Possible Hypersensitivity Reactions

Common Reactions
Isolated rash
  • Variable in appearance, may include erythema, pruritus, maculopapular, morbilliform or urticarial rash
  • Onset usually within the first three days of starting drug and resolve promptly after discontinuation
  • Fever suggests DRESS
Morbilliform rash with fever and systemic symptoms;
  • Rash, eosinophilia, systemic symptoms including fever, organ involvement
  • Onset usually 1-2 weeks after starting drug
  • Dapsone hypersensitivity "sulfone syndrome" is similar, with fever, rash, sometimes hepatitis, lymphadenopathy, and/or hemolytic anemia
IgE-mediated reaction (anaphylaxis)
  • Immediate onset pruritus, urticaria, angioedema, wheezing, hypotension (anaphylaxis)
  • Thought to be rare
  • Strongly associated with antimicrobial sulfonamides and dapsone (vs. non-antimicrobial sulfonamides which are not associated with increased risk)
    • Celecoxib may be independently associated with a higher incidence of SJS
Uncommon reactions
Serum Sickness
  • Occasionally caused by sulfonamide antimicrobials
  • Onset ~10 d - 2 wk after starting drug, with fever, rash (often urticarial), arthralgia, and lymphadenopathy
Hemolytic anemia
  • G6PD deficiency is a contraindication to treatment with sulfonamides
    • Sulfonamide antibiotics, dapsone, and probenecid are higher risk, non-antimicrobials are generally lower risk

Sulfonamide Cross-reactivity and Types

Sulfa cross-reactivity chart.png
sulfonamide chart.png

Sulfonamide nonantibiotics chart.png

Sulfasalazine cross-reactivity

  • Sulfasalazine is split in the GI tract into 5-aminosalyclic acid and sulfapyridine (which is a sulfanilamide). A patient with a sulfonamide allergy should avoid sulfasalzine, and patients who react to sulfasalazine should avoid antibacterial sulfonamides (sulfanilamides)

Protease-inhibitor cross-reactivity

  • Amprenavir and fosamprenavir are protease inhibitors used for HIV
  • They induce a high degree of rashes (19-29%) and desensitization protocols have been described
  • It is prudent to avoid these medications if there is a known allergy to a sulfanilamide
    • Note that neither clinical nor in-vitro data on cross-reactivity with other sulfanilamides is currently available

Testing (Pichler)

  • Pichler: skin and in-vitro testing of various kinds is not standardized but the specificity is good, which makes a positive result valuable
    • ID skin tests might be helpful in both immediate and nonimmediate reactions.
      • SMX (80 mg/mL) has been shown to be nonirritating
    • Patch tests (10% in dimethyl sulfoxide or petrolatum) are used in Europe in patients with nonimmediate reactions however its sensitivity seems to be lower than that of late (24 hours) reading of ID tests


  • Avoidance
  • In nonimmediate mild rashes (without mucosal or other organ involvement) to SMX, treatment can be continued ("treating through") or readministered after desensitization; these approaches are most often used for HIV patients and requires monitoring for systemic adverse effects (fever, eosinophilia, lymphadenopathy, hepatitis)

  • "Desensitization" via graded administration - in a study of 72 non-HIV adults with mild adverse reactions to TMP-SMX (rash, hives, angioedema, nausea/vomiting, malaise), overall success rate was 90% using the following outpatient protocols:

    Bactrim 1 day graded dose protocol.png

    Bactrim multiday graded dose protocol.png