Efficacy of trovafloxacin against penicillin-susceptible and multiresistant strains of Streptococcus pneumoniae in a mouse pneumonia model

Abstract

The increasing emergence of penicillin-resistant and multidrug-resistant strains of Streptococcus pneumoniae will create a serious therapeutic problem in coming years. Trovafloxacin is a novel naphthyridone quinolone with promising activity against S. pneumoniae, including penicillin-resistant strains (MIC for 90% of the isolates tested, 0.25 microg/ml). We compared its in vivo efficacy with that of other fluoroquinolones (ciprofloxacin, temafloxacin, and sparfloxacin) and a reference beta-lactam (amoxicillin) in a model of acute experimental pneumonia. Immunocompetent Swiss mice were infected by peroral tracheal delivery of a virulent, penicillin-susceptible strain (MIC, 0.03 microg/ml); leukopenic Swiss mice were infected with three poorly virulent, penicillin-resistant strains (MICs, 4 to 8 microg/ml) and a ciprofloxacin-resistant strain (MIC, 32 microg/ml). Treatments were started 6 h (immunocompetent mice) or 3 h (leukopenic mice) after infection. Doses ranging from 12.5 to 300 mg/kg were given at 12- or 8-h intervals for 3 days. Trovafloxacin (25 mg/kg) was the most effective agent in vivo against penicillin-susceptible and -resistant strains. Corresponding survival rates were 2- to 4-fold higher than with 50-mg/kg sparfloxacin or temafloxacin and 8- to 16-fold higher than with 100-mg/kg ciprofloxacin. The ratios of the area under the concentration-time curve to the MIC in serum and lung tissue were more favorable with trovafloxacin than with the other quinolones. Efficacy in vivo correlated with pharmacokinetic parameters. Trovafloxacin shows potential for the treatment of infections due to penicillin-susceptible and -resistant S. pneumoniae but appears to be ineffective against a ciprofloxacin-resistant strain.

FIG. 1

Survival of immunocompetent mice challenged with a penicillin-susceptible pneumococcal strain (P-4241) and treated with four different quinolones (trovafloxacin [Trova], ciprofloxacin [Cipro], sparfloxacin [Sparflo], and temafloxacin [Tema]) and amoxicillin (Amo). Antibiotics were injected s.c. twice a day for 3 days. The values in parentheses are doses in milligrams per kilogram.

FIG. 2

Survival of leukopenic mice challenged with penicillin-resistant strains P-54988 (A; penicillin MIC, 4 μg/ml), P-12698 (B; penicillin MIC, 4 μg/ml), and P-15986 (C; penicillin MIC, 8 μg/ml; erythromycin MIC, >32 μg/ml) and treated with four different quinolones (trovafloxacin [Trova], ciprofloxacin [Cipro], sparfloxacin [Sparflo], and temafloxacin [Tema]) and amoxicillin (Amo). Antibiotics were injected s.c. twice a day for 3 days. The values in parentheses are doses in milligrams per kilogram.

FIG. 3

Concentration-time curves fitted to a one-compartment model with plotted experimental data for trovafloxacin in the sera and lungs of mice given a single s.c. injection of 25 mg/kg. A healthy control group and a group challenged with strain P-4241 6 h before drug administration are compared.