Second Meeting of the Subcommittee of the Expert Committee on the Selection and Use of Essential Medicines Geneva, 29 September to 3 October 2008

Sulfadiazine in children Sulfadiazine - tablet 500 mg and injection 250mg/4ml - is listed in the WHO Model List of Essential Medicines for Children in the complementary list as ‘other antibacterials’. This review is on uses, safety, efficacy and dosage of sulfadiazine in children.

Summary Sufadiazine is recommended as the preferred drug for the treatment of different forms of toxoplasmosis, a protozoal infection. Under ‘6.5.4 anti pneumocystis and anti toxoplasmosis medicines’ of EML only sulfamethoxazole-trimethoprim is listed. Sulfadiazine is one of the options for treating nocardiosis, an infrequent bacterial infection in children. Cotrimoxazole is preferred by some. Although sulfadiazine was used for many indications including UTI, meningococcal meningitis and prevention of rheumatic fever, it is currently not recommended for these conditions. This drug is poorly soluble in urine and causes crystalluria more often than other sulfonamides. Recommended route of administration is oral. It is costlier compared to cotrimoxazole. Injectable formulations may not be available internationally. BNF C (2006) recommends sufadiazine, orally, only for toxoplasmosis

Recommendations Shift to section 6.5.4 of EML C Delete injection

Review Sulfonamides are the earliest group of antibacterial medicines to be used widely for treatment. However, indications for their use decreased considerably because of increasing bacterial resistance to sulfonamides and because newer more effective drugs became available.

1 Pharmacokinetics [1, 2] Approximately 70% to 100% of an oral dose is absorbed rapidly from the GI tract. Peak plasma levels are achieved in 3 to 6 hours. Following a single dose of 3 g, peak concentration is approximately 50 µg/ml. Wide variations in blood levels may occur with identical doses. In a group of infants receiving 50-100mg/day of sulfadiazine for congenital toxoplasmosis, plasma concentrations varied from 60-86 µg/ml [3]. Concentrations of 50-150 µg/ml are considered therapeutic for most infections and 120-150 µg/ml optimal for serious infections. Blood concentrations should generally not exceed 200µg/ml. About 50% of the drug is bound to plasma protein. Sulfadiazine is excreted primarily in urine, partly unchanged. Administration of alkali accelerates renal clearance. The elimination half-life is roughly 17 hours and is significantly longer in those with renal damage. It diffuses well into tissues and body fluids including CSF, pleural, peritoneal, synovial and ocular fluids and may reach 50% to 80% of blood levels. Spectrum of activity Sulfadiazine exhibits in vitro inhibitory activity against several aerobic gram-positive and gram-negative bacteria, Nocardia sp., Actinomyces sp., Chlamydia trachomatis and protozoa Plasmodium falciparum, and Toxoplasma gondii. Sulfadiazine also is active against, Paracoccidioides brasiliensis. However resistance to sulfonamides is widespread and increasing among bacteria like streptococci, staphylococci, Enterobacteriaceae, and Neisseria sp. The cost of one 500mg tablet varies from US $ 0.0135 to 1.45 (International Drug Price Indicator Guide). Injection is not listed. Cost of cotrimoxazole tablet (200+40 mg) is US$ 0.0074

Uses Sulfadiazine is administered orally. Adequate fluid intake to avoid crystallopathy has to be ensured. Dose needs to be adjusted in those with renal impairment

Toxoplasmosis Toxoplasmosis, a protozoal infection may be congenital or acquired later in life. Congenital toxoplasmosis may be asymptomatic, mild or have neurological and ocular manifestations. Acquired toxoplasmosis in the immunocompetent host, is most often

2 (70-90%) asymptomatic. In the immunocompromised, encephalitis (TE) is the most common manifestation [4]. There is paucity of data on the prevalence of clinical toxoplasmosis in communities. It is an important cause of posterior uveitis in immunocompetent patients [4]. In Brazil, toxoplasma retinochoroidits was seen in 20% of children with visual impairment [5]. In a survey done in Trinidad, 0.4% of 504 cord blood samples had IgM toxoplasma antibodies, suggesting presence of disease [6]. In the pre antiretroviral therapy era, the 12-month incidence of TE was approximately 33% in patients with advanced immunosuppression, seropositive for T. gondii (approx 15% in the US, 50%--75% in certain European countries) and not receiving prophylaxis. The incidence has decreased substantially since then [7]

Toxoplasma Encephalitis: A Cochrane review (2006) on therapy for TE in adult patients with AIDS identified three studies – two comparing sulfadiazine + pyrimethamine with clindamycin + pyrimethamine and the third comparing sulfadiazine + pyrimethamine with cotrimoxzole. There were no significant differences between regimes in clinical cure rates [8]. Compared to clindamycin, sulfadiazine had better results although not significant. Another trial (2007) on 43 patients also showed sulfadiazine containing regime and co trimoxazole to be comparable[9]. However, a more recent clinical trial (2008) has concluded that sulfadiazine along with pyrimathamine and folinic acid is the best option although there was no difference in failure rates between this regime and cotrimoxazole, both given for 6 wks [10]. Pyrimethamine, sulfadiazine and leucovorin is recommended in guidelines as the preferred therapy for TE [11, 12]. The recommended dose in children and infants > 2 months is 120—200 mg/kg/day (max 6gms) orally in four divided doses for 6wks. Loading of 75mg/kg is recommended by some[4, 12, 13]

