Penicillin allergy

Penicillin AllergyLalita Tearprasert; MD

IntroductionPrevalenceImpact of penicillin allergyChemical structure and classificationsCross reactivityReactions to penicillinRisk factorsDiagnosis : In vitro, In vivoNatural evolutionDesensitization, Graded challengeResensitization

Introduction

Accidentally discovered Penicillin in 1928Sir Alexander Fleming (Scottish biologist, pharmacologist and botanist)Noticed antibacterial properties in a mold (Penicillium notatum)

growing on a bacterial culture plateFirst called the substance “mould juice”

and then “penicillin”

Penicillin eventually came into use during World War II as the result of the work of a team of scientists led by Howard Florey at the University of Oxford

His coworker Ernst Chain, and Fleming shared the 1945 Nobel Prize

Prevalence

Penicillin is the most prevalent medication allergy

About 10% of patients reporting a history of penicillin allergy, but up to 90% of these individuals are able to tolerate penicillins - Penicillin specific IgE antibodies are known to rapidly wane over time - Some reactions, particularly cutaneous eruptions, were the result of an underlying viral or bacterial infection - Mislabel

Khan and Solensky. J Allergy Clin Immunol 2010;125:S126-37.

Practice parameter : Drug allergy 2010.

Prakongwong T. J Med Assoc Thai 2010; 93 (Suppl. 6): S106-S111.

Patients labeled as allergic are more likely to be treated with broad spectrum antibiotics such as quinolones and vancomycin leading to - the development of bacterial resistances - high medical cost

Solensky R.J Allergy Clin Immunol 2012. Volume 130, Number 6.

Impact of penicillin allergy

Chemical structure

Bicyclic structure composed of a 4-member beta-lactam ring and a 5-member thiazolidine ring

Low molecular weight moleculeNative state: InertSpontaneous conversion under physiologic conditions to

a number of products that can covalently bind tissue and serum proteins leading to formation of new hapten-protein structures that may induce production of specific IgE responses

Middleton's Ed 8. Drug allergy. 1274-95.

Al-Ahmad M, et al. Asia Pac Allergy 2014;4:106-112.

Transformation products - Major antigenic determinants (95% of the tissue-bound penicillin) >> Penicilloyl group - Minor antigenic determinants >> Penicilloate and Penilloate

Khan and Solensky. J Allergy Clin Immunol 2010;125:S126-37.

Minor determinant–specific IgE responses to β-lactams are of major clinical importance because of their association with anaphylaxis, whereas penicilloyl IgE responses may be more associated clinically with urticarial reactions

Classifications

Torres & Blanca. Med Clin N Am 94 (2010) 805–820.

Substitution at the R1 side chains resulting in various antibiotics with different chemical structures

Amoxycillin is the drug most frequently allergy

Cross-reactivity

Cross-reactivity : bicyclic nucleus (beta-lactam ring) or side chain Cross-reactivity is not equal among all BLs and that the immunologic mechanism and the primary drug inducing the sensitization need to be taken into account

Beta- lactams

Similar chemical configurationsLow molecular weightBeta-lactam ring

Difference

Penicillin : 5-membered thiazolidine ring Cephalosporin : 6-membered dihydrothiazine ring

Differences in degradation >> cross-reactivity minimal - Penicillin forms a stable penicilloate ring, preservation of the thiazolidine ring - Cephalosporin undergo rapid fragmentation of the beta-lactam and dihydrothiazine rings

Pichichero ME. Pediatrics Vol. 115 No. 4 April 2005.

Penicillin & Cephalosporin

Since 1980, studies show that approximately 2% of penicillin skin test–positive patients react to treatment with cephalosporins, but some of these reactions may be anaphylactic reactions. (C)

Patients with a history of allergy to penicillin are not skin tested but given cephalosporins directly, the chance of a reaction is probably less than 1%. However, some of these reactions were fatal anaphylaxis

Cross-reactivity increases in cases where penicillins and cephalosporins share the same side chain

First generation cephalosporins can cross-react with penicillins more than second and third generation

Cross-reactivity between penicillin and cephalosporins can therefore be explained through similarity of the R1 side chain

Pichichero ME. Pediatrics Vol. 115 No. 4 April 2005.

