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Penicillin AllergyLalita Tearprasert; MD
IntroductionPrevalenceImpact of penicillin allergyChemical structure and classificationsCross reactivityReactions to penicillinRisk factorsDiagnosis : In vitro, In vivoNatural evolutionDesensitization, Graded challengeResensitization
Scope
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
Practice parameter : Drug allergy 2010.
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
Practice parameter : Drug allergy 2010.
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
Practice parameter : Drug allergy 2010.
Middleton's Ed 8. Drug allergy. 1274-95.
Al-Ahmad M, et al. Asia Pac Allergy 2014;4:106-112.
Middleton's Ed 8. Drug allergy. 1274-95.
Middleton's Ed 8. Drug allergy. 1274-95.
Transformation products - Major antigenic determinants (95% of the tissue-bound penicillin) >> Penicilloyl group - Minor antigenic determinants >> Penicilloate and Penilloate
Middleton's Ed 8. Drug allergy. 1274-95.
Khan and Solensky. J Allergy Clin Immunol 2010;125:S126-37.
Major
Minor
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
Middleton's Ed 8. Drug allergy. 1274-95.
Torres & Blanca. Med Clin N Am 94 (2010) 805–820.
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
Torres & Blanca. Med Clin N Am 94 (2010) 805–820.
Practice parameter : Drug allergy 2010.
Cross-reactivity between penicillin and cephalosporins can therefore be explained through similarity of the R1 side chain
Torres & Blanca. Med Clin N Am 94 (2010) 805–820.
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)
Practice parameter : Drug allergy 2010.
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)
Practice parameter : Drug allergy 2010.
Practice parameter : Drug allergy 2010.
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
Middleton's Ed 8. Drug allergy. 1274-95.
Practice parameter : Drug allergy 2010.
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
Middleton's Ed 8. Drug allergy. 1274-95.
Practice parameter : Drug allergy 2010.
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
Middleton's Ed 8. Drug allergy. 1274-95.
Practice parameter : Drug allergy 2010.
Reactions to penicillin
Middleton's Ed 8. Drug allergy. 1274-95.
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
Middleton's Ed 8. Drug allergy. 1274-95.
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
Middleton's Ed 8. Drug allergy. 1274-95.
Torres & Blanca. Med Clin N Am 94 (2010) 805–820.
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
Torres & Blanca. Med Clin N Am 94 (2010) 805–820.
Solensky R.J Allergy Clin Immunol 2012. Volume 130, Number 6.
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
Practice parameter : Drug allergy 2010.
Torres & Blanca. Med Clin N Am 94 (2010) 805–820.
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
Practice parameter : Drug allergy 2010.
Torres & Blanca. Med Clin N Am 94 (2010) 805–820.
Geng B. World Allergy Organization Journal 2015, 8(Suppl 1):A228.
Torres MJ. et al.Clinical & Experimental Allergy, 2016 (46) 264–274.
USA, canada
Europe
Solensky R.J Allergy Clin Immunol 2012. Volume 130, Number 6.
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)
Practice parameter : Drug allergy 2010.
Torres & Blanca. Med Clin N Am 94 (2010) 805–820.
Geng B. World Allergy Organization Journal 2015, 8(Suppl 1):A228.
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)
Solensky R.J Allergy Clin Immunol 2012. Volume 130, Number 6.
Solensky and Macy. J Allergy Clin Immunol Pract 2015;3:883-7.
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
Practice parameter : Drug allergy 2010.
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
Practice parameter : Drug allergy 2010.
1.) Vague and/or distant history of penicillin allergy >> graded challenge 2.) Recent or convincing reaction histories >> rapid induction of drug tolerance (Desensitization)
Practice parameter : Drug allergy 2010.
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
Solensky R.J Allergy Clin Immunol 2012. Volume 130, Number 6.
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.
Solensky and Macy. J Allergy Clin Immunol Pract 2015;3:883-7.
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
Practice parameter : Drug allergy 2010.
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
Macy E. Curr Allergy Asthma Rep (2014) 14:476.
Torres & Blanca. Med Clin N Am 94 (2010) 805–820.
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.
Middleton's Ed 8. Drug allergy. 1274-95.
Macy E. Curr Allergy Asthma Rep (2014) 14:476.
CAP System FEIA
Fluorescense immunoassay method Phadia AB, Uppsala, SwedenSensitivity from 12.5% to 45%Specificity ranges from 83.3% to 100%
Torres & Blanca. Med Clin N Am 94 (2010) 805–820.
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
Middleton's Ed 8. Drug allergy. 1274-95.
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%
Middleton's Ed 8. Drug allergy. 1274-95.
Song WJ, et al. Asia Pac Allergy 2013;3:266-280.
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
Practice parameter : Drug allergy 2010.
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
Torres & Blanca. Med Clin N Am 94 (2010) 805–820.
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
Middleton's Ed 8. Drug allergy. 1274-95.
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
Macy E. Curr Allergy Asthma Rep (2014) 14:476.
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
Torres & Blanca. Med Clin N Am 94 (2010) 805–820.
Torres & Blanca. Med Clin N Am 94 (2010) 805–820.
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
Middleton's Ed 8. Drug allergy. 1274-95.
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
Macy E. Curr Allergy Asthma Rep (2014) 14:476.
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.
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
Practice parameter : Drug allergy 2010.
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)
Practice parameter : Drug allergy 2010.
Induction of drug tolerance
(Desensitization)
Practice parameter : Drug allergy 2010.
Middleton's Ed 8. Drug allergy. 1274-95.
Torres & Blanca. Med Clin N Am 94 (2010) 805–820.
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
Practice parameter : Drug allergy 2010.
Middleton's Ed 8. Drug allergy. 1274-95.
Torres & Blanca. Med Clin N Am 94 (2010) 805–820.
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
Practice parameter : Drug allergy 2010.
Cernadas et al. General considerations on rapid desensitization for drug hypersensitivitya consensus statement. 2010.
Practice parameter : Drug allergy 2010.
Cernadas et al. General considerations on rapid desensitization for drug hypersensitivitya consensus statement. 2010.
Practice parameter : Drug allergy 2010.
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
Practice parameter : Drug allergy 2010.
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
Practice parameter : Drug allergy 2010.
R. Mirakian et al. Clinical & Experimental Allergy, 2015 (45) : 300–327.
R. Mirakian et al. Clinical & Experimental Allergy, 2015 (45) : 300–327.
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.
Romano and Cuabet. J Allergy Clin Immunol Pract 2014;2:3-12.