Sulfadiazine

Sulfadiazine is an oral sulphonamide used mainly with pyrimethamine for toxoplasmosis, and for Nocardia infection and rheumatic fever prophylaxis in penicillin allergy. Systemic use for common bacterial infection has been replaced by safer drugs. Topical silver sulfadiazine is a different preparation for burns.

Classification. Sulphonamide.

Mechanism. Competes with para-aminobenzoic acid and inhibits dihydropteroate synthase, blocking folate synthesis; bacteriostatic. With pyrimethamine the combination is synergistic against Toxoplasma.

Spectrum. Toxoplasma gondii (with pyrimethamine), Nocardia, Streptococcus pyogenes, and some Enterobacterales, Haemophilus and Neisseria (resistance is common).

Pharmacokinetics. Well absorbed orally. Half-life 10 hours. Protein binding about 50%. Good CSF penetration. Acetylated in the liver and excreted by the kidneys; poorly soluble, so crystals form in acid urine.

Maximum 8 g daily.

Adults, oral.

• Toxoplasmosis, treatment (encephalitis, chorioretinitis, immunocompromised): 1 g every 6 hours if under 60 kg, or 1.5 g every 6 hours if 60 kg or more.
• Combine with pyrimethamine (200 mg loading dose, then 50 mg daily if under 60 kg or 75 mg daily if 60 kg or more) and folinic acid 10 to 25 mg daily, for at least 6 weeks.
• Toxoplasmosis, secondary prophylaxis: 500 to 1000 mg every 6 hours with pyrimethamine 25 to 50 mg daily and folinic acid 10 to 25 mg daily, until CD4 recovery.
• Nocardia infection (alternative): 4 to 8 g daily in 4 divided doses for 6 to 12 months, depending on site.
• Rheumatic fever prophylaxis in penicillin allergy: 1 g once daily if over 30 kg, 500 mg once daily if 30 kg or less.

Children. Congenital toxoplasmosis 50 mg/kg every 12 hours with pyrimethamine and folinic acid for 12 months. Older children with toxoplasmosis 25 to 50 mg/kg every 6 hours (maximum 1.5 g a dose). Not for infants under 2 months except in congenital toxoplasmosis.

Alternatives. Clindamycin with pyrimethamine, trimethoprim sulfamethoxazole, atovaquone.

Contraindications. Sulphonamide hypersensitivity; porphyria; infants under 2 months (except congenital toxoplasmosis); severe renal or hepatic failure.

Adverse effects. Nausea, vomiting, rash, fever, headache. Serious: Stevens-Johnson syndrome and toxic epidermal necrolysis, crystalluria and kidney stones, acute kidney injury, marrow suppression (neutropenia, thrombocytopenia, folate deficiency), haemolysis in glucose 6-phosphate dehydrogenase deficiency, hepatitis, drug fever, serum sickness.

Interactions. Warfarin (INR rise), phenytoin, methotrexate, sulphonylureas (hypoglycaemia), ciclosporin; other marrow-suppressing drugs such as zidovudine; methenamine (crystalluria).

Common prescribing errors. Omitting folinic acid with pyrimethamine, inadequate fluid intake, missing G6PD deficiency, and treating a rash as minor.

Special groups. - Pregnancy: used for toxoplasmosis when benefit outweighs risk; avoid near term (neonatal kernicterus).

Breastfeeding: avoid in jaundiced, premature or G6PD-deficient infants; otherwise acceptable. - Older adults: higher risk of kidney and marrow toxicity. - Kidney impairment: creatinine clearance 10 to 50 mL/min give the usual dose every 8 to 12 hours; under 10 mL/min every 12 to 24 hours, with levels if available. - Liver impairment: avoid in severe disease. - Region: used in HIV programmes where toxoplasma encephalitis is a frequent cause of focal brain lesions; availability is variable.

Administration. Oral with a full glass of water. Aim for 2 to 3 litres of fluid daily and, if crystalluria occurs, alkalinise the urine. Divide the daily dose evenly.

Baseline and monitoring. - Baseline: creatinine, full blood count, liver tests, G6PD status where available, pregnancy status. - During treatment: full blood count and creatinine twice weekly at first then weekly; urinalysis for crystals; ask about rash.

Stop rules. Stop for rash with fever or mucosal involvement, jaundice, severe cytopenia, haematuria or acute kidney injury.

Referral and escalation. Refer for toxoplasma encephalitis, severe cutaneous reaction, marrow suppression and kidney injury.