R2 side chain

R1 side chain

Should avoid drug with identical R-group side chains or or receive them via rapid induction of drug tolerance

Cephalosporin Administration to Patients With a History of Penicillin Allergy

Skin testing to the cephalosporin followed by graded challenge appears to be a safe method for administration of some cephalosporins in penicillin allergic patients. (B)

Patients who have a history of a possible IgE-mediated reaction to penicillin, regardless of the severity of the reaction, may receive cephalosporins with minimal concern about an immediate reaction if skin test results for penicillin major and minor determinants are negative. (B)

Not a common consensus regarding the managementThe following are options that may be considered

(1) substitute a non–beta-lactam antibiotic (2) perform penicillin skin testing (3) perform cephalosporin skin test and if the result is negative perform a graded challenge (4) treat with the cephalosporin (should be considered only in the absence of a severe and/or recent penicillin allergy reaction history)

If penicillin and cephalosporin skin testing is unavailable, depending on the reaction history, cephalosporins may need to be given via graded challenge or rapid induction of drug tolerance. (E)

Penicillin & Carbapenam

Limited data indicate lack of significant allergic cross-reactivity between penicillin and carbapenems. (B)

No standardized skin test reagents are available, and skin testing with nonirritating concentrations of the native antibiotic has questionable predictive value

Biswas P et al. Int J Basic Clin Pharmacol. 2014 Aug;3(4):586-590.

Penicillin skin test–negative patients may safely receive carbapenems

Penicillin skin test–positive patients and patients with a history of penicillin allergy who do not undergo skin testing should receive carbapenems via graded challenge

Penicillin & Monopenam

Monobactam class (prototype: aztreonam) is poorly immunogenic and very weakly cross-reactive with other

β-lactams, possibly because of the absence of a second nuclear ring structure

Aztreonam does not cross-react with other beta-lactams except for ceftazidime, with which it shares an identical R-group side chain (B)

Penicillin and cephalosporin allergic patients may safely receive aztreonam, with the exception of patients who are allergic to ceftazidime

Reactions to penicillin

Immediate < 1 hr.

Delayed 24-48 hr.

Risks of Anaphylaxis

Idsoe O, et al. Bull WHO. 1968;38:159–188.

0.004% to 0.015% , with a fatality rate of 0.002% to 0.0015%

Penicillin parenteral : 1-2 per 10,000 --> 0.01-0.02% Practice parameter : Drug allergy 2010.

Risk factors

R. Mirakian et al. Clinical & Experimental Allergy, 2015 (45) : 300–327.

Ability of aminopenicillins (e.g., ampicillin, amoxicillin) to polymerize may be a determinant of the high rate of late-occurring exanthems especially when given to patients - viral infection - acute lymphocytic leukemia - mononucleosis - coadministered with allopurinol The basis for these interactions is not known

Diagnosis

1.) History : Immediate VS Delayed2.) Investigations

In vivo evaluations (Skin testing) - Immediate reactions : SPT, ID - Delayed reactions : Patch test, ID

In vitro evaluations - Immediate reactions : IgE-antibody - Delayed reactions : Lymphocyte activation test (LAT)3.) Drug provocation test

History of allergy

Immediate-type penicillin allergy cannot be accurately diagnosed by history alone

Reaction history is known to be a poor predictor of skin test results, and therefore penicillin allergy cannot be diagnosed accurately solely based on the history

Immediate VS Delayed, Dosage, Route, Previous exposure

Most reliable method for evaluating IgE-mediated penicillin allergy (B)

Usually are applied first as a safety measure, and then intradermal tests are recommended in case of negative puncture results

Performed electivelyPositive test: a wheal of 3 mm or more in diameter with

surrounding flare greater than the wheal

Geng B. World Allergy Organization Journal 2015, 8(Suppl 1):A228.

