Toxoplasma gondii (Toxoplasmosis)

Updated March, 2009

Jose G. Montoya, M.D.,  Jacques Couvreur, M.D., Catherine Leport, M.D.

PARASITOLOGY Guided Medline Search

Life Cycle

                Toxoplasma gondii, an obligate intracellular protozoan parasite is a coccidia, which primarily exists in three forms: tachyzoite, bradzoite, and oocysts (111). Tachyzoite is the proliferative form, which characterizes the acute stage of infection or the reactivation of a latent infection. The identification of the tachyzoite form establishes that the patient’s symptoms are due to toxoplasmosis and it is the form which is susceptible to antitoxoplasma drugs. Tissue cysts are formed within the host cell and are demonstrable approximately on the eighth day of infection. The cysts contain thousands of bradyzoites which can persist as viable parasites throughout the life of the host. The cyst wall protects the bradyzoites against the antimicrobial agent. The bradyzoite replicates more slowly than the tachyzoite and probably does not have the same susceptibility to drugs. The visualization of tissue cysts in biopsy specimens does not necessarily establish that the patient’s symptoms are related to toxoplasmosis as they may simply reflect that the patient is chronically infected with the parasite. In this setting, the patient’s specific clinical scenario and further histological clues such as number of cysts and presence of inflammatory cells around the cysts can help to determine whether the patient has reactivated their dormant T. gondii infection or they have a different explanation for their symptoms. Oocysts are the result of an intra-epithelial stage leading to gametogony and sporogony which is exclusively observed in the intestine of cats and other members of the feline family infected by oral route. Millions of oocysts are eliminated within the feces of the cat from the fifth to the 20th days following ingestion of infective material, and sporulate 1 to 5 days after excretion into infectious forms known as sporozoites. Sporozoites are highly infectious when ingested. Oocysts can remain viable in warm moist soil for a year or more.

EPIDEMIOLOGY Guided Medline Search

              Toxoplasmosis is a worldwide zoonosis. The prevalence of the infection, usually asymptomatic, increases with increasing age. Seroprevalence rates of the infection with the parasite have been declining worldwide but are still notoriously high in Europe, Africa, and South America, where the rates may be greater than 50% and in some of these places rates may be actually increasing (120). Toxoplasmosis ought to be entertained in the traveler returning from these areas of the world but systematic studies assessing the incidence of the disease in this patient population have not been performed. Currently, in the United States, the age-adjusted T. gondii seroprevalence among persons 6-49 years old was determined to be at 10.8% (95% confidence limits [CL] 9.6%, 11.9%), and among women 15-44 years old, 11.0% (95% CL 9.5%, 12.4%) (69). In immunocompetent individuals, the initial infection usually leads to a chronic latent infection that is effectively controlled by the host immune system.

                Immunosuppressed patients are at notably higher risk for toxoplasmosis including patients with hematologic malignancy (especially Hodgkin's disease), transplant recipients (bone marrow and solid organ transplants) and AIDS patients. Toxoplasma encephalitis (TE) has been reported in up to 30% of AIDS patients with CD4 counts of less than 100 cells/mm3 and who are not taking effective anti-toxoplasma prophylaxis nor highly active antiretroviral therapy (HAART). Toxoplasma encephalitis has significantly declined in countries where HAART and prophylactic drugs for opportunistic infections are available and guidelines for their use are properly implemented and followed.

              Humans acquire Toxoplasma infection by ingestion of oocysts excreted by infected cats or by eating raw or undercooked meat containing cysts. Oocysts can be transmitted to humans through soil related activities including gardening, handling infected cat’s feces, or eating poorly washed vegetables. Transmission of oocyts via contaminated and untreated water has been documented in several countries (9, 16). Most of the meat responsible for the transmission of T. gondii in the United States is pork, lamb and wild game (40). The contribution of each of these major sources of the parasite to the transmission in humans in the United States (e.g. meat vs water vs soil related), have not been determined yet.

               T. gondii can also be transmitted via transplanted organs and laboratory accidents.

CLINICAL MANIFETATIONS

In the Immunocompetent Host : Acute acquired toxoplasmosis is subclinical in about 90% of immunocompetent humans. The most common sign is cervical lymphadenopathy which can persist for months.. The clinical presentation may mimic infectious mononucleosis or cytomegalovirus infection with sore throat, hepatosplenomegaly, and presence of atypical lymphocytes in blood smears. In addition, immunocompetent patients may develop alone or in combination the following symptoms or syndromes; fever, hepatitis, myocarditis, myositis and ocular disease (see below). A heightened level of suspicion for toxoplasmosis should be exercised in patients with any of these syndromes unexplained by other etiologies and particularly among returning travelers.

In the Pregnant Woman: In pregnant women, acute toxoplasmosis is usually subclinical and is diagnosed by routine serologic testing of pregnant females. When the primary infection is acquired during gestation, the parasite can be transmitted to the fetus via the placenta. Women who have been infected prior to pregnancy (more than months prior to conception) rarely give birth to an infected baby unless they are significantly immunocompromised.

Congenital Disease: Congenital toxoplasmosis is subclinical infection in about 85% of the infants whose mothers have been treated during pregnancy (26, 98). Theses proportions are in influenced by two factors: the date of maternal infection, treatment given to the mother, parasite load and the genetics of the host and the parasite. There is practically no risk of materno-fetal transmission when the infection occurs before conception in an immunocompetent mother. The later the infection during pregnancy, the higher the risk (38, 41) of transmission. The incidence of fetal infection goes from 2% if the maternal infection occurs before 10 weeks to nearly 90% if the infection occurs in the last weeks of pregnancy. On the other hand, the earlier the maternal infection occurs, the higher is the risk of patient disease and brain injury. The 26th week is a milestone since fetopathy is most often subclinical for maternal infection after this date. Maternal treatment with spiramycin appears to decrease the proportion of infected infants, particularly when administered within 8 weeks of seroconversion (132).  The proportion of infected newborns was 61% when the mother was not treated and 23% in the group receiving spiramycin treatment (25). Congenital toxoplasmosis, even subclinical, can be complicated by secondary are ups of retinochoroiditis which can occur in up to 80% of the cases, particularly during puberty and adolescence (143) and which can be prevented to some extent by early treatment of the children (57, 139). Isolation of Toxoplasma from the placenta is regularly associated with toxoplasmic fetopathy while the investigation can turn negative in a proportion of infected infants. This proportion varies according to the treatment given during pregnancy. The examination is negative in 10% with no treatment, in 25% with spiramycin treatment and in 50% when the mother received spiramycin and the pyrimethamine/sulfadiazine combination in alternating courses (25).

