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Population pharmacokinetics of pyrimethamine and sulfadoxine in children treated for congenital toxoplasmosis.

The population pharmacokinetics of pyrimethamine (PYR) and sulfadoxine (SDX) for a group of 32 children with congenital toxoplasmosis was investigated by nonparametric modeling analysis. A one-compartment model was used as the structural model, and individual pharmacokinetic parameters were estimated by Bayesian modeling. PYR (1.25 mg/kg of body weight) and SDX (25 mg/kg) were administered orally every 10 days for 1 year, with adjustment of the dose to body weight every 3 months. Drug concentrations were measured by high-performance liquid chromatography. A total of 101 measurements in serum were available for both drugs. Mean absorption rate constants, volumes of distribution, elimination rate constants, and half-lives were 0.915 h(-1), 4.379 liters/kg, 0.00839 h(-1), and 5.5 days for PYR and 1.659 h(-1), 0.392 liters/kg, 0.00526 h(-1), and 6.6 days for SDX, respectively. Wide interindividual variability was observed. The estimated minimum and maximum concentrations of PYR in serum differed 8- and 25-fold among patients, respectively, and those of SDX differed 4- and 5-fold, respectively. Increases in the concentration of PYR were observed for eight children, and increases in the SDX concentration were observed for seven children. Serum PYR-SDX concentrations are unpredictable even when the dose is standardized for body weight. The concentrations of the PYR-SDX combination that are most efficacious for children have not yet been established. A model such as ours, associated with long-term follow-up, is needed to study the correlation between exposure to these two drugs and clinical outcome in children.

Antiprotozoal Agents↗

[Congenital toxoplasmosis in own studies].

Clinical picture of congenital Toxoplasma gondii has been presented in 20 children. The infection was diagnosed in 18 children in the first and in 2 children in the sixth month of life. Clinical symptoms were observed in as many as 12 children. The most frequent symptoms were those concerning central nervous system, organ of vision in the form of hydrocephalus, spastic paresis, epilepsy, intracranial calcification, choroiditis, retinitis and vision impairment. The presented analysis indicates an urgent need of introduction of screening in pregnant women and infants and widespreading of prophylactic activity aiming at raising awareness of the existing threat of T. gondii infection.

Animals↗

Prevention of congenital toxoplasmosis.

In utero infection with Toxoplasma gondii may result in congenital defects such as hydrocephalus, chorioretinitis and mental retardation; these defects may be present at birth or may develop later in life. Prevention of this disease can be achieved in different ways. The most effective measure is to prevent the acquisition of the disease during pregnancy by avoiding risk factors for Toxoplasma gondii infection. Health education may decrease the incidence of toxoplasmosis during pregnancy by 60%. A second preventive measure is based on serologic screening during pregnancy to identify infected women. Treatment during pregnancy results in a significant reduction in the incidence of sequelae including severe handicaps. A third possible intervention is treating infected neonates. Antibiotic treatment of infected children has a beneficial effect on the development of sequelae and the sooner therapy is started after birth, the better the outcome. This overview presents the potential benefits and harms of these different options available for the prevention of congenital toxoplasmosis.

Animals↗

Congenital toxoplasmosis presenting as massive neonatal ascites.

A preterm infant with isolated transudative ascites caused by Toxoplasma gondii is described. In the absence of obvious congenital malformations, toxoplasmosis should be considered in the differential diagnosis of fetal and neonatal non-immune ascites.

Ascites↗

Comparative value of polymerase chain reaction and conventional biological tests for the prenatal diagnosis of congenital toxoplasmosis.

