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THINK YOU ARE
ALLERGIC TO PENICILLIN?
MAYBE NOT
Ivan Cardona,
MD
Allergy &
Asthma Assoc.
of Maine
QUESTION
 Up to 10% of patients report a history of
“Penicillin allergy.” What % of these patients
truly have an IgE-mediated reaction to penicillin?
A)
B)
C)
D)
2%
10%
25%
50%
ANSWER
 Up to 10% of patients are labeled as “Penicillin
allergic.” What % of these patients truly has an
IgE-mediated reaction to penicillin?
A) 2%
B) 10%
In other words 9 out of 10 who report PCN
allergy
are not truly allergic
C) 25%
D) 50%
RELEVANCE
 We see many patients (~10%) who
have PCN allergy (or think they do!)
 Beta-lactams account for >50% of ADR
 It is important to know how to appropriately evaluate
for PCN allergy (.03% anaphylactic)
 Rate of anaphylaxis to IV PCN 1-2/10000 patients
 Patients labeled PCN allergy get alternative
antibiotics that may be less effective, more toxic,
more expensive, and contribute to development of
drug resistant bacteria (e.g. Vanc-Res-Enterococcus,
C. Difficile diarrhea)
WHY OVER-REPORTING
OF PCN ALLERGY?
 Symptom confusion:
 Symptoms may be caused by underlying illness
 Drug to drug interactions
 Antibiotic side-effects
 Poor recollection of previous reaction from years ago
 Assumption by patient or provider that PCN allergy
was inherited from a parent with PCN allergy
 PCN allergy diminishes or resolves after several years
have passed in many patients
 50% lose their sensitivity at 5 years
 80% lose their sensitivity at 10 years
DANGERS/COSTS OF
PCN ALLERGY LABEL
 Retrospective matched cohort study of 51,582
“Penicillin Allergic” patients hospitalized in Kaiser
Foundation South California Hospitals 2010 -2012
 Longer hospital stays (.59 day/person)
 Treated with more fluoroquinolones, clindamycin,
and vancomycin
 23.4% more C difficile
 14% more MRSA
 30% more vancomycin-resistant Enterococcus
 $20 Million increase cost/year for this group of
patients
Macy E, Contreras R. JACI. 2014;133(3):790-6
OBJECTIVES
 Learn how to classify adverse drug reactions and
drug allergies
 Discuss the essential questions in the history to
evaluate for drug allergy
 Review the diagnostic tools and management for
suspected penicillin allergy
RECOMMENDED READ
2010 Primer on Allergic and Immunologic Diseases
Khan DA, Solensky R. Drug allergy. J Allergy Clin
Immunol 2010;125:S126:37.
ADVERSE DRUG REACTIONS
 Noxious, unintended, undesired reaction to drug
 Type A (Predictable) Reactions – 80%
 Dose-dependent, related to pharmacologic properties of
drug, can occur in any individual
 Overdose: Hepatic failure with acetaminophen
 Side effects: Gastritis with NSAIDs
 Drug interactions: Bleeding with concurrent
erythromycin, warfarin
ADVERSE DRUG REACTIONS
 Type B (Unpredictable) Reactions
 Dose-independent, unrelated to pharmacologic
properties of drug, occurs in susceptible pts only
 Intolerance: Psychologic disturbance while on
steroids
 Idiosyncracy: Hemolytic anemia with sulfa drugs in
patient with G6PD deficiency
 Pseudoallergy/Anaphylactoid reaction: Urticaria with
radiocontrast material, vancomycin, opiates
 Drug Allergy: Urticaria with penicillin
(Immunologically mediated response)
MECHANISM OF DRUG ALLERGY
 Most drugs not reactive in native state
 Must be converted (via enzymes or spontaneous
degradation – like PCN) to reactive intermediates
 Identity of many drug intermediates not known  no
accurate diagnostic test
 Most drugs are too small to elicit immune response
independently
 Haptenation: drug (hapten) binds to carrier protein to
become immunogenic
HAPTENATION
• PCN is immunologically inert, but haptenates form reactive
intermediates
DRUG ALLERGY:
IMMUNOLOGICALLY-MEDIATED ADR’S
Type I
IgE
Ag
Y
YY
Y
Urticaria
Angioedema
Anaphylaxis
Mast
Cell &
Basophil
b-lactams
Type III
Vasculitis
Serum sickness:
-Urticaria
-Arthralgias
-Fever
Y
Y
IgG or IgM on
circulating Ags
with IC
deposited
postcap venules
ATG
Infliximab
Type II
Ag
IgG or IgM on
cell surface
Ags with
subsequent IC
Y
Y
Type IV
DTH
Hemolytic
anemia
Thrombocyt.
