Ocular toxoplasmosis: the treatment dilemma

Abstract

Yusuf and colleaugues1Yusuf I.H. Sahare P. Hildebrand G.D. DRESS syndrome in a child treated for toxoplasma retinochoroiditis.J AAPOS. 2013; 5: 521-523Abstract Full Text Full Text PDF Scopus (8) Google Scholar present a case of drug-induced rash and eosinophilia with systemic symptoms (DRESS) in a child treated with classic toxoplasmosis triple therapy: sulfadiazine, pyrimethamine, prednisone, and folinic acid. Idiosyncratic drug reactions, although uncommon, can potentially carry serious consequences for the patient and can be frightening for the treating physician. This case serves as a reminder that the medications ophthalmologists treat patients with are not benign and can sometimes cause more problems than the condition they are intended to treat. Treatment of toxoplasmosis is complicated by a dearth of comparative studies between different modalities. The standard therapy for toxoplasmosis has been “triple therapy” with sulfadiazine, pyrimethamine, and prednisone for more than 60 years.2Montoya J.G. Liesenfeld O. Toxoplasmosis.Lancet. 2004; 363: 1965-1976Abstract Full Text Full Text PDF PubMed Scopus (2435) Google Scholar The question of whether to even treat ocular toxoplasmosis is murky, as the studies examining treatment versus control of active retinochoroidal lesions are of poor quality.3Gilbert R.E. See S.E. Jones L.V. Stanford M.S. Antibiotics versus control for toxoplasma retinochoroiditis.Cochrane Database Syst Rev. 2002; : CD002218PubMed Google Scholar Although never demonstrated in a randomized controlled trial, it is generally well agreed on that macular lesions, lesions involving the optic nerve, and cases with intense inflammation should be treated. A number of comparative studies have been undertaken that examine new and different treatment regimens for ocular toxoplasmosis. Trimethoprim-sulfamethoxazole (TMP-SMX),4Soheilian M. Sadoughi M.M. Ghajarnia M. et al.Prospective randomized trial of trimethoprim/sulfamethoxazole versus pyrimethamine and sulfadiazine in the treatment of ocular toxoplasmosis.Ophthalmology. 2005; 112: 1876-1882Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar intravitreal clindamycin with dexamethasone,5Bosch-Driessen L.H. Verbraak F.D. Suttorp-Schulten M.S. et al.A prospective, randomized trial of pyrimethamine and azithromycin vs pyrimethamine and sulfadiazine for the treatment of ocular toxoplasmosis.Am J Ophthalmol. 2002; 134: 34-40Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar and azithromycin with pyrimethamine6Soheilian 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: 134-141Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar have all been compared against treatment with sulfadiazine and pyrimethamine in randomized controlled trials. These have shown no difference in outcomes, including rate of recurrence, time to resolution of inflammation, or final visual acuity, between the newer treatments and sulfadiazine with pyrimethamine. Atovaquone, an antimalarial drug, has not been tested in a controlled setting ocular toxoplasmosis but has shown some efficacy against toxoplasmosis encephalitis in AIDS patients.7Chirgwin 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; 34: 1243-1250Crossref PubMed Scopus (85) Google Scholar However, triple therapy remains the most commonly used regimen for treating ocular toxoplasmosis by uveitis specialists.8Holland G.N. Lewis K.G. An update on current practices in the management of ocular toxoplasmosis.Am J Ophthalmol. 2002; 134: 102-114Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar The role of oral steroids in the treatment of toxoplasmosis has not been studied in a randomized setting.9Jasper S. Vedula S.S. John S.S. Horo S. Sepah Y.J. Nguyen Q.D. Corticosteroids for ocular toxoplasmosis.Cochrane Database Syst Rev. 2013; : CD007417PubMed Google Scholar Soheilian et al.4Soheilian M. Sadoughi M.M. Ghajarnia M. et al.Prospective randomized trial of trimethoprim/sulfamethoxazole versus pyrimethamine and sulfadiazine in the treatment of ocular toxoplasmosis.Ophthalmology. 2005; 112: 1876-1882Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar studied TMP-SMX compared to pyrimethamine and sulfadiazine while Bosch-Driessen et al.5Bosch-Driessen L.H. Verbraak F.D. Suttorp-Schulten M.S. et al.A prospective, randomized trial of pyrimethamine and azithromycin vs pyrimethamine and sulfadiazine for the treatment of ocular toxoplasmosis.Am J Ophthalmol. 2002; 134: 34-40Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar examined pyrimethamine plus azithromycin versus pyrimethamine plus sulfadiazine. In these instances, oral steroids were commenced 3 days after starting antiparasitic treatment. Intravitreal dexamethasone, however, was administered at the same time as intravitreal clindamycin.6Soheilian 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: 134-141Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar Most uveitis specialists use oral prednisone in combination with antiparasitic therapies in the treatment of the disease.8Holland G.N. Lewis K.G. An update on current practices in the management of ocular toxoplasmosis.Am J Ophthalmol. 2002; 134: 102-114Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar However, there is little in the literature to support or refute the use of steroids in the treatment of toxoplasmosis, with 1 exception: giving systemic steroids without antiparasitic treatment is the only therapy that has ever been shown to negatively affect outcomes of toxoplasma retinochoroiditis and should not be undertaken.10Bosch-Driessen L.E. Berendschot T.T. Ongkosuwito J.V. Rothova A. Ocular toxoplasmosis: clinical features and prognosis of 154 patients.Ophthalmology. 