Ocular Disease: Retinochoroiditis is the most common complication of Toxoplasma infection (94, 115). Ocular toxoplasmosis most often occurs in congenital infection but it can also complicate post-natally acquired toxoplasmosis in immunocompetent children or adults (14, 27, 44, 96, 101). Due to particular epidemiologic conditions, an exceptional prevalence of 21% has been documented in an adult community of southern Brazil. In immunosuppressive illnesses, particularly AIDS, it is a sign of relapse of a previously-acquired infection. However for unknown reasons, ocular disease occurs less frequently than cerebral toxoplasmosis in AIDS patients. In immunodeficient patients, retinal lesions are often multiple, active, atypical, large and bilateral (100).

Recognizing Eye Infections. Infect Med. 2008:376-384

In the Immunocompromised Patient: Before the AIDS epidemic, less than 50 cases in immunosuppressed patients had been reported in the literature (67, 86, 121). Clinical presentation was highly variable, from a prolonged unexplained fever to various visceral manifestations, the most frequent being neurological and/ or pulmonary lesions (89). Diagnosis was confirmed by histology in approximately half of the cases.

In AIDS Patients: In HIV infected patients, the main presentation is toxoplasmic encephalitis, although ocular, pulmonary or disseminated disease can also occur (83,84). Thus, in 1982, when the first cases of toxoplasmic encephalitis occurred in AIDS patients, diagnosis was unexpected and optimal treatment unknown (55, 80, 84). The number of cases grew rapidly, leading to several thousands of cases ten to fifteen years later. In the French hospital database on HIV with 60,000 patients, the incidence changed from 29% pt-years in 1992 to 14% pt-years in 1995 and 2.6% pt-years in 1998. The later decline was observed after the introduction of HAART in 1995 in addition to prophylaxis with TMP/SMX. Patients with toxoplasmic encephalitis present with fever, headache, and neurological manifestations such as confusion, coma, motor defect, visual abnormalities, or seizures.

In non-AIDS Immunocompromised Patients: patients with allogeneic hematopoetic stem cell transplants (HSCT) and infected with T. gondii prior to the transplant are at risk of developing life-threatening toxoplasmosis by recrudescence of their latent infection. This risk is particularly high in the setting of graft versus host disease. Fever or pneumonia alone can be the only manifestations of toxoplasmosis in these patients. The presence of brain abscess(es) should also alert the clinician to the possibility of toxoplasmosis. Seronegative solid organ transplant patients who received their organ from a seropositive donor (D+/R-) are at risk to develop toxoplasmosis and may develop clinical syndromes similar to those describe in patients with bone marrow transplantation.

LABORATORY and RADIOLOGICAL DIAGNOSIS Guided Medline Search

                Confirmed or presumptive diagnosis of T. gondii infection and toxoplasmosis can be accomplished by the use in various combinations of different laboratory methods including serological tests, polymerase chain reaction (PCR), histological analysis, attempts to isolate the parasite and imaging studies. Which tests to use and their interpretation are significantly influenced by the type of patient and the specific clinical syndrome.

Serologic Tests for Specific Antibodies: the detection of T. gondii –specific IgG, IgM, IgA and IgE antibodies have been used to establish whether the patient has been exposed to the parasite (IgG positive) and whether the infection has been acquired recently or in the distant past. Patients with negative results for both IgG and IgM do not have serological evidence of prior exposure to the parasite and should be approached as not infected (except patients with HSCT in whom serological testing is not reliable). Patients with positive results for IgG but negative for IgM, have been infected probably for several months. Positive or negative IgG and negative IgM serological tests results obtained in commercial laboratories are probably reliable. In contrast, positive results in any IgM test should not be interpreted as necessarily indicative of a recently acquired infection. The IgM test is an important initial step that if positive raises the possibility of but is not diagnostic of an acute infection. In fact, sixty percent of patients with positive IgM test results obtained in commercial laboratories are found to be chronically infected when their serum undergoes confirmatory testing at a reference laboratory [e.g. –the Toxoplasma Serology Laboratory at the Palo Alto Medical Foundation (PAMF- TSL), Palo Alto, CA. Website: http://www.pamf.org/serology/; Phone number: 650 853 4828] (76, 110, 144). Additional IgG-based tests such as avidity and the differential agglutination have been successfully used at PAMF-TSL to establish whether patients have been infected recently or in the distant past in the settings of pregnancy, ocular disease, lymphadenopathy, myocarditis, myositis, hepatitis (97), PAMF-TSL is a not-for profit laboratory created in 1962 by Dr. Jack S. Remington and serves as a “gold standard” for the Food Drug and Administration (FDA), Centers for Disease Control and Prevention (CDC) and clinicians throughout the United States and Canada. Assistance for the interpretations of test results and in the management is also available for clinicians at PAMF-TSL. For neonates suspected to be congenitally infected and who have not been recently transfused, a positive IgM test result after 5 days of life by the ISAGA method or a positive IgA result after 10 days of life by the ELISA method, is diagnostic of congenital toxoplasmosis.

Polymerase chain reaction (PCR): amplification of T. gondii DNA in amniotic fluid is the method of choice for the diagnosis of congenital toxoplasmosis during gestation. PCR in cerebrospinal fluid, blood or urine may also proved helpful in diagnosis of congenital disease in the neonate.

Isolation of T. gondii: Isolation establishes the infection is acute. Isolation can be done by tissue culture or mouse inoculation. Cell culture is more widely available, but mouse inoculation is more sensitive.

PCR: PCR can be applied to body fluids (blood, CSF, bronchoalveolar lavage) and tissue (brain). Sensitivity is variable, but specificity is high so a positive test is useful. PCR is particularly useful for diagnosis of intrauterine toxoplasmosis and disseminated disease, especially in HIV patients.

Pathology: The visualization of tachyzoites in infected tissue with an immunoperoxidase stain or smears of body fluids (amniotic fluid, CSF, bronchoalveolar fluid) establishes the diagnosis of acute infection.

Radiologic Examinations: CT and MRI scans showing calcifications in the brain or multiple ring-enhancing lesions are major diagnostic modalities suggesting the presence of Toxoplasma encephalitis. The other major differential diagnostic possibility is CNS lymphoma. Brain biopsy may be indicated in a patient with a solitary lesion.

PATHOGENESIS Guided Medline Search

                Following ingestion of the tissue cyst or oocyst form by humans, gastric digestive juices disrupt their outer wall releasing its infective forms, bradyzoites and sporozoites, respectively. Bradyzoites and sporozoites rapidly invade intestinal lumen enteroepithelial cells where they become tachyzoites. Further spread of the parasite follows its release from disrupted cells with invasion of contiguous cells and the lymphatic and blood compartments. Because T. gondii can infect essentially all nucleated cells and tissues, its dissemination is widespread. It is during this parasitemic phase that the main target organs, brain, eye, heart and skeletal muscle are infected. If the parasite is acquired for the first time during pregnancy, the placenta may be infected and congenital infection may occur.

