Sulphonamide Antibiotic Allergy

Sulphonamide antibiotic allergy is a hypersensitivity reaction to sulphonamide antimicrobials such as sulfamethoxazole (in co-trimoxazole) and sulfadiazine. Reactions are mostly delayed rashes, but severe reactions occur.

Pathophysiology. Reactive metabolites (hydroxylamine, nitroso derivatives) bind proteins and, in susceptible patients, cause T cell mediated reactions. Immediate IgE-mediated reactions are rare.

Allergy is higher in patients with HIV infection, where reactions occur in a large minority. Slow acetylation and glutathione deficiency are risk factors.

The cross-reactive feature is the N4 arylamine group, which non-antibiotic sulphonamides (furosemide, thiazides, celecoxib, sumatriptan, sulphonylureas) lack, so cross-reactivity between antibiotic and non-antibiotic sulphonamides is not supported.

• Delayed maculopapular rash 7 to 14 days after starting
• Fever and drug induced liver injury
• DRESS: rash, fever, eosinophilia, hepatitis, lymphadenopathy
• Stevens-Johnson syndrome and toxic epidermal necrolysis
• Urticaria or anaphylaxis (rare)
• Cytopenias, interstitial nephritis, aseptic meningitis
• Photosensitivity and fixed drug eruption

• History: drug, time to onset, features, and severity of the reaction, with an assessment of any systemic features.
• No reliable test: skin tests and specific IgE are unreliable for sulphonamide antibiotics.
• Blood tests during a reaction: full blood count, eosinophils, liver enzymes, creatinine.
• Graded challenge: for benign delayed rash only, in a monitored setting, when the drug is needed.
• Do not challenge after severe cutaneous reactions, DRESS or organ injury.
• HIV test if status is not known.

Differential diagnosis.

• Viral exanthem and infection related rash
• Reaction to another co-prescribed drug (anticonvulsants, allopurinol, penicillins)
• Allergy to non-antibiotic sulphonamides (unrelated)
• Lupus flare
• Serum sickness like reaction
• Drug fever

• Stop the drug at the first sign of rash, fever or mucosal involvement.
• Severe cutaneous reactions: stop the drug, give supportive and specialist care, and avoid all sulphonamide antibiotics permanently.
• Benign delayed rash: if the drug is needed (for Pneumocystis prophylaxis or toxoplasmosis), a graded introduction (stepwise escalation over about 6 days from a very small dose to the full dose) in a monitored setting may be used. Co-trimoxazole 960 mg three times weekly is the usual prophylaxis dose in adults.
• Alternatives for Pneumocystis prophylaxis: atovaquone 1500 mg orally once daily with food, dapsone 100 mg orally once daily (check G6PD first), or inhaled pentamidine 300 mg every 4 weeks.
• Alternatives for urinary infection: nitrofurantoin or trimethoprim alone, depending on culture.
• Non-antibiotic sulphonamides (furosemide, thiazides, celecoxib, sulphonylureas, sumatriptan) are not contraindicated by sulphonamide antibiotic allergy.
• Anaphylaxis: adrenaline 0.5 mg intramuscularly (children 0.01 mg/kg, maximum 0.5 mg) into the anterolateral thigh, repeated after 5 minutes if no improvement, plus oxygen and intravenous fluids, and observation for at least 6 hours.
• Medical alert for confirmed allergy.

Special groups.

• HIV infection: reactions are more frequent, so graded introduction is often tried when co-trimoxazole prophylaxis is needed.

Monitoring. Daily review during graded introduction. Full blood count, liver enzymes and creatinine at day 7 and day 14 of any course. Review immediately for rash, fever or mucosal symptoms.

Referral and escalation. Refer to a drug allergy service or infectious diseases for patients needing co-trimoxazole after a prior reaction. Emergency for blistering rash, mucosal involvement or airway swelling.