Current Allergy and Asthma Reports

, Volume 2, Issue 1, pp 16–25 | Cite as

Allergic adverse reactions to sulfonamides

  • Geneviève Choquet-Kastylevsky
  • Thierry Vial
  • Jacques Descotes


Antimicrobial sulfonamides were the first antimicrobial agents used effectively to treat infectious diseases. However, because they may cause severe adverse drug reactions (ADRs) and because more effective agents have since been developed, sulfonamides now are used for only a few indications in specific groups, such as AIDS patients. Skin reactions, from benign rash to potentially lethal toxidermias, are the most frequent ADRs to sulfonamides. Other major ADRs include acute liver injury, pulmonary reactions, and blood dyscrasias. Although the mechanisms involved have not been fully elucidated, reactive metabolites appear to play a pivotal role. The hydroxylamine and nitroso metabolites of sulfamethoxazole, the most frequently used sulfonamide today, can bind covalently to proteins because of their chemical reactivity, resulting in the induction of specific adverse immune responses. Therefore, changes in the activity of metabolic and detoxification pathways are associated with a greater risk for developing allergic reactions to sulfonamides. Allergies to sulfonamides, particularly sulfamethoxazole (often used in combination with trimethoprim as co-trimoxazole), are more frequent in AIDS patients, but the reason for this increased risk is not fully understood. No valid tools are available to predict which patients have a greater risk for developing allergies to sulfonamides. Diagnosis is essential to avoid a possible evolution toward severe reactions and readministration of the offending drug. In patients who absolutely require further treatment, successful desensitization may be achieved.


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References and Recommended Reading

