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Ocular toxoplasmosis: the treatment dilemma
Ocular toxoplasmosis: the treatment dilemma Julie M. Schallhorn, MD, MS, and John Gonzales, MD usuf and colleaugues1 present a case of druginduced 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.2 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.3 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),4 intravitreal clindamycin with dexamethasone,5 and azithromycin with pyrimethamine6 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.7 However, triple therapy remains the most commonly used regimen for treating ocular toxoplasmosis by uveitis specialists.8 The role of oral steroids in the treatment of toxoplasmosis has not been studied in a randomized setting.9 Soheilian et al.4 studied TMP-SMX compared to pyrimethamine and sulfadiazine while Bosch-Driessen et al.5 examined pyrimethamine plus azithromycin versus pyrimethamine
Y
See accompanying report on page 521 Author affiliation: Francis I. Proctor Foundation, University of California, San Francisco, California Correspondence: John Gonzales, MD and Julie M. Schallhorn, MD, MS, 95 Kirkham Street, San Francisco, California 94122 (email: [email protected]). J AAPOS 2013;17:454-455. Copyright Ó 2013 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/$36.00 http://dx.doi.org/10.1016/j.jaapos.2013.08.001
454
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.6 Most uveitis specialists use oral prednisone in combination with antiparasitic therapies in the treatment of the disease.8 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.10 There is evidence to support that treatment of patients with recurrent ocular toxoplasmosis will experience a decrease in recurrence from long-term therapy. An openlabel 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.11 Data from the AIDS literature also support the use of TMP-SMX for prophylaxis against recurrence of toxoplasma encephalitis.12 Pyrimethamine alone has been shown to be ineffective in prophylaxis against toxoplasma encephalitis in AIDS patients.13 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.14 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.15 Both TMPSMX 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.15 Macrolide antibiotics have a modestly increased risk of Steven-Johnson syndrome and toxic epidermal necrolysis16 but can cause cardiac arrhythmias and QT prolongation.17 Oral (but not intravitreal) clindamycin has been implicated as a risk factor for Clostridium difficile colitis.18 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.19 Undertaking treatment with any medication carries the risk of potential side effects, even those that are extremely
Journal of AAPOS
Volume 17 Number 5 / October 2013 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.
Schallhorn and Gonzales
8.
9.
10.
11.
12.
References 1. Yusuf IH, Sahare P, Hildebrand GD. DRESS syndrome in a child treated for toxoplasma retinochoroiditis. J AAPOS 2013;5:521-3. 2. Montoya JG, Liesenfeld O. Toxoplasmosis. Lancet 2004;363: 1965-76. 3. Gilbert RE, See SE, Jones LV, Stanford MS. Antibiotics versus control for toxoplasma retinochoroiditis. Cochrane Database Syst Rev 2002;CD002218. 4. 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;112:1876-82. 5. 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;134:34-40. 6. 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;118:134-41. 7. 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
Journal of AAPOS
13.
14. 15.
16.
17. 18.
19.
455
syndrome: ACTG 237/ANRS 039 Study. AIDS Clinical Trials Group 237/Agence Nationale de Recherche sur le SIDA, Essai 039. Clin Infect Dis 2002;34:1243-50. Holland GN, Lewis KG. An update on current practices in the management of ocular toxoplasmosis. Am J Ophthalmol 2002;134: 102-14. Jasper S, Vedula SS, John SS, Horo S, Sepah YJ, Nguyen QD. Corticosteroids for ocular toxoplasmosis. Cochrane Database Syst Rev 2013;CD007417. Bosch-Driessen LE, Berendschot TT, Ongkosuwito JV, Rothova A. Ocular toxoplasmosis: clinical features and prognosis of 154 patients. Ophthalmology 2002;109:869-78. Silveira C, Belfort R Jr, Muccioli C, et al. The effect of long-term intermittent trimethoprim/sulfamethoxazole treatment on recurrences of toxoplasmic retinochoroiditis. Am J Ophthalmol 2002; 134:41-6. Bucher HC, Griffith L, Guyatt GH, 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;15:104-14. Leport C, Ch^ene 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;173:91-7. Gilbert RE, Stanford MR. Is ocular toxoplasmosis caused by prenatal or postnatal infection? Br J Ophthalmol 2000;84:224-6. Husain Z, Reddy BY, Schwartz RA. DRESS syndrome: Part I. Clinical perspectives. J Am Acad Dermatol 2013;68:693.e1-693.e14. quiz 706-8. Mockenhaupt M. The current understanding of Stevens-Johnson syndrome and toxic epidermal necrolysis. Expert Rev Clin Immunol 2011;7:803-13;quiz 814-15 Guo D, Cai Y, Chai D, Liang B, Bai N, Wang R. The cardiotoxicity of macrolides: a systematic review. Pharmazie 2010;65:631-40. Thomas C, Stevenson M, Riley TV. Antibiotics and hospital-acquired Clostridium difficile-associated diarrhoea: a systematic review. J Antimicrob Chemother 2003;51:1339-50. Richards RN. Side effects of short-term oral corticosteroids. J Cutan Med Surg 2008;12:77-81.
