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DRUG ALLERGY TO ANTIBIOTICS: GENERAL REVIEW

DRUG ALLERGY TO ANTIBIOTICS: GENERAL REVIEW. Ricardo Cardona Villa, M.D. MSc in Immunology - Allergist Chief of Clinical Allergology Service IPS Universitaria - Clínica León XIII Medical School Universidad de Antioquia. Urticarial plaques associated with cephalexin.

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DRUG ALLERGY TO ANTIBIOTICS: GENERAL REVIEW

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  1. DRUG ALLERGY TO ANTIBIOTICS: GENERAL REVIEW Ricardo Cardona Villa, M.D. MSc in Immunology - Allergist Chief of Clinical Allergology Service IPS Universitaria - Clínica León XIII Medical School Universidad de Antioquia

  2. Urticarial plaques associated with cephalexin Carder K.R. Hypersensitivity reactions in neonates and infants. Dermatologic Therapy, Vol. 18, 2005, 160–175

  3. Urticaria associated with ampicillin allergy Rebecca S. Gruchalla R.B and Pirmohamed M. Antibiotic Allergy. N Engl J Med 2006;354:601-9. Photograph courtesy of Peter Friedmann, University of Southampton, United Kingdom.

  4. Maculopapular rash associated with flucloxacillin allergy Rebecca S. Gruchalla R.B and Pirmohamed M. Antibiotic Allergy. N Engl J Med 2006;354:601-9. Photograph courtesy of Peter Friedmann, University of Southampton, United Kingdom.

  5. Exanthematous drug eruption caused by amoxicillin McKenna J.K. and Leiferman, K.M. Dermatologic drug reactions. Immunol Allergy Clin N Am 24 (2004) 399– 423

  6. Acute generalized exanthematous pustulosis from amoxicillin McKenna J.K. and Leiferman, K.M. Dermatologic drug reactions. Immunol Allergy Clin N Am 24 (2004) 399– 423

  7. Leukocytoclastic vasculitis McKenna J.K. and Leiferman, K.M. Dermatologic drug reactions. Immunol Allergy Clin N Am 24 (2004) 399– 423

  8. Toxic epidermal necrolysis McKenna J.K. and Leiferman, K.M. Dermatologic drug reactions. Immunol Allergy Clin N Am 24 (2004) 399– 423

  9. Allergic contact dermatitis to topical antibiotics Kathryn A. Gehrig k.A. and Warshaw E.M. Allergic contact dermatitis to topical antibiotics: Epidemiology, responsible allergens, and management. J Am Acad Dermatol 2008;58:1-21.

  10. ADRs have been classified by Rawlins and Thompson in four types: • Type A reactions • Type B reactions that are uncommon (approximately 10% to 15%), not predictable, and occur only in susceptible individuals • Others: type C and type D reactions. Rawlins M, Thompson W. Mechanisms of adverse drug reactions. In: Davies D, editor. Textbook of adverse drug reactions. New York: Oxford Press; 1991. p. 18–45. Schnyder B. Approach to the Patient with Drug Allergy. Immunol Allergy Clin N Am 29 (2009) 405–418

  11. Allergic reactions are, by definition, immunologically mediated. A single drug may initiate multiple immune responses, and multiple antigenic determinants may be formed from a single drug. Pathogenic Features Park BK, Pirmohamed M, Kitteringham NR. Role of drug disposition in drug hypersensitivity: a chemical, molecular, and clinical perspective. Chem Res Toxicol 1998;11:969-88. Schnyder B, Mauri-Hellweg D, Zanni M, Bettens F, Pichler WJ. Direct, MHCdependent presentation of the drug sulfamethoxazole to human alpha/beta T cell clones. J Clin Invest 1997;100:136-41.

  12. The reaction is not an expectedpharmacologic effect. Several criteria characterize an allergic reaction Demoly Pascal. Classification and Epidemiology of hipersensitivity drug reactions. Immunology Allergy Clin N Am. 24(2004) 345-356.

  13. The reaction is not an expectedpharmacologic effect. A period of sensitization precedesthe reaction. Several criteria characterize an allergic reaction Demoly Pascal. Classification and Epidemiology of hipersensitivity drug reactions. Immunology Allergy Clin N Am. 24(2004) 345-356.

  14. The reaction is not an expectedpharmacologic effect. A period of sensitization precedesthe reaction. The reaction may occur at a dose much lowerthan that required for a pharmacologic effect. Several criteria characterize an allergic reaction Demoly Pascal. Classification and Epidemiology of hipersensitivity drug reactions. Immunology Allergy Clin N Am. 24(2004) 345-356.