Congenital toxoplasmosis: Pyrimethamine, sulfadiazine and folinic acid is the recommended treatment for neonates also [4, 12]. One hundred and thirty two children with congenital toxoplasmosis, treated during the first of year of life with sulfadiazine, pyrimethamine and leucovorin had lesser chance of developing new chorio retinal lesions on long term follow up [14]. Another long term follow up study (Mean age 10.5 yrs) also showed that treatment of babies with congenital toxoplasmosis with sulfadiazine and pyrimethamine for the first year of life can

3 considerably reduce unfavourable out comes [15]. Other studies also support this finding [16]. Recommendation is 100 mg/kg/day orally in 2 or 4 divided doses for 12 months [4, 12].

Active ocular toxoplasmosis: Both sulfadiazine containing regime and cotrimoxazole preformed equally well in one RCT where all 59 patients improved equally well [17].

Sulfadiazine is therefore recommended for all forms of toxoplasmosis, in combination with pyrimethamine and folinic acid. There is some indication that in vitro resistance may be developing to this drug [18].

For secondary prophylaxis after treatment of acute TE in HIV-infected children and infants, CDC recommends 85-120 mg/kg/day orally in 2 - 4 divided doses along with pyrimethamine and leucovorin [19]. Australian Medicines Handbook also recommends for this indication.

Nocardiosis Nocardia spps are susceptible to sulfonamides in vitro and are recommended as first line drugs [20]. In the US 500 to 1000 new cases occur per year and about 15% have HIV infection also [21]. Nocardiosis occurs as opportunistic infection in other conditions with immunosuppression also [22]. About 80% of those infected present as invasive pulmonary disease while 20% present as cellulites [21]. Keratitis and mycetoma are also manifestations of nocardiosis. Data on the magnitude of this infection in children is scanty. Case reports of different manifestations in children exist. In a case series, 13/15 mycetomas in children were due to nocardia spp [23] There is no clinical data to support choice of therapy. Sulfadiazine or cotromoxazole is recommended [1, 20]. Cotrimoxazole is considered better by some authorities and judging from case reports, it is most often used for nocardiosis. It is reported as useful in a case series [24]. All isolates were susceptible in another study [25]. Treatment for cellulites is for 3-12 months[26] and that for pulmonary infection 6-12 months [20]. Sulfadiazine dosage recommended for adults is 6 to 8 g daily. A second antibiotic in addition to sulfonamide is recommended. Australian Medicines Handbook recommends sulfadiazine for this indication as well, but has only adult dosage.

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Other infections Sulfadiazine is rarely used to treat other infections like UTI due to susceptible organisms. They are no longer recommended for empirical therapy of UTI, meningococcal meningitis or shigellosis because of resistance [1]. They are no longer used for rheumatic fever prophylaxis. It may be used for the treatment of paracoccidioidomycosis Adverse events [1, 2] Numerous adverse reactions to sulfadiazine have been reported and about 5% of individuals develop adverse ractions[1]. Six out of 48 infants developed neutropenia and one had elevated bilirubin in a case series. No other adverse events were noted [3] Crystalluria - Compared with many newer sulfonamides, sulfadiazine is less soluble and more likely to crystallize in concentrated acidic urine, especially in dehydrated patients and in those with impaired renal function. Crystallopathy and acute renal failure can develop [27]. Adequate fluid intake can help to minimize crystalluria and the subsequent development of renal failure. Blood dyscrasias- Agranulocytosis can occur in 0.01% patients on sulfadiazine. Aplastic anemia is rare, but more frequent in patients with AIDS. Acute hemolytic anemia is more likely to occur in individuals with glucose-6-phosphate dehydrogenase deficiency, but is less frequent with sulfadiazine (0.05%). Thrombocytopenia and leukopenia can also occur. Complete blood counts should be monitored and the drug discontinued if abnormalities occur. A serious, but infrequent adverse effect of sulfadiazine is methemoglobinemia. Hypersensitivity- A variety of skin manifestations like rash, erythema multiforme, toxic epidermal necrolysis, Steven Johnson syndrome etc can occur. Hepatitis, and anaphylactoid reactions are reported. The overall incidence of allergic reactions to sulfadiazine may be higher in HIV-infected patients than in non-HIV-infected individuals Gastrointestinal adverse effects reported with sulfadiazine include abdominal pain, anorexia, diarrhea, nausea/vomiting, pancreatitis, and stomatitis- Kernicterus - The administration of sulfonamides to newborn infants, especially if premature, can lead to the displacement of bilirubin from plasma albumin causing kernicterus. Reports of this complication are extremely rare.