                Tachyzoites and the immune response they trigger appear to be responsible for the clinically symptomatic cases of T. gondii infection during the acute phase or during reactivation of the latent infection. In both instances the preferred term is toxoplasmosis (it is best to limit the use of the term infection to the asymptomatic presence of the parasite and of toxoplasmosis when symptoms are present). Tachyzoites are an easy target of the immune system in immuncompetent individuals and are easily killed by complement associated antibodies, reactive nitrogen and oxygen intermediates, acidification, osmotic fluctuations, and intracellular tryptophan depletion. Only tachyzoites that successfully reach the intracellular milieu and are protected by the newly formed parasitophorous vacuole escape the killing of the innate and adaptive immune mechanisms. Once inside the cell tachyzoites undergo stage conversion into the structurally different and metabolically slower bradyzoite form. Bradyzoites divide within the host cell and give rise to the tissue cyst which conform to the shape of the infected tissue. Tissue cyst formation primarily takes place in the central nervous system, retina, heart and skeletal muscles during the first week of infection. Tissue cysts are responsible for the chronic and latent stage of the infection. It is not known whether these cysts may be responsible for symptoms or chronic clinical syndromes in humans. A significant impairment in T-cell mediated immunity (e.g. AIDS, allogeneic hematopoietic bone marrow transplantation, administration of anti-CD52 monoclonal antibody or campath) may lead to the reversion of bradyzoites back to the rapidly multiplying tachyzoite form and result in toxoplasmosis by recrudescence of the dormant infection in different tissues. In this setting, tachyzoites may disseminate to tissues not necessarily infected during the primary infection and cause widely spread and significant pathology in severely immunocompromised individuals. In such instances the mortality reaches 100% if untreated. In most individuals primary T. gondii infection does not result in clinically apparent disease (toxoplasmosis). It is believed that well coordinated innate, humoral and cellular immune responses eventually transition the acute phase of the infection into the life-long, chronic and apparently asymptomatic stage. It is likely that it is the interplay of factors such as parasite inoculum, and genetics of the host and the parasite what determines the severity and wide spectrum of toxoplasmosis. Re-infection with T. gondii is very likely to occur but difficult to document and its clinical relevance is just being recognized.

                Humoral immune responses such as the production of immunoglobulin G (IgG), IgM, IgA, and IgE are probably responsible for lysing extracellular tachyzoites and partially limiting the parasite burden in tissues. However, it is the cell-mediated immunity what ultimately controls the infection and allows the survival of the host. Macrophages, natural killer cells, CD4+ T (primarily those with a Th1 profile) and CD8+ T cells are essential for the control of the dissemination of the parasite. Cytokines such as IFN-γ, IL-2, IL-12 TNF-α, IL-1, IL-4, IL-6, IL-7, IL-15 have been shown to be crucial mediators of this protection. Co-stimulatory molecules such as CD28 and CD40 ligand are critical for the regulation of IL-12 and IFN-γ production in response to the parasite. Tissue-specific immune responses, such as that in the central nervous system are being currently elucidated.

Mege JL, Meghari S, Honstettre A, Capo C, Raoult D.  The Two faces of interleukin 10 in human infectious diseases.  Lancet Infectious Diseases 2006:7;557-569.

Review Article:  Radke et al. Host Cell-Directed Interactions with Toxoplasma Influence Pathogenesis. Microbe / Volume 2, Number 5, 2007.

Population Genetics Of Toxplasma Gondii

                Population genetic analysis performed in both animal and human strains has demonstrated that T. gondii can be broadly categorized into one of three clonal genotypes (types I to III) which may reflect important biological and clinically relevant differences (72, 122, 125, 122).  In animal and in vitro models, Type I strains display a greater capacity for migration and dissemination and enhanced growth rate and virulence than type II strains. Type III strains are common in animals but have been observed significantly less often in cases of human toxoplasmosis. Type I and II strains are significantly more often associated with disease in humans (64).

                Recent genotyping studies performed in T. gondii isolates worldwide suggest a trend towards a type I/III strain predominance in South America, and type II in Europe as well as small genetic differences among T. gondii populations from Eurasia, Africa, and North America but large differences between them and South American populations. More recently, serotyping analysis of infected pregnant women in the United States revealed that approximately 40% are infected with Type I/III (22) whereas in Colombia (South America) 100% of pregnant women were found to be infected with Type I/III strains (106). Recently, a community outbreak of acute toxoplasmosis with an unusually severe clinical presentation was reported from the Surinamese village of Patam, near the French Guianan border (32). In this outbreak immunocompetent patients were reported to have developed life-threatening pneumonia and hepatitis. The genotype analysis revealed that only 1 strain was responsible for the outbreak. The unique genetics of this strain may have played a role in the unusual severity of the clinical presentation of toxoplasmosis in these otherwise immunocompetent patients. It is hoped that future studies will continue to elucidate the possible correlation between types and geographical distribution of T. gondii strains, and the wide spectrum of disease observed in patients with toxoplasmosis. It is likely that these studies will help to select patients at higher risk of more severe disease and worse prognosis, for more aggressive therapeutic intervention.

SUSCEPTIBILITY IN VIVO AND IN VITRO Guided Medline Search In Vitro and In Vivo

Single Drugs

Pyrimethamine: Pyrimethamine (Daraprim), a substituted phenylpyrimidine antimicrobial drug, is a folic acid antagonist which inhibits the dihydrofolate reductase (DHFR), a major enzyme in the purine pathway of the parasite (73). Its parasitostatic and cytopathogenic effects were clearly demonstrated by in vitro studies (33, 42, 60). Its activity has been documented in animal experiments (108). It can cure acute murine toxoplasmosis but cannot eradicate cysts in chronic infection.

Sulfonamides: The activity of sulfonamides on Toxoplasma gondii is rather parasitostatic (2, 87). No cytopathogenic effect on parasites was observed on inhibitory concentrations. The main effect of sulfonamides is an inhibition of another enzyme essential in the purine pathway of the parasite: the dihydrofolate-synthetase.

Spiramycin: Spiramycin, a macrolide antibiotic has favorable effects in vitro and in experimental murine toxoplamosis. It acts by inhibiting protein synthesis of T. gondii. However its antiparasitic activity is considered to be lower than that of pyrimethamine or sulfadiazine. Spiramycin is primarily used during pregnancy in an attempt to prevent fetal infection in women who have acquired their primary T. gondii infection early in gestation (≤ 18 weeks). This indication (to prevent transmission of the parasite to the fetus) is supported by several groups of investigators in Europe and the United States despite that doubts regarding its efficacy have been recently cast (53).

