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An Examination of Penicillin Allergy. Resident Grand Rounds February 12, 2002 David H. Priest, MD. Outline. Introduction What is a true penicillin allergy? How can we determine who is truly allergic?

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an examination of penicillin allergy

An Examination of Penicillin Allergy

Resident Grand Rounds

February 12, 2002

David H. Priest, MD

outline
Outline
  • Introduction
  • What is a true penicillin allergy?
  • How can we determine who is truly allergic?
  • What are the antimicrobial resistance and economic benefits of clarifying penicillin allergy?
  • A brief comment on cephalosporins.
  • Who cares?! Infections for which penicillin is preferred or absolutely indicated.
  • Approaching the patient with penicillin allergy.
  • Conclusions and questions.
introduction
Introduction
  • Insert case here.
  • 10% of population claims to be allergic to penicillin.
  • In reality, 1-3% have an IgE-mediated response to penicillin.
  • Claims of penicillin allergy along with a wave of newer antibiotics (such as fluoroquinolones) have prompted physicians to avoid penicillins no matter how mild the reported reaction - increasing vancomycin and broad-spectrum abx use.
  • Two large issues seem to hang over modern medicine antimicrobial resistance and cost - leading to recent studies on the issue of penicillin allergy.
what is a true penicillin allergy first some pathophysiology
What is a true penicillin allergy? First some pathophysiology.
  • Penicillin is simple in structure and of low molecular weight.
  • Low molecular weight substances that are able to illicit an immune response are called haptens.
  • Alone, haptens cannot cause an immune response and must bind to native proteins in the plasma and cell surfaces to form hapten-carrier complexes.
  • These complexes form antigens that IgE recognizes.
pathophysiology continued
Pathophysiology continued:
  • Most haptens are the breakdown products (isomers) of penicillin. This breakdown occurs in the vial, tablet or powder prior to administration.
  • The beta-lactam ring is unstable and when it binds to a protein it acylates lysine residues resulting in a penicilloyl epitope known as benzylpenicilloyl (BSO) or the ...major determinant.
pathophysiology continued6
Pathophysiology continued:
  • The major determinant is produced in the largest amount and therefore is immunodominant in PCN specific immune responses.
  • Beta lactam rings can also make molecular rearrangements with carboxyl and thiol groups forming less dominant minor determinants.
  • The terms major and minor determinant refer only to the amount of hapten available for binding and not to the importance of each hapten in an immunologic response.
pathophysiology continued7
Pathophysiology continued:
  • These hapten-carrier complexes are recognized as antigen by IgE on mast cells and basophils.
  • Minor determinant cause 90-95% of IgE-mediated reactions (anaphylaxis).
  • Major determinant is more often associated with urticaria although anaphylaxis is possible (also associated with accelerated or delayed rxn secondary to IgG or IgM)
pathophysiology continued8
Pathophysiology continued:
  • This is an important clinical distinction because patients can have an IgE-mediated rxn to the minor determinant alone - so skin tests should include both major and minor determinant.
pathophysiology continued10
Pathophysiology continued:
  • Prior to 1970, PCN preparations were often contaminated with trace quanities of macromolecules and drug polymers which increased the frequency of allergic reactions. Recent “purified” PCNs have reduced these reactions.
  • Rashes are common in a variety of infections. (HIV, Hep B, Coxsackie virus, Echo virus, etc.)
  • Therefore, patients with infections who take PCN and develop a rash should not automatically be labeled with PCN allergy.
types of allergic reactions
Types of Allergic Reactions
  • Type I - Immediate Reactions- IgE-mediated systemic rxns of mast cells and basophils

- Usually occur within 1 hour of admin. - Consist of any combination of diffuse erythema, pruritus, urticaria, angioedema, bronchospasm, laryngeal edema, hyperperistalsis, hypotension and cardiac arrhythmias.

- 0.004%-0.015% of tx courses - Most often in adults 20-49 years. - More common if hx of atopy or parenteral admin - Fatal outcomes in 1 per 50,000-100,000 admin.

- Skin testing does have a role in evaluation of these pts.

type i reactions cont
Type I Reactions cont.
