Possible Hypersensitivity Reactions

Common Reactions	Note
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; DRESS	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
SJS and TEN	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

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)

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

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: