Antibiotic Allergy: General review

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, 160175
3
Urticaria associated with ampicillin allergy
Rebecca S. Gruchalla R.B and Pirmohamed M.
Antibiotic Allergy. N Engl J Med 2006354601-9.

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 2006354601-9.

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 2008581-21.
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. 1845. Schnyder B. Approach to the
Patient with Drug Allergy. Immunol Allergy Clin N
Am 29 (2009) 405418
11
Pathogenic Features

• 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.

Park BK, Pirmohamed M, Kitteringham NR. Role of
drug disposition in drug hypersensitivity a
chemical, molecular, and clinical perspective.
Chem Res Toxicol 199811969-88. 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 1997100136-41.
12
Several criteria characterize an allergic
reaction

• The reaction is not an expected pharmacologic
  effect.

Demoly Pascal. Classification and Epidemiology of
hipersensitivity drug reactions. Immunology
Allergy Clin N Am. 24(2004) 345-356.
13
Several criteria characterize an allergic
reaction

• The reaction is not an expected pharmacologic
  effect.
• A period of sensitization precedes the reaction.

Demoly Pascal. Classification and Epidemiology of
hipersensitivity drug reactions. Immunology
Allergy Clin N Am. 24(2004) 345-356.
14
Several criteria characterize an allergic
reaction

• The reaction is not an expected pharmacologic
  effect.
• A period of sensitization precedes the reaction.
• The reaction may occur at a dose much lower than
  that required for a pharmacologic effect.

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

• 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)

• 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. 57596.)

18
Is a fishing net adequate for our purposes ?
http//www.monografias.com/trabajos59/fabula-lanza
dor-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
Middletons. 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, 16732737
24

• The World Allergy Organization has recommended
  the use of the adjectives immediate and delayed
• 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 113832-836.
25
Gell and Coombs classification
26
Schematic representation of overlapping immune
functions
27
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
(No Transcript)
29
type IVd neutrophils
IL 5, IL4/IL13 (Th2 cells)
INF ?, TNFa (Th1 cells)
CXCL 8, GM-SCF (T cell)
type IVc CD4 and CD8 Cytotoxic T cell
Perforin/Granzyme B (CTL)
30
type IVd neutrophils
IL 5, IL4/IL13 (Th2 cells)
INF ?, TNFa (Th1 cells)
CXCL 8, GM-SCF (T cell)
type IVc CD4 and CD8 Cytotoxic T cell
Perforin/Granzyme B (CTL)
IL 5, IL4/IL13
cell B
31
type IVd neutrophils
IL 5, IL4/IL13 (Th2 cells)
INF ?, TNFa (Th1 cells)
CXCL 8, GM-SCF (T cell)
type IVc CD4 and CD8 Cytotoxic T cell
Perforin/Granzyme B (CTL)
IgG
cell B
IgG
type III
IL 5, IL4/IL13
cell B
C, O2
32
type IVd neutrophils
IL 5, IL4/IL13 (Th2 cells)
INF ?, TNFa (Th1 cells)
CXCL 8, GM-SCF (T cell)
type IVc CD4 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
33
type IVd neutrophils
IL 5, IL4/IL13 (Th2 cells)
INF ?, TNFa (Th1 cells)
CXCL 8, GM-SCF (T cell)
type IVc CD4 and CD8 Cytotoxic T cell
Perforin/Granzyme B (CTL)
Th1
IL 10, TGF ß
IgG
IL 12 ß
cell B
Th2
IgG
type III
IL 5, IL4/IL13
type IVd neutrophils
cell B
C, O2
34
type IVd neutrophils
IL 5, IL4/IL13 (Th2 cells)
INF ?, TNFa (Th1 cells)
CXCL 8, GM-SCF (T cell)
type IVc CD4 and CD8 Cytotoxic T cell
Perforin/Granzyme B (CTL)
Th1
IL 10, TGF ß
IgG
IL 12 ß
cell B
Th2
IgG
type III
IL 5, IL4/IL13
type IVd neutrophils
cell B
C, O2
35
type IVd neutrophils
IL 5, IL4/IL13 (Th2 cells)
INF ?, TNFa (Th1 cells)
CXCL 8, GM-SCF (T cell)
type IVc CD4 and CD8 Cytotoxic T cell
Perforin/Granzyme B (CTL)
Th1
IL 10, TGF ß
IgG
IL 12 ß
cell B
Th2
IgG
type III
IL 5, IL4/IL13
type IVd neutrophils
cell B
C, O2
36
Areas of Uncertainty

• The mechanisms underlying
• antibiotic allergy
• have not been clearly elucidated.

