Rebecca A' Gruchalla, MD

1
Rebecca A. Gruchalla, MD
2
Clinical Assessment of Drug-Induced Disease
II-Antibiotic Allergy and Multiple Antibiotic
Sensitivities

• Rebecca S. Gruchalla, M.D., Ph.D.
• Professor, Internal Medicine and Pediatrics
• UT Southwestern Medical Center
• Dallas, Texas

3
Scope of the Problem

• WHO Adverse Drug Reaction (ADR) Definition
• Any noxious, unintended, and undesired effect of
  a drug that occurs at doses used in humans for
  prevention, diagnosis or treatment

4
Classification of ADRs

• Type A Reactions
• Predictable, common and related to the
  pharmacologic actions of the drug may occur in
  any individual (toxicity, side effects, secondary
  effects, drug interactions)

5
Classification of ADRs

• Type B Reactions
• Unpredictable, uncommon and usually not related
  to the pharmacologic actions of the drug occur
  only in susceptible individuals (intolerance,
  idiosyncratic reactions, hypersensitivity
  reactions, pseudoallergic reactions)

6
Features Of Allergic Drug Reactions

• Immunologic drug reactions are preceded by a
  period of sensitization
• First dose reactions imply that the patient
  either was previously sensitized to the drug or
  that the reaction was not allergic in nature

• Allergic drug reactions are restricted to a
  limited number of syndromes that have a known or
  a presumed immunopathologic basis
• Allergic drug reactions are temporally related to
  drug exposure

7
Classification of Allergic Reactions to Drugs

• Gell and Coombs Classification
• Immediate hypersensitivity reactions
• Cytotoxic antibody reactions
• Immune complex reactions
• Delayed-type hypersensitivity reactions (extended
  classification Pichler W. Ann Intern Med
  139683-93, 2003)

8
Expanded Type IV Hypersensitivity Classification
9
Penicillin-Induced Urticaria
10
Drug-Induced Maculopapular Eruption
11
Classification Problems

• In some instances, classification is easy
• In most instances, classification is difficult
  since the mechanism responsible for the reaction
  is not known
• Hypersensitivity reactions are uncommon,
  unpredictable and can not be reproduced in animal
  models

12
Drug HypersensitivityThe Hapten Hypothesis

• In order for hypersensitivity reactions to
  occur, most drugs must be bioactivated
• Drug metabolism is a detoxification process
• First step oxidation, reduction, hydrolysis
  (phase I reactions)
• Second step conjugation (phase II reactions)
• When a drug is bioactivated to a reactive form,
  prompt detoxification occurs

13
The Role Of Drug Metabolizing Enzymes In Drug
Bioactivation/Inactivation
Drug
Phase I metabolism
Phase II metabolism
Stable metabolites
Bioactivation
Bioinactivation
Reactive metabolite
14
The Role Of Drug Metabolizing Enzymes In Drug
Bioactivation/Inactivation
Reactive metabolite
Covalent binding and immunogen formation
Cytotoxicity
Genotoxicity

Necrosis
Carcinogenicity Teratogenicity
Hypersensitivity!
15
Sites of Drug Metabolism

• The liver is the main drug-metabolizing organ
• Drug-induced hepatic reactions are rare, but they
  do occur
• Autoimmune hepatitis (tienilic acid halothane
  dihydralazine) occurs when autoantibodies are
  formed against the neoantigen formed by the drug
  metabolite and the cytochrome isozyme

16
Importance of the Skin in Drug Metabolism

• The skin is very metabolically active
• Neutrophils, monocytes, macrophages,
  keratinocytes and Langerhans cells all have
  drug-metabolizing enzymes
• The skin also is a very active immunologic organ
  containing numerous cell types that play a
  strategic role in antigen presentation

17
Evaluation of the Drug-Allergic Patient

• History!!
• History!!
• History!!

18
Evaluation of the Drug-Allergic Patient

• Identify all medication usage and dosages
• Determine when a medication was initiated and
  establish a temporal relationship
• Determine if there was a prior hx of drug
  exposure
• Characterize the reaction type
• Consider use of a drug hypersensitivity
  questionnaire (Demoly P et al., Allergy
  54999-1003, 1999)

19
Evaluation of the Drug-Allergic Patient

• Determine if the patient has renal or hepatic
  disease
• Determine the propensity a drug has for causing a
  particular type of reaction
• Perform a complete PE - urticaria?, petechia?
  mucous membrane involvement?
• Distinguish between maculopapular eruptions and
  urticaria

20
Penicillin and Other ?-Lactam Drugs
21
Penicillins and CephalosporinsShare a Common
Beta-lactam Ring Structure
22
General Structure of Penicillins and Major and
Minor Determinants
23
Cephalosporin AllergyCross-reactivity with
Penicillin

