Efficacy of epiroprim (Ro11-8958), a new dihydrofolate reductase inhibitor, in the treatment of acute Toxoplasma infection in mice

Toxoplasma gondii is a major cause of focal encephalitis in patients with acquired immunodeficiency syndrome. Epiroprim, an inhibitor of dihydrofolate reductase, was evaluated in vitro and in a mouse model of acute infection for activity against T. gondii. The 50% inhibitory concentration (IC₅₀) of epiroprim for T. gondii dihydrofolate reductase was 0.9 μM, similar to that of pyrimethamine, but epiroprim was 650-fold more selective than pyrimethamine for T. gondii compared with human dihydrofolate reductase. While intraperitoneally administered epiroprim (300 mg/kg/day for 14 days) alone was ineffective in mice acutely infected with the RH strain of T. gondii, 100% survival was seen when it was combined with orally administered sulfadiazine (375 mg/kg/day), which alone was also ineffective. Increases in survival were seen in combination with doses of sulfadiazine as low as 0.375 mg/ kg/day. Orally administered epiroprim combined with dapsone also prolonged survival. Thus, epiroprim is an active and potentially less toxic alternative to pyrimethamine for the treatment of toxoplasmosis.