  • “Accelerated rxns” are IgE-mediated and can occur from 1-72 hours after administration. These often have urticaria, angioedema, laryngeal edema, and/or wheezing but... Life threatening reactions occurring beyond 1 hour of PCN administration are rare.
ige mediated reaction
IgE-mediated reaction:
  • IgE on mast cells/basophils recognize hapten-carrier complexes as antigen
  • Leads to a release of mediators of inflammation (histamine, serotonin, prostatgladins etc.)
  • Causes increased capillary permeability (edema), changes in smooth muscle tone, and increased production of viscid mucous in target tissues.
types of allergic reactions14
Types of Allergic Reactions
  • Types II, III, IV, and idiopathic - Classified based on underlying immune response (usually not immediate)- Are not IgE-mediated - Skin testing has no role in these rxn
  • Refer to chart in handout - note that 1%-4% of pts. receiving pcn will have a maculopapular or morbilliform rash at 72 hours after admin.
slide15
How can we determine who is truly allergic? The explanation of skin testing and its utility in several medical settings
  • Skin testing should include both major and minor determinant to improve sensitivity.
  • A minority of patients will react to minor determinant alone and these individuals have an increased risk of IgE-mediated anaphylaxis.
  • Currently, in the US there is no commercial source for the minor determinant. Often fresh PCN G is used for this purpose.
  • In recent months, there has also been some manufacturing difficulty with the major determinant.
skin testing
Skin Testing
  • Two basic types of skin testing: 1. Epicutaneous (scratch test and prick test) 2. Intradermal
  • Often a scratch or prick test is done first and if negative an intradermal test.
  • Used with a diluent negative control and a positive histamine controlled.
skin testing17
Skin Testing
  • Tests are read at 15 minutes and scored from negative to 4+ based on erythema and wheal size.
skin testing18
Skin Testing
  • Centers that wish to skin test must custom-make their materials or receive permission from the FDA to import them from Germany.
  • Skin testing takes 40 minutes and costs about $17 dollars per patient.
  • Several studies have examined the safety, cost, risks and how predictive skin tests are of PCN allergy in a variety of settings.
outpatient std clinic
Outpatient STD Clinic
  • Gadde et al. Clinical experience with pencillin skin testing in a large inner-city STD clinic. JAMA. 1993.
  • Purpose: 1. To determine the prevalence of (+) PCN skin tests among outpatients with well-defined but variable history of PCN allergy. 2. To determine the reproducibility, safety, and NPV of skin testing with major and minor determinant mixture.
outpatient std clinic20
Outpatient STD Clinic
  • Design: Serial consenting patients with current indications for PCN therapy were skin-tested with major and minor determinant. Those with (-) skin tests received therapeutic benzylpenicillin or ampicillin. 72 hour follow-up was conducted for adverse reactions.
outpatient std clinic21
Outpatient STD Clinic
  • Methods: 5063 consecutive patients in Baltimore STD clinic. 66% male, 90% African-American. Follow-up was 94% complete.
outpatient std clinic22
Outpatient STD Clinic
  • Results: (+) skin tests found in 7.1% of 776 individuals with a history of PCN allergy and in 1.7% of 4287 patients without a history of PCN allergy.
  • A previous history of anaphylaxis or urticaria was associated with a higher rate of (+) skin tests (17.3% and 12.4%)
outpatient std clinic23
Outpatient STD Clinic
  • Results cont: The interval from the last administration of PCN did not affect the skin test results.
  • 13 patients had reactions to the skin test itself (one had “mild anaphylaxis”, 11 had urticaria, one had a large local reaction).
outpatient std clinic24
Outpatient STD Clinic
  • Results cont: After PCN was given to those with (-) skin tests, IgE-mediated rxns occurred in 0.5% (18/3997) of those with a (-) hx. 3 pts. had an immediate rxn and 15 had an accelerated rxn. Most had urticaria and no anaphylaxis was observed.
outpatient std clinic25
Outpatient STD Clinic
  • Results cont: 2.9% (17/596) of those with a (-) skin test and a (+) hx of PCN allergy had an IgE-mediated rxn to PCN.