Y
See accompanying report on page 521 Author affiliation: Francis I. Proctor Foundation, University of California, San Francisco, California Correspondence: John Gonzales, MD and Julie M. Schallhorn, MD, MS, 95 Kirkham Street, San Francisco, California 94122 (email: [email protected]). J AAPOS 2013;17:454-455. Copyright Ó 2013 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/$36.00 http://dx.doi.org/10.1016/j.jaapos.2013.08.001
454
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.6 Most uveitis specialists use oral prednisone in combination with antiparasitic therapies in the treatment of the disease.8 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.10 There is evidence to support that treatment of patients with recurrent ocular toxoplasmosis will experience a decrease in recurrence from long-term therapy. An openlabel 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.11 Data from the AIDS literature also support the use of TMP-SMX for prophylaxis against recurrence of toxoplasma encephalitis.12 Pyrimethamine alone has been shown to be ineffective in prophylaxis against toxoplasma encephalitis in AIDS patients.13 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.14 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.15 Both TMPSMX 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.15 Macrolide antibiotics have a modestly increased risk of Steven-Johnson syndrome and toxic epidermal necrolysis16 but can cause cardiac arrhythmias and QT prolongation.17 Oral (but not intravitreal) clindamycin has been implicated as a risk factor for Clostridium difficile colitis.18 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.19 Undertaking treatment with any medication carries the risk of potential side effects, even those that are extremely
Journal of AAPOS
Volume 17 Number 5 / October 2013 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.
Schallhorn and Gonzales
8.
9.
10.
11.
12.
References 1. Yusuf IH, Sahare P, Hildebrand GD. DRESS syndrome in a child treated for toxoplasma retinochoroiditis. J AAPOS 2013;5:521-3. 2. Montoya JG, Liesenfeld O. Toxoplasmosis. Lancet 2004;363: 1965-76. 3. Gilbert RE, See SE, Jones LV, Stanford MS. Antibiotics versus control for toxoplasma retinochoroiditis. Cochrane Database Syst Rev 2002;CD002218. 4. 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;112:1876-82. 5. 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;134:34-40. 6. 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;118:134-41. 7. 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
Journal of AAPOS
13.
14. 15.
16.
17. 18.
19.
455
syndrome: ACTG 237/ANRS 039 Study. AIDS Clinical Trials Group 237/Agence Nationale de Recherche sur le SIDA, Essai 039. Clin Infect Dis 2002;34:1243-50. Holland GN, Lewis KG. An update on current practices in the management of ocular toxoplasmosis. Am J Ophthalmol 2002;134: 102-14. Jasper S, Vedula SS, John SS, Horo S, Sepah YJ, Nguyen QD. Corticosteroids for ocular toxoplasmosis. Cochrane Database Syst Rev 2013;CD007417. Bosch-Driessen LE, Berendschot TT, Ongkosuwito JV, Rothova A. Ocular toxoplasmosis: clinical features and prognosis of 154 patients. Ophthalmology 2002;109:869-78. Silveira C, Belfort R Jr, Muccioli C, et al. The effect of long-term intermittent trimethoprim/sulfamethoxazole treatment on recurrences of toxoplasmic retinochoroiditis. Am J Ophthalmol 2002; 134:41-6. Bucher HC, Griffith L, Guyatt GH, 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;15:104-14. Leport C, Ch^ene 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;173:91-7. Gilbert RE, Stanford MR. Is ocular toxoplasmosis caused by prenatal or postnatal infection? Br J Ophthalmol 2000;84:224-6. Husain Z, Reddy BY, Schwartz RA. DRESS syndrome: Part I. Clinical perspectives. J Am Acad Dermatol 2013;68:693.e1-693.e14. quiz 706-8. Mockenhaupt M. The current understanding of Stevens-Johnson syndrome and toxic epidermal necrolysis. Expert Rev Clin Immunol 2011;7:803-13;quiz 814-15 Guo D, Cai Y, Chai D, Liang B, Bai N, Wang R. The cardiotoxicity of macrolides: a systematic review. Pharmazie 2010;65:631-40. Thomas C, Stevenson M, Riley TV. Antibiotics and hospital-acquired Clostridium difficile-associated diarrhoea: a systematic review. J Antimicrob Chemother 2003;51:1339-50. Richards RN. Side effects of short-term oral corticosteroids. J Cutan Med Surg 2008;12:77-81.