RIFABUTIN IS ACTIVE IN MURINE MODELS OF TOXOPLASMOSIS

Rifabutin, a semisynthetic derivative of rifamycin S, was examined alo ne and in combination with other drugs for activity in treatment of sy stemic toxoplasmosis and toxoplasmic encephalitis in murine models. On e hundred percent of the mice infected with a lethal inoculum of tachy zoites or cysts of Toxoplasma gondii were protected against death by t reatment with doses of 400 or 300 mg of rifabutin per kg administered alone for 10 days. Doses of 200 mg/kg protected at least 80% of the mi ce, and doses of 100 mg/kg protected 10 to 40% of the infected mice ag ainst death. Doses of 50 mg/kg were not protective but caused a delay in time to death. Combination of nonprotective (50-mg/kg) or slightly protective (100-mg/kg) doses of rifabutin with doses of sulfadiazine, pyrimethamine, clindamycin, or atovaquone that did not confer any prot ection against death from toxoplasmosis when administered alone result ed in remarkable enhancement of the in vivo activities of all of these drugs. Seventy-five percent of the infected mice survived when treate d with 100 mg of rifabutin per kg per day combined with the ineffectiv e dose of 10 mg of pyrimethamine per kg. A dose of 50 mg of rifabutin per kg in combination with the ineffective dosages of clindamycin (25 mg/kg/day), atovaquone (5 mg/kg/day), and sulfadiazine (80 mg per lite r of drinking water) protected at least 80, 60, and 60% of the mice ag ainst death, respectively. The inflammatory responses in the brains of mice treated for 30 days with 200 mg of rifabutin per kg per day were significantly reduced compared with those in the brains of untreated controls. These observations suggest that clinical trials with rifabut in for treatment and prevention of human toxoplasmosis may be justifie d, particularly when the drug is used in combination with other drugs with activity against T. gondii.