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 micrograms/ml, whereas a maximum concentration in serum of 0.22 micrograms/ml was found for
pyrimethamine. Ten monkeys were infected intravenously with T. gondii at 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 amniotic fluid 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 serum varied from 0.05 to 0.14 micrograms/ml for
pyrimethamine and from 1.0 to 5.4 micrograms/ml for
sulfadiazine. In addition,
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 concentration. when administered early after the onset of
infection, the combination of
pyrimethamine and
sulfadiazine was clearly effective in reducing the number of parasites in the fetus to undetectable levels.