  15. Several criteria characterize an allergic reaction • The clinical symptoms are characteristic of an allergic reaction • Resolution occurs within an expected interval, usually days, after discontinuation of the offending agent Demoly Pascal. Classification and Epidemiology of hipersensitivity drug reactions. Immunology Allergy Clin N Am. 24(2004) 345-356.

  16. Several criteria characterize an allergic reaction • The clinical symptoms are characteristic of an allergic reaction • Resolution occurs within an expected interval, usually days, after discontinuation of the offending agent • Chemical cross-reactivity may occur Demoly Pascal. Classification and Epidemiology of hipersensitivity drug reactions. Immunology Allergy Clin N Am. 24(2004) 345-356.

  17. Classification ofallergic reactions to drugs Gell and Coombs classification (1960): The physiological mechanisms (Gell P. and Coombs R. Clinical aspects of immunology Blalckwell Scient Publ Oxford; 1964). (Coombs PRA, Gell PGH. Classification of allergic reactions responsible for clinical hypersensitivity and disease. In: Gell RRA, editor. Clinical aspects of immunology. Oxford: Oxford University Press; 1968. p. 575–96.) Levine classification (1966): The time taken for symptoms to appear Immediately: Less than an hour Fast: 6-48 hours later. Delayed: After 48 hours. (Immunologic mechanisms of penicillin allergy. A haptenic model system for the study of allergic diseasess of man. NEJM 1966; 275: 1115-25)

  18. Is a fishing net adequate for our purposes ? http://www.monografias.com/trabajos59/fabula-lanzador-redes/Image23883.gif

  19. My personal opinion is that, like our fisherman here • Our fishing net is not big enough to catch all drug allergies

  20. My personal opinion is that, like our fisherman here • AND • Our fishing net allows too many of them to escape

  21. OR MAYBE... • We need to discover new knowledge or create a new system that captures everything.

  22. Multivalency theory of haptenic drug allergy Middleton’s. allergy: Principles and Practices. Seventh edition. 2009

  23. A schematic comparison of the p-i concept with the hapten model Gerber B.O. And and Pichler W.J. Cellular mechanisms of T cell mediated drug hypersensitivity. Current Opinion in Immunology 2004, 16:732–737

  24. The World Allergy Organization has recommended the use of the adjectives immediateanddelayed referring to the onset of the symptoms, as helpful in distinguishing whether the probable immunologic mechanism is antibody mediated or T-lymphocyte-mediated. Johansson S.G., Bieber T., Dahl R., et al: Revised nomenclature for allergy for global use: Report of the Nomenclature Review Committee of the World Allergy Organization October 2003.  J Allergy Clin Immunol  2004; 113:832-836.

  25. Gell and Coombs classification Ricardo Cardona V. y Carlos Serrano ,Alergia: Abordaje Clínico, Diagnóstico y Tratamiento. Cap. 1, Aspectos Básicos de la Alergia y Reacciones de Hipersensibilidad. Ed. Panamericana (en prensa)

  26. Schematic representation of overlapping immune functions Werner J. Pichler, MD Immune mechanism of drug hypersensitivity Immunol Allergy Clin N Am 24 (2004) 373–397

  27. T Cell Th 9 Th17 Revised Gell and Coombs classification of drug reactions Th17 Th2 T Reg Th9 Th1 Pichler, W.J. Immune mechanism of drug hypersensitivity. Immunol Allergy Clin N Am 24 (2004) 373– 397 Scheme adapted from Janeway CA, Travers P, Walport M, Shlochik M. Immunobiology. New York: Garland Publishing; 2001

  28. type IVa macrophage type IVb eosinophils type IVd neutrophils IL 5, IL4/IL13 (Th2 cells) INF γ, TNFα (Th1 cells) CXCL 8, GM-SCF (T cell) type IVcCD4 and CD8 Cytotoxic T cell Perforin/Granzyme B (CTL)

  29. type IVa macrophage type I type IVb eosinophils type IVb eosinophils type IVd neutrophils IL 5, IL4/IL13 (Th2 cells) INF γ, TNFα (Th1 cells) CXCL 8, GM-SCF (T cell) type IVcCD4 and CD8 Cytotoxic T cell Perforin/Granzyme B (CTL) IL 5, IL4/IL13 cell B

