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Open Access 01-12-2017 | Systematic Review

Adverse Event Profile of Pyrimethamine-Based Therapy in Toxoplasmosis: A Systematic Review

Authors: Ruben R. Ben-Harari, Elizabeth Goodwin, Julio Casoy

Published in: Drugs in R&D | Issue 4/2017

Abstract

Introduction

Approximately a third of the population worldwide is chronically infected with Toxoplasma gondii. Pyrimethamine-based regimens are recommended for the treatment of toxoplasmosis.

Objective

The aim was to evaluate the safety profile of pyrimethamine-based treatment for the three main Toxoplasma manifestations: toxoplasmic encephalitis (TE), ocular toxoplasmosis, and congenital toxoplasmosis.

Methods

PubMed, Cochrane Library, and Google Scholar databases were searched through August 1, 2016. Randomized, observational, prospective/retrospective, and cohort studies were eligible. Thirty-one studies were included with a total of 2975 patients. Of these, 13 were in congenital toxoplasmosis (n = 929), 11 in ocular toxoplasmosis (n = 1284), and seven in TE (n = 687). Across manifestations, adverse event (AE)-related treatment discontinuation and/or change in therapy involved ≤37% of patients and occurred in >55% of studies: 100% for ocular toxoplasmosis, 57.1% for TE, and 61.5% for congenital toxoplasmosis. The most commonly observed AEs were bone marrow suppression, dermatologic, and gastrointestinal (GI). The prevalence of bone marrow suppression-related AEs was ≤50% in congenital toxoplasmosis, ≤42.7% in TE, and ≤9.0% in ocular toxoplasmosis. The frequency of GI and dermatologic AEs were ≤100 and ≤11.1%, respectively, for ocular toxoplasmosis, ≤10.7 and ≤17.9% for TE, and ≤10.8 and ≤2.1% for congenital toxoplasmosis. Steven–Johnson syndrome was reported in two patients with ocular toxoplasmosis and one with TE.

Conclusion

The AE profile associated with pyrimethamine-based treatments differed by each manifestation of toxoplasmosis and within a given manifestation. Hematologic AEs occurred across all manifestations indicating the importance of monitoring the blood of patients administered pyrimethamine-based regimens.

Dubey JP, Lindsay DS, Speer CA. Structures of Toxoplasma gondii tachyzoites, bradyzoites, and sporozoites and biology and development of tissue cysts. Clin Microbiol Rev. 1998;11(2):267–99.PubMedPubMedCentral

Tenter AM, Heckeroth AR, Weiss LM. Toxoplasma gondii: from animals to humans. Int J Parasitol. 2000;30(12–13):1217–58.CrossRefPubMedPubMedCentral

Aspöck H. Prevention of congenital toxoplasmosis in Austria: experience of 25 years. Congenital toxoplasmosis. New York: Springer; 2000. p. 277–92.CrossRef

Maenz M, Schluter D, Liesenfeld O, et al. Ocular toxoplasmosis past, present and new aspects of an old disease. Prog Retinal Eye Res. 2014;39:77–106.CrossRef

Halonen SK, Weiss LM. Toxoplasmosis, Chapter 8. In: Hector H, Garcia HBT, Oscar HDB, editors. Handbook of clinical neurology. New York: Elsevier; 2013. p. 125–45.

Rabaud C, May T, Amiel C, et al. Extracerebral toxoplasmosis in patients infected with HIV. A French National Survey. Medicine (Baltimore). 1994;73(6):306–14.CrossRef

Jones JL, Holland GN. Annual burden of ocular toxoplasmosis in the US. Am J Trop Med Hyg. 2010;82(3):464–5.CrossRefPubMedPubMedCentral

Vora NM, Holman RC, Mehal JM, et al. Burden of encephalitis-associated hospitalizations in the United States, 1998–2010. Neurology. 2014;82(5):443–51.CrossRefPubMed

Kaye A. Toxoplasmosis: diagnosis, treatment, and prevention in congenitally exposed infants. J Pediatr Health Care. 2011;25(6):355–64.CrossRefPubMed

10.

Cuervo G, Simonetti AF, Alegre O, et al. Toxoplasma myocarditis: a rare but serious complication in an HIV-infected late presenter. Aids. 2016;30(14):2253–4.CrossRefPubMed

11.

Remington JS, McLeod R, Thulliez P, et al. Toxoplasmosis. In: Remington J, Klein J, editors. Infectious diseases of the fetus and newborn infant. 6th ed. Philadelphia: WB Saunders; 2006. p. 947–1091.CrossRef

12.

Montoya JG, Liesenfeld O. Toxoplasmosis. Lancet. 2004;363(9425):1965–76.CrossRefPubMed

13.