Clindamycin: The effect of clindamycin on T. gondii has been established in murine models of acute and chronic toxoplasmosis (3). The efficacy of clindamycin plus pyrimethamine has been shown to be comparable to that of sulfadiazine plus pyrimethamine in AIDS patients with toxoplasma encephalitis (30).

Other Macrolides: The inhibitory activity of macrolides has been shown in vitro. This inhibitory effect increases progressively with the concentration, so that the maximal effect is observed for very high concentrations. The mechanism of action is unknown. The effect has been studied in animal models, where the macrolides seem to be inadequate unless unusually high doses are used. Partial protection has been achieved with spiramycin, roxithromycin, clarithromycin, and azithromycin (3, 5, 61). Roxithromycin is protective for mice with acute toxoplasmosis even with the highly virulent RH strain of Toxoplasma but does not prevent cyst forming in the brain (6, 20).

Hydroxynaphtoquinones: Atovaquone (566 C 80) is the best documented and the most promising agent in this class (65). It is active in vitro and in vivo (118) and may be the most active compound against cysts.  Atovaquone (administered orally as a suspension) combined with either pyrimethamine or sulfadiazine as treatment for acute disease for patients with toxoplasma encephalitis has been shown to be effective, with 6-week response rates of 75% (21/28 patients) for atovaquone-pyrimethamine and 82% (9/11) for atovaquone-sulfadiazine. Thus, atovaquone/pyrimethamine can be used as an alternative treatment for patients intolerant to sulfonamides, and atovaquone/sulfadiazine for patients who are intolerant to pyrimethamine (21, 74).

Other Folate Inhibitors (e.g. trimethoprim, trimetrexate and piritrexime): Their mechanism of action is similar to that of pyrimethamine, with inhibition of the DHFR (73) and have been found to be effective in vitro and in animal models against T. gondii, (particularly when combined with sulfonamide drugs) (56). Trimethoprim in combination with sulfamethoxazole (TMP/SMX) (at 10 mg/kg/d of the trimethoprim component divided in two doses) has reported to have similar efficacy to the pyrimethamine/sulfadiazine regimen (with a more rapid radiologic response in the TMP/SMX group) in AIDS patients with toxoplasma encephalitis; this provides an alternative regimen for situations in which parenteral therapy is required or when pyrimethamine/sulfadiazine is not available (18, 127, 134, 135).

Miscellaneous Drugs: Dapsone is active in vitro and in vivo. The combination dapsone 100 mg/kg/day with pyrimethamine 18.5 mg/kg/day protected 100% of infected mice with no relapses after discontinuation of the treatment (32). Qinghaosu (artemisinin), a drug extracted from a Chinese herb and its derivatives, has in vitro activity against trophozoites of Toxoplasma (6) as well as exquisite activity against malaria parasites and several herpes viruses. The inhibitory effect of trioxans could be related to a similar mode of action.

Immunomodulators: The role of cellular immunity in the defense against Toxoplasma gondii has been clearly established. Reinforcement of immunity with gamma-interferon has been shown in animal models. It has a synergistic effect with antiparasitic drugs. Gamma-interferon is highly effective in vitro and moderately in vivo. It may act by activating macrophages and stimulating natural killers and humoral response (92) and by interfering in the metabolism of Toxoplasma. Gamma-interferon was effective in toxoplasmic encephalitis in mice chronically infected (130). Favorable synergistic effects were obtained with the combination interferon/roxythromycin in murine encephalitis (61). Gamma-interferon protects mice against lethal infection (6). Recombinant interleukin 2 significantly decreased mortality in mice and lowered the number of cysts in their brain (124). IL-12 improves survival of T-cell–deficient mice during T. gondii infection, likely through enhanced production of IFN-γ by natural killer cells (52). The combination of IL-12 plus clindamycin or atovaquone has been shown to be effective murine toxoplasmosis as well (8).

Combination Drugs

Pyrimethamine-sulfonamides: The activity of pyrimethamine is increased 6 to 8 fold by combination with sulfonamide drugs (133). Consequently both drugs are a combination of choice to achieve synergistic activity against trophozoites. In vitro studies with cultures on fibroblasts revealed that this activity is important with pyrimethamine: 0.02 mcg/ml and sulfadiazine 0.1 mcg/ml (33) while the inhibitory concentration (IC50) of sulfadiazine alone is 2.5 mcg/ml. This synergistic effect has been confirmed in animals models (108).

                Sulfadiazine is widely used. Sulfapyrazine, sulfamerazine and sulfadimidine are similar in efficacy. Trisulfapyrimidine combination (sulfadimidine, sulfamerazine and sulfadiazine) can be used. The antiparasitic activity of the metabolites of sulphonamide drugs is not documented. The combination pyrimethamine-sulfadoxine is synergistic and proved effective in murine toxoplasmosis (87). Parasitologic eradication was 100% with immediate treatment following inoculation and 32% when treatment was delayed for 72 hours. One major concern with the clinical use of pyrimethamine-sulfadoxine is the relatively high rate of side effects observed by several investigators.

Other Combinations: The combination of pyrimethamine/clindamycin has been shown to be effective in AIDS patients with toxoplasma encephalitis (30). In this same patient population combinations such as TMP/SMX (134, 135), pyrimethamine-atovaquone or atovaquone-sulfadiazine (21, 74) have been shown to be clinically effective as well.

               The combination of clarithromycin-sulfadiazine is highly synergistic (5). Both the combinations rifabutine/ atovaquone for 30 days or rifabutine/clindamycin for 15 days gave remarkable results in toxoplasmic encephalitis of mice with significant lessening of inflammation of the brain. It is synergistic and results in prolongation of survival in mice, but it does not prevent relapses (117). Clinical trials with prolonged duration of therapy are warranted. The combinations rifabutine-pyrimethamine and rifabutine-sulfadiazine did not significantly reduce brain inflammation when compared with each drug alone (7). In mice with acute toxoplasmosis a 93% survival rate was reached only with the combination trimetrexate: 37 mg/kg/day and sulfadiazine, 375 mg/kg/day. The combination of dapsone with sulfamethazine 100 mg/kg/day is active in vivo and the combination is additive.

ANTIPARASITIC THERAPY Smart search

Drugs of Choice Guided Medline Search

Pyrimethamine: Pyrimethamine is the drug of choice but it should always be used in combination with an effective second drug. The efficacy is limited to the time of its administration. The possibility of relapses following discontinuation of the drug in immunosuppressed patients warrants prolonged duration of treatment following the acute phase of the infection.