5 Drug interactions especially with anticonvulsants and anticoagulants can occur. Drug fever has been reported with sulfadiazine

References 1. Goodman & Gilman's The Pharmacological Basis of Therapeutics, 11th Edition, ed. L.L. Brunton, et al. 2006. 2. Sulfadiazine. Gold Standard Inc, 2007. 3. Schmidt, D.R., et al., Treatment of infants with congenital toxoplasmosis: tolerability and plasma concentrations of sulfadiazine and pyrimethamine. Eur J Pediatr, 2006. 165(1): p. 19-25. 4. Bonfioli, A.A. and F. Orefice, Toxoplasmosis. Semin Ophthalmol, 2005. 20(3): p. 129-41. 5. Haddad, M.A., et al., Causes of visual impairment in children: a study of 3,210 cases. J Pediatr Ophthalmol Strabismus, 2007. 44(4): p. 232-40. 6. Adesiyun, A.A., et al., Congenital toxoplasmosis in two health institutions in Trinidad. West Indian Med J, 2007. 56(2): p. 166-70. 7. MMWR, Treating Opportunistic Infections Among HIV-Infected Adults and Adolescents Recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association/Infectious Diseases Society of America. 2004. 53 (RR 15); 1-112. 8. Dedicoat, M. and N. Livesley, Management of toxoplasmic encephalitis in HIV-infected adults (with an emphasis on resource-poor settings). Cochrane Database Syst Rev, 2006. 3: p. CD005420. 9. Arens, J., 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): p. 956-8. 10. Kongsaengdao, S., et al., Randomized controlled trial of pyrimethamine plus sulfadiazine versus trimethoprim plus sulfamethoxazole for treatment of toxoplasmic encephalitis in AIDS patients. J Int Assoc Physicians AIDS Care (Chic Ill), 2008. 7(1): p. 11-6. 11. Infectious complications associated with HIV infection: parasitic infections. New York State Department of Health. Infectious complications associated with HIV infection: parasitic infections. New York (NY), 2006. 12. Mofenson L.M, et al., Treating opportunistic infections among HIV-exposed and infected children: recommendations from CDC, the National Institutes of Health, and the Infectious Diseases Society of America. MMWR 53(RR-14), 2004: p. 1-92. 13. Neurologic complications in HIV-infected children and adolescents. New York State Department of Health. Neurologic complications in HIV-infected children and adolescents. New York (NY), 2003. 14. Phan, L., et al., Longitudinal study of new eye lesions in treated congenital toxoplasmosis. Ophthalmology, 2008. 115(3): p. 553-559 e8. 15. McLeod, R., et al., Outcome of treatment for congenital toxoplasmosis, 1981- 2004: the National Collaborative Chicago-Based, Congenital Toxoplasmosis Study. Clin Infect Dis, 2006. 42(10): p. 1383-94. 16. Galanakis, E., et al., Outcome of toxoplasmosis acquired during pregnancy following treatment in both pregnancy and early infancy. Fetal Diagn Ther, 2007. 22(6): p. 444-8.

6 17. Soheilian, M., et al., Prospective randomized trial of trimethoprim/sulfamethoxazole versus pyrimethamine and sulfadiazine in the treatment of ocular toxoplasmosis. Ophthalmology, 2005. 112(11): p. 1876- 82. 18. Meneceur, P., et al., Toxoplasma gondii: In Vitro Susceptibility of Various Genotypic Strains to Pyrimethamine, Sulfadiazine and Atovaquone. Antimicrob Agents Chemother, 2008. 19. MMWR, Guidelines for Preventing Opportunistic Infections Among HIV- Infected Persons Recommendations of the U.S. Public Health Service and the Infectious Diseases Society of America. 2002. 51(RR08);1-46. 20. Filice, G.A., Nocardiosis. Harrisons Internal Medicine (On line), 2005. 21. CDC, Nocardiosis. Disease listing. 22. Pintado, V., et al., Infection with Nocardia species: clinical spectrum of disease and species distribution in Madrid, Spain, 1978-2001. Infection, 2002. 30(6): p. 338-40. 23. Bonifaz, A., et al., Mycetoma in children: experience with 15 cases. Pediatr Infect Dis J, 2007. 26(1): p. 50-2. 24. Shivaprakash, M.R., et al., Nocardiosis in a tertiary care hospital in North India and review of patients reported from India. Mycopathologia, 2007. 163(5): p. 267-74. 25. Munoz, J., et al., Clinical and microbiological features of nocardiosis 1997- 2003. J Med Microbiol, 2007. 56(Pt 4): p. 545-50. 26. Stevens DL, et al., Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis, 2005(41): p. 1373-406. 27. Yarlagadda, S.G. and M.A. Perazella, Drug-induced crystal nephropathy: an update. Expert Opin Drug Saf, 2008. 7(2): p. 147-58.

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