Risk of Stevens-Johnson Syndrome with Trimethoprim-Sulfamethoxazole (Bactrim)
Stevens-Johnson syndrome (SJS) is a rare but potentially fatal adverse reaction to trimethoprim-sulfamethoxazole, occurring in approximately 1 in 200,000 courses of therapy, with the FDA issuing a black box warning specifically highlighting this risk. 1, 2
Quantified Risk Data
The absolute risk of SJS with trimethoprim-sulfamethoxazole is extremely low but well-documented:
- Fatal reactions occur in less than 1 in 100,000 children treated 2
- SJS and exfoliative dermatitis occur in approximately 1 in 200,000 courses of therapy 2
- Trimethoprim-sulfamethoxazole is classified as a "high risk" medication for inducing SJS/TEN alongside allopurinol, carbamazepine, phenytoin, and oxicam NSAIDs 3, 4
FDA Black Box Warning
The FDA drug label carries a black box warning stating: "FATALITIES ASSOCIATED WITH THE ADMINISTRATION OF SULFONAMIDES, ALTHOUGH RARE, HAVE OCCURRED DUE TO SEVERE REACTIONS, INCLUDING STEVENS-JOHNSON SYNDROME, TOXIC EPIDERMAL NECROLYSIS" 1. The label explicitly mandates that sulfonamide-containing products should be discontinued at the first appearance of skin rash or any sign of adverse reaction, as a skin rash may progress to more severe reactions including SJS 1.
Population-Specific Risk Variations
HIV-Infected Patients
- Adverse reactions to trimethoprim-sulfamethoxazole are significantly more frequent and severe in HIV-infected patients compared to the general population 5
- In HIV-infected adults, 40-65% experience adverse reactions to trimethoprim-sulfamethoxazole, occasionally requiring drug discontinuation 2
- In contrast, only 15% of HIV-infected children experience adverse reactions, with 82% being cutaneous (maculopapular or urticarial rash) 2
Pediatric Patients
- Mild cutaneous reactions (erythematous maculopapular rash) occur in 16% of children with leukemia receiving trimethoprim-sulfamethoxazole three times weekly for prophylaxis 2
- The lower rate of serious reactions in children compared to adults makes trimethoprim-sulfamethoxazole the recommended first-line agent for PCP prophylaxis in HIV-infected children over 1 month of age 2
Clinical Recognition and Timing
Drug-induced SJS typically occurs 5-28 days following drug initiation, with the highest risk period being the first month of therapy 6. Early warning signs that should prompt immediate drug discontinuation include 1:
- Skin rash of any type
- Sore throat
- Fever
- Arthralgia
- Pallor, purpura, or jaundice
- Mucocutaneous tenderness
- Hemorrhagic erosions
Critical Management Principle
The single most important intervention is immediate discontinuation of trimethoprim-sulfamethoxazole at the first sign of rash or hypersensitivity 1, 2. If life-threatening toxicity occurs (anaphylaxis, Stevens-Johnson syndrome, or hypotension), the drug should be permanently discontinued 2. For less severe reactions, the drug should be temporarily discontinued and may be cautiously retried within 2 weeks, though desensitization protocols exist for patients who require the medication 2.
Comparative Context
While trimethoprim-sulfamethoxazole carries a well-established risk of SJS, it remains lower than some other high-risk medications. The British Association of Dermatologists notes that mortality from SJS/TEN appears lower in children than adults, making long-term sequelae management particularly important in pediatric survivors 2.