Medication Summary
Currently recommended drugs in the treatment of toxoplasmosis act primarily against the tachyzoite form of T gondii; thus, they do not eradicate the encysted form (bradyzoite). Pyrimethamine is the most effective agent and is included in most drug regimens. Leucovorin (ie, folinic acid) should be administered concomitantly to prevent bone marrow suppression. Unless circumstances preclude using more than 1 drug, a second drug (eg, sulfadiazine, clindamycin) should be added. [65, 66, 67]
The efficacy of azithromycin, clarithromycin, atovaquone, dapsone, and cotrimoxazole is unclear; therefore, they should be used only as alternatives in combination with pyrimethamine. The most effective available therapeutic combination is pyrimethamine plus sulfadiazine or trisulfapyrimidines (eg, a combination of sulfamerazine, sulfamethazine, and sulfapyrazine). These agents are active against tachyzoites and are synergistic when used in combination. According to another in vitro study, ivermectin significantly inhibited replication of the tachyzoites of T gondii RH strain. [68]
Careful attention to dosing regimen is necessary because it differs depending on patient variables (eg, immune status, pregnancy). Pyrimethamine may be used with sulfonamides, quinine, and other antimalarials, and with other antibiotics.
A study shows that combination of the immunomodulatory agents, levamisole and Echinacea, and pyrimethamine plus sulfadiazine for the treatment of toxoplasmosis increases the survival of mice. [69]
Nonpregnant patients
Immunocompetent, nonpregnant patients typically do not require treatment. Treatment of nonpregnant patients is described below.
The 6-week regimen is as follows:
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Pyrimethamine (100mg loading dose orally followed by 25-50 mg/day) plus sulfadiazine (2-4 g/day divided 4 times daily) OR
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Pyrimethamine (100-mg loading dose orally followed by 25-50 mg/day) plus clindamycin (300 mg orally 4 times daily)
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Folinic acid (leucovorin) (10-25 mg/day) should be given to all patients to prevent hematologic toxicity of pyrimethamine
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Trimethoprim (10 mg/kg/day) sulfamethoxazole (50 mg/kg/day) for 4 weeks
Sulfadiazine or clindamycin can be substituted for azithromycin 500 mg daily or atovaquone 750 mg twice daily in immunocompetent patients or in patients with a history of allergy to the former drugs.
Consider steroids in patients with radiologic midline shift, clinical deterioration after 48 hours, or elevated intracranial pressure.
Pregnant patients
The diagnosis of acute infection often is difficult to make during pregnancy, and the administration of empiric antimicrobial therapy is discouraged.
Substantial controversy exists regarding the efficacy of treatment during pregnancy in terms of reducing the risk for fetal exposure and the subsequent development of clinical disease such as retinochoroiditis or CNS abnormalities.
Controversy also exists regarding the optimal regimen for treating maternally acquired infection. Spiramycin and pyrimethamine-sulfonamide are used, but given the infrequency of fetal infection and the asymptomatic nature of most fetal infections, treatment effects are difficult to measure. Spiramycin appears to be somewhat more easily tolerated than pyrimethamine-sulfonamide.
A dosing regimen for pregnant patients is as follows:
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Spiramycin 1 g orally every 8 hours
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If the amniotic fluid test result for T gondii is positive: 3 weeks of pyrimethamine (50 mg/day orally) and sulfadiazine (3 g/day orally in 2-3 divided doses) alternating with a 3-week course of spiramycin 1 g 3 times daily for maternal treatment OR
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Pyrimethamine (25 mg/day orally) and sulfadiazine (4 g/day orally) divided 2 or 4 times daily until delivery (this agent may be associated with marrow suppression and pancytopenia) AND
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Leucovorin 10-25 mg/day orally to prevent bone marrow suppression
Patients with AIDS
Patients with AIDS are treated with pyrimethamine 200 mg orally initially, followed by 50-75 mg/day orally plus folinic acid 10 mg/day orally plus sulfadiazine 4-8 g/day orally for as long as 6 weeks, followed by lifelong suppressive therapy or until immune reconstitution.
Suppressive therapy for patients with AIDS (CD4 count < 100 cells/μL) is pyrimethamine 50mg/day orally plus sulfadiazine 1-1.5 g/day orally plus folinic acid 10 mg/day orally for life or until immune reconstitution.