  • Reactions were typically mild with only 2 patients having “mild anaphylaxis” and both had a history of IgE-mediated rxn. Both responded to epinephrine. No deaths were reported.
outpatient std clinic26
Outpatient STD Clinic
  • Results cont: Of the patients with a (+) skin test, 90% had major determinant sensitivity and 10% had minor determinant sensitivity alone.
  • 97% of those with a history of PCN allergy were able to tolerate full dose PCN after a (-) skin test. No deaths occurred.
outpatient std clinic27
Outpatient STD Clinic
  • Conclusions: 1. Skin testing with major and minor determinant is safe. 2. Both reagents are needed to maximize identification of sensitized subjects. 3. PCN skin testing can facilitate the safe use of PCN in 90% of those patients with a hx of PCN allergy.
hospitalized adults
Hospitalized Adults
  • Sogn et al. A clinical trial to test the predictive value of skin testing with major and minor determinant in hospitalized adults. Arch. Int. Med. 1992.
  • Hypothesis of the authors was that a pt.-given history of PCN allergy was not predictive of subsequent rxn to PCN.
hospitalized adults cont
Hospitalized Adults cont.
  • Study - 8 centers who gave major and minor deteminants followed by PCN with 48 hr. observation in those with (-) tests. Pts. all had infections for which PCN was required.
  • 1539 patients enrolled (1422 completed) - 825 had hx of PCN rxn (54%!) - 104 were unsure - 610 had no hx of PCN rxn
hospitalized adults cont30
Hospitalized Adults cont.
  • No adverse rxn to the skin tests.
  • 566/726 pts. with a (+) hx had (-) skin tests and received PCN. Only 9/566 (1.2%) had a “possible IgE-mediated rxn” - No life-threatening anaphylaxis.
  • 568/600 pts. with a (-) hx had (-) skin tests and received PCN with no rxns.
hospitalized adults cont31
Hospitalized Adults cont.
  • 9/167 pts. with a (+) skin test did receive PCN usually by “cautious incremental dosing”. 2/9 had IgE-mediated rxn and both pts. had been reactive to both determinants. No deaths occurred.
  • Conclusions: (-) skin tests have a high NPV and the rxn rate in (+) skin test pts. was higher.
icu setting
ICU Setting
  • Arroliga et al. A pilot study of penicillin skin testing in patients with a history of pencillin allergy admitted to a medical ICU. Chest. 2000.
  • Methods: 24 pts. with hx of PCN allergy enrolled over a 3 month period. 21 pts. underwent skin testing with benzylpenicilloyl and PCN G along with histamine controls.
icu setting cont
ICU Setting cont.
  • Previous allergic rxn: unknown in 11 pts., 6 had hx of rash, 4 had hx of urticaria.
  • Results: 20/21 pts. had a (-) skin test with (+) histamine control. One pt. had (-) skin test and (-) control. All pts. received PCN without rxn and no pts. had a rxn to skin tests.
icu setting cont34
ICU Setting cont.
  • As a result of skin tests - 11 pts. had abx changed (48%).
  • Conclusions: A very small study but illustrates a potential venue for skin testing and suggests safety of testing in patients without a history of Type I rxn.
safety of skin testing
Safety of Skin Testing
  • Valyasevi et al. Frequency of systemic rxn to PCN skin testing. Annals of Allergy, Asthma, and Immunology. 2000.
  • Design: A retrospective chart review of 1710 pts. with a history of PCN allergy who underwent skin testing with both determinants to determine the safety of skin testing.
safety of skin testing cont
Safety of Skin Testing cont.
  • 86/1710 pts. had a (+) skin test and 2 pts. had a systemic rxn. Neither patient required hospitalization and responded to tx. No deaths.
  • Overall systemic rxn rate = 0.12%
  • Systemic rxn rate with (+) test = 2.3%
safety of skin testing cont37
Safety of Skin Testing cont.
  • Conclusions: Rxn rate is low. Do skin prick tests first. Avoid skin tests in those with a previous systemic rxn. Those who perform skin tests should be ready to tx systemic rxns.
the potential antimicrobial reisistance and economic benefits of clarifying penicillin allergy
The potential antimicrobial reisistance and economic benefits of clarifying penicillin allergy
  • Two issues are at the forefront of modern medicine in 2002 - antimicrobial resistance and health care cost.