  30. type IVa macrophage type IVa macrophage type I type IVb eosinophils type IVb eosinophils type II type IVd neutrophils IL 5, IL4/IL13 (Th2 cells) INF γ, TNFα (Th1 cells) CXCL 8, GM-SCF (T cell) type IVcCD4 and CD8 Cytotoxic T cell Perforin/Granzyme B (CTL) IgG cell B IgG type III IL 5, IL4/IL13 cell B C, O2

  31. type IVa macrophage type IVa macrophage type I type IVb eosinophils type IVb eosinophils type II type IVd neutrophils IL 5, IL4/IL13 (Th2 cells) INF γ, TNFα (Th1 cells) CXCL 8, GM-SCF (T cell) type IVcCD4 and CD8 Cytotoxic T cell Perforin/Granzyme B (CTL) IgG cell B IgG type III IL 5, IL4/IL13 type IVd neutrophils cell B C, O2

  32. type IVa macrophage type IVa macrophage type I type IVb eosinophils type IVb eosinophils type II Pre Th type IVd neutrophils IL 5, IL4/IL13 (Th2 cells) INF γ, TNFα (Th1 cells) CXCL 8, GM-SCF (T cell) type IVcCD4 and CD8 Cytotoxic T cell Perforin/Granzyme B (CTL) Th1 IL 10, TGF β IgG IL 12 β cell B Th2 IgG type III IL 5, IL4/IL13 type IVd neutrophils cell B C, O2

  33. type IVa macrophage type IVa macrophage type I type IVb eosinophils type IVb eosinophils type IVb eosinophils type II Pre Th type IVd neutrophils IL 5, IL4/IL13 (Th2 cells) INF γ, TNFα (Th1 cells) CXCL 8, GM-SCF (T cell) type IVcCD4 and CD8 Cytotoxic T cell Perforin/Granzyme B (CTL) Th1 IL 10, TGF β IgG IL 12 β cell B Th2 IgG type III IL 5, IL4/IL13 type IVd neutrophils cell B C, O2

  34. type IVa macrophage type IVa macrophage type I type IVb eosinophils type IVb eosinophils type IVb eosinophils type II Pre Th type IVd neutrophils IL 5, IL4/IL13 (Th2 cells) INF γ, TNFα (Th1 cells) CXCL 8, GM-SCF (T cell) type IVcCD4 and CD8 Cytotoxic T cell Perforin/Granzyme B (CTL) Th1 IL 10, TGF β IgG IL 12 β cell B Th2 IgG type III IL 5, IL4/IL13 type IVd neutrophils cell B C, O2

  35. The mechanisms underlying antibiotic allergy have not been clearly elucidated. Areas of Uncertainty ..Some people believe that everything they see is true; like “the world is flat”...

  36. Indications for ‘skin prick test’ and ‘intradermal test’ Erythematous eruption/flushing Bronchospasm/asthma Conjunctivitis Anaphylaxis Angioedema Urticaria Rhinitis Kranke B.and Aberer W. Skin testing for IgE-mediated drug allergy. Immunol Allergy Clin N Am 2009;29:503-516

  37. No indications for ‘skin prick test’ and ‘intradermal test’ Drug-induced autoimmune diseases: Bullous pemphigoid, Pemphigus vulgaris, Systemic lupus erythematosus. Kranke B.and Aberer W. Skin testing for IgE-mediated drug allergy. Immunol Allergy Clin N Am 2009;29:503-516

  38. No indications for ‘skin prick test’ and ‘intradermal test’ Drug-induced autoimmune diseases: Bullous pemphigoid, Pemphigus vulgaris, Systemic lupus erythematosus. Severe vasculitis syndromes Kranke B.and Aberer W. Skin testing for IgE-mediated drug allergy. Immunol Allergy Clin N Am 2009;29:503-516

  39. No indications for ‘skin prick test’ and ‘intradermal test’ Severe exfoliative skin reactions: Acute generalized exanthematic pustulosis, drug reaction with eosinophilia and systemic symptoms or drug hypersensitivity syndrome, exfoliative dermatitis, multilocalized bullous fixed drug eruption, Stevens-Johnson syndrome, toxic epidermal necrolysis. Kranke B.and Aberer W. Skin testing for IgE-mediated drug allergy. Immunol Allergy Clin N Am 2009;29:503-516

  40. SPT and IDT with the major and minor determinates of penicillin Kranke B.and Aberer W. Skin testing for IgE-mediated drug allergy. Immunol Allergy Clin N Am 2009;29:503-516

  41. Medical history taking is critical in the evaluationof antibiotic allergy and in distinguishing allergic reactions from other adverse reactions Clinical assessment Ancient Greek painting in a vase, showing a physician (iatros) bleeding a patient Rebecca S. Gruchalla R.B and Pirmohamed M. Antibiotic Allergy. N Engl J Med 2006;354:601-9.

