in bacterial concentration was seen. From 6 to 12 h bacterial regrowth occurred in all dosage groups. Using a four dose regimen administered every half-life of trova in CSF (20 mg/kg loading, 10 mg/kg q2h X 3), 74% of CSF cultures were sterile after 24 h. Conclusions: 1) The Cpeak, AUC, and bacterial killing in CSF were directly related. 2) In CSF trova exhibits a concentration-dependent bacterial killing. 3) Trova is a potentially useful agent for therapy of highly beta-lactam-resistant pneumococcal meningitis when administered every half life.