              Daily oral administration is necessary for curative treatment in acute infection. There is no parenteral form. Pyrimethamine in immunocompetent adults at a daily dose of 25 mg (0.3 mg/kg) leads to serum concentrations of 0.9 to 1.7 mcg ml. In HIV patients a dose of 50 to 75 mg/day leads to serum concentrations of 1 to 4.5 mcg/ml; peak levels occur at 3.3 hours and half- life is 114 hours (72). A minimal serum concentration of 0.75 mcg/ml in the presence of sulfonamides and of 3.0 mcg/ml in the absence of sulfonamide may be necessary to treat toxoplasmic encephalitis in HIV infected patients (142). In infants the mean serum concentration at 4 h after a daily dose of 1 mg/kg was 1.3 mcg/ml. It was 0.7 mcg/ml at 4 h when the same dose was given every other day (94). In a given individual, serum concentrations remain relatively stable at steady state over weeks on an identical dosage. In infants less than one month of age, serum concentrations did not differ from values obtained in older children on the same dosage. Concentrations of pyrimethamine achieved in infants' sera with standard dosages had good inhibitory effect in vitro on most virulent strains including the RH strain (94). CSF concentrations of pyrimethamine range 10 to 25 % those of the serum in patients with leukemia or AIDS patients with toxoplasmic encephalitis (142). Its degree of penetration through the blood/brain barrier remains to be established. In infants, on a daily dose of 1 mg/kg, ventricular fluid concentrations were 0.04 to 0.11 mcg/ml on a time post-dose of 4 to 54 hours i. e. approximately 10 to 25% of serum levels (94). In patients undergoing neurosurgery (79), the mean concentration in brain tissue was 0.9+/-0.33 mcg/gr 12 hours following a 100 mg dose. By the 24th hour it increased to a maximum of 1.56 mcg/gr. By the 48th hour it was 1.02 mcg/gr. Ratio of brain tissue to serum level varied from 2.5, 5.2 to 4.1 at 12 hours, 24 hours and 48 hours respectively. Half-life of the drug was 40 hours in brain tissue and 28 hours in serum, which implies that a dose of 50-100 mg every other day is convenient for prophylactic therapy in AIDS.

                Pyrimethamine is metabolized in liver and its pharmacokinetics is not altered by renal insufficiency. The lack of correlation between serum concentrations and varying pharmacokinetics between patients suggest genetic differences in metabolizing the drug. Consequently, monitoring with serum concentrations of pyrimethamine levels can be useful. The possibility of interaction between pyrimethamine and other drugs affecting hepatic enzymes including phenobarbital must always be considered. Metabolism of pyrimethamine can be altered in liver disease.

Combination of Pyrimethamine and Sulfonamides: This synergistic combination of pyrimethamine and sulfadiazine remains a mainstay in the treatment of human toxoplasmosis but its untoward effects have led to use other drugs. Pyrimethamine-sulfadoxine can be used for protracted treatment. It is available both orally and parenterally. Any drug rash following the first dose can be a subsequent contraindication, although effective desensitization protocols have been reported (111). This combination is uncommonly used in immunocompromised patients. Yet it is the only form of pyrimethamine available for injections.

Combination of Trimethoprim and Sulfamethoxazole: this combination has been found equally effective to that of pyrimethamine and sulfadiazine for the treatment of AIDS patients with toxoplasma encephalitis (134). Combination of atovaquone and pyrimethamine or sulfadiazine: these regimens have also found to be effective in patients with toxoplasma encephalitis and AIDS (21).

Clindamycin: Clindamycin is completely absorbed following oral administration with peak levels of 4 and 8 mcg/ml after ingestion of 300 and 600 mg respectively (82). The half-life is approximately 2.7 hours. The drug is excreted in urine and bile, and partially metabolized in active and inactive metabolites. Approximately 90 % is bound to plasma proteins. The drug is widely distributed with adequate levels in the iris, choroid and retina. Diffusion in CSF and brain tissue is uncertain.

Spiramycin: This antibiotic is now exclusively used to prevent materno-fetal transmission of the parasite. In pregnant women treated with a daily dose of 3 g, comparison study of concentration in maternal serum, cord blood and placenta tissue revealed average concentrations of 1.9 mcg/ml, 0.78 mcg/ml and 6.2 mcg/gr respectively (51). The serum feto-maternal ratio was 0.47 by the 21-24th weeks of pregnancy and 0.74 at birth (46). Administration of spiramycin during pregnancy in infected women is associated with a significant decrease of the risk of placenta infection (33) and reduces by a 60% risk of materno-fetal transmission of the parasite (38). The in vivo effects of spiramycin are explained by its rapid uptake from serum, its high concentrations, and persistence in tissues especially in the placenta. A curative activity of spiramycin for postnatally treated congenital toxoplasmosis or in acquired toxoplasmosis has not been demonstrated. It failed to protect AIDS patients against neurotoxoplasmosis (81). Indication for its use is the prevention of fetopathy in women with acquired toxoplasmosis during pregnancy (138). The usual dosage is 3 g/day oral route in 2 or 3 divided doses. This drug is well-tolerated and the treatment can be maintained for months.

Special Situations (Tables 1 and 2)

Acute Acquired Infection in the Immunocompetent Patient: This situation does not necessarily require antimicrobial therapy except in patients with severe symptomatic disease including those with lymphadenopathy, myositis, myocarditis, hepatitis. Patients with ocular disease are usually treated as well.

Acute Acquired Infection in the Pregnant Woman: Although spiramycin can reduce the risk of materno-fetal transmission of the parasite, it has no documented activity on established fetopathy. Alternative treatment for the infected mother is directed at of in utero treatment of the infected fetus (1). Pyrimethamine-sulfadiazine treatment can be given if fetal infection is documented (positive PCR in amniotic fluid) or highly suspected (e.g abnormal ultrasound or infection) after the 18th month of pregnancy following written consent and under close supervision (see below). Pyrimethamine-sulfadiazine is also recommended for women likely to have acquired their acute infection after 18 weeks of gestation. Due to the increased risk of materno-fetal transmission of the parasite in late pregnancy, antimicrobial therapy might be indicated  (119). Pyrimethamine 50 mg/day and sulfadiazine 3g/day can be given up to the time of delivery with hematological monitoring. Both drugs freely cross the placenta. This treatment has significant activity on biological signs of the disease: reduction of the incidence of positive Toxoplasma isolation from the placenta from 77 to 42%, tapering of antibody synthesis in the newborns with reduction specific IgM from 69% to 17 %, and lowering of the mean specific IgG titer. The combination was effective for 52 newborns in whose mothers were treated; there was selection bias in that fetuses with severe fetopathy had been terminated and were not included in this series (28). The possibility of using trimethoprim-sulfamethoxazole for the utero treatment of congenital toxoplasmosis has been discussed elsewhere (35).

Congenital Toxoplasmosis: Any infant with congenital toxoplasmosis should be treated throughout the first year of life regardless of the presence or absence of overt disease. The aim of this treatment is to treat active disease when it is present and to prevent secondary complications (111).