When toxoplasmosis is acquired during pregnancy, there is a risk of severe congenital defect in the foetus. Maternal treatment with spiramycin limits the transplacental passage of the parasite to the foetus but does not prevent infection in all cases. Prenatal diagnosis should be based on specific and fast methods to prescribe the more potent combination of sulfadiazine and pyrimethamine. This study evaluates PCR in the prenatal diagnosis of toxoplasmosis; PCR was based on the detection of the gene coding for the P30 surface protein. Amniotic fluid from 44 women with suspected foetal infection was tested by PCR and results were compared to those of conventional diagnostic tests on foetal blood and amniotic fluid. PCR was positive in 7 out of 10 samples from proven congenital toxoplasmosis cases. Sensitivity of PCR was similar to cell culture and mouse inoculation of amniotic fluid but was superior to tests carried out on foetal blood (specific IgM, eosinophil and platelet counts, gamma glutamyl transferase, mouse inoculation). In two cases, PCR was positive with no detected infection of the foetus. In this study, the combination of fast detection methods, ie cell culture and PCR of amniotic fluid, eosinophil and platelet counts, GGT activity and specific IgM, enabled us to confirm 10/10 cases of congenital toxoplasmosis in less than a week. PCR therefore appears to be an additional test which improves early prenatal diagnosis of toxoplasmosis.

Amniotic Fluid↗

Congenital ocular toxoplasmosis.

Congenital ocular toxoplasmosis is a significant cause of blindness. Retinochoroiditis is the most common finding, but other ocular manifestations include microphthalmus, nystagmus, strabismus, and ptosis. The serologic tests and lymphocyte stimulation test are the most useful aids in making the diagnosis. Pyrimethamine, sulfonamides, and corticosteroids are useful to treat active lesions. Primary care physicians, obstetricians, and ophthalmologists may help to prevent transmission of the disease and its serious ocular sequelae.

Chorioretinitis↗

Prenatal diagnosis of congenital toxoplasmosis with a polymerase-chain-reaction test on amniotic fluid.

BACKGROUND: Congenital infection with Toxoplasma gondii can produce serious sequelae. However, there is little consensus about screening during pregnancy, and the tests used to establish a prenatal diagnosis of toxoplasmosis are complex and slow. We evaluated a simpler approach that is based on a polymerase-chain-reaction (PCR) test. METHODS: Prenatal diagnostic tests, including ultrasonography, amniocentesis, and fetal-blood sampling, were performed in 2632 women with T. gondii infection acquired during pregnancy. In 339 consecutive women, a competitive PCR test for T. gondii was performed on amniotic fluid, and its results were compared with those of conventional diagnostic tests. The PCR test targets the B1 gene of T. gondii, uses an internal control, and can be completed in a day. Positive tests were confirmed by serologic testing of newborns or by autopsy in terminated pregnancies. RESULTS: Overall, the risk of fetal infection was 7.4 percent, but it increased sharply with gestational age. Congenital infection was demonstrated in 34 of 339 fetuses by conventional methods, and the PCR test was positive in all 34. In three other fetuses, only the PCR test gave positive results, and follow-up testing confirmed the presence of congenital toxoplasmosis. The PCR test gave one false negative result but no false positive results. The PCR test performed better than conventional parasitologic methods (sensitivity, 97.4 vs. 89.5 percent; negative predictive value, 99.7 vs. 98.7 percent). CONCLUSIONS: For the prenatal diagnosis of congenital T. gondii infection, an approach based on a PCR test performed on amniotic fluid is rapid, safe, and accurate.

Amniotic Fluid↗

Congenital toxoplasmosis due to maternal reinfection during pregnancy.

A case of congenital toxoplasmic chorioretinitis was diagnosed (specific-immunoglobulin G [IgG] and -IgM comparative Western blot analysis) in a baby whose mother was immune during pregnancy. Maternal sera showed an increase in specific IgG and emergence of both IgM and IgA during pregnancy. The mother was probably reinfected through contact with kittens.

Antibodies, Protozoan↗

[Medullary aplasia during treatment for congenital toxoplasmosis in a twin pregnancy].

The authors report a case of a patient who in the 24th week of a twin pregnancy became sero-positive for toxoplasmosis. This was diagnosed by cordocentesis as being infected, and the treatment was therefore started with pyrimethamine and sulfadiazine and folic acid at the 28th week of pregnancy. At 35 weeks, the patient had an acute medullary aplasia due to the absence of the folates. The mother's state was improved rapidly by giving her folinic acid and the twins were normal haematologically. In this case, the authors point out how important the folates are in a pregnancy, especially in twin pregnancies, and point out the precautions that have to be taken when treatment with pyrimethamine and sulfadiazine is started for congenital toxoplasmosis.