Olliaro P. Drug resistance hampers our capacity to roll back malaria. Clin Infect Dis. 2005;41(Suppl 4):S247–57.CrossRefPubMed

14.

Khan Assir MZ, Ahmad HI, Akram J, et al. An outbreak of pyrimethamine toxicity in patients with ischaemic heart disease in Pakistan. Basic Clin Pharmacol Toxicol. 2014;115(3):291–6.CrossRefPubMed

15.

Beuerman VA, Burnham CJ. Toxoplasmic uveitis; treatment with pyrimethamine and sulfadiazine. Am J Ophthalmol. 1956;42(2):217–27.CrossRefPubMed

16.

Lapetina F. Toxoplasmosis and dermatomyositis: a causal or casual relationship? Pediatr Med Chir. 1989;11(2):197–203.PubMed

17.

Yang Z, Ahn HJ, Park YH, et al. Afatinib reduces STAT6 signaling of host ARPE-19 cells infected with Toxoplasma gondii. Korean J Parasitol. 2016;54(1):31–8.CrossRefPubMedPubMedCentral

18.

Rajapakse S, Chrishan Shivanthan M, Samaranayake N, et al. Antibiotics for human toxoplasmosis: a systematic review of randomized trials. Pathog Glob Health. 2013;107(4):162–9.CrossRefPubMedPubMedCentral

19.

Dedicoat M, Livesley N. Management of toxoplasmic encephalitis in HIV-infected adults (with an emphasis on resource-poor settings). Cochrane Database Syst Rev. 2006;3:CD005420.

20.

Hernandez AV, Thota P, Pellegrino D, et al. A systematic review and meta-analysis of the relative efficacy and safety of treatment regimens for HIV-associated cerebral toxoplasmosis: is trimethoprim-sulfamethoxazole a real option? HIV Med. 2017;18(2):115–24.CrossRefPubMed

21.

Yan J, Huang B, Liu G, et al. Meta-analysis of prevention and treatment of toxoplasmic encephalitis in HIV-infected patients. Acta Trop. 2013;127(3):236–44.CrossRefPubMed

22.

Pradhan E, Bhandari S, Gilbert RE, et al. Antibiotics versus no treatment for toxoplasma retinochoroiditis. Cochrane Database Syst Rev. 2016;5:CD002218.

23.

Palella FJ Jr, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med. 1998;338(13):853–60.CrossRefPubMed

24.

Connolly MP, Goodwin E, Schey C, et al. Toxoplasmic encephalitis relapse rates with pyrimethamine-based therapy: systematic review and meta-analysis. Pathog Glob Health. 2017;2017:1–14.

25.

Vidal JE, Oliveira AC. AIDS-related cerebral toxoplasmosis in Sao Paulo State, Brazil: marked improvements in the highly active antiretroviral therapy-era but the challenges continue. Braz J Infect Dis. 2013;17(3):379–80.CrossRefPubMed

26.

Mayor AM, Fernandez Santos DM, Dworkin MS, et al. Toxoplasmic encephalitis in an AIDS cohort at Puerto Rico before and after highly active antiretroviral therapy (HAART). Am J Trop Med Hyg. 2011;84(5):838–41.CrossRefPubMedPubMedCentral

27.

Fayer R, Dubey JP, Lindsay DS. Zoonotic protozoa: from land to sea. Trends Parasitolol. 2004;2004:20.

28.

Acers TE, Okla L. Toxoplasmic retinochoroiditis: a double blind therapeutic study. Arch Ophthalmol. 1964;71(1):58–62.CrossRefPubMed

29.

Baharivand N, Mahdavifard A, Fouladi RF. Intravitreal clindamycin plus dexamethasone versus classic oral therapy in toxoplasmic retinochoroiditis: a prospective randomized clinical trial. Int Ophthalmol. 2013;33(1):39–46.CrossRefPubMed

30.

Balaskas K, Vaudaux J, Boillat-Blanco N, et al. Azithromycin versus sulfadiazine and pyrimethamine for non-vision-threatening toxoplasmic retinochoroiditis: a pilot study. Med Sci Monit. 2012;18(5):Cr296–302.CrossRefPubMedPubMedCentral

31.

Bosch-Driessen LH, Verbraak FD, Suttorp-Schulten MS, et al. A prospective, randomized trial of pyrimethamine and azithromycin vs pyrimethamine and sulfadiazine for the treatment of ocular toxoplasmosis. Am J Ophthalmol. 2002;2002:34–40.CrossRef

32.

