IN-VITRO AND IN-VIVO ACTIVITIES OF ROXITHROMYCIN IN COMBINATION WITH PYRIMETHAMINE OR SULFADIAZINE AGAINST TOXOPLASMA-GONDII

The efficacy of roxithromycin alone or in combination with pyrimethami ne or sulphadiazine was examined in vitro and in a murine model of acu te toxoplasmosis. In-vitro studies were performed with MRCS fibroblast tissue cultures, with quantification of toxoplasma growth by an enzym e-linked immunosorbent assay. For in-vivo studies, mice were infected with 10(4) tachyzoites of the virulent RH strain and then treated pero rally for 10 days from day 1 after infection. The efficacy of each dru g regimen was assessed by determination of survival rates and sequenti al titration of parasites in blood, brain and lungs, using a tissue cu lture method. In vitro, roxithromycin inhibited toxoplasma growth at a concentration of greater than or equal to 0.02 mg/L; the 50% inhibito ry concentration was estimated to be 1.34 mg/L. No synergistic effect was observed when it was combined with pyrimethamine or sulphadiazine. In vivo, roxithromycin alone at 50 or 200 mg/kg/day slightly prolonge d survival compared with untreated mice, but a striking synergistic ef fect was observed when roxithromycin was administered in combination w ith pyrimethamine or sulphadiazine at subtherapeutic doses, i.e., 12.5 and 100mg/kg/day, respectively. Combination regimens consistently res ulted in a marked reduction of the parasite burdens in blood and tissu e, compared with those in mice treated with any of the agents alone. T hese results suggest that in-vivo activities of either pyrimethamine o r sulphadiazine against T. gondii are reinforced by roxithromycin and such combinations should be considered in development of alternative t reatments for human toxoplasmosis.