Trovafloxacin in combination with vancomycin against penicillin-resistant pneumococci in the rabbit meningitis model

Abstract

Trovafloxacin, a new fluoroquinolone, produced bactericidal activity (-0.33 +/- 0.13 delta log10 CFU/ml.h; intravenously [i.v.] administered dose, 15 mg/kg) comparable to that of vancomycin (-0.39 +/- 0.18 delta log10 CFU/ml.h; i.v. admininistered dose, 20 mg/kg) in the treatment of experimental meningitis in rabbits due to a pneumococcal strain highly resistant to penicillin (MIC of penicillin G, 4 micrograms/ml). The combination of both drugs significantly increased (P < 0.05) the killing rate (-0.60 +/- 0.23 delta log10 CFU/ml.h) compared to that produced by either monotherapy. These results were also confirmed in vitro.

FIG. 1

Mean trovafloxacin concentrations in CSF at 0.75, 2.5, 4, 6, and 8 h after intravenous injection of 15 mg of alatrofloxacin per kg. The concentration of trovafloxacin remained above the MIC (0.12 μg/ml) during the entire treatment period. Vertical bars show ± SD.

FIG. 2

Mean vancomycin concentration in the CSF at 0.75, 2.5, 4, 6, and 8 h after intravenous injection of vancomycin (20 mg/kg). Vancomycin was injected intravenously at 4 h at the same dose. The MIC for vancomycin was 0.25 μg/ml, and the concentrations in CSF remained above the MIC for the entire treatment period. Vertical bars show ± SD.

FIG. 3

Killing rates of trovafloxacin (■) in vitro at concentrations ranging from 0.06 μg/ml (1/2 of the MIC) to 0.6 μg/ml (5× the MIC). □, data for untreated controls (C). Experiments were performed in triplicate, and killing rates are expressed as means ± SDs.

FIG. 4

Bactericidal activity of vancomycin in vitro. Concentrations of vancomycin ranging from 0.06 μg/ml (1/4 of the MIC) to 2.5 μg/ml (10× the MIC) were tested. □, data for untreated controls (C). Experiments were performed in triplicate, and results are expressed as means ± SDs.

FIG. 5

Killing rates of trovafloxacin (T) (0.12 μg/ml; 1× the MIC), vancomycin (V) (0.12 μg/ml; 1/2 of the MIC), and the combination of the two substances (V+T) in vitro. The experiments were performed in triplicate, and results are expressed as means ± SDs. ∗, P < 0.05 versus either single-drug therapy.