Study of treatment of congenital Toxoplasma gondii infection in rhesus monkeys with pyrimethamine and sulfadiazine

Abstract

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 g/ml, whereas a maximum concentration in serum of 0.22 g/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 g/ml for pyrimethamine and from 1.0 to 5.4 g/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 drug 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.

Toxoplasmosis

“…Concentrations of pyrimethamine in the fetus ranged from 50% to 100% (mean 66%) of simultaneous serum concentrations in the mothers. These results agree with those obtained in monkeys by Schoondermark-van de Ven and coworkers [782]. Trenque and colleagues concluded that the effective concentrations of both drugs at 14 days after the last dose justifies twice-monthly dosing of the drug combination in cases of documented fetal infection [781].…”

Prediction of congenital toxoplasmosis by polymerase chain reaction analysis of amniotic fluid

“…Our study lacked power to detect an effect of treatment vs no treatment due to small numbers of untreated women. In contrast, a study using a monkey model and a non‐encysting strain of Toxoplasma gondii found that treatment with pyrimethamine–sulphonamide reduced the sensitivity of PCR analysis of amniotic fluid 33 . Failure to detect an effect of treatment may be due to rapid encystment of the parasite, the small number of false negative results or the relatively crude classification of results as positive or negative.…”

Why prevent, diagnose and treat congenital toxoplasmosis?

“…The evidence demonstrating that active infection can be treated and outcome improved developed as follows: antimicrobial treatment of T. gondii in tissue culture animal models eliminates actively replicating parasites and leads to prevention or resolution of signs of disease in these models (Eyles & Coleman 1953a, b, 1955a, Frenkel & Hitchings 1957, Garin et al 1968, 1985, Brus et al 1971, Beverley et al 1973, Feldman 1973, Sheffield & Melton 1975, Grossman & Remington 1979, Garin Paillard 1984, Mack & McLeod 1984, Picketty et al1990 McLeod et al 1992, Hohlfels et al 1994, Schoondermark-van de Ven et al 1995, Derouin 2001, Meneceur et al 2008, Mui et al 2008); treatment of ocular toxoplasmosis, toxoplasmosis in immune-compromised persons of congenital toxoplasmosis in humans abrogates symptoms and signs of active infection and improves outcomes (Perkins et al 1956, Kräubig 1963, Thalhammer 1969, Couvreur et al 1984a, 1993, Desmonts & Couvreur 1984, Daffos et al 1988, Hohlfeld et al 1989, 1994a, b, Dannemann et al 1992, McLeod et al 1992, 2006a, McAuley et al 1994, Patel et al 1996, Torre et al 1998, Boyer 2000, 2005, 2008, Thulliez 2001, Brézin et al 2003, Kim 2006, Berrebi et al 2007, Petrof & McLeod 2002, SYROCOT et al 2007, Kieffer et al 2008), the more rapidly human congenital toxoplasmosis is diagnosed and treated, the shorter the time available for tissue destruction by the parasite and thus the better the outcomes (Remington et al 2006, SYROCOT et al 2007, Kieffer et al 2008); and detection of the infection acquired during the gestation the fetus and rapid initiation of treatment, is often associated with favorable outcomes (Daffos et al 1988, Hohlfeld et al 1989, Foulon et al 1999, Binquet et al 2003, Brèzin et al 2003, Kodjikian et al 2006, Remington et al 2006, Kieffer et al 2008). …”