Patients with AIDS, CNS toxoplasmosis, and evidence of midline shift or increased intracranial pressure may also benefit from steroid therapy.
Diagnosing toxoplasmosis in the absence of definitive tissue or culture evidence may be perilous because serology may be misleading and a false-positive IgM result is somewhat common. Consequently, empiric therapy should be avoided.
Retinitis
The mere presence of a focus of retinitis is not always an indication for treatment. Small, peripheral lesions generally heal spontaneously and may be followed conservatively. On the other hand, lesions in the vascular arcade, lesions near the optic disc (Jensen papillitis), lesions in the papillomacular bundle, or large lesions (irrespective of location) are treated. Patients with severe, debilitating vitreitis also are treated aggressively. (See the image below.)
In a prospective trial, treatment with several regimens failed to shorten the duration of inflammatory activity or to prevent recurrences. However, treatment did reduce the size of the ultimate retinochoroidal scar.
In addition, experts differ on their preferred initial treatment. In a report, one third of respondents preferred triple therapy (ie, pyrimethamine, sulfadiazine, prednisone), and a little more than one quarter of respondents preferred quadruple therapy (ie, pyrimethamine, sulfadiazine, clindamycin, prednisone).
Trimethoprim-sulfamethoxazole seems to be as effective as pyrimethamine and sulfadiazine, but with a significantly improved safety profile, whereas intermittent trimethoprim-sulfamethoxazole prophylaxis over 12 months is capable of preventing recurrences of the ocular toxoplasmosis. [70]
Sulfonamide
Class Summary
These agents exert bacteriostatic action through competitive antagonism with para-aminobenzoic acid (PABA). Microorganisms that require exogenous folic acid and do not synthesize folic acid (pteroylglutamic acid) are not susceptible to the action of sulfonamides. Resistant strains are capable of using folic acid precursors or preformed folic acid.
Sulfonamide antimicrobials exist as 3 forms in serum: free, conjugated (ie, acetylated and possibly others), and protein bound. The free form is considered therapeutically active.
Sulfadiazine
Through competitive antagonism of PABA, sulfadiazine interferes with microbial growth. It is useful in the treatment of toxoplasmosis.
Trimethoprim and sulfamethoxazole (Bactrim DS, Septra DS)
Trimethoprim/sulfamethoxazole exerts bacteriostatic action through competitive antagonism with PABA. The double-strength tablet contains 800 mg of sulfamethoxazole and 160 mg of trimethoprim. The regular strength tablet contains 400 mg of sulfamethoxazole and 80 mg of trimethoprim.
Antibiotics, Other
Class Summary
Antimicrobials with activity against mycobacteria may be used
Dapsone
Dapsone is bactericidal and bacteriostatic against mycobacteria. Its mechanism of action is similar to that of sulfonamides, ie, it is a competitive antagonist of PABA, preventing the formation of folic acid and inhibiting bacterial growth.
Lincosamide Antimicrobials
Class Summary
These agents are used to treat serious skin and soft-tissue staphylococcal infections. They are also effective against aerobic and anaerobic streptococci (except enterococci). They inhibit bacterial growth, possibly by blocking the dissociation of peptidyl transfer ribonucleic acid (t-RNA) from ribosomes, causing RNA-dependent protein synthesis to arrest.
Clindamycin (Cleocin)
Clindamycin is an alternative to sulfonamides. It may be beneficial when used with pyrimethamine in the acute treatment of CNS toxoplasmosis in patients with AIDS.
Antiprotozoal Agents
Class Summary
Protozoal infections occur throughout the world and are a major cause of morbidity and mortality in some regions. Immunocompromised patients are especially at risk. Primary immunodeficiency is rare, whereas secondary deficiency is more common. Immunosuppressive therapy, cancer and its treatment, HIV infection, and splenectomy may increase vulnerability to infection. Infectious risk is proportional to neutropenia duration and severity. Protozoal infections are typically more severe in immunocompromised patients than in immunocompetent patients.