Neutropenia
Quinidine
Exanthems
Contact dermatitis
SJS/TEN
DRESS
APC Penicillin, Sulfas
T cell
Neomycin
Anticonvulsants
QUESTION
 In evaluation of a patient with drug allergies,
which of the following is generally the best tool
to help guide management?
A)
B)
C)
D)
E)
Skin testing
In vitro testing (drug-specific serum IgE)
Detailed history
Gel and Coombs classification
Physical exam findings
ANSWER
 In evaluation of a patient with drug allergies,
which of the following is generally the best tool
to help guide management?
A)
B)
C)
D)
E)
Skin testing
In vitro testing (drug-specific serum IgE)
Detailed history
Gel and Coombs classification
Physical exam findings
DRUG ALLERGY EVALUATION
HISTORY IS KEY!!!
 How long ago did the reaction occur?
 PCN-specific IgE Abs can wane over time with avoidance
(eg, 80% of PCN allergic pts will be negative in 10 yrs)
 Which systems (eg, cutaneous, respiratory, GI) were
involved in rxn, and what were the characteristics?
 Joint pain e.g. may suggest serum sickness
 When during the course did the rxn occur – during/after?
 Why was the medication prescribed?
 Sx of underlying disease may be misattributed to drug
(eg, scarlatina—Scarlet Fever rash)
DRUG ALLERGY EVALUATION
HISTORY IS KEY!!!
 What were the symptoms involved in the reaction?
 E.g. scaling/peeling/vesicles/bullae typically not IgE-mediated
 Were you taking concurrent medications at time of rxn?
 Abx usually blamed but opiates/NSAIDs could be culprits
 What was the therapeutic management required for rxn?
 Suggests severity of reaction
 Had you taken the same drug previously?
 Type I rxns require sensitization
DRUG ALLERGY EVALUATION
HISTORY IS KEY!!!
 Have you taken the same or similar med since?
 Have you experienced sx similar to rxn in absence of drug?
 eg, Chronic recurrent idiopathic urticaria can be confused
for drug allergy
 Did you have an underlying condition ( eg, viral illness) that
favors rxns to certain drugs?
 eg, EBV/Mononucleosis for aminopenicillin rxns
DIAGNOSTIC TOOLS &
MANAGEMENT OF
PCN ALLERGY
QUESTION
 A reliable and valid test to determine an IgE mediated reaction exists for which of the
following drug(s)?
A)
B)
C)
D)
E)
Cephalosporins
Penicillins
Sulfonamides
All of the above
None of the above
ANSWER
 A reliable and valid test to determine an IgE mediated reaction exists for which of the
following drug(s)?
A) Cephalosporins
B) Penicillins
Because we know the reactive
intermediates
C) Sulfonamides
D) All of the above
E) None of the above
IMMUNOCHEMISTRY OF PENICILLIN
DIAGNOSTIC TESTING
 In fact can ONLY test for IgE-mediated rxns
 And reliably ONLY FOR PCN IgE-mediated rxns
 Skin tests
1) Skin prick test
2) Intradermal test
 Useful only if positive (exception: penicillin)
 In vitro assays
3) Serum IgE (RAST, ImmunoCAP)
 Unclear sensitivity/specificity
QUESTION
 Which of the following is true regarding penicillin
allergy?