Penicillin skin test

Penicillin skin test reagents

Late 1960 : Development of skin test reagents for penicillin

The combination of penicillin : first-line reagent for the penicillin skin test - Major determinant (benzylpenicilloyl-polylysine [PPL]) - Minor determinant mixture (MDM) recommended by both the American Practice Parameters on Drug Allergy and the European Guidelines on the Diagnosis of Immediate Allergic Reactions to Beta-lactams

Solensky and Macy. J Allergy Clin Immunol Pract 2015;3:883-7.

Levine B. et al. Ann NY Acad Sci 1967;145:298-309.

Allergy Asthma Proc 33:152–159, 2012.

Should be performed with both major and minor determinants (B) - NPV for immediate reactions 100% - PPV for immediate reactions 40-100%

Recommended for skin testing - Penicilloyl polylysine (PPL) (PRE-PEN) - MDM (BP and benzylpenilloic acid) However, in countries where AX is the most important drug involved in sensitization, this determinant is also required for diagnosis

Torres MJ. et al.Clinical & Experimental Allergy, 2016 (46) 264–274.

USA, canada

Europe

Allergy Asthma Proc 33:152–159, 2012.

The accessibility of reagents is somewhat limitedSpain manufactures the Kit DAP-penicillin (Diater Laboratorios,

Madrid, Spain), which is comprised of separated vials of PPL and MDM and mainly used in allergy centers in Europe

www.Pre-pen.com

Pre-Pen : commercially available since 1974 (except for 2004-2009) Approved by FDA

75% of penicillin skin test–positive patients showed positive responses to only penicilloylpolylysine (NPV of penicillin skin testing without penicilloylpolylysine is poor)

Penicillin skin testing without the major determinant is not recommended because this would fail to identify many patients (B)

Importance of major determinants in penicillin skin testing

Importance of minor determinants in penicillin skin testing

In large-scale studies about 10% of patients with positive skin test responses have positive results to penicilloate, penilloate, or both (and negative results to PPL and penicillin G)

Penicillin challenges of individuals skin test negative to penicilloyl-polylysine and penicillin G have similar reaction rates compared with individuals skin test negative to the full set of major and minor penicillin determinants

Skin testing with only PPL and penicillin G (without other minor determinants), the NPV in several studies was greater than 95%

Skin testing with PPL and penicillin G appears to have adequate in the evaluation of penicillin allergy

When MDM are not available, Penicillin G has been used as an alternative, with PPL

Evaluation of penicillin allergy is based on the reaction history and likelihood of needing treatment with penicillins (C) The time elapsed since the reaction is useful because penicillin

specific IgE antibodies wane over time

Patients with IgE-mediated penicillin allergy 5 years after reacting --> 50% lose their sensitivity 10 years after reacting --> 80% lose their sensitivity

Unavailable penicillin skin testing

1.) Vague and/or distant history of penicillin allergy >> graded challenge 2.) Recent or convincing reaction histories >> rapid induction of drug tolerance (Desensitization)

Contraindication for penicillin skin test, DPT, Desensitization

Histories of severe non–IgE-mediated reactions - Stevens-Johnson syndrome - DRESS - Toxic epidermal necrolysis - Interstitial nephritis - Hemolytic anemia are not candidates for skin testing, challenge or desensitization penicillins should avoid indefinitely

Macy E. Curr Allergy Asthma Rep (2014) 14:476.

IgE antibodies directed at the R-group side chain (rather than the core penicillin determinants)

Able to tolerate other penicillin class compoundsSkin test results that are positive to a nonirritating concentration of either amoxicillin or ampicillin but test negative to penicillin major

and minor determinants

IgE-mediated

Parker CW, et al. J Exp Med 1962;115:803-19.