                 The overall frequency of subclinical disease is 75% among infants with documented fetal infections and whose mothers received spiramycin. Consequently, the possibility of subclinical disease vs. absence of infection is a diagnostic challenge in a given newborn. The main indicators for treatment include the date of maternal infection, the treatment given to the mother, a fetal diagnosis, i. e. amniotic fluid examination for toxoplasmosis on a prenatal amniotic fluid sample, when performed, the existence of serological signs of active infection in the postnatal period (specific IgM or IgA) and the results of the parasitological examination of the placenta. Isolation of Toxoplasma is diagnostic of fetopathy but isolation can be negative in a proportion of infected infants: 10% when the mother was not treated, 25% if the mother was given spiramycin and 50% if the mother received spiramycin and the pyrimethamine-sulfdiazine combination in alternating courses (25). So, negative PCR in the amniotic fluid and negative parsitological examination of the placenta cannot rule out the possibility of fetal infection. The decision to treat may be based on clinical suspicion until serological follow-up establishes the correct diagnosis.

                The combination of pyrimethamine/sulfadiazine is the basis of all the regimens proposed (Table 2). This regimen gave encouraging results, especially in minimizing ocular recurrences (24). The Chicago Collaborative Treatment Trial recommended continuous treatment during the first year (91). In overt disease, acute signs including active retinochoroidal disease, can become quiescent within two weeks or less following the institution of therapy. Visual loss did not occur in most treated patients (95). Almost all infants without hydrocephaly showed intellectual development within normal IQ ranges. Half of the patients with hydrocephaly who underwent a shunting procedure developed normally (91, 116, 131). Ocular recurrences were reduced. In infants treated early after birth, intracranial calcifications had diminished or resolved in 75% of the cases by age 1 (103). A serologic rebound occurred in 97.7% of the cases following discontinuation of the treatment, but this did not lead to an increased risk of ocular relapse (39).

Ocular Toxoplasmosis: Ocular toxoplasmosis, either primary or relapsing, is a medical emergency and in most cases requiring immediate antiparasitic treatment (Table 1). The treatment must be continued until for at least 15 days following the disappearance of the inflammatory process on ophthalmoscopic examination and possibly angiographic examination. Treatment should be 6 to 8 weeks in duration. Within 14 days, resolution of lesions occurs with appearance of a scar and halt in further visual loss (95). Atovaquone has been used as an alternative treatment (104). Corticosteroids are usually added for patients with severe inflammatory responses or sings (e.g. CSF protein ≥ 1 gm/dL or chorioretinitis that threatens the macula) (Table 2).

Sobrin L, et al. Intravitreal clindamycin for toxoplasmic retinochoroiditis. Retina 2007;27:952-957.

Infection in the Immunocompromised Host: In immunosuppressed patients, treatment of an acute episode of toxoplasmosis is mandatory (Table 1). Mortality approaches 100% if left untreated. The modalities and duration of therapy depend upon several factors: clinical presentation, need for oral administration, cause, degree and duration of the immunosuppression. Most of the trials have been conducted in AIDS patients (85, 105, 113) and regimens used for HIV patients can be used for other immunosuppressed patients (126). The requirement for maintenance therapy has to be modified according to the intensity and duration of the immunosuppression. It can probably be discontinued in transplant recipients when doses of the transplant immunosuppressive drugs are reduced.

Infection in AIDS Patients: The number of cases of toxoplasmosis in HIV infected patients has markedly decreased due primarily to the wide use of trimethoprim-sulfamethoxazole as primary prophylaxis for both pneumocystosis and toxoplasmosis, and the introduction of highly active antiretroviral therapy (HAART) leading to immune restoration. The following recommendations are based on data from trials conducted before 1996 (136).

Standard Regimen for CurativeTreatment

Acute stage therapy: The regimen of choice is the combination of pyrimethamine and sulfadiazine (Table 1). Folinic acid is added to prevent the hematologic toxicity of pyrimethamine (50, 99). Its dose can be increased up to 50 mg/day in case of cytopenia. The duration of acute stage therapy is not less than 3 weeks. If a complete clinical and radiological response is obtained at week 3, therapy can be concluded. Otherwise the treatment is continued up to week 6 in order to achieve maximal recovery (80, 141, 145). A partial or complete clinical response to this combination is achieved in 70-75 % cases of toxoplasmic encephalitis in HIV-infected patients, and the probability of survival after an acute episode is 90-95 % (30). The response rate is expected to be similar for other sites of infection such as the eye. Hematogenous dissemination of the parasite with a septic shock presentation leads to a poor prognosis regardless of therapy (83).

                Treatment is usually initiated upon a suspicion of toxoplasmic encephalitis, based on the occurrence of fever, neurological manifestations, and suggestive lesions on brain CT scan or MRI. A favorable response to specific empiric therapy is suggestive of the diagnosis. The diagnosis of toxoplasmic encephalitis is less likely in HIV infected patients with a negative Toxoplasma serology, single lesion by MRI study and/or in those who are taking trimethoprim-sulfamethoxazole for primary prophylaxis against pneumocystosis.

Maintenance Therapy: The requirement for maintenance therapy to prevent relapse has been well established in AIDS patients (80). In fact the relapse rate was approximately 30% despite zidovudine therapy (31). Maintenance therapy is based on the same combination of drugs used at doses reduced by half. (Table 1). This combination has been shown to be more effective than the pyrimethamine-clindamycin alternative combination in preventing relapse: the rate of relapse was 6% patient-years with sulfadiazine vs 23% patient-years with clindamycin in the European study (71). Maintenance therapy can be safely discontinued in patients with CD4 counts that are sustained to levels above 200 cells/µl and have been undetectable for their HIV viral load for 3 to 6 months.

Alternative Regimens for Curative Treatment (Table 1)

Pyrimethamine-Clindamycin: The alternative regimen for acute therapy in patients who are unable to tolerate sulfadiazine is the combination of pyrimethamine and clindamycin (112). The response rate is approximately 70%, and in one study 86% of the patients who had a favorable response improved by day 7 of therapy. Early improvement was strongly associated with a favorable response at week 6. The patients who fail to respond or did not have toxoplasmic encephalitis had neurologic progression by day 12 of therapy. The rate of adverse effects due to the pyrimethamine-clindamycin combination is 30-50%, requiring discontinuation of this regimen in 20% cases. The adverse effects are primarily gastrointestinal, with a risk of Clostridium difficile colitis. The combination can be used for maintenance therapy with a lower success rate than the conventional regimen at a dose reduced by half (71).

Combinations of Trimethoprim/Sulfamethoxazole, Pyrimthamine/Atovaquone or Ataovaquone/Sulfadizine: As mentioned above, these combinations are also effective in AIDS patients with toxoplasma encephalitis.

