Drugs for Treatment of Toxoplasmosis
The major drugs used for the therapy of toxoplasmosis are targeted at the folate pathway of the parasite. The best-established regimen is a combination of pryrimethamine and sulfadiazine. Both of these agents inhibit parasite folate metabolism. Pyrimethamine in adults should be started with a loading dose of 100-200 mg over 1 day in divided doses, followed by a daily dose of 25-100 mg/day for 3-4 weeks. The drug is available only in 25 mg tablets, is well absorbed from the gastrointestinal tract, and has a 4-5 day half-life. The pediatric dosage is 2 mg/kg/day for 3 days (followed by a maximum dose of 25 mg/ day for 4 weeks) (Anonymous, 2000). Sulfadiazine is the preferred sulfonamide, and should be given at 4-6g/day in four divided doses for adults and 100-200 mg/kg/day in children, for the same duration as the pyrimethamine. Leukovorin (folinic acid) 10-25 mg should be administered simultaneously with each dose of pyrimethamine to ameliorate bone marrow suppression. Marrow toxicity should be monitored by complete blood count in each week of pyrimethamine therapy.
Alternatives to the standard regimen include the use of spiramycin, a macrolide, which has been used for treatment of infection in pregnant women. The drug has been extensively used in Europe, but there are no published randomized comparisons and the published studies are insufficient to establish unambiguously that the drug can prevent congenital infection (Wallon et al., 1999). There is evidence that it has inhibitory activity for T. gondii (Chang and Pechere, 1988), although other macrolides, notably azithromycin, have higher activity (Araujo et al., 1991). Spiramycin use in pregnancy has not been shown to be teratogenic, and it appears to decrease the severity of disease (Foulon et al., 1999b; Hohlfeld et al., 1989). Clindamycin, a lincomycin, inhibits T. gondii by an unknown mechanism that involves the parasite organelle called the apicoplast (Fichera and Roos, 1997). The kinetics of killing are unusual, in that multiple rounds of parasite replication proceed normally after exposure to the drug before death occurs (Fichera et al., 1995). Clindamycin has been used in combination with sulfadiazine for therapy of toxoplasmic retinochoroiditis and encephalitis.
Other drugs that have activity against T. gondii include dapsone, azithromycin, clarithromycin, roxithromycin, atovaquone, minocycline and rifabutin (Montoya and Remington, 2000).
Toxoplasmosis in those with normal immune mechanisms is usually a self-limited disease and does not require drug therapy. No drugs currently available are capable of eliminating the bradyzoite cyst stage, and therefore do not eradicate infection. Indications for treating immunocompetent adults are thus limited to control of clinically severe or persistent disease, and to the prevention of future pathology in infected infants and pregnant women. Treatment during pregnancy is aimed at prevention of fetal infection, or minimizing fetal damage if infection broaches the placenta. Treatment of the infected infant is required to prevent unchecked damage that will result in symptomatic disease. Management of gestational and neonatal toxoplasmosis is covered below. Clinical situations requiring treatment of immunocompetent adults include severe or protracted lymphadenitis and retino-choroiditis. Indications for treating lymphadenitis include symptomatic disease that persists for a month or more, especially if fever or fatigue is manifest. Treatment with the standard regimen of pyrimethamine and sulfadiazine for 2-4 weeks is usually recommended. Retinochoroiditis involving the macula or causing significant vitreous inflammation should be treated for 1 month with both anti-Toxoplasma drugs and corticosteroids to reduce inflammation (Tabbara, 1995). Im-munosuppressed patients require continued therapy to control progressive disease, which must be extended for the period of cell-mediated immunosuppression in order to prevent relapse.
Management of Toxoplasmosis in Pregnant Women and Treatment of Congenital Disease
Screening for Toxoplasma seroconversion in pregnancy is established practice in western Europe, where rates of maternal infection are high and the system for sampling and uniform analysis of specimens has been centralized in public health facilities. In the USA, rates of acute maternal infection are thought by many to be below the threshold of cost-effectiveness, and neither uniform recommendations for prenatal screening have been accepted, nor are the laboratory resources available for uniform serol-ogy or amniotic fluid analysis. As an alternative approach, screening of newborns for IgM antibodies to T. gondii is practiced by several state public health laboratories in the USA to identify subclinical as well as symptomatic congenital infections. Neither approach is financially feasible in developing countries, even where rates of maternal infection are high.