..Some people believe that everything they see is
true like the world is flat...
37
Indications for skin prick test and
intradermal test
Erythematous eruption/flushing Bronchospasm/asthma
Conjunctivitis Anaphylaxis Angioedema Urticaria R
hinitis
Kranke B.and Aberer W. Skin testing for
IgE-mediated drug allergy. Immunol Allergy Clin N
Am 200929503-516
38
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 200929503-516
39
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 200929503-516
40
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 200929503-516
41
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 200929503-516
42
Clinical assessment

• Medical history taking is critical in the
  evaluation of antibiotic allergy and
• in distinguishing
• allergic reactions from other adverse reactions

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 2006354601-9.

43
Diagnosis tests

• 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.

• 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
44
Diagnosis tests

• Other Testing
• The measurement of IL-2, IL-5, IL-13 or IFN-gamma
  or a combination there of might be a useful in
  vitro tool for detection of T-cell sensitization
  to drugs

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 12691278
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) 555566
45
Diagnosis tests

• 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

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
46
Diagnosis tests

• 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.

Romano A, Blanca M, Torres MJ, Bircher A, et
al. Diagnosis of nonimmediate reactions to
beta-lactam antibiotics. Allergy
2004591153-1160. 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
47
Clinical History of reaction
Delayed (gt 1 hour) (Urticaria, AE, rash)
Immediate (lt 1hour) (urticaria, AE, Anaphylaxis)
Late with intradermal or epicutaneous with drug
envolved
Skin test() Specific IgE (CAP)
Any Positive
Both negative
Negative
Positive
PEC()
Allergy
PEC()
Allergy
Negative
Positive
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
No Allergy
Allergy
Allergy
No Allergy
Cardona R, Serrano C, Alergia Abordaje Clínico,
Diagnóstico y Tratamiento. Cap. 58, Alergia a
betalactaminos. Ed. Panamericana (In Press)
48
Clinical History of reaction
Delayed (gt 1 hour) (Urticaria, AE, rash)
Immediate (lt 1hour) (urticaria, AE, Anaphylaxis)
Late with intradermal or epicutaneous with drug
envolved
Skin test() Specific IgE (CAP)
Any Positive
Both negative
Negative
Positive
PEC()
Allergy
PEC()
Allergy
Negative
Positive
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
No Allergy
Allergy
Allergy
No Allergy
Cardona R, Serrano C, Alergia Abordaje Clínico,
Diagnóstico y Tratamiento. Cap. 58, Alergia a
betalactaminos. Ed. Panamericana (In Press)
49
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
50
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51
Drug Provocation Test Contraindications

• Autoimmune diseases
• Bullous pemphigoid, Pemphigus vulgaris,
• Systemic lupus erythematosus

• Severe exfoliative skin reactions
• AGEP, DRESS/Drug-induced hypersensitivity
  syndrome, Exfoliative dermatitis, SJS,
• Toxic epidermal necrolysis

Aberer W. And Kranke B. ProvocationTests in Drug
Hypersensitivity. Immunol Allergy Clin N Am 29
(2009) 567584
52
Drug Provocation Test Contraindications
Severe vasculitis syndrome

Specific organ manifestations Blood cytopenia,
hepatitis, nephritis, pneumonitis
Aberer W. And Kranke B. ProvocationTests in Drug
Hypersensitivity. Immunol Allergy Clin N Am 29
(2009) 567584
53
Genetic susceptibility to drug hypersensitivity
Culprit drug Disease HLA Ethnicity
Carbamazepine SJS/TEN HLA-B 1502 Han-Chinese
Allopurinol SJS/TEN/HSS HLA-B 5801 Han-Chinese
Abacavir HSS HLA-B 5701 Caucasians
54
Summary

• Drug allergy and
• hypersensitivity have been recognized for
  decades,
• but there are still large gaps in our knowledge

Bousquet P-J., Demoly P. Romano A. Drug
allergy and hypersensitivity still a hot topic.
Allergy 2009 64 179182
55
Thanks !!