A) History is adequate for diagnosis
B) Skin testing has high negative predictive
value
C) Cross-reactivity with cephalosporins is high
D) Resensitization is common
ANSWER
 Which of the following is true regarding penicillin
allergy?
A) History is adequate for diagnosis
B) Skin testing has high negative predictive
value
C) Cross-reactivity with cephalosporins is high
D) Resensitization is common
PENICILLIN SKIN TESTING
 Penicillin G (as a surrogate for MDM)
 Pre Pen (Penicilloyl – Major Antigenic Determinant)
 Minor Determinant Mixture (Penicilloate, Penilloate)
 MDM not available in US
 Omitting from skin testing may fail to detect 1-2%
 High Negative Predictive Value (~99%) [PPV~50%]
 10-20% PCN allergic are skin test (+) only to MDM
 If skin test (-)  Oral Challenge
 Serum IgE testing: 97-100% spec; but 45% sensitivity
 So can R/I but cannot R/O; Not available for MDM
 Resensitization rare if tolerated PCN after skin ( -)
WHO SHOULD BE PCN-ALLERGY TESTED?
Patients with ambiguous or unclear h/o PCN allergy
Patients with vague history of rxn >10 yrs ago
Patient claiming a “family history” of PCN allergy
Pre-op screening of patients with PCN allergy label:
Mayo Clinic
Cleveland Clinic
Mayo Hospital Jacksonville, Florida
San Diego Kaiser Clinic (inpatient testing)
Univ. of Pennsylvania Hospital (pre-transplant program)
Northwestern Memorial Hospital (pre-transplant program)
Mercy and Maine Medical Center (perhaps near future??)
1.Macy,E. JACI in practice 2013;1:258-63
2.Gerace, K. Abstract 366. AAAAI 2015 Annual meeting
CONTRAINDICATIONS FOR PCN TESTING
Contraindications
 History of severe skin reactions, such as SJS, TEN,
DRESS, Exfoliative dermatitis, Bullous pemphigoid,
Pemphigus vulgaris, Drug-induced Lupus, etc,
 Organ specific drug reactions like Hemolytic anemia,
Cytopenia, Nephritis, Hepatitis, Pneumonia
 Serum sickness, Drug-induced vasculitis
 Reported anaphylaxis within the last 5 years
 Antihistamines should be held in previous 48-72 hrs
TESTING AGENTS
PRP : PRE-PEN
 Major determinant
 90% sensitivity
PG : PenG (diluted 10,000 units/mL)
 Minor determinant
 Increase test to 98% sensitivity
+ : Histamine (positive control)
- : Saline (negative control)
TESTING PROCEDURE
STEP 1: PRICK/PUNCTURE TESTING
Positive = 3mm or larger than
the negative control
Wait 15-20 minutes to read
results. Measure & Record.
Both PRE-PEN and PenG are
negative so proceed to
intradermals.
_
+
PRP
Actual Patient Results photo
PG
TESTING PROCEDURE
STEP 2: INTRADERMAL TESTING
•
•
Create bleb 2-3 mm under skin (similar
to PPD)
Circle the perimeter of the bleb
Wait 15-20 minutes to read results.
Measure & Record.
