Activity of gatifloxacin alone or in combination with pyrimethamine or gamma interferon against Toxoplasma gondii

The activity of gatifloxacin against Toxoplasma gondii, either alone or in combination with pyrimethamine or gamma interferon (IFN-gamma), was examine d in vitro and in vivo. In vitro, gatifloxacin significantly inhibited intr acellular replication of tachyzoites of the RH strain with a 50% inhibitory concentration of 0.21 mug/ml at 48 h after addition of the drug to the cul tures. Toxicity far host cells was not observed at this concentration. A sy nergistic effect (combination indices < 0.5) was demonstrated in vitro foll owing 48 h of treatment with the combination of gatifloxacin and pyrimetham ine (1:1 ratio). Doses of gatifloxacin of 100 and 200 mg/kg of body weight/ day administered orally to mice far 10 days resulted in significant (P valu es of 0.056 and <0.0001, respectively) prolongation in time to death follow ing infection with a lethal inoculum of tachyzoites. A dose of 400 mg/kg re sulted in 20% survival (P = 0.0001). Mortality was 100% in untreated contro l mice and in mice treated with 25 or 50 mg/kg/day. Treatment of infected m ice with a combination of gatifloxacin at 200 mg/kg/day and pyrimethamine a t 12.5 mg/kg/day resulted in 85% survival, whereas 100 and 80% of mice trea ted with gatifloxacin alone or pyrimethamine alone, respectively, died (P < 0.0001). Moreover, a gatifloxacin dose of 200 mg/kg/day administered orall y for 10 days plus 2 <mu>g of recombinant murine IFN-gamma /day administere d intraperitoneally for 10 days resulted in significant survival compared w ith IFN-gamma alone (P < 0.0001) or gatifloxacin alone (P < 0.007).