  1. 1.
    Cribb A, Miller M, Leeder JS, et al.: Reactions of the nitroso and hydroxylamine metabolites of sulfamethoxazole with reduced glutathione. Implications for idiosyncratic toxicity. Drug Metab Dispos 1991, 19:900–906.PubMedGoogle Scholar
  2. 2.
    Hertl M, Merk HF: Lymphocyte activation in cutaneous drug reactions. J Invest Dermatol 1995, 105:95S-98S.PubMedCrossRefGoogle Scholar
  3. 3.
    Kalish RS, LaPorte A, Wood JA, Johnson KL: Sulfonamidereactive lymphocytes detected at very low frequency in the peripheral blood of patients with drug-induced eruptions. J Allergy Clin Immunol 1994, 94:465–472.PubMedCrossRefGoogle Scholar
  4. 4.
    Rieder MJ, Sisson E, Bird IA, Almawi WY: Suppression of Tlymphocyte proliferation by sulphonamide hydroxylamines. Int J Immunopharmacol 1992, 14:1175–1180.PubMedCrossRefGoogle Scholar
  5. 5.
    Wolkenstein P, Charue D, Laurent P, et al.: Metabolic predisposition to cutaneous adverse drug reactions: role in toxic epidermal necrolysis caused by sulfonamides and anticonvulsants. Arch Dermatol 1995, 131:544–551.PubMedCrossRefGoogle Scholar
  6. 6.
    Lawson DH, Kick H: Adverse reactions to co-trimoxazole in hospitalised medical patients. Am J Med Sci 1978, 275:53–57.PubMedCrossRefGoogle Scholar
  7. 7.
    Björkman A, Phillips-Howard PA: Adverse reactions to sulfa drugs: implications for malaria chemotherapy. Bull WHO 1991, 69:297–304.PubMedGoogle Scholar
  8. 8.
    Van der Klauw MM, Stricker BHC, Herings RMC, et al.: A population based case-cohort study of drug-induced anaphylaxis. Br J Clin Pharmacol 1993, 35:400–408.PubMedGoogle Scholar
  9. 9.
    Breathnach SM, Hintner H: Adverse Drug Reactions and the Skin. Oxford: Blackwell Science; 1992:394.Google Scholar
  10. 10.
    Roujeau JC, Stern RS: Severe adverse cutaneous reactions to drugs. N Engl J Med 1994, 333:1272–1285.CrossRefGoogle Scholar
  11. 11.
    Cribb A, Lee B, Trepanier L, Spielberg S: Adverse reactions to sulphonamide and sulphonamide-trimethoprim antimicrobials: clinical syndromes and pathogenesis. Adv Drug React Toxicol Rev 1996, 15:9–50.Google Scholar
  12. 12.
    Hunziker T, Künzi UP, Braunschweig S, et al.: Comprehensive hospital drug monitoring (CHDM): adverse skin reactions, a 20-year survey. Allergy 1997, 52:388–393.PubMedCrossRefGoogle Scholar
  13. 13.
    Roujeau JC, Kelly JP, Naldi L, et al.: Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. N Engl J Med 1995, 333:1600–1607.PubMedCrossRefGoogle Scholar
  14. 14.
    Myers MW, Jick H: Hospitalization for serious blood and skin disorders following use of cotrimoxazole. Br J Clin Pharmacol 1997, 43:446–448.PubMedCrossRefGoogle Scholar
  15. 15.
    Vial T, Biour M, Descotes J, Trepo C: Antibiotic-associated hepatitis: update from 1990. Ann Pharmacother 1997, 31:204–220.PubMedGoogle Scholar
  16. 16.
    Kaufman DW, Kelly JP, Jurgelon JM, et al.: Drugs in the aetiology of agranulocytosis and aplastic anaemia. Eur J Haematol Suppl 1996, 60:23–30.PubMedGoogle Scholar
  17. 17.
    Coombs RRA, Gell PGH: Classification of allergic reactions responsible for drug hypersensitivity reactions. In Clinical Aspects of Immunology, edn. 2. Edited by Coombs RRA, Gells PGH. Philadelphia: FA Davis; 1968:575–596.Google Scholar
  18. 18.
    Descotes J, Choquet-Kastylevsky G: Gell & Coombs classification: is it still valid? Toxicology 2001, 158:43–49.PubMedCrossRefGoogle Scholar
  19. 19.
    Griem P, Wulferink M, Sachs B, et al.: Allergic and autoimmune reactions to xenobiotics: how do they arise? Immunol Today 1998, 19:133–141. A very extensive review embracing the various features of the immunologic mechanisms of drug allergies.PubMedCrossRefGoogle Scholar
  20. 20.
    de Weck AL: Trends and opportunities in allergy research in Europe. Clin Exp Allergy 1991, 21(suppl 1):112–118.PubMedCrossRefGoogle Scholar