More common in some parts of Europe, compared with North America

Selective Amoxycillin allergy

non IgE-mediated

Approximately 5% to 10%Delayed maculopapular rashRisk - concurrent viral illness esp. EBV (nonpruritic rash)

- allopurinol - chronic lymphocytic leukemia

Most patients will tolerate future administration of penicillin other than ampicillin and amoxicillin

Histories are known to be a poor predictor of skin test results. Penicillin skin testing should be considered even in patients with a history suggestive of amoxicillin/ampicillin-associated maculopapular rashes

before a future course of penicillin is given

If the puncture tests are negative, intradermal testing followsUsing the same test materials, 0.02 ml is administered

intradermally through individual 27 gauge tuberculin syringesPositive test: a wheal of 3 mm or more in diameter with

surrounding flare greater than the whealHx Immediate reaction : Read and recorded after 15 min

Hx Delayed reaction : Readings are taken at 48 and 72 hoursRare systemic reactions

Penicillin Intradermal test

Specific IgE Antibodies

2 main methods 1.) Detection of antibodies in serum by solid-phase immunoassays - CAP/ RAST 2.) Detection on the basis of basophil activation on contact with the hapten - BAT

Commercially available serologic tests used to diagnose penicillin allergy are not clinically useful at this time

Blanca et al. Allergy 2009: 64: 183–193.

CAP System FEIA

Fluorescense immunoassay method Phadia AB, Uppsala, SwedenSensitivity from 12.5% to 45%Specificity ranges from 83.3% to 100%

Diagnostic sensitivity for penicilloyl-IgE - 65% to 85% compared with penicilloyl-polylysine skin tests - 32% to 50% compared with a combination of skin testing and provocative challenge

Minor determinant penicillin IgE antibodies are not reliably detected by available allergosorbent-type immunoassays

Skin testing remains the diagnostic procedure of choice for IgE-dependent penicillin allergy

Basophil activation test (BAT)

Flow cytometry assessment of drug-induced basophil activation by means of increased surface markers such as CD63 and CD203c

BAT for diagnoses of beta-lactam allergies - Sensitivities : ranged from 28.6% to 55% (approximately 50%, in patients with positive clinical history and skin tests) - Specificity was more than 90%

Song WJ, et al. Asia Pac Allergy 2013;3:266-280.

Sensitivity of in vitro tests for penicillin specific IgE was as low as 45% compared with skin testing

Negative in vitro test result does not rule out an IgE-mediated allergy

In vitro tests for IgE directed against penicilloylpolylysine, penicillin G, penicillin V, amoxicillin, and ampicillin are

commercially available, but they are not suitable alternatives to skin testing because these assays have unknown predictive value, which limits their usefulness

Patch tests

Can be done with BP, AM, AX, and the culprit BL, using a concentration of 5% in petrolatum

Readings 15 minutes after removal of the strips and again 48 and 72 hours later

Intradermal and/or patch tests with a late reading at 48 to 72 hours have usually been recommended for the diagnosis of nonimmediate reactions to BL

Lymphocyte transformation tests (LAT)Measures the proliferation of T cells to a drug in vitro,

from which one concludes a previous in vivo reaction due to a sensitization

Often strongly positive in drug-allergic subjects, but the response usually was not distinguishable from patients receiving equally intense and recent therapy but without reactions

Drug provocation testGold standard testUsed to confirm a clinically significant IgE-mediated penicillin allergyOral challenge with a typical therapeutic dose followed by 1 h

of observation<1 % will have a delayed onset : typically diffuse macular papular rash after 2–5 daysUsed for evaluation of delayed onset beta-lactam associated rashes in children, most of whom also have evidence for viral infections at the time of their beta-lactam-associated ADRs

The methodology is not yet standardized

Giving increasing doses up to a maximum amount of one-fifth of the therapeutic dose

If good tolerance exists in this first step, then at least 48 hours later, increasing doses are usually given up to a full therapeutic dose (mostly on an outpatient basis in milder reactions)

A full therapeutic dose should be given for a number of days similar to a therapeutic regimen, because delayed appearing reactions highly depend on the cumulative dose

Reagents & Conc. for SPT, ID & DPT

DPT should not be performed if - an acute reaction occurred within the last 4 to 6 weeks - antihistamines or oral steroids are being used - active signs of underlying disease such urticaria, uncontrolled asthma (i.e., forced expiratory volume in 1 second [FEV1] value less than 70% of predicted), or uncontrolled cardiac, renal, or hepatic disease or current upper airway infection