Spiramycin (3-4g/day in divided doses) is recommended for treatment of pregnant women with evidence of recent T. gondii infection until it can be determined whether the fetus is infected by assay of amniotic fluid. If the fetus is determined to be infected in utero after the first trimester, when pyrimethamine is contraindi-cated because of teratogenic potential, therapy with pyrimethamine, sulfadiazine and leukovorin are given until delivery. If direct evidence of fetal infection is not produced, the pregnancy should be monitored by periodic fetal ultrasonography and spiramycin continued. Repeat amniocentesis is indicated if signs of fetal infection are found. The newborn should be tested for infection at the time of delivery and treated for congenital disease if evidence of infection is found. Several treatment regimens have been employed for congenital toxoplasmosis, differing in dosage and drug combinations, but it is clear that treatment must be continued for at least 1 year. A practical dosage regimen of pyrimethamine and sulfonamides has been described by a collaborative congenital toxoplasmosis treatment trial, based at the University of Chicago (Dr Rima McLeod, 773-834-4125) (McAuley et al, 1994). This is a continuous regimen of pyri-methamine, sulfadiazine and leukovorin in specific formulations that are practical to administer to infants. Prednisone is recommended when active retinochoroiditis is present or if CSF protein levels exceed 1000mg/dl. This approach has been found to decrease the long-term sequelae of developmental delay, hearing and visual problems and seizure disorder in most treated infants.
Treatment of Acute Disease in Immunocompromised Persons, Maintenance Therapy and Prophylaxis
Active toxoplasmosis in immunosuppressed patients is a potentially lethal disease and requires therapy until symptoms resolve and for 4-6 weeks thereafter. Following acute therapy, a prophylactic regimen should be continued for the duration of functional immunosuppression. The standard combination of pyrimethamine, sulfa-diazine and leukovorin is the mainstay of therapy, but reactions to one or more of these drugs may require alternative regimens, especially in patients with AIDS. Clindamycin 600 mg orally or intravenously four times/day in combination with pyrimethamine at standard dosage has been used for treatment of adult AIDS patients with toxoplasmic encephalitis who have had serious reactions to sulfonamides. This combination also has a high incidence of serious side-effects. Alternative regimens include pyri-methamine and leukovorin, with the addition of atovaquone (Anonymous, 2000), or clarithromy-cin, azithromycin or dapsone (Montoya and Remington, 2000).
Secondary prophylaxis or maintenance therapy should be continued for the duration of immunosuppression (Kovacs and Masur, 2000). The most effective regimen is the combination of sulfadiazine 500-1000 mg four times/day and pyrimethamine 25-75 mg/day with leukovorin 10mg/day. An alternative is clindamycin 300 mg orally four times/day, or 450 mg orally three times/day with oral pyrimethamine 25-75 mg/ day and oral leukovorin 10-25 mg/day. Primary prophylaxis to prevent reactivation of toxoplas-mosis should be given to all HIV-infected persons who have a positive serological test for antibodies to T. gondii and CD4+ T lymphocyte counts less than 100/^ of blood. Trimethoprim-sulfamethoxazole, one double-strength tablet orally per day, is the first choice for this indication, but all regimens used for Pneumocystis carinii are effective for primary prophylaxis, except aerosolized pentamidine (Kovacs and Masur, 2000). Trimethoprim-sulfamethoxazole, one single strength tablet/day or the combination of dap-sone 50 mg/day plus pyrimethamine 50mg/week (with leukovorin 25 mg/week) or atovaquone (750 mg suspension twice daily) are alternatives (Kovacs and Masur, 2000).
rodents have low incidence of toxoplasmosis, and pose little risk of transmission. Hand washing is the most practical and important preventative measure to be recommended, to decrease the ingestion of both oocysts and tissue-born brady-zoite cysts from raw meat. Incidental transmission of oocysts may be facilitated by insects such as cockroaches (Chinchilla et al., 1994) and dogs that roll in cat feces may carry infectious oocysts on their fur (Frenkel, 1995; Frenkel et al., 1995).
A live vaccine, based on a strain of T. gondii that does not persist in the tissues of vaccinated animals, is available in New Zealand, the UK and Europe, that prevents T. gondii abortion in sheep (Buxton and Innes, 1995). This may decrease the incidence of T. gondii infection among herds and eventually decrease the burden of infectious cysts in meat. Careful husbandry practices in swine, including cooking feed and excluding cats from farms, may decrease Toxoplasma levels in herds. A live vaccine using a mutant strain of T. gondii (T-263) is under development in the USA to reduce oocyst shedding by cats (Choromanski et al., 1995). It will not change the epidemiology of disease, but could be recommended to cat owners who are willing to pay to decrease the risk of transmission of toxoplasmosis from their pets. The possibility of a human vaccine is still remote. No drugs are available that can eradicate tissue cysts in animal tissues. Freezing to — 12°C, cooking to an internal temperature of 67°C, or y-irradiation (0.5 kGy) will kill tissue cysts in meat. Drying meat does not reliably kill cysts.
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