• Penicillin contamination may have caused early
  studies of allergy to penicillin and
  cephalosporins to overestimate the degree of
  cross-reactivity
• Literature review by Lin (Arch Int Med 152930-7,
  1992) Of 15,987 patients who were treated with
  cephaloridine, cephalexin, cephalothin,
  cefazolin, or cefamandole, 8.1 of those with a
  history of penicillin allergy had reactions, as
  compared with 1.9 of those without such a history

24
Reported Reactions to Cephalosporins in Patients
with a History of Penicillin AllergyKelkar P and
Li JT. New Engl J Med 345804-9, 2001
25
Reported Reactions to Cephalosporins in Patients
with a History of Penicillin AllergyKelkar P and
Li JT. New Engl J Med 345804-9, 2001
26
Reported Reactions to Cephalosporins in Patients
with a History of Penicillin AllergyKelkar P and
Li JT. New Engl J Med 345804-9, 2001
27
Crossreactivity between Penicillins and
Cephalosporins?Apter A et al., Am J Med 119354
e11-e20, 2006

• Evaluated the risk of an allergic reaction to a
  cephalosporin in patients with prior PCN
  reactions
• Retrospective cohort study (United Kingdom
  General Practice Research Database) Patients who
  had received a prescription for PCN followed by a
  prescription for a cephalosporin
• Allergic-like reactions were identified 30 days
  after each prescription
• Comparison was made with a population of patients
  who had received a prescription for a PCN
  followed by a prescription for a sulfonamide

28
Crossreactivity between Penicillins and
Cephalosporins?Apter A et al., Am J Med 119354
e11-e20, 2006

• 3,375,162 patients received a penicillin and
  506,679 (15) received a subsequent cephalosporin
• Adjusted RR of an allergic-like event in those
  who received a cephalosporin and who had had a
  prior PCN-related allergic event was 10.1
  (7.4-13.6)
• Adjusted RR of an allergic-like event in those
  who received a sulfonamide and who had had a
  prior PCN-related allergic event was 7.2
  (3.8-13.5)
• Risk of anaphylaxis after a cephalosporin was
  lt0.001

29
Crossreactivity between Penicillins and
Cephalosporins?Apter A et al., Am J Med 119354
e11-e20, 2006

• Conclusion
• Patients with allergic-like events after
  penicillin had a markedly increased risk of
  events after either subsequent cephalosporins or
  sulfonamide antibiotics. Cross-reactivity is not
  an adequate explanation for this increased risk,
  and the risk of anaphylaxis is very low. Thus,
  our data indicate that cephalosporins can be
  considered for patients with penicillin allergy.

30
Sulfonamides - General

• A sulfonamide is any compound that contains a
  sulfonamide moiety (SO2NH2)

31
Sulfonamide Antimicrobials

• Sulfonamide antimicrobials contain an aromatic
  amine (unlike other sulfonamide-containing meds)
• Sulfonamide antimicrobials also contain a
  substituted ring at the N1 position

32
Sulfonamide Antimicrobial Reactions

• Usually cutaneous
• Occur in 2 to 4 of patients without AIDS
• Occur in over 40 of patients with AIDS
• Clinical reactions anaphylaxis, urticaria,
  erythroderma, fixed drug eruption, erythema
  multiforme, macular exanthems, SJS, TEN

33
Sulfonamide-Induced Reactions
Urticaria
Erythema Multiforme
Morbilliform Drug Eruption
Stevens Johnson Syndrome
Toxic Epidermal Necrolysis
Fixed Drug Eruption
34
Absence of Cross-Reactivity between Sulfonamide
Antibiotics and Sulfonamide NonantibioticsStrom
BL et al., N Engl J Med 3491628-35, 2003

• Of 969 patients with an allergic reaction after a
  sulfonamide antibiotic, 9.9 had an allergic
  reaction after receiving a sulfonamide
  nonantibiotic
• Of 19,257 who had no allergic reaction after a
  sulfonamide antibiotic, 1.6 had an allergic
  reaction after receiving a sulfonamide
  nonantibiotic

35
Absence of Cross-Reactivity between Sulfonamide
Antibiotics and Sulfonamide NonantibioticsStrom
BL et al., N Engl J Med 3491628-35, 2003

• However, the risk of an allergic reaction was
  even greater after the receipt of a penicillin
  among patients with a prior reaction to a
  sulfonamide antibiotic

36
Absence of Cross-Reactivity between Sulfonamide
Antibiotics and Sulfonamide NonantibioticsStrom
BL et al., N Engl J Med 3491628-35, 2003

• Conclusion
• Thus, while there appears to be an association
  between sulfonamide antimicrobial allergy and
  reactions to sulfonamide nonantimicrobial drugs,
  this association appears to be due to a
  predisposition to allergic reactions rather than
  to cross-reactivity with sulfonamide-based drugs

37
Shifting Gears
38
Drug Allergy Diagnosis and Treatment
39
Question 1

• You have been consulted to evaluate a patient who
  appeared to have had an anaphylactic reaction to
  a drug while in the OR. What test would help
  confirm this diagnosis?
• A. Serum histamine
• B. Drug-specific IgE by RAST
• C. Urine N-methyl histamine
• D. Tryptase

