Adjunctive bradyzoite-directed therapy for reducing complications of congenital toxoplasmosis.

Congenital toxoplasmosis is caused by in utero infection of the fetus with the intracellular parasite Toxoplasma gondii. Upon infection, the parasite forms life-long cysts in fetal brain and eyes which are resistant to the currently accepted therapy of pyrimethamine and sulfadiazine. These cysts commonly reactivate later in life causing chorioretinitis and visual impairment, and rarely cause neurological complications. I hypothesize that adjunctive, bradyzoite-directed therapies have the potential to alleviate a significant burden of disease by reducing cyst burden in neonatal brain and eyes. Atovaquone is perhaps the most promising drug for further evaluation given its low side-effect profile, established safety, and efficacy in animal models reducing cyst burden. Very limited observational data in humans suggests atovaquone may prevent Toxoplasma-associated chorioretinitis recurrence. Clinical trials are needed to evaluate it and other potential drugs as adjunctive treatment in congenital toxoplasmosis.

Study of treatment of congenital Toxoplasma gondii infection 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 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.

Diagnosis of transplacentally induced toxoplasmosis in pigs.

Seventeen sows were fed 1,000 Toxoplasma gondii oocysts of isolates GT-1 or PT-1 at 32 to 92 days of gestation, and the products of conception were examined for T gondii antibodies and parasites. Twelve of these sows were euthanatized near term between 21 and 62 days after being fed T gondii; fetal body fluids or fetal sera were examined for agglutinating T gondii antibodies, and tissues were bioassayed in mice for T gondii parasites. Six sows produced pigs that had been transplacentally infected with T gondii; one of them aborted a T gondii-infected fetus 17 days after ingesting oocytes. Agglutinating antibodies were detected in fetuses infected in utero, but transplacental transfer of T gondii antibodies was not observed in noninfected fetuses. Transcolostrally acquired T gondii antibodies disappeared by 3 months of age. Diagnosis of transplacental toxoplasmosis was confirmed on the basis of detection of T gondii organisms in fetal tissues by use of histologic examination and bioassay in mice. In conclusion, finding of T gondii antibodies in body fluids could serve as a rapid screening test for transplacental T gondii infection in pigs.