2002; 109: 869-878Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar There is evidence to support that treatment of patients with recurrent ocular toxoplasmosis will experience a decrease in recurrence from long-term therapy. An open-label prospective randomized study from Brazil demonstrated a decrease in recurrence rate from 23% to 6% in patients treated with oral TMP-SMX three times a week over the course of 20 months.11Silveira C. Belfort Jr., R. Muccioli C. et al.The effect of long-term intermittent trimethoprim/sulfamethoxazole treatment on recurrences of toxoplasmic retinochoroiditis.Am J Ophthalmol. 2002; 134: 41-46Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar Data from the AIDS literature also support the use of TMP-SMX for prophylaxis against recurrence of toxoplasma encephalitis.12Bucher H.C. Griffith L. Guyatt G.H. Opravil M. Meta-analysis of prophylactic treatments against Pneumocystis carinii pneumonia and toxoplasma encephalitis in HIV-infected patients.J Acquir Immune Defic Syndr Hum Retrovirol. 1997; 15: 104-114Crossref PubMed Scopus (66) Google Scholar Pyrimethamine alone has been shown to be ineffective in prophylaxis against toxoplasma encephalitis in AIDS patients.13Leport C. Chêne G. Morlat P. et al.Pyrimethamine for primary prophylaxis of toxoplasmic encephalitis in patients with human immunodeficiency virus infection: a double-blind, randomized trial. ANRS 005-ACTG 154 Group Members. Agence Nationale de Recherche sur le SIDA. AIDS Clinical Trial Group.J Infect Dis. 1996; 173: 91-97Crossref PubMed Scopus (75) Google Scholar Differentiating prenatal from postnatal toxoplasmosis in an older child or adults is difficult except in the setting of clear signs of intrauterine infection present at birth, such as intracranial calcifications, hydrocephalus, and microcephaly.14Gilbert R.E. Stanford M.R. Is ocular toxoplasmosis caused by prenatal or postnatal infection?.Br J Ophthalmol. 2000; 84: 224-226Crossref PubMed Scopus (105) Google Scholar In terms of therapy for active retinochoroiditis in older children and adults, however, it makes no difference how the infection was acquired. It is also recommended that treatment is commenced in newborns and immunocompromised patients afflicted with the parasite. Although these drugs are all generally well tolerated, they are not without side effects and all have been linked to potentially life-threatening drug reactions. Pyrimethamine can cause bone-marrow suppression because of its disruption of folate metabolism, and requires monitoring of blood counts. Like sulfadiazine, TMP-SMX has also been shown to cause DRESS syndrome.15Husain Z. Reddy B.Y. Schwartz R.A. DRESS syndrome: Part I. Clinical perspectives.J Am Acad Dermatol. 2013; 68 (quiz 706-8): 693.e1-693.e14Abstract Full Text Full Text PDF PubMed Scopus (294) Google Scholar Both TMP-SMX and sulfadiazine carry a higher than normal risk of inducing Steven-Johnson syndrome and toxic epidermal necrolysis, but the absolute risk of developing either is extremely low.15Husain Z. Reddy B.Y. Schwartz R.A. DRESS syndrome: Part I. Clinical perspectives.J Am Acad Dermatol. 2013; 68 (quiz 706-8): 693.e1-693.e14Abstract Full Text Full Text PDF PubMed Scopus (294) Google Scholar Macrolide antibiotics have a modestly increased risk of Steven-Johnson syndrome and toxic epidermal necrolysis16Mockenhaupt M. The current understanding of Stevens-Johnson syndrome and toxic epidermal necrolysis.Expert Rev Clin Immunol. 2011; 7 (quiz 814-15): 803-813Crossref PubMed Scopus (214) Google Scholar but can cause cardiac arrhythmias and QT prolongation.17Guo D. Cai Y. Chai D. Liang B. Bai N. Wang R. The cardiotoxicity of macrolides: a systematic review.Pharmazie. 2010; 65: 631-640PubMed Google Scholar Oral (but not intravitreal) clindamycin has been implicated as a risk factor for Clostridium difficile colitis.18Thomas C. Stevenson M. Riley T.V. Antibiotics and hospital-acquired Clostridium difficile-associated diarrhoea: a systematic review.J Antimicrob Chemother. 2003; 51: 1339-1350Crossref PubMed Scopus (249) Google Scholar Even the short-term use of oral prednisone is not entirely without risk, as it has been linked to avascular necrosis, mood disruptions, and psychosis.19Richards R.N. Side effects of short-term oral corticosteroids.J Cutan Med Surg. 2008; 12: 77-81Crossref PubMed Scopus (43) Google Scholar Undertaking treatment with any medication carries the risk of potential side effects, even those that are extremely rare, such as DRESS syndrome. The occurrence of these can be mitigated by choosing a medication with the best safety profile for the condition and carefully considering the indications for treatment in every patient. The treating ophthalmologist should discuss the potential for these side effects with the patient before initiating therapy, and evidence of the discussion should be documented in the chart. Serious or life-threatening idiosyncratic drug reactions will unfortunately happen from time to time. Appropriate awareness of these reactions and surveillance by the treating ophthalmologist, as demonstrated by the authors in this article, is currently the clinician's best tool in preventing serious complications. DRESS syndrome in a child treated for toxoplasma retinochoroiditisJournal of American Association for Pediatric Ophthalmology and Strabismus {JAAPOS}Vol. 17Issue 5PreviewChildren treated for toxoplasma retinochoroiditis may experience a range of severe adverse drug responses. Drug reaction with eosinophilia and systemic symptoms syndrome is a life-threatening idiosyncratic drug reaction with a 10% mortality. We present a case of drug reaction with eosinophilia and systemic symptoms syndrome in a child on standard combination treatment with oral sulfadiazine, pyrimethamine, folinic acid, and steroids for toxoplasma retinochoroiditis. Early clinical recognition and appropriate treatment led to a complete recovery and no longterm sequelae. Full-Text PDF