  21. 21.
    Chosidow O, Bourgault L, Roujeau JC: Drug rashes. What are the targets of cell-mediated cytotoxicity? Arch Dermatol 1994, 130:627–629.PubMedCrossRefGoogle Scholar
  22. 22.
    Patel BM: Skin rash with infectious mononucleosis and ampicillin. Pediatrics 1967, 40:910–911.PubMedGoogle Scholar
  23. 23.
    Coopman SA, Johnson RA, Platt R, Stern RS: Cutaneous disease and drug reaction in HIV infection. N Engl J Med 1993, 328:1670–1674.PubMedCrossRefGoogle Scholar
  24. 24.
    Renton K, Knickle L: Regulation of cytochrome P 450 during infectious disease. Can J Physiol Pharmacol 1990, 68:777–781.PubMedGoogle Scholar
  25. 25.
    Coleman JW, Blanca M: Mechanisms of drug allergy. Immunol Today 1998, 19:196–198. Another very extensive review embracing the various features of the immunologic mechanisms of drug allergies.PubMedCrossRefGoogle Scholar
  26. 26.
    Shear NH, Spielberg SP, Grant DM, et al.: Differences in metabolism of sulfonamides predisposing to idiosyncratic toxicity. Ann Intern Med 1986, 105:179–184.PubMedGoogle Scholar
  27. 27.
    Mauri-Hellweg D, Bettens F, Mauri D, et al.: Activation of drug specific CD4+ and CD8+ T cells in individuals allergic to sulfonamides, phenytoin, and carbamazepine. J Immunol 1995, 155:462–472.PubMedGoogle Scholar
  28. 28.
    Shapiro LE, Shear NH: Mechanisms of drug reactions: the metabolic track. Semin Cutan Med Surg 1996, 15:217–227.PubMedCrossRefGoogle Scholar
  29. 29.
    Hess DA, Rieder MJ: The role of reactive drug metabolites in immune-mediated adverse drug reactions. Ann Pharmacother 1997, 31:1378–1387.PubMedGoogle Scholar
  30. 30.
    Zanni MP, Mauri-Hellweg D, Brander C, et al.: Characterization of lidocaine-specific T cells. J Immunol 1997, 158:1139–1148.PubMedGoogle Scholar
  31. 31.
    Padovan E, Bauer T, Tongio MM, et al.: Penicilloyl peptides are recognized as T cell antigenic determinants in penicillin allergy. Eur J Immunol 1997, 27:1303–1307.PubMedCrossRefGoogle Scholar
  32. 32.
    Pichler WJ, Schnyder B, Zanni MP, et al.: Role of T cells in drug allergy. Allergy 1998, 53:225–232. Still another very extensive review embracing the various features of the immunologic mechanisms of drug allergies.PubMedCrossRefGoogle Scholar
  33. 33.
    Schnyder B, Mauri-Hellweg D, Zanni M, et al.: Direct, MHCdependent presentation of the drug sulfamethoxazole to human alphabeta T cell clones. J Clin Invest 1997, 100:136–141.PubMedCrossRefGoogle Scholar
  34. 34.
    Schnyder B, Burkhart C, Schnyder-Frutig K, et al.: Recognition of sulfamethoxazole and its reactive metabolites by drugspecific CD4+ T cells from allergic individuals. J Immunol 2000, 164:6647–6654. Experimental proof of the different haptens recognized by the immune system during sulfa allergies.PubMedGoogle Scholar
  35. 35.
    Cribb A, Spielberg SP: Hepatic microsomal metabolism of sulfamethoxazole to the hydroxylamine. Drug Metab Dispos 1990, 18:784–787.PubMedGoogle Scholar
  36. 36.
    Rieder MJ, Uetrecht J, Shear NH, et al.: Diagnosis of sulfonamide hypersensitivity reactions by in vitro "rechallenge" with hydroxylamine metabolites. Ann Intern Med 1989, 110:286–289.PubMedGoogle Scholar
  37. 37.
    von Greyerz S, Zanni MP, Frutig K, et al.: Interaction of sulfonamide derivatives with the TCR of sulfamethoxazolespecific human alpha beta+ T cell clones. J Immunol 1999, 162:595–602. A major study leading to the understanding of the mechanisms of drug allergies and the presentation of drug to specific T lymphocytes.Google Scholar
  38. 38.
    Hertl M, Merk HF: Lymphocyte activation in cutaneous drug reactions. J Invest Dermatol 1995, 105:95S-98S.PubMedCrossRefGoogle Scholar
  39. 39.