Pyrimethamine (Daraprim)
This is a folic acid antagonist that selectively inhibits plasmodial dihydrofolate reductase. Pyrimethamine is highly selective against plasmodia and T gondii. A synergistic effect occurs when it is used conjointly with a sulfonamide to treat toxoplasmosis. Folinic acid should be given to all patients to prevent hematologic toxicity of pyrimethamine
Atovaquone (Mepron)
Atovaquone is a hydroxynaphthoquinone that inhibits the mitochondrial electron transport chain by competing with ubiquinone at the ubiquinone-cytochrome-c-reductase region (complex III). Inhibition of electron transport by atovaquone results in inhibition of nucleic acid and adenosine triphosphate (ATP) synthesis in parasites.
Macrolides
Class Summary
Spiramycin is a macrolide antibiotic with an antibacterial spectrum similar to erythromycin and clindamycin. It is bacteriostatic at serum concentrations but may be bactericidal at achievable tissue concentrations. The mechanism of action is unclear, but it acts on the 50S subunit of bacterial ribosomes and interferes with translocation. Absorption from the GI tract is irregular (20-50% of the oral dose is absorbed). Following oral administration, peak plasma levels are achieved within 2-4 hours. Spiramycin has a longer half-life than erythromycin and sustains higher tissue levels.
Azithromycin (Zithromax, Zmax)
Azithromycin acts by binding to the 50S ribosomal subunit of susceptible microorganisms, thereby interfering with microbial protein synthesis. Nucleic acid synthesis is not affected.
Azithromycin concentrates in phagocytes and fibroblasts, as demonstrated by in vitro incubation techniques. In vivo studies suggest that concentration of the drug in phagocytes contributes to drug distribution to inflamed tissues. Azithromycin treats mild to moderate microbial infections.
Spiramycin
This is the drug of choice for maternal or fetal toxoplasmosis. It is an alternative therapy in other patient populations when pyrimethamine and sulfadiazine cannot be used.
Corticosteroids
Class Summary
These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli. In cases in which anterior uveitis is present, topical corticosteroids are used to treat the inflammation.
Prednisone
Prednisone is used to limit inflammatory damage. The use of oral corticosteroids without antibiotic coverage may produce an immunodeficiency state that results in the rapid spread of tachyzoites and widespread retinitis. Antiparasitic agents should be stopped only after the steroids have been stopped. The steroids should never be used without antiparasitic coverage in the treatment of ocular toxoplasmosis.
Corticosteroids are probably not indicated in patients who are immunosuppressed. Some specialists wait 24-48 hours after the initiation of antibiotic therapy before starting prednisone, while others begin antibiotics and prednisone simultaneously.
Prednisolone acetate 1% (Pred Forte, Omnipred)
This agent decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing increased capillary permeability. The frequency of application depends on degree of ocular inflammation.
Antidotes
Class Summary
These agents are used to replenish folic acid when the patient is being treated with folic acid antagonists.
Leucovorin
This agent is also called folinic acid. Leucovorin is a derivative of folic acid that is used with folic acid antagonists, such as sulfonamides and pyrimethamine.
Cycloplegics/Mydriatics
Class Summary
As in any eye with uveitis, posterior synechiae often form if a pupil is not mobilized. Anticholinergic agents, such as cyclopentolate, atropine, and homatropine, block the sphincter muscle of the iris and the muscle in the ciliary body that is responsible for accommodation to produce mydriasis and paralysis of accommodation.
Cyclopentolate 0.5%, 1%, 2% (AK-Pentolate, Cyclogyl, Cylate)
This agent prevents the muscle of the ciliary body and the sphincter muscle of the iris from responding to cholinergic stimulation. It induces mydriasis in 30-60 minutes and cycloplegia in 25-75 minutes. Infants should not be given concentrations of more than 0.5%.
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Toxoplasma gondii tachyzoites (Giemsa stain).
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Toxoplasma gondii tachyzoites in cell line.
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Toxoplasma gondii in infected monolayers of HeLa cells (Giemsa stain).
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Ophthalmic toxoplasmosis. Used with permission of Anton Drew, ophthalmic photographer, Adelaide, South Australia.
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Macular scar secondary to congenital toxoplasmosis. Visual acuity of the patient is 20/400.
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Papillitis secondary to toxoplasmosis, necessitating immediate systemic therapy.
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Acute macular retinitis associated with primary acquired toxoplasmosis, requiring immediate systemic therapy.
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Peripapillary scars secondary to toxoplasmosis.
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Perimacular scars secondary to toxoplasmosis.
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Inactive retinochoroidal scar secondary to toxoplasmosis.