Positive = Original bleb has GROWN
3mm or larger
TESTING PROCEDURE
STEP 3: ORAL CHALLENGE
 Final step to ensure patient/provider confidence
 Administer an initial dose of 1/10 of the
therapeutic dose of Amoxicillin
 Observe for 30 min. If no reaction, then a full dose
of Amoxicillin is given
 Patient observed for one hour
ACAAI Drug and Anaphylaxis Committee Expert Opinion 2015
CEPHALOSPORINS
 2-3% of penicillin skin test (+) pts will react to
cephalosporins
 Older studies indicated 10% of pts with PCN allergy
would react to cephalosporin
 Prior to 1980 cephalosporins were contaminated by
PCN
 Partially responsible for the 1 st and 2 nd generation
cephalosporin package inserts that state “up to 10%
cross reactivity” to cephalosporins in PCN-allergic pts
(NOT TRUE TODAY)
Solensky R. et al. Ann Allergy Asthma Immunol 2010; 105:259-73
Solensky, R (2015). Penicillin-allergic patients: Use of cephalosporins, carbapenems, and monobactams. In
D.S. Basow (Ed.), UpToDate. Retrieved from http://www.uptodate.com/home/index.html.
CEPHALOSPORINS
 CASE: Pt with history of penicillin allergy requiring
cephalosporin
 B/c up to 3% will react to cephalosporins (some with
anaphylaxis)  PCN allergy testing recommended
 Penicillin skin test
 (–)  Give cephalosporin
 (+)  Give cephalosporin (with different R-group) via
Graded Challenge
 So PCN skin testing should be considered before giving a
cephalosporin in patients with h/o PCN allergy
 If history inconsistent with IgE-mediated rxn or no
penicillin skin test available  Graded Challenge
R-CHAINS/R-GROUPS
 With a reported cephalosporin allergy, testing and oral
challenge should be with a cephalosporin that does not share
the same R -chain
OTHER BETA LACTAMS
 Monobactam (e.g. Aztreonam)
 Does NOT cross react with PCNs or Cephalosporins
(except Ceftazidime -same R-group) and may be given
without PCN skin testing
 Carbepenems (e.g. Imipenem, Meropenem)
 Behave like cephalosporins (i.e. low cxr with PCN)
 So PCN testing recommended or do a graded challenge
 Beta Lactamase Inhibitors (e.g. Clavulanate,
Sulbactam, tazobactam)
 Little or no data on allergenicity
QUESTION
 So what if the patient truly has a PCN allergy (e.g.
good history and/or positive PCN testing) and
actually needs PCN and there are no alternative
agents (e.g. Syphilis)?
 Drug Desensitization (usually in the ICU)
 Induction of temporary tolerance
 Must continue tx to remain desensitized
 Does not prevent non-IgE-mediated rxns (eg, SJS, DRESS)
 Start at ~1/10,000 of full dose  double dose q15 min
MANAGEMENT
 Type I
 Skin testing and oral challenge (if ? PCN allergy)
 Avoidance
 Drug Desensitization
 Types II, III
 Avoidance
 Type IV
 If cutaneous exanthem: May continue drug
 If SJS/TEN, DRESS: Strict avoidance
TAKE HOME POINTS
 Classification of ADRs is useful in determining
appropriate diagnostic procedures and options for
further treatment
 History is the most important initial diagnostic tool
in PCN/drug allergy evaluation
 PCN skin testing has potential to play a public health
role by decreasing use of broad-spectrum Abx and
lowering health care costs
REFERENCES
 Gruchalla RS, Piromohamed M. Antibiotic allergy. N Engl J
Med 2006;354:601-609.
 Khan DA , Solensky R. Drug allergy. J Allergy Clin Immunol
2010;125:S126:37.
 Pichler WJ. An approach to the patient with drug allergy.
UpToDate, 2010 . 1-23.
 Solensky R, Khan DA . Drug Allergy: An Updated Practice
Parameter. Ann Allergy Asthma Immunol 2010;105:2-78.
 Tam S. Drug allergy. In Allergy and Asthma: Practical
Diagnosis and Management. Mahmoudi M, ed. McGraw Hill,
New York, 2008. 236-246.
THANK YOU!!!
 Special thanks to my colleague Carah Santos, M.D.,
for sharing some of her well-designed slides and
 Thank you to the American College of Allergy Asthma
and Immunology for their assistance in data
collection
 And Thank you to the Maine Assoc. of Physician
Assistance for inviting me to speak today.
Questions, Comments??