    Carr A, Swanson C, Penny R, Cooper DA: Clinical and laboratory markers of hypersensitivity to trimethoprimsulfamethoxazole in patients with Pneumocystis carinii pneumonia and AIDS. J Infect Dis 1993, 167:180–185.PubMedGoogle Scholar
  40. 40.
    Hattori N, Hino H: Generalized erythematous skin eruptions due to trimethoprim itself and co-trimoxazole. J Dermatol 1998, 25:269–271.PubMedGoogle Scholar
  41. 41.
    Bijl AM, Van der Klauw MM, Van Vliet AC, Stricker BH: Anaphylactic reactions associated with trimethoprim. Clin Exp Allergy 1998, 28:510–512.PubMedCrossRefGoogle Scholar
  42. 42.
    Akerlund B, Tynell E, Bratt G, et al.: N-acetylcysteine treatment and the risk of toxic reactions to trimethoprim-sulphamethoxazole in primary Pneumocystis carinii prophylaxis in HIV-infected patients. J Infect 1997, 35:143–147.PubMedCrossRefGoogle Scholar
  43. 43.
    Walmsley SL, Khorasheh S, Singer J, Djurdjev O: A randomized trial of N-acetylcysteine for prevention of trimethoprimsulfamethoxazole hypersensitivity reactions in Pneumocystis carinii pneumonia prophylaxis (CTN 057). J Acquir Immune Defic Syndr Hum Retrovirol 1998, 19:498–505.PubMedGoogle Scholar
  44. 44.
    Lehmann DF, Liu A, Newman N, Blair DC: The association of opportunistic infections with the occurrence of trimethoprim/ sulfamethoxazole hypersensitivity in patients infected with human immunodeficiency virus. J Clin Pharmacol 1999, 39:533–537. A good study on the link between opportunistic infections and sulfa allergies in AIDS patients.PubMedGoogle Scholar
  45. 45.
    Hennessy S, Strom BL, Berlin JA, Brennan PJ: Predicting cutaneous hypersensitivity reactions to cotrimoxazole in HIVinfected individuals receiving primary Pneumocystis carinii pneumonia prophylaxis. J Gen Intern Med 1995, 10:380–386.PubMedCrossRefGoogle Scholar
  46. 46.
    Caumes E, Roudier C, Rogeaux O, et al.: Effect of corticosteroids on the incidence of adverse cutaneous reactions to trimethoprim-sulfamethoxazole during treatment of AIDSassociated Pneumocystis carinii pneumonia. Clin Infect Dis 1994, 18:319–323.PubMedGoogle Scholar
  47. 47.
    Yoshizawa S, Yasuoka A, Kikuchi Y, et al.: A 5-day course of oral desensitization to trimethoprim/sulfamethoxazole (T/S) in patients with human immunodeficiency virus type-1 infection who were previously intolerant to T/S. Ann Allergy Asthma Immunol 2000, 85:241–244.PubMedCrossRefGoogle Scholar
  48. 48.
    Gruchulla RS, Pesenko RD, Do TT, Skiest DJ: Sulfonamideinduced reactions in desensitized patients with AIDS. The role of covalent protein haptenation by sulfamethoxazole. J Allergy Clin Immunol 1998, 101:371–378.CrossRefGoogle Scholar
  49. 49.
    Lee BL, Delahunty T, Safrin S: The hydroxylamine of sulfamethoxazole and adverse reactions in patients with acquired immunodeficiency syndrome. Clin Pharmacol Ther 1994, 56:184–189.PubMedCrossRefGoogle Scholar
  50. 50.
    Pirmohamed M, Alfirevic A, Vilar J, et al.: Association analysis of drug metabolizing enzyme gene polymorphisms in HIVpositive patients with co-trimoxazole hypersensitivity. Pharmacogenetics 2000, 10:705–713. Good analysis of the role of metabolism for sulfa allergies in HIVinfected patients.PubMedCrossRefGoogle Scholar
  51. 51.
    Carr A, Gross AS, Hoskins JM, et al.: Acetylation phenotype and cutaneous hypersensitivity to trimethoprim-sulphamethoxazole in HIV-infected patients. AIDS 1994, 8:333–337.PubMedCrossRefGoogle Scholar
  52. 52.
    Gompels MM, Simpson N, Snow M, et al.: Desensitization to co-trimoxazole (trimethoprim-sulphamethoxazole) in HIVinfected patients: is patch testing a useful predictor of reaction? J Infect 1999, 38:111–115.PubMedCrossRefGoogle Scholar
  53. 53.