  • Can the clarification of PCN allergy provide relief to both of these issues? Several studies suggest that it can.
the potential antimicrobial reisistance and economic benefits of clarifying penicillin allergy39
The potential antimicrobial reisistance and economic benefits of clarifying penicillin allergy
  • Macy. Elective penicillin skin testing and amoxicillin challenge: effect on outpatient antibiotic use, cost, and clinical outcomes. JACI. 1998.
  • Purpose: To test the effect of PCN skin testing on subsequent outpatient abx use and cost and to evaluate concerns over PCN skin testing in advance of therapeutic PCN use causing resensitization.
the potential antimicrobial reisistance and economic benefits of clarifying penicillin allergy40
The potential antimicrobial reisistance and economic benefits of clarifying penicillin allergy
  • 236 patients included in a previous study that tested a custom made MDM. They received skin tests and subsequent amoxicillin challenge to gauge the utility of that MDM. Their PCN allergy status was established.
  • Review computerized pharmacy records and outpt. medical records with prescriptions, clinic visit rates and adverse reactions over a 2 year period (year prior to and year after skin tests).
the potential antimicrobial reisistance and economic benefits of clarifying penicillin allergy41
The potential antimicrobial reisistance and economic benefits of clarifying penicillin allergy
  • Results: 1. PCN use up 13.7% to 39.8%2. abx use down overall-779 courses to 191 pts. down to 558 courses in 169 pts. 3. Pts. with (-) skin test who required an abx - use of PCN up from 20.4% to 47.4%4. Total abx cost fell 32% - $17,211.88 to $11,648.27 - after cost per person if (-) skin test down 7% but if (+) test up 3%
the potential antimicrobial reisistance and economic benefits of clarifying penicillin allergy42
The potential antimicrobial reisistance and economic benefits of clarifying penicillin allergy
  • Results cont:5. Overall clinic visit rate unchanged but a shift from primary care to specialty care was noted.6. 15 pts. with (+) skin tests received cephalosporins (33 courses) with only one reaction (a rash in a one year old)7. 5/93 pts. (5.4%) with (-) skin tests had adverse rxn (all to amoxicillin) and 3/5 had several subsequent courses of PCN. Rxn rate to non-penicillins was also 5.4%
the potential antimicrobial reisistance and economic benefits of clarifying penicillin allergy43
The potential antimicrobial reisistance and economic benefits of clarifying penicillin allergy
  • Conclusions:1. Skin testing is safe and affects frequency of abx use and type of abx given.2. Skin testing decreased cost3. Those who receive amoxicillin oral challenge in the earlier study were not resensitized4. Increased f/u subspecialty care may have contributed to decreased abx use (?confounding the study).
the potential antimicrobial reisistance and economic benefits of clarifying penicillin allergy44
The potential antimicrobial reisistance and economic benefits of clarifying penicillin allergy
  • Harris et al. Penicillin skin testing: a way to optimize antibiotic utilization. AJM. 1999.
  • Design: A pilot study of pts. seen over a 70 day period. Two groups were established:1. therapeutic - hospitalized pts. with hx of PCN allergy requiring abx tx. = 28 pts.2. prophylactic - pts. in a preadmission testing clinic before elective surgery who were to receive perioperative abx. = 16 pts.
the potential antimicrobial reisistance and economic benefits of clarifying penicillin allergy45
The potential antimicrobial reisistance and economic benefits of clarifying penicillin allergy
  • Pts. received skin prick tests and if (-) then intradermal skin tests with major/minor determinant, histamine, and (-) control
  • 24 pts. had a hx of rash and the other 20 had a hx of GI symptoms, pruritus, or unknown rxn
  • Results: 38/44 pts. had (-) skin test (21/24 in rash group, 17/20 in other group) 3 pts. had (+) tests and 3 pts. (+/-)
the potential antimicrobial reisistance and economic benefits of clarifying penicillin allergy46
The potential antimicrobial reisistance and economic benefits of clarifying penicillin allergy
  • Recommendations were made to housestaff about changing abx and 36/44 had abx. changed.