Rothova A, Meenken C, Buitenhuis HJ, et al. Therapy for ocular toxoplasmosis. Am J Ophthalmol. 1993;1993:517–23.CrossRef

33.

Soheilian M, Sadoughi MM, Ghajarnia M, et al. Prospective randomized trial of trimethoprim/sulfamethoxazole versus pyrimethamine and sulfadiazine in the treatment of ocular toxoplasmosis. Ophthalmology. 2005;2005:1876–82.CrossRef

34.

Soheilian M, Ramezani A, Azimzadeh A, et al. Randomized trial of intravitreal clindamycin and dexamethasone versus pyrimethamine, sulfadiazine, and prednisolone in treatment of ocular toxoplasmosis. Ophthalmology. 2011;118(1):134–41.CrossRefPubMed

35.

Canamucio CJ, Hallett JW, Leopold IH. Recurrence of treated toxoplasmic uveitis. Am J Ophthalmol. 1963;55:1035–9.CrossRefPubMed

36.

Lam S, Tessler HH. Quadruple therapy for ocular toxoplasmosis. Can J Ophthalmol. 1993;28(2):58–61.PubMed

37.

Borkowski PK, Brydak-Godowska J, Basiak W, et al. The impact of short-term, intensive antifolate treatment (with pyrimethamine and sulfadoxine) and antibiotics followed by long-term, secondary antifolate prophylaxis on the rate of toxoplasmic retinochoroiditis recurrence. PLoS Negl Trop Dis. 2016;10(8):e0004892.CrossRefPubMedPubMedCentral

38.

Helfenstein M, Zweifel S, Barthelmes D, et al. Ocular toxoplasmosis: therapy-related adverse drug reactions and their management. Klin Monbl Augenheilkd. 2017;234(4):556–60.CrossRef

39.

40.

Chirgwin K, Hafner R, Leport C, et al. Randomized phase II trial of atovaquone with pyrimethamine or sulfadiazine for treatment of toxoplasmic encephalitis in patients with acquired immunodeficiency syndrome: ACTG 237/ANRS 039 Study. AIDS Clinical Trials Group 237/Agence Nationale de Recherche sur le SIDA, Essai 039. Clin Infect Dis. 2002;2002:1243–50.CrossRef

41.

Podzamczer D, Miro JM, Ferrer E, et al. Thrice-weekly sulfadiazine-pyrimethamine for maintenance therapy of toxoplasmic encephalitis in HIV-infected patients. Spanish Toxoplasmosis Study Group. Eur J Clin Microbiol Infect Dis. 2000;19(2):89–95.CrossRefPubMed

42.

Chaddha DS, Kalra SP, Singh AP, et al. Toxoplasmic encephalitis in acquired immunodeficiency syndrome. J Assoc Phys India. 1999;47(7):680–4.

43.

Amogne W, Teshager G, Zenebe G. Central nervous system toxoplasmosis in adult Ethiopians. Ethiop Med J. 2006;44(2):113–20.PubMed

44.

Arens J, Barnes K, Crowley N, et al. Treating AIDS-associated cerebral toxoplasmosis—pyrimethamine plus sulfadiazine compared with cotrimoxazole, and outcome with adjunctive glucocorticoids. S Afr Med J. 2007;97(10):956–8.PubMed

45.

Goswami RP, Goswami RP, Rahman M, et al. Alternative treatment approach to cerebral toxoplasmosis in HIV/AIDS: experience from a resource-poor setting. Int J STD AIDS. 2015;26(12):864–9.CrossRefPubMed

46.

Arendt G, von Giesen HJ, Hefter H, et al. Long-term course and outcome in AIDS patients with cerebral toxoplasmosis. Acta Neurol Scand. 1999;100(3):178–84.CrossRefPubMed

47.

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;42(10):1383–94.CrossRefPubMed

48.

Guerina NG, Hsu HW, Meissner HC, et al. Neonatal serologic screening and early treatment for congenital Toxoplasma gondii infection. The New England Regional Toxoplasma Working Group. N Engl J Med. 1994;330(26):1858–63.CrossRefPubMed

49.

Lipka B, Milewska-Bobula B, Filipek M. Monitoring of plasma concentration of pyrimethamine (PYR) in infants with congenital Toxoplasma gondii infection—own observations. Wiad Parazytol. 2011;57(2):87–92.PubMed

50.

Schmidt DR, Hogh B, Andersen O, et al. Treatment of infants with congenital toxoplasmosis: tolerability and plasma concentrations of sulfadiazine and pyrimethamine. Eur J Pediatr. 2006;165(1):19–25.CrossRefPubMed

51.

