Study of Treatment of CongenitalToxoplasma gondiiInfection in Rhesus Monkeys with Pyrimethamine and Sulfadiazine

The efficacy of the combination of pyrimethamine and sulfadiazine for the treatment of congenital Toxoplasma gondii infection in rhesus monkeys was studied. The dosage regimen for pyrimethamine and sulfadiazine was established by pharmacokinetic studies in two monkeys. Those studies showed that the distributions of both drugs followed a one-compartment model. The serum elimination half-lives were found to be 5.2 h for sulfadiazine and 44.4 h for pyrimethamine. Sulfadiazine reached a maximum concentration in serum of 58.7 mg/ml, whereas a maximum concentration in serum of 0.22 mg/ml was found for pyrimethamine. Ten monkeys were infected intravenously withT. gondiiat day 90 of pregnancy, which is comparable to the second trimester of organogenetic development in humans. Treatment was administered to six monkeys, in whose fetuses infection was diagnosed antenatally. From the moment that fetal infection was proven, the monkeys were treated throughout pregnancy with 1 mg of pyrimethamine per kg of body weight per day and 50 mg of sulfadiazine per kg of body weight per day orally. The therapy was supplemented with 3.5 mg of folinic acid once a week. No toxic side effects were found with this drug regimen. The parasite was no longer detectable in the next consecutive amnioticfluid sample, taken 10 to 13 days after treatment was started. Furthermore,T. gondii was also not found in the neonate at birth. The parasite was still present at birth in three of four untreated fetuses that served as controls. Both drugs crossed the placenta very well. Concentrations in fetal serumvariedfrom0.05to0.14 mg/mlforpyrimethamineandfrom1.0to5.4 mg/mlforsulfadiazine.Inaddition, pyrimethamine was found to accumulate in the brain tissue, with concentrations being three to four times higher than the corresponding concentrations in serum. Thirty percent of the sulfadiazine was found to reach the brain tissue when compared with the corresponding serum drug concentration. When administered early aftertheonsetofinfection,thecombinationofpyrimethamineandsulfadiazinewasclearlyeffectiveinreducing the number of parasites in the fetus to undetectable levels.