    Harle DG, Baldo BA, Wells JV: Drugs as allergens: detection and combining site specificities of IgE antibodies to sulfamathoxazole. Mol Immunol 1988, 25:1347–1354.PubMedCrossRefGoogle Scholar
  54. 54.
    Sullivan TJ: Cross-reactions among furosemide, hydrochlorothiazide, and sulfonamides. JAMA 1991, 265:120–121.PubMedCrossRefGoogle Scholar
  55. 55.
    Holtzer CD, Flaherty JF Jr, Coleman RL: Cross-reactivity in HIV-infected patients switched from trimethoprimsulfamethoxazole to dapsone. Pharmacotherapy 1998, 18:831–835. Well-explained rationale for the occurrence of cross-reactivities between sulfonamides.PubMedGoogle Scholar
  56. 56.
    Knowles S, Shapiro L, Shear NH: Should celecoxib be contraindicated in patients who are allergic to sulfonamides? Revisiting the meaning of ‘sulfa’ allergy. Drug Safety 2001, 24:239–247. Another well-explained rationale for the occurrence of cross-reactivities between sulfonamides.PubMedCrossRefGoogle Scholar
  57. 57.
    Silverstein FE, Faich G, Goldstein JL, et al.: Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis. The CLASS study: a randomized controlled trial. JAMA 2000, 284:1247–1255.PubMedCrossRefGoogle Scholar
  58. 58.
    Patterson R, Bello AE, Lefkowith J: Immunologic tolerability profile of celecoxib. Clin Ther 1999, 21:2065–2079.PubMedCrossRefGoogle Scholar
  59. 59.
    Jung AC, Paauw DS: Management of adverse reactions to trimethoprim-sulfamethoxazole in human immunodeficiency virus-infected patients. Arch Intern Med 1994, 154:2402–2406.PubMedCrossRefGoogle Scholar
  60. 60.
    Koopmans PP, Burger DM: Managing drug reactions to sulfonamides and other drugs in HIV infection: desensitization rather than rechallenge. Pharm World Sci 1998, 20:253–257.PubMedCrossRefGoogle Scholar
  61. 61.
    Caumes E, Guermonprez G, Lecomte C, et al.: Efficacy and safety of desensitization with sulfamethoxazole and trimethoprim in 48 previously hypersensitive patients infected with human immunodeficiency virus. Arch Dermatol 1997, 133:465–469.PubMedCrossRefGoogle Scholar
  62. 62.
    Carr A, Penny R, Cooper DA: Efficacy and safety of rechallenge with low-dose trimethoprim-sulphamethoxazole in previously hypersensitive HIV-infected patients. AIDS 1993, 7:65–71.PubMedCrossRefGoogle Scholar
  63. 63.
    Nguyen MT, Weiss PJ, Wallace MR: Two-day oral desensitization to trimethoprim-sulfamethoxazole in HIV-infected patients. AIDS 1995; 9:573–575.PubMedCrossRefGoogle Scholar
  64. 64.
    Bonfanti P, Pusterla L, Parazzini F, et al.: The effectiveness of desensitization versus rechallenge treatment in HIV-positive patients with previous hypersensitivity to TMP-SMX: a randomized multicentric study. C.I.S.A.I. Group. Biomed Pharmacother 2000, 54:45–49. The only randomized trial comparing desensitization and rechallenge protocols.PubMedCrossRefGoogle Scholar
  65. 65.
    Caumes E, Guermonprez G, Winter C, et al.: A life-threatening adverse reaction during trimethoprim-sulfamethoxazole desensitization in a previously hypersensitive patient infected with human immunodeficiency virus. Clin Infect Dis 1996, 23:1313–1314.PubMedGoogle Scholar
  66. 66.
    Barbaud A, Béné MC, Faure G: Immunological physiopathology of cutaneous adverse drug reactions. Eur J Dermatol 1997, 7:319–323.Google Scholar
  67. 67.
    Para MF, Finkelstein D, Becker S, et al.: Reduced toxicity with gradual initiation of trimethoprim-sulfamethoxazole as primary prophylaxis for Pneumocystis carinii pneumonia: AIDS Clinical Trials Group 268. J Acquir Immune Defic Syndr 2000, 24:337–343.PubMedGoogle Scholar

Copyright information

© Current Science Inc 2002

Authors and Affiliations

  • Geneviève Choquet-Kastylevsky
    • 1
  • Thierry Vial
    • 1
  • Jacques Descotes
    • 1
  1. 1.BioMérieux, Chemin de l’OrmeMarcy l’EtoileFrance

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