  • Therapeutic group: Prior to testing: 11 pts - vancomycin 12 pts - fluoroquinolones 10 pts - clindamycin After testing: 15 pts - cephalosporins 7 pts - penicillins 1 pt - both* all infections were cured.
the potential antimicrobial reisistance and economic benefits of clarifying penicillin allergy47
The potential antimicrobial reisistance and economic benefits of clarifying penicillin allergy
  • Prophylactic group: Prior to test: 11 pts - vancomycin 2 pts - cipro and gentamicin After test: All pts received cefazolin* no post-op infections
  • 46 days of vancomycin use avoided/estimated 7% reduction in use of parenteral vancomycin
  • Avoidance of cost calculated in therapeutic group - reduction from $4,810 - $2,440 with a yearly projected savings of $12,400
the potential antimicrobial reisistance and economic benefits of clarifying penicillin allergy48
The potential antimicrobial reisistance and economic benefits of clarifying penicillin allergy
  • No adverse drug reactions
  • Conclusions: - suggests that skin testing can reduce cost and vancomycin use without increasing # of pts. with adverse events or allergic rxn.
the potential antimicrobial reisistance and economic benefits of clarifying penicillin allergy49
The potential antimicrobial reisistance and economic benefits of clarifying penicillin allergy
  • Perencevich et al. Benefits of negative penicillin skin test results persist during subsequent hospital admissions. CID. 2001.
  • 2 year follow-up to Harris’ study
  • Charts of pts. who had a hx of PCN allergy but subsequent (-) skin test were reviewed to see the effect of skin test on abx use and adverse events
the potential antimicrobial reisistance and economic benefits of clarifying penicillin allergy50
The potential antimicrobial reisistance and economic benefits of clarifying penicillin allergy
  • Results: 38 pts. reviewed Mean follow-up = 575 days 48 readmissions (14 pts.) Abx given in 35/48 admissions Beta-lactam use totaled 158 days All pts. received at least 1 beta-lactam All infxn were cured No drug rxn noted All pts. that received vancomycin had documented MRSA infxn All pts. denied PCN allergy on admission
the potential antimicrobial reisistance and economic benefits of clarifying penicillin allergy51
The potential antimicrobial reisistance and economic benefits of clarifying penicillin allergy
  • Conclusions:1. Suggests that the predictive power of (-) skin tests is long standing2. Shows an effect on prescribing patterns and a “down-stream” effect on pt. care.3. No evidence of resensitization
what about cephalosporins
What about cephalosporins?
  • Many physicians avoid cephalosporins is pt. is allergic to PCN. Cross-reactivity = 6-8%
  • Type of ReactionFrequencyDermatologic 1.0-2.8%+ direct antiglobulin test 1.0-2.0%Anaphylaxis 0.0001-0.1%Fever 0.5-0.9%Eosinophilia 2.7-8.2%
what about cephalosporins53
What about cephalosporins?
  • PCN related compounds are produced by the cephalosporium mold and early cephalosporins contained trace amounts of PCN - likely leading to an overestimation of cross-reactivity in the past.
  • Currently, no cephalosporin allergy skin test exists in the US. Assays for IgE antibodies to cephalosporins are in use in Australia. The clinical significance of this assay is unclear at this time. Major (cephalosporoyl) and minor (cephalosporanyl) determinants for cephalosporins may be used for skin testing in the near future.
what about cephalosporins54
What about cephalosporins?
  • Three approaches to using cephalosporins in pts. with PCN allergy.1. avoid all beta-lactams - the most popular = increased cost and resistance2. use common sense - not as common as you might think. Take good hx and give cephalosporin if rxn to PCN was not life threatening3. test pts. with skin testing - if strong indication for cephalosporin and pt. has hx of IgE rxn to PCN
clinical applications what infections might require penicillin
Clinical applications: What infections might require penicillin?
  • All treponemal infections, particularly in pregnant pts.
  • Pseudomonas pneumonias in seriously ill pts. in which double coverage is needed.
  • Neutropenic fever in which pseudomonas coverage is required.
  • And several other infections that may be surprising . . .
clinical applications cont
Clinical Applications cont.