40
Diagnostic Tests For Immunologically-Mediated
Type B Rxns

• General laboratory tests (LFTs, BUN/creatinine,
  CBC, urinalysis, CXR)
• Biochemical/immunological markers that confirm
  the activation of certain pathways (total
  hemolytic complement, anti-nuclear antibodies,
  24-hour urine for histamine metabolites, tryptase)

41
Question 2

• If a skin test to a particular antibiotic is
  negative and the concentration used for testing
  is known to non-irritating, then it can be
  concluded that IgE antibodies to that antibiotic
  are not present.
• A. True
• B. False

42
Diagnosis Of Drug AllergyIn Vivo Skin Testing

• Large molecular weight compounds (foreign
  antisera, hormones, enzymes, toxoids)
• Penicillin
• Other antibiotics?

43
Penicillin Skin Testing

• PrePen is no longer available in the US
• The AAAAI is working with potential
  manufacturers

44
Tryptase

• Selective marker of mast cells
• Beta-tryptase is stored in secretory granules and
  it is actively released when mast cells
  degranulate
• Beta-tryptase levels are elevated after
  anaphylaxis (gt5 ng/ml)
• Tryptase levels should be obtained 1-2 hours
  after the onset of anaphylaxis

45
Tryptase Levels During Intraoperative
AnaphylaxisMatsson P et al. Agents and Actions
33218-20, 1991
46
Acute Drug Desensitization

• Definition
• process by which a drug-allergic individual is
  converted from a highly sensitive state to a
  state in which the drug is tolerated
• Procedure
• cautious administration of incremental doses of
  the drug over hours to days
• primarily used in IgE mediated reactions
• may be employed in certain non-IgE mediated,
  immune reactions

47
Drug Desensitization

• IgE Sensitivity
• beta-lactam antibiotics
• aminoglycosides
• clarithromycin
• insulin
• vaccines
• quaternary ammonium muscle relaxants

• Non-IgE Sensitivity
• trimethoprim-sulfamethoxazole
• aspirin
• vancomycin
• clindamycin
• anti-tubercular agents

48
Important Facts about Drug Desensitization

• Ensure procedure is performed in a hospital
  setting and that personnel can treat allergic
  reactions
• Administer drug doses at 15 minute intervals
• Monitor vital signs, PE and peak flows
• Keep a flowchart of the data
• Epinephrine and H1 and H2 blockers should be by
  the bedside

49
Drug Provocation?Messaad D et al., Ann Intern
Med 1401001-6, 2004

• 1372 drug provocation tests performed in patients
  who had experienced immediate-type
  hypersensitivity reactions
• 241 (17.6) positive challenges (12.4 of these
  reactions were anaphylaxis)
• Provocation reproduced original symptoms, albeit
  milder
• All adverse reactions were completely reversed by
  steroids, H1-antihistamines and epinephrine, if
  needed

50
Question 3

• Does the multiple drug allergy syndrome exist?
• A. yes
• B. no
• C. maybe

51
Multiple Drug Allergy Syndrome

• The multiple drug allergy syndrome appears to
  be a propensity to make immune responses to
  haptens and then to express a broad range of
  immunopathologic responses, rather than a
  propensity to react in specific ways to specific
  classes of drugs
• (Sullivan, Middletons Allergy Principles and
  Practice, 1993)

52
Historical Evidence for MDAS

• 1966 - Smith et al. noted for the first time
  that a history of a prior allergic reaction to
  any drug was a risk factor for penicillin allergy
  (N Engl J Med 274998-1002)
• 1989 - Sullivan et al. found that 21 of 312
  patients who had histories of penicillin allergy
  developed immunopathologic reactions to other
  classes of antibiotics (abstract)
• 1991 - Kamada et al. found that 40 of children
  evaluated for drug allergy had had reactions to
  more than one class of antibiotics (Allergy Proc
  12347-50, 1991)

53
Question 4

• Patients who have reactions to multiple classes
  of drugs are more likely to have which of the
  following?
• A. A family history of drug allergy
• B. A history of asthma and/or eczema
• C. An immunodeficiency disorder

54
Evidence Against MDAS

• 1996 Khoury and Warrington did not find a
  difference in the frequency of allergic reactions
  to non-?-lactam antibiotics between patients with
  and without a clinical history of penicillin
  allergy (J Allergy Clin Immunol 98462-4)

55
Prevalence of MDAS

• Depends upon the definition of MDAS
• Prevalence is very low if documented IgE-mediated
  reactions only are included
• Prevalence is high if definition is liberalized
  to include all patients with clinical histories
  of adverse reactions associated with two
  unrelated drugs

56
Drug Allergy Action PlanGruchalla RS J Allergy
Clin Immunol 108475-88, 2001

• Perhaps a type of drug-allergy action plan
  should be developed for our patients who present
  with drug reaction histories. If a game plan
  were provided to the patient and the referring
  MD, the patients and the MDs fears might be
  lessened