Ivan Cardona, MD

Allergy & Asthma Assoc. of Maine

THINK YOU ARE ALLERGIC TO PENICILLIN?

MAYBE NOT

Up to 10% of patients report a history of “Penicillin allergy.” What % of these patients truly have an IgE-mediated reaction to penicillin?

A) 2%B) 10%C) 25%D) 50%

QUESTION

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 allergicC) 25%D) 50%

ANSWER

We see many patients (~10%) who have PCN allergy (or think they do!)Beta-lactams account for >50% of ADRIt is important to know how to appropriately

evaluate for PCN allergy (.03% anaphylactic)Rate of anaphylaxis to IV PCN 1-2/10000 patientsPatients 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)

RELEVANCE

Symptom confusion:Symptoms may be caused by underlying illnessDrug to drug interactionsAntibiotic side-effectsPoor recollection of previous reaction from years agoAssumption 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

WHY OVER-REPORTING OF PCN ALLERGY?

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 difficile14% more MRSA30% more vancomycin-resistant Enterococcus $20 Million increase cost/year for this group of

patients

Macy E, Contreras R. JACI. 2014;133(3):790-6

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

OBJECTIVES

2010 Primer on Allergic and Immunologic Diseases

Khan DA, Solensky R. Drug allergy. J Allergy Clin Immunol 2010;125:S126:37.

RECOMMENDED READ

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 acetaminophenSide effects: Gastritis with NSAIDsDrug interactions: Bleeding with concurrent erythromycin, warfarin

ADVERSE DRUG REACTIONS

Type B (Unpredictable) ReactionsDose-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)

ADVERSE DRUG REACTIONS

Most drugs not reactive in native stateMust 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 independentlyHaptenation: drug (hapten) binds to carrier protein to become immunogenic

MECHANISM OF DRUG ALLERGY

HAPTENATION

• PCN is immunologically inert, but haptenates form reactive intermediates

DRUG ALLERGY:IMMUNOLOGICALLY-MEDIATED ADR’S

Type I Type II

Type IV Type III

Ag

Mast Cell & Basophil

T cell

IgEYYYYIgG or IgM on cell surface Ags with subsequent IC

YY

IgG or IgM on circulating Ags with IC deposited postcap venules

YYAPC

UrticariaAngioedemaAnaphylaxis-lactams

Hemolytic anemiaThrombocyt.NeutropeniaQuinidine

VasculitisSerum sickness:-Urticaria-Arthralgias-FeverATGInfliximab

ExanthemsContact dermatitisSJS/TENDRESSPenicillin, SulfasNeomycinAnticonvulsants

Ag

DTH

In evaluation of a patient with drug allergies, which of the following is generally the best tool to help guide management?

A) Skin testingB) In vitro testing (drug-specific serum IgE)C) Detailed historyD) Gel and Coombs classificationE) Physical exam findings

QUESTION

In evaluation of a patient with drug allergies, which of the following is generally the best tool to help guide management?

A) Skin testingB) In vitro testing (drug-specific serum IgE)C) Detailed historyD) Gel and Coombs classificationE) Physical exam findings

ANSWER

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 EVALUATIONHISTORY 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 EVALUATIONHISTORY 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

DRUG ALLERGY EVALUATIONHISTORY IS KEY!!!

DIAGNOSTIC TOOLS & MANAGEMENT OF

PCN ALLERGY

A reliable and valid test to determine an IgE-mediated reaction exists for which of the following drug(s)?

A) CephalosporinsB) PenicillinsC) SulfonamidesD) All of the aboveE) None of the above

QUESTION

A reliable and valid test to determine an IgE-mediated reaction exists for which of the following drug(s)?

A) CephalosporinsB) Penicillins Because we know the reactive intermediatesC) SulfonamidesD) All of the aboveE) None of the above

ANSWER

IMMUNOCHEMISTRY OF PENICILLIN

In fact can ONLY test for IgE-mediated rxns And reliably ONLY FOR PCN IgE-mediated rxns

Skin tests1) Skin prick test2) Intradermal test Useful only if positive (exception: penicillin)

In vitro assays3) Serum IgE (RAST, ImmunoCAP) Unclear sensitivity/specificity

DIAGNOSTIC TESTING

Which of the following is true regarding penicillin allergy?

A) History is adequate for diagnosisB) Skin testing has high negative predictive

valueC) Cross-reactivity with cephalosporins is highD) Resensitization is common

QUESTION

Which of the following is true regarding penicillin allergy?

A) History is adequate for diagnosisB) Skin testing has high negative predictive

valueC) Cross-reactivity with cephalosporins is highD) Resensitization is common

ANSWER

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 ChallengeSerum IgE testing: 97-100% spec; but 45% sensitivity

So can R/I but cannot R/O; Not available for MDMResensitization rare if tolerated PCN after skin (-)

PENICILLIN SKIN TESTING

WHO SHOULD BE PCN-ALLERGY TESTED?

Patients with ambiguous or unclear h/o PCN allergyPatients with vague history of rxn >10 yrs agoPatient claiming a “family history” of PCN allergyPre-op screening of patients with PCN allergy label:

Mayo ClinicCleveland ClinicMayo Hospital Jacksonville, FloridaSan 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??)

2.Gerace, K. Abstract 366. AAAAI 2015 Annual meeting1.Macy,E. JACI in practice 2013;1:258-63

CONTRAINDICATIONS FOR PCN TESTING

ContraindicationsHistory 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 vasculitisReported anaphylaxis within the last 5 yearsAntihistamines should be held in previous 48-72 hrs

TESTING AGENTS

PRP : PRE-PENMajor determinant90% sensitivityPG : PenG (diluted 10,000 units/mL)Minor determinantIncrease test to 98% sensitivity + : Histamine (positive control)

- : Saline (negative control)

TESTING PROCEDURESTEP 1: PRICK/PUNCTURE TESTING

Positive = 3mm or larger than the negative control

+_PRP

PG

Wait 15-20 minutes to read results. Measure & Record.

Both PRE-PEN and PenG are negative so proceed to intradermals.

+ _PRP PG

Actual Patient Results photo

TESTING PROCEDURESTEP 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

PRP

C

PG

TESTING PROCEDURESTEP 3: ORAL CHALLENGE

Final step to ensure patient/provider confidenceAdminister an initial dose of 1/10 of the

therapeutic dose of AmoxicillinObserve for 30 min. If no reaction, then a full

dose of Amoxicillin is givenPatient observed for one hour

ACAAI Drug and Anaphylaxis Committee Expert Opinion 2015

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 1st and 2nd generation cephalosporin package inserts that state “up to 10% cross reactivity” to cephalosporins in PCN-allergic pts

(NOT TRUE TODAY)

CEPHALOSPORINS

Solensky R. et al. Ann Allergy Asthma Immunol 2010; 105:259-73Solensky, 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.

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

CEPHALOSPORINS

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

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

challengeBeta Lactamase Inhibitors (e.g. Clavulanate,

Sulbactam, tazobactam) Little or no data on allergenicity

OTHER BETA LACTAMS

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

QUESTION

Type I Skin testing and oral challenge (if ? PCN allergy)AvoidanceDrug Desensitization

Types II, IIIAvoidance

Type IV If cutaneous exanthem: May continue drug If SJS/TEN, DRESS: Strict avoidance

MANAGEMENT

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

TAKE HOME POINTS

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.

REFERENCES

Questions, Comments??

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.