  • MSSA pneumonia - Gonzalez et al. looked at clinical characteristics of patients with bacteremic pneumonias due to MSSA and MRSA. CID. 1999. - Pts. with MSSA bacteremic pneumonias (n=41) had better outcomes if tx with cloxacillin (24.4%) compared to vancomycin (41.5%). - Pts. treated with vancomycin had a mortality rate of 47% compared to no deaths in those treated with cloxacillin.
clinical applications cont57
Clinical Applications cont.
  • Staph endocarditis - Dodek et al. looked at treating S. aureus endocarditis in pts. with PCN allergy. CID. 1999. - Examined the expected utility of abx. tx versus the cost of tx. - Pts. with a hx of immediate type PCN allergy and a PCN (Beta-lact. resistent) sensitive S. aureus endocarditis should undergo skin testing because PCN therapy was a more effective and less expensive therapy than vancomycin.
approaching the patient with penicillin allergy practical advice
Approaching the patient with penicillin allergy: Practical Advice.
  • Salkind et al. Is this patient allergic to pcn? An evidence-based analysis of the likelihood of penicillin allergy. JAMA. 2001.
  • Meta-analysis of 4 studies that compared the clinical hx with skin test results.
  • Results: Presence of any hx of allergy increases the likelihood of a (+) skin test (LR 1.9; 95% CI, 1.5-2.5)Absence of pcn allergy hx decreases likelihood that pt. will have a (+) skin test (LR 0.5; 95% CI, 0.4-0.6)
  • Conclusions: Clinicians should systematically document adverse rxn to PCN. Most pts. can take it safely. Authors suggest an approach to hx taking....
approaching the patient with penicillin allergy practical advice59
Approaching the patient with penicillin allergy: Practical Advice.
  • Patient’s age at time of rxn?
  • Does the pt. recall the rxn? If not, who told them about it?
  • How long after receiving PCN did the rxn begin?
  • What were the characteristics of the reaction?
  • What was the route of administration?
  • Why was the pt. taking PCN?
  • What other meds were they taking? Why & When given?
  • What happened when the PCN was stopped?
  • Has the pt. taken abx similar to PCN before or since the rxn? (amox, amp, cephalosporins) If yes, result?
slide60
Approaching the patient with penicillin allergy: Practical Advice. (from A Practical Approach to Infectious Diseases by Reese and Betts)
conclusions
Conclusions
  • The vast majority of patients who claim to have penicillin allergy do not have an IgE-mediated allergy and are unlikely to have any kind of reaction at all. Previous reactions may have been secondary to infection, other medications, or impurities in older preparations of penicillin.
  • The avoidance of penicillin by physicians may be contributing to increasing antimicrobial resistance and health care costs.
conclusions62
Conclusions
  • Penicillin skin testing is safe, predictive of penicillin allergy, and cost effective. Unfortunately, the availability of minor determinants limits its use at this time although many allergists still do skin testing.
  • Penicillin is the drug of choice for several types of infections and recent literature suggests it may better than other agents (particularly vancomycin) in other infections.
conclusions63
Conclusions
  • Cephalosporins rarely cause anaphylactic reactions and can be used safely in most patients including those with penicillin allergy. Avoiding cephalosporins should be considered if patients have a known IgE-mediated reaction to penicillins.
conclusions64
Conclusions
  • A careful history can shed light on a claim of penicillin allergy that has been passed from physician to physician in the medical record. Physicians should not discount claims of penicillin allergy but instead take better histories and attempt to clarify the type of reaction.
  • Physicians should only avoid penicillin and penicillin skin testing in patients with suspected or known IgE-mediated reactions.
conclusions65
Conclusions
  • Several “entry points” into the medical system such as pre-operative assessment clinics, STD clinics, and oncology clinics could be first to implement aggressive skin testing. This clarifying of penicillin allergies would have a “trickle-down” effect, spreading into other areas of the medical community often because pts. themselves recall that they “are no longer allergic to PCN”.
special thanks to
Special Thanks To:
  • My family, Tammy & Nathan
  • Dr. Mary Beth Fasano
  • Dr. Bob Preli
  • Dr. Laurie Keating