Combinations of Pyrimethamine and Macrolides: Given the high rate of adverse events with the two previous combinations, other active regimens in those AIDS patients who did not tolerate sulfadiazine and clindamycin have been tried. Limited studies have suggested that the combinations of pyrimethamine with clarithromcyin (2 g/day) or azithromycin (500 mg/day) might be effective (43). The rate of adverse effects requiring discontinuation was approximately 20 % in the two studies. Increase in serum transaminase levels and hearing loss were reported.

ADJUNCTIVE THERAPY Guided Medline Search

Congenital Toxoplamosis: Termination of the fetus can be discussed only if diagnosis in fetal infection is documented with evidence of fetal abnormalities on ultrasonographic examination (13). In infants with latent infection treated with the combination pyrimethamine-sulfonamides, prednisone initial dose 1mg/kg/day oral route in two divided doses, can be used to treat an inflammatory process, high cerebrospinal protein content, and severe uveitis. The dose must be tapered once the process has subsided.

Ocular Toxoplasmosis: Corticosteroid treatment has been used. Prednisone or methylprednisone 80 mg/day in adults or 1.5 mg/kg/day in children. The treatment is continued until the inflammatory process has subsided. The dosage is then progressively tapered to avoid a rebound phenomenon. Corticosteroids cannot be used without concomitant antiparasitic treatment which must be given for at least two weeks after discontinuation of the corticosteroids (80, 84).

AIDS: Although the advantage of the adjunctive use of steroids in AIDS with toxoplasmic encephalitis has never been demonstrated by controlled trials, corticosteroids are commonly used when clinical or radiological signs of intense brain edema are present. The doses and durations are variable, e. g. solumedrol 240 mg/day for 3 days, followed by 120 mg/day for 3 other days, then 60 mg/day until marked clinical improvement (10-20 days). Glycerol or mannitol have also been used to treat intracranial hypertension and reduce sequelae (80, 84).

ENDPOINTS FOR MONITORING THERAPY Guided Medline Search

Monitoring of Adverse Events

Pyrimethamine: The most important side effects are related to the antifolinic activity of the drug. It can cause gradual but reversible depression of bone marrow: neutropenia, thrombocytopenia, megaloblastic anemia. These side effects can be prevented by routine oral administration of folinic acid (calcium leukovorin) 5 to 10 mg three times a week in infants and up to 50 mg daily in HIV infected patients. In contrast to folic acid, folinic acid does not inhibit the activity of the parasite except in in vitro studies at very high concentrations. Indeed Toxoplasma gondii has an inability to assimilate exogenous folates, folic and folinic acid, and has to synthesize them from a precursor: paraminobenzoic acid. Neutrophil counts should be assessed twice a week and platelets and hematocrit levels once a month in HIV infected patients (91). When the neutrophil count falls below 1000/mm3 or platelets below 90,000/mm3, increasing the dosage of folinic acid is mandatory. Withdrawal of the drug should be considered if the neutrophil count falls below 500/mm3. The cytopenias are reversible with withdrawal of the drug. In infants, high serum concentrations of pyrimethamine require higher dosage of folinic acid or the withdrawal of pyrimethamine. Leucovorin must be given for an additional week following discontinuation of pyrimethamine. In HIV infected patients, folinic acid 10-20mg/day is added for acute therapy of toxoplasmic encephalitis including pyrimethamine regimen to avoid hematotoxic effects (50, 99, 137). High dosages of pyrimethamine can result in seizures. Patients with a serum concentration of 5 mcg/ ml or more are at risk. A loading dose of 2 mg/kg in children weighing 25 kg or more is excessive (94). Intoxication with pyrimethamine can warrant exchange transfusion.

Sulfonamides: Monitoring the treatment with sulfonamides includes attention to urine output, water metabolism, and blood counts, light microscopy of urine for crystalluria and creatininemia (29). The treatment of nephrolithiasis is discontinuation of the drug. Hydration and alkalinisation of the urine can be used as a preventive measure. Trisulfamides can be substituted for sulfadiazine since the risk of nephrolithiasis is less.

Pyrimethamine Sulfonamides Combination: The rate of adverse effects due to the pyrimethamine-sulfadiazine combination is approximately 50%, and discontinuation of one or both drugs is required in 20-25% cases (30, 71). The most frequent are cytopenias, rashes and fever. To determine which of the two drugs is responsible, each drug should be discontinued and reintroduced separately.

Clindamycin: The most frequent adverse events are gastrointestinal manifestations, possibly due to pseudomembranous colitis induced by Clostridium difficile. Other adverse effects seen in AIDS patients, most often treated with a combination of clindamycin and pyrimethamine, were rash, liver function test abnormalities, neutropenia and thrombocytopenia (30, 71).

Spiramycin: Spiramycin is not teratogenic.

VACCINES Guided Medline Search

                Experimental data supports the concept that a successful human Toxoplasma gondii vaccine may be feasible. However no vaccine is available at the present time.

PREVENTION Guided Medline Search Smart search

General

                Hygienic measures are the first step prior to contemplating any drug prophylaxis. Fruits and vegetables should be washed. Meat must be well cooked or frozen. Seronegative patients are at risk: pregnant women and immunocompromised subjects should avoid acquisition of the parasite (10). Contact with cat feces should be avoided because the oocysts sporulate after 4-5 days. Gloves should be worn and hands should be washed after handling potentially contaminated material including garden soil, sandboxes, or raw meat.

Antiparasitic Agent Prophylaxis

Congenital Toxoplasmosis: Management of seroconverters is determined by the risk of materno-fetal transplacental transmission of Toxoplasma (23). The average risk is 40%. It is reduced by about one-half with spiramycin treatment. The date of maternal infection is of relevance to transmission. There is no risk if infection occurred before conception in an immunocompetent mother. The later the infection date during pregnancy, the higher the risk of transmission (38). Fetal infection is unusual when maternal infection occurs during the first two weeks of pregnancy. Among women with seroconversion, the incidence of materno-fetal transmission increases as the pregnancy progresses. In women treated with spiramycin, the incidence of fetal infection goes from 2%, if maternal infection occurred between 3 to 10 weeks, to over 30% when maternal infection occurred after 31 weeks (62). The incidence reaches 90% in infections of the last two weeks. The reverse is true for the clinical pattern. The earlier the maternal infection occurs during pregnancy, the higher the risk of patent disease and brain injury to the fetus. The 26th week is a milestone: for maternal infections; after this date, most fetal infections are subclinical.

                Prophylaxis against fetal infection can be realised with spiramycin 3g a day, oral route, as soon as possible and throughout pregnancy in recently infected women. The fact that it reduces by half the risk of materno fetal transmission of the parasite (38) has been questioned (47, 48, 140). However, it may reduce the severity of fetopathy and the sequelae of the disease in infected infants (49). When PCR in amniotic fluid is negative, spiramycin must be given until delivery since delayed materno-fetal transmission can occur. Azithromycin has been given to 17 pregnant women with primary infection. On a dosage of 500 mg once daily for 3 days a week for 1 to 4 weeks. Concentrations in placental tissue were 10 fold or more higher than in amniotic fluid or maternal or cord blood (129).