Faucher B, Garcia-Meric P, Franck J, et al. Long-term ocular outcome in congenital toxoplasmosis: a prospective cohort of treated children. J Infect. 2012;64(1):104–9.CrossRefPubMed

52.

Hohlfeld P, Daffos F, Thulliez P, et al. Fetal toxoplasmosis: outcome of pregnancy and infant follow-up after in utero treatment. J Pediatr. 1989;115(5 Pt 1):765–9.CrossRefPubMed

53.

Mombro M, Perathoner C, Leone A, et al. Congenital toxoplasmosis: 10-year follow up. Eur J Pediatr. 1995;154(8):635–9.CrossRefPubMed

54.

Stray-Pedersen B. Infants potentially at risk for congenital toxoplasmosis: a prospective study. Am J Dis Child. 1980;134(7):638–42.CrossRefPubMed

55.

Villena I, Aubert D, Leroux B, et al. Pyrimethamine–sulfadoxine treatment of congenital toxoplasmosis: follow-up of 78 cases between 1980 and 1997. Reims Toxoplasmosis Group. Scand J Infect Dis. 1998;30(3):295–300.CrossRefPubMed

56.

Hotop A, Hlobil H, Gross U. Efficacy of rapid treatment initiation following primary Toxoplasma gondii infection during pregnancy. Clin Infect Dis. 2012;54(11):1545–52.CrossRefPubMed

57.

Carellos EV, de Andrade JQ, Romanelli RM, et al. High frequency of bone marrow depression during congenital toxoplasmosis therapy in a cohort of children identified by neonatal screening in Minas Gerais, Brazil. Pediatr Infect Dis J. 2017 [Epub ahead of print].

58.

Teil J, Dupont D, Charpiat B, et al. Treatment of congenital toxoplasmosis: safety of the sulfadoxine–pyrimethamine combination in children based on a method of causality assessment. Pediatr Infect Dis J. 2016;35(6):634–8.CrossRefPubMed

59.

Capobiango JD, Bregano RM, Navarro IT, et al. Congenital toxoplasmosis in a reference center of Parana, Southern Brazil. Braz J Infect Dis. 2014;18(4):364–71.CrossRefPubMed

60.

Guerina NG. Congenital infection with Toxoplasma gondii. Pediatr Ann. 1994;23(3):138–42, 147–51.CrossRefPubMed

61.

62.

Barnes KI, Little F, Smith PJ, et al. Sulfadoxine–pyrimethamine pharmacokinetics in malaria: pediatric dosing implications. Clin Pharmacol Ther. 2006;80(6):582–96.CrossRefPubMed

63.

Trenque T, Simon N, Villena I, et al. Population pharmacokinetics of pyrimethamine and sulfadoxine in children with congenital toxoplasmosis. Br J Clin Pharmacol. 2004;57(6):735–41.CrossRefPubMedPubMedCentral

64.

Corvaisier S, Charpiat B, Mounier C, et al. Population pharmacokinetics of pyrimethamine and sulfadoxine in children treated for congenital toxoplasmosis. Antimicrob Agents Chemother. 2004;48(10):3794–800.CrossRefPubMedPubMedCentral

65.

Klinker H, Langmann P, Richter E. Plasma pyrimethamine concentrations during long-term treatment for cerebral toxoplasmosis in patients with AIDS. Antimicrob Agents Chemother. 1996;40(7):1623–7.PubMedPubMedCentral

66.

Couvreur J, Nottin N, Desmonts G. Treatment of congenital toxoplasmosis. Clinical and biological results (author’s transl). Ann Pediatr. 1980;27(10):647–52.

67.

Schmidt DR, Hogh B, Andersen O, et al. The national neonatal screening programme for congenital toxoplasmosis in Denmark: results from the initial four years, 1999–2002. Arch Dis Child. 2006;2006:661–5.CrossRef

68.

Stray-Pedersen B. A prospective study of acquired toxoplasmosis among 8,043 pregnant women in the Oslo area. Am J Obstet Gynecol. 1980;136(3):399–406.CrossRefPubMed

Title: Adverse Event Profile of Pyrimethamine-Based Therapy in Toxoplasmosis: A Systematic Review
Authors: Ruben R. Ben-Harari
Elizabeth Goodwin
Julio Casoy
Publication date: 01-12-2017
Publisher: Springer International Publishing
Published in: Drugs in R&D / Issue 4/2017
Print ISSN: 1174-5886
Electronic ISSN: 1179-6901
DOI: https://doi.org/10.1007/s40268-017-0206-8

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Adverse Event Profile of Pyrimethamine-Based Therapy in Toxoplasmosis: A Systematic Review

Abstract

Introduction

Objective

Methods

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Introduction

Objective

Methods

Conclusion

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