Pediatric Toxoplasmosis Medication
- Author: Itzhak Brook, MD, MSc; Chief Editor: Russell W Steele, MD more...
The currently recommended drugs for T gondii infection act primarily against the tachyzoite form but do not eradicate the encysted form (bradyzoite). Effective treatment mandates the administration of combination of 2 agents effective against the pathogen. Leucovorin (folinic acid) should be administered concomitantly to avoid bone marrow suppression. Pyrimethamine is the most effective agent and is included in most drug regimens. Unless circumstances arise that preclude using more than one drug, a second drug, such as sulfadiazine, atovaquone, or clindamycin, should be added. Other effective agents include sulfamerazine and sulfamethazine, which are not available in the United States.
The efficacy of azithromycin, clarithromycin, atovaquone, dapsone, and cotrimoxazole (ie, trimethoprim-sulfamethoxazole) 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 trisulfapyrimidine (ie, combination of sulfamerazine, sulfamethazine, and sulfapyrazine). These agents are active against tachyzoites and are synergistic when used in combination.
A study that compared the effects of trimethoprim-sulfamethoxazole vs placebo in reducing the risk of recurrences of Toxoplasma gondii retinochoroiditis reported that trimethoprim/sulfamethoxazole therapy resulted in a 100% reduction in the recurrence of Toxoplasma gondii retinochoroiditis over 1 year of treatment.[11, 12]
Children with renal insufficiency or glucose-6-phosphate-dehydrogenase (G6PD) deficiency and those receive anticonvulsants or antiretrovirals require special attention. Because sulfadiazine is excreted in the kidneys, its dose may require adjustment for those with renal insufficiency. Sulfadiazine should not be administered to children with G6PD deficiency because it can cause hemolysis. It should be substituted with another agent such as clindamycin. Because high-dose pyrimethamine can cause hemolytic anemia in individuals with G6PD deficiency, these patients should be under close observation. Dosing adjustments may be necessary when sulfadiazine is given to those receiving phenytoin as its half-life may be prolonged.
Additional therapy with corticosteroids (prednisone, 1 mg/kg/day) should be considered with markedly elevated CSF protein (>1 g/dL) and vision-threatening chorioretinitis. Corticosteroids are administered until the elevated CSF protein or active chorioretinitis resolves. The efficacy of corticosteroid therapy has not been observed in controlled studies. No adverse effects of corticosteroids have been noted in cohort studies.
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. In serum, these agents exist in 3 forms: free, conjugated (ie, acetylated and possibly others), and protein bound. The free form is considered to be therapeutically active.
This is a bacteriostatic agent that acts synergistically with pyrimethamine to treat T gondii.
Blocks 2 consecutive steps in the biosynthesis of nucleic acids and proteins essential to many bacteria
Trimethoprim: Inhibits dihydrofolate reductase, thereby blocking production of tetrahydrofolic acid from dihydrofolic acid
Sulfamethoxazole: Inhibits bacterial synthesis of dihydrofolic acid by competing with para-aminobenzoic acid
Antiprotozoal and antimycobacterial agents
Protozoal infections occur throughout the world and are a major cause of morbidity and mortality in some regions. Patients who are immunocompromised are especially at risk. Primary immune deficiency 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.
Dapsone, a sulfone that has been widely used in the treatment of leprosy, has been administered in combination with pyrimethamine for prophylaxis against malaria.
Dapsone with trimethoprim is used as an alternative to trimethoprim-sulfamethoxazole for the treatment of mild to moderate Pneumocystis carinii pneumonia; dapsone alone can be used for prophylaxis. Dapsone and pyrimethamine have also been used in patients with HIV and low CD4+ T-cell counts to prevent T gondii encephalitis.
Mechanism of action similar to that of sulfonamides—competitive antagonists of PABA prevent formation of folic acid, inhibiting growth.
Pyrimethamine is a folic acid antagonist that selectively inhibits dihydrofolate reductase. It is highly selective against plasmodia and T gondii. Pyrimethamine has a synergistic effect when used conjointly with a sulfonamide to treat T gondii.
Inhibits electron transport chain in mitochondria, which in turn inhibits synthesis of nucleic acid and ATP.
These agents inhibit bacterial growth, possibly by blocking the dissociation of peptidyl transfer ribonucleic acid (tRNA) from ribosomes, causing RNA-dependent protein synthesis to arrest.
Clindamycin is used as an alternative to sulfonamides. It may be beneficial when used with pyrimethamine in short-term treatment of CNS toxoplasmosis in patients with AIDS.