Ocular Toxoplasmosis: Repeated exacerbations raise the question of a prolonged prophylaxis with the pyrimethamine-sulfonamide combination. The pyrimethamine-sulfadoxine combination, 1 tablet for 20 kg every 10 days for 6, 12 months or more can then be used but clinical and hematological monitoring is necessary (106).

AIDS: The 30-40% prevalence of toxoplasmic encephalitis in HIV infected patients, in some European countries, and the mortality rate of 20% prompted efforts to prevent reactivation in patients who are seropositive for Toxoplasma gondii (66, 136). The risk of primary infection is low in seronegative patients, approximately 2% patient-years (17). For these patients hygienic measures are recommended, as above. Monitoring of Toxoplasma gondii serology should be performed once or twice a year, especially in countries where the seroprevalence is high (12). In patients who are seropositive for Toxoplasma gondii, two approaches are considered: 1) assess the risk factors for occurrence of toxoplasmic encephalitis, in order to identify the population of patients who should be given prophylaxis (11, 55, 78) and 2) determine the efficacy and safety of drugs which could be used for chemoprophylaxis.

Risk Factors in Patients Seropositive for Toxoplasma gondii: The severity of the immune defect is one major factor. CDC stage B or C, clinical manifestations, and CD4 cell count lower than 100/mm3 are independent factors associated with an increased risk of toxoplasmic encephalitis. The probability of toxoplasmic encephalitis at one year reaches 24% in patients with CDC stage C manifestations and 20% in patients with CD4 below 50/mm3 (36). Furthermore, the IgG anti Toxoplasma gondii antibody titre determined by ELISA at baseline was a good independent prognostic marker for risk of toxoplasmic encephalitis (36). The risk increased by 3 fold in patients with titers >150 IU/ml. Bands 22, 25, and 69 of IgG on Western blot were associated with an increased risk of toxoplasmic encephalitis (78).

Regimens for Primary Prophylaxis: Although no trials have yet been published, patients who were given trimethoprim-sulfamethoxazole for primary or secondary prophylaxis of pneumocystosis had a very low incidence of toxoplasmic encephalitis (19, 59, 88, 90, 109, 123). Thus, trimethoprim-sulfametoxazole is the drug of choice for toxoplasmic encephalitis prophylaxis (136). A prospective randomised trial, ANRS 040, is ongoing in France to determine the most convenient dose of trimethoprim-sulfametoxazole for this indication: one single strength tablet per day versus one double strength tablet per day. Some authors propose an every-other day administration (114). The pyrimethamine-dapsone combination has been shown to be effective in preventing toxoplasmic encephalitis (54). However the rate of cross-intolerance between dapsone and trimethoprim-sulfamethoxazole is approximately 40% (70). ANRS 005 - ACTG 154 was an international double blind placebo controlled study to assess pyrimethamine, 50 mg thrice weekly for primary prophylaxis of toxoplasmic encephalitis (77). The results of the pyrimethamine regimen were not different from placebo: 13% patient-years incidence in each arm. . Rash was the only adverse effect which was significantly more frequent in the pyrimethamine arm. In the on-treatment analysis, the incidence of toxoplasmic encephalitis was 4% in the pyrimethamine arm and 12%, in the placebo arm. In the CPCRA study with a similar design but no addition of folinic acid, a trend towards a higher mortality was seen in the pyrimethamine arm (68). In patients who are intolerant to trimethoprim-sulfametoxazole, a French and Spanish trial assessed the efficacy of pyrimethamine, 50 mg three times a week, compared to atovaquone suspension, 1500 mg/day. This trial had to be discontinued due to low recruitment with the advent of highly antiretroviral therapy. Thus, at the present time, HIV-infected patients who are given trimethoprim-sulfametoxazole for prophylaxis of pneumocystosis have minimal risk of toxoplasmic encephalitis. If intolerance to trimethoprim-sulfamethoxazole occurs, no simple solution is available. The indications of prophylaxis have to be individualized based on the clinical stage of HIV infection, the CD4 cell count, and the Toxoplasma gondii antibody titre.

Prophylaxis in the Era of HAART: Since 1996, the widespread use of highly active antiretroviral therapy (HAART) has modified the risk of toxoplasmosis in HIV infected patients. Because efficacy of HAART is accompanied by a significant increase in CD4 cell count with at least partial restoration of the qualitative deficiency of the immune system, the rate of toxoplasmosis has been reduced to less than 5% patient-years in most cohort studies or therapeutic trials. Thus, USPHS consensus panels recommended that primary prophylaxis, be discontinued for toxoplasmosis in patients with CD4 greater that 200/mm3 for than 6 months, and viral control. The possibility for discontinuing secondary prophylaxis has also been suggested (58, 136).

Prophylaxis for Other Immunosuppressed Hosts: Among organ transplants, heart or heart- lung transplant recipients carry the greatest risk of toxoplamosis (63, 86, 128, 146). Corticosteroids increase the risk of toxoplasmosis. Conversely cyclosporine has antiparasitic activity as demonstrated in vitro and animal experiments and should be preferred to treat rejections in patients at risk for toxoplasmosis (93). In heart or heart and lung recipients who are seronegative for the parasite and who are transplanted with a heart from a donor who is seropositive for Toxoplasma gondii, pyrimethamine 50 mg/day has markedly reduced the risk of toxoplasmosis (63, 86, 146). Trimethoprim-sulfamethoxazole is a possible alternative which has not been widely assessed. In bone-marrow recipients, the risk of toxoplasmosis is the highest in those who are seropositive for the parasite and who receive bone-marrow from a donor who is seronegative for Toxoplasma gondii (34, 45, 89, 102). The pyrimethamine-sulfadoxine or trimethoprim-sulfamethoxazole combinations have been proposed for children. In these transplant patients, the duration of chemoprophylaxis has not been defined and depends upon the duration of an immunosuppressive therapy. Limited data are available for other causes of immunosuppression (15). It has been suggested that patients with a cellular immune defect, such as those with long term corticosteroid therapy, should be considered for prophylaxis of toxoplasmosis when the CD4 cell count is lower than 100/mm3. Pyrimethamine or trimethoprim-sulfamethoxazole should be proposed as long as the immune defect persists.

TABLES

Table 1: Drugs Used in Immunocompetent and Immunocompromised Patients with Toxoplasmosis in the Setting of Acute Infection or Reactivation* (Primary Therapy)

Table 2: Drugs Used in Pregnant Women Who Have Likely Acquired T. gondii Infection During Gestation and Infants Suspected or Confirmed  to have Congenital Toxoplasmosis

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