Relatively contraindicated in patients with histories of TEN, SJS, DRESS, DiHS, AGEP , or severe organ-specific involvements

Natural evolutionCurrent evidence indicates that patients with immediate allergic reactions to penicillins may convert from skin test-positive to -negative after a variable period of time and results indicate that in penicillin allergy the rate of negativization differs between patients with cross-reactivity and those with a selective IgE response

Group B : selective response to amoxicillin

Group A : response to benzylpenicilloyl or minor determinant mixture

Blanca M. et al. J Allergy Clin Immunol 1999;103:918-24.

After a 5-year follow-up, only 40% of those with positive skin tests results to BP determinants tested negative, whereas 100% of those with a selective response to AX tested negative.

Increasing age and increasing TSR were associated with a lower rate of positive PenST results

Macy E. et al.The Permanente Journal/ Spring 2009/ Volume 13 No. 2.

Fernandez et al. Allergy 2009: 64: 242–248.

The objective of a graded challenge is to cautiously introduce a drug in patients who are unlikely to be allergic to itDoes not modify an individual's immune response to a given drugThe number of steps in the procedure may be 2 or severalThe intervals between doses are dependent on the type of previous reaction, and the entire procedure may take hours

or days to complete

Graded challenge

More caution should be exercised for graded challenge procedures that use a parenteral route of administration

because more likely to produce severe anaphylaxisContraindicated : a severe non–IgE-mediated reaction

(such as SJS, TEN, or exfoliative dermatitis)If penicillin skin testing is performed with only penicilloyl-polylysine and penicillin G, initial administration of penicillin may need to be done via graded challenge (ie, 1/100 of the dose, followed by the full dose)

Induction of drug tolerance

(Desensitization)

Useful especially in Type 1 allergy (immediate reactions)

Indicated when an offending drug cannot be replaced or significant more effective or fewer side effects than other alternatives

Before desensitization, an accurate diagnosis needs to be done, and the benefits must outweigh the risks

Administering progressive doses of a drug every 15 to 30 minutes for IgE-mediated reactions until a full therapeutic dose is clinically tolerated (render effector cells less reactive)

Typically are done within hours, and the typical starting dose is in the microgram range

Performed via oral, intravenous, or subcutaneous routes (no comparative studies to compare the safety of different routes)

The resulting state is temporary, and its maintenance requires continued administration of the offending drug

Classical protocols for oral and intravenous desensitization to penicillin start at 1/10,000 to 1/100 of the target dose; doubled doses are administered every 15–20 min over the course of several hours until the therapeutic dose is reached

In patients with histories of severe anaphylaxis (e.g., hypotension with loss of consciousness, severe bronchospasm), the initial dose should be between 1/1,000,000 and 1/10,000 of the full therapeutic one

Most cases, can be accomplished within 4 to 12 hours

Risk of acute allergic reactions, which occur in mild form in 30% to 80% of penicillin-allergic patients undergoing desensitization

Cernadas et al. General considerations on rapid desensitization for drug hypersensitivitya consensus statement. 2010.

Resensitizaion

Redevelopment of penicillin allergy in patients with a history of penicillin allergy who later demonstrate negative penicillin skin test resultsResensitization after oral treatment with penicillin is rare in both pediatric and adult patients (B)

Routine repeat penicillin skin testing is not indicated in patients with a history of penicillin allergy who have tolerated 1 or more

oral courses of oral penicillin

Resensitization after high-dose parenteral treatment with

penicillin appears to be more likely --> Repeat penicillin skin testing in this situation may be warranted (C)

Consideration may be given to retesting individuals with recent or particularly severe previous reactions

Consider to repeat penicillin skin test

R. Mirakian et al. Clinical & Experimental Allergy, 2015 (45) : 300–327.

The Standards of Care Committee of the British Society for Allergy and Clinical Immunology (BSACI)

Thank you

Romano and Cuabet. J Allergy Clin Immunol Pract 2014;2:3-12.

Penicillin allergy

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