Azithromycin, which belongs to the azalide subclass of macrolide antibiotics, is administered orally. Azithromycin is derived from erythromycin; however, it differs chemically from erythromycin in that a methyl-substituted nitrogen atom is incorporated into the lactone ring.
Azithromycin acts by binding to the 50S ribosomal subunit of susceptible microorganisms, in that way 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 in phagocytes may contribute to drug distribution to inflamed tissues. The drug is used to treat mild to moderate microbial infections.
Semisynthetic macrolide antibiotic that reversibly binds to P site of 50S ribosomal subunit of susceptible organisms and may inhibit RNA-dependent protein synthesis by stimulating dissociation of peptidyl t-RNA from ribosomes, thereby inhibiting bacterial growth.
This product is not available in the US. Spiramycin is the drug of choice for maternal or fetal toxoplasmosis. It is used as an alternative therapy in other patient populations when pyrimethamine and sulfadiazine cannot be used.
Supplemental folinic acid is coadministered to prevent hematologic adverse effects caused by bone marrow suppression.
Leucovorin, also called folinic acid, is a derivative of folic acid used with folic acid antagonists, such as sulfonamides and pyrimethamine.
Glucocorticoids have anti-inflammatory properties and cause profound and varied metabolic effects, modifying the body’s immune response to diverse stimuli.
This agent elicits mild mineralocorticoid activity and moderate anti-inflammatory effects; controls or prevents inflammation by controlling rate of protein synthesis, suppressing migration of polymorphonuclear leukocytes (PMNs) and fibroblasts, reversing capillary permeability, and stabilizing lysosomes at cellular level; in physiologic doses, corticosteroids are administered to replace deficient endogenous hormones; in larger (pharmacologic) doses, they decrease inflammation
Hill DE, Chirukandoth S, Dubey JP. Biology and epidemiology of Toxoplasma gondii in man and animals. Anim Health Res Rev. 2005 Jun. 6(1):41-61. [Medline].
Ferguson W, Mayne PD, Lennon B, Butler K, Cafferkey M. Susceptibility of pregnant women to toxoplasma infection--potential benefits for newborn screening. Ir Med J. 2008 Jul-Aug. 101(7):220-1. [Medline].
Trikha I, Wig N. Management of toxoplasmosis in AIDS. Indian J Med Sci. 2001. 55:87-98. [Medline].
Jones JL, Lopez A, Wilson M, et al. Congenital toxoplasmosis: a review. Obstet Gynecol Surv. 2001. 56:296-305. [Medline].
Peyron F, Garweg JG, Wallon M, Descloux E, Rolland M, Barth J. Long-term impact of treated congenital toxoplasmosis on quality of life and visual performance. Pediatr Infect Dis J. 2011 Jul. 30(7):597-600. [Medline].
Berrebi A, Assouline C, Bessieres MH, et al. Long-term outcome of children with congenital toxoplasmosis. Am J Obstet Gynecol. 2010 Jul 14. [Medline].
Bonfioli AA, Orefice F. Toxoplasmosis. Semin Ophthalmol. 2005 Jul-Sep. 20(3):129-41. [Medline].
Foulon W, Naessens A, Ho-Yen D. Prevention of congenital toxoplasmosis. J Perinat Med. 2000. 28:337-45. [Medline].
Paquet C, Yudin MH. Toxoplasmosis in pregnancy: prevention, screening, and treatment. J Obstet Gynaecol Can. 2013 Jan. 35(1):78-9. [Medline].
McLeod R, Boyer K, Karrison T, et al. Outcome of treatment for congenital toxoplasmosis, 1981-2004: the National Collaborative Chicago-Based, Congenital Toxoplasmosis Study. Clin Infect Dis. 2006 May 15. 42(10):1383-94. [Medline].
Felix JP, Lira RP, Zacchia RS, Toribio JM, Nascimento MA, Arieta CE. Trimethoprim-sulfamethoxazole versus placebo to reduce the risk of recurrences of Toxoplasma gondii retinochoroiditis: randomized controlled clinical trial. Am J Ophthalmol. 2014 Apr. 157 (4):762-766.e1. [Medline].
Harding A. Trimethoprim-Sulfamethoxazole Prevents Ocular Toxoplasmosis Recurrence. Reuters Health Information. Available at http://www.medscape.com/viewarticle/819812. January 27, 2014; Accessed: September 17, 2015.