  42. Skin Testing: Skin testing is the basic diagnostic tool, although in patients with a history of severe reactions, in vitro tests may be the recommended choice. Diagnosis tests • Skin testing is highly accurate for the identification of penicillin allergy. • Blanca M., Romano A., Torres M.J., Fernández J, et al. Update on the evaluation of hypersensitivity reactions to betalactams. Allergy 2009. 64, 183-193

  43. Other Testing: The measurement of IL-2, IL-5, IL-13 or IFN-gammaor a combination there of might be a useful in vitro tool for detection of T-cell sensitization to drugs Diagnosis tests Lochmatter P., Beeler A., Kawabata T.T., Gerber B.O., Pichler W. J. Drug-specific in vitro release of IL-2, IL-5, IL-13 and IFN-gamma in patients with delayed-type drug hypersensitivity . Allergy 2009: 64: 1269–1278 The basophil activation test as a funtional in vitro test in immediate-type drug allergy. • Hausmann O.V et al. The basophil activation test in immediate-type drug allergy. Immunol Allergy Clin N Am 29 (2009) 555–566

  44. Other Testing: Drug-specific T cells, which are involved in some hypersensitivity reactions, may be detected with the use of in vitro lymphocyte transformation tests Diagnosis tests • Blanca M., Romano A., Torres M.J., Fernández J, et al. Update on the evaluation of hypersensitivity reactions to betalactams. Allergy 2009. 64, 183-193 • Bernstein I.L., James T., Li J.T., Bernstein D.I.,Hamilton R., et al, Allergy Diagnostic Testing: An Updated Practice Parameter. • ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY. VOLUME 100, MARCH, 2008: S1-S148

  45. Other Testing: Drug provocation test.The ENDA document stated that the DPT was, at that time, the best tool to confirm a causal relationship between drug administration and non-immediate adverse reactions. Diagnosis tests • Romano A, Blanca M, Torres MJ, Bircher A, et al. Diagnosis of nonimmediate reactions to beta-lactam antibiotics. Allergy 2004;59:1153-1160. • Blanca M., Romano A., Torres M.J., Fernández J, et al. Update on the evaluation of hypersensitivity reactions to betalactams. • Allergy 2009. 64, 183-193

  46. Clinical History of reaction Delayed (> 1 hour) (Urticaria, AE, rash) Immediate (< 1hour) (urticaria, AE, Anaphylaxis) Late with intradermal or epicutaneous with drug envolved Skin test(*) Specific IgE (CAP) Both negative Any Positive Positive Negative PEC(**) Allergy Allergy PEC(**) Positive Negative Positive Negative Reaction over two Years ago Allergy Complete curse of the treatment Allergy Yes No Reaction Tolerance Skin test + PEC (**)(^^) Both Negative No Allergy Any positive Allergy No Allergy Allergy No Allergy Cardona R, Serrano C, Alergia: Abordaje Clínico, Diagnóstico y Tratamiento. Cap. 58, Alergia a betalactaminos. Ed. Panamericana (In Press)

  47. Clinical History of reaction Delayed (> 1 hour) (Urticaria, AE, rash) Immediate (< 1hour) (urticaria, AE, Anaphylaxis) Late with intradermal or epicutaneous with drug envolved Skin test(*) Specific IgE (CAP) Both negative Any Positive Positive Negative PEC(**) Allergy Allergy PEC(**) Positive Negative Positive Negative Reaction over two Years ago Allergy Complete curse of the treatment Allergy Yes No Reaction Tolerance Skin test + PEC (**)(^^) Both Negative No Allergy Any positive Allergy No Allergy Allergy No Allergy Cardona R, Serrano C, Alergia: Abordaje Clínico, Diagnóstico y Tratamiento. Cap. 58, Alergia a betalactaminos. Ed. Panamericana (In Press)

  48. Identification and future management of the most common drug reactions Volcheck G.W. Clinical evaluation and manegement of drug hypersensitivity.Immunol Allergy Clin N Am 24(2004) 357-371

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