Adult↗

Experimental congenital toxoplasmosis. I. The vagina as a portal of entry of toxoplasma in the mouse.

Toxoplasmosis can be transmitted to mice by the introduction of Toxoplasma into the vagina. Pregnant mice were more susceptible to infection than non-pregnant animals in the ratio of 3 to 1. Obvious signs of vaginitis were not observed. Many of the infected mice remained entirely free of external signs, while a minority showed neurological or respiratory disturbances. Pregnant animals, especially those infected 6 to 10 days following conception, often died in the terminal stages of pregnancy or shortly after parturition. The possibility that the vagina may serve as one of the portals of entry of Toxoplasma in the human being and that infection may occur by sexual contact or by contamination by feces or other Toxoplasma-containing materials is discussed. The high susceptibility of the pregnant mouse to toxoplasmosis under the conditions of these experiments suggests a possible explanation for the higher incidence of congenital as compared to postnatal human toxoplasmosis and for the associated asymptomatic maternal infection. The infected but clinically normal human mothers may be compared to some vaginally infected pregnant mice which remained symptom-free.

Animals↗

[Congenital toxoplasmosis in Switzerland. Seroprevalence, risk factors and recommendations for prevention].

In 10,000 cord blood samples from the region of Basel (representing approximately equal to 42% of all live births of 1983 to 1985) anti-Toxoplasma antibodies were determined by agglutination and indirect immunofluorescence (IFA) tests. 47.3% were seronegative. 2.8% (n = 283) exhibited high titers in IFA (greater than 300 IU/ml) suggestive of acute or persistent infection. Questionnaires on potential risk factors were sent to 280 mothers with high antibody titers ("cases"), and to 279 randomised seronegative mothers (controls); 388 questionnaires (75.3%) were returned. Compared to controls, infections in cases were significantly associated with farm work, flower production, or food industry, consumption of lamb meat or improperly heated beefsteak, cat ownership. Risks of infection were significantly reduced when meat was kept in the deep freezer, or by consumption of chicken (probably as a surrogate for lamb and beef meat). Cases had significantly lower average serum concentrations of beta-carotene and tocopherol than controls, while average retinol and cholesterol levels were comparable in both groups. The 283 cord blood samples from the cases were subjected to 4 serological tests for specific IgM and 41 samples were reactive in greater than or equal to 1 test. 35 of the 41 children were reinvestigated greater than or equal to 6 months after delivery. In 8 children specific IgM persisted. Review of delivery charts confirmed that all 8 were asymptomatic at the time of delivery. Also on follow-up clinical examinations were normal. The incidence of congenital, latent toxoplasmosis in the area is thus estimated to nearly 1/1000 live births. These data will be used to promote preventive measures in pregnant women.

Antibodies↗

[Early diagnosis and surveillance of congenital toxoplasmosis. The comparative immunological profiles method].

More than 8000 samples (sera, cord blood, CSF, etc.) from patients who had, or were likely to have, toxoplasmosis were studied by the CIP-ELIFA technique. The first stage in this technique is immunoelectrodiffusion on a microporous cellulose acetate membrane. In the second stage, immunodetection and isotypic characterization of the precipitating systems are rapidly carried out by immunofiltration with anti-IgG, IgM, IgA or IgE-labelled antibodies (enzyme-linked immunofiltration assay or ELIFA). Several samples are jointly laid out on the same membrane for compared immunological profiles (CIP). When applied to the mother-foetus relationship in toxoplasmosis, this procedure provides an early diagnosis of congenital infestation in 85% of the cases. Positive criteria are based on evidence of specific IgM, IgE or IgA in the child, but also on the detection of foetal or neonatal antitoxoplasmosis IgG which can be distinguished from the IgG transmitted by the mother. Polyisotypic supervision is of considerable value for assessment of prognosis and of therapeutic effectiveness at the end of treatment. Satisfactory isotypic characterization can only be achieved by using particular functional antigens.

Antibodies↗