Sulfonamides

Sulphonamides are synthetic bacteriostatic antimicrobials and the first systemic antibacterials. Their use alone is now limited to a few indications (toxoplasmosis, nocardiosis, topical burns care and malaria chemoprevention combinations), because resistance is widespread. Their main role is in combination with trimethoprim or pyrimethamine.

Mechanism. Structural analogues of para-aminobenzoic acid that compete for dihydropteroate synthase, blocking folate synthesis. Human cells use dietary folate and are not affected, but bacteria and protozoa that synthesise folate are. Sequential blockade with a dihydrofolate reductase inhibitor (trimethoprim, pyrimethamine) is synergistic and bactericidal.

Pharmacokinetics. Well absorbed orally; widely distributed including CSF; acetylation in the liver (slow acetylators are at higher risk of toxicity); renal elimination of drug and acetylated metabolites, which are poorly soluble in acid urine. Half-lives: sulfadiazine about 10 hours, sulfamethoxazole 10 hours, sulfadoxine 4 to 8 days.

Resistance. Plasmid-borne sul1, sul2 and sul3 genes, and chromosomal dihydropteroate synthase mutations. In malaria, dhfr and dhps mutations reduce sulfadoxine-pyrimethamine efficacy.

• Sulfadiazine: oral, used with pyrimethamine for toxoplasmosis; rheumatic fever prophylaxis in penicillin allergy; silver sulfadiazine topical for burns.
• Sulfamethoxazole: given with trimethoprim (co-trimoxazole).
• Sulfadoxine: long-acting, combined with pyrimethamine for malaria chemoprevention.
• Sulfacetamide: ophthalmic and topical.
• Sulfasalazine: an aminosalicylate prodrug used for inflammatory bowel disease and arthritis; sulphonamide-related reactions apply.

Adult regimens (normal renal function).

• Toxoplasmosis (treatment): sulfadiazine 1 g (under 60 kg) or 1.5 g (60 kg or more) orally every 6 hours with pyrimethamine (200 mg loading, then 50 to 75 mg daily) and folinic acid 10 to 25 mg daily, for at least 6 weeks; co-trimoxazole is an alternative.
• Rheumatic fever secondary prevention in penicillin allergy: sulfadiazine 1 g daily (500 mg daily if under 27 kg).
• Nocardiosis: high-dose sulfamethoxazole as co-trimoxazole, or sulfadiazine 4 to 8 g daily in divided doses, usually with a second agent in severe disease.
• Burns: silver sulfadiazine 1 percent cream once or twice daily to the wound; avoided in pregnancy near term, neonates, and G6PD deficiency (haemolysis).
• Malaria chemoprevention in pregnancy: sulfadoxine-pyrimethamine as a single dose of three tablets (500 mg/25 mg each), given at each scheduled antenatal visit from the second trimester, at least 4 weeks apart. Efficacy is lowered where dhps resistance mutations are common, but the regimen remains used in much of East Africa.

Selection. Reserve single-agent sulphonamides for toxoplasmosis, nocardiosis, burns and malaria chemoprevention. Maintain fluid intake of at least 2 to 3 litres daily to prevent crystalluria.

Contraindications. Hypersensitivity; infants under 2 months (kernicterus) except toxoplasmosis and PCP under specialist care; late pregnancy; porphyria; severe hepatic or renal impairment.

Serious effects. Rash, Stevens-Johnson syndrome and toxic epidermal necrolysis; DRESS; haemolysis in G6PD deficiency; methaemoglobinaemia; agranulocytosis and aplastic anaemia; crystalluria and obstructive nephropathy; hepatitis; hyperkalaemia with trimethoprim; aseptic meningitis. Rash is more frequent in HIV infection.

Interactions. Warfarin, sulphonylureas (hypoglycaemia), phenytoin, methotrexate, ciclosporin, dapsone. Cross-reactivity with non-antibiotic sulphonamides (thiazides, loop diuretics, sulphonylureas, celecoxib) is low and generally not a reason to withhold them.

Monitoring. Full blood count, renal function, liver tests and urinalysis during prolonged treatment; G6PD status before dapsone-like exposure when possible; stop at first rash.

Special groups. Pregnancy: avoided in the third trimester; folate antagonism in the first trimester. Breastfeeding: avoided for infants under 2 months and in G6PD deficiency. Renal impairment: reduce dose and keep hydration. Children over 2 months: weight-based dosing.