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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. Introduction What is a true penicillin allergy? How can we determine who is truly allergic?

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An Examination of Penicillin Allergy

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  1. An Examination of Penicillin Allergy Resident Grand Rounds February 12, 2002 David H. Priest, MD

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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)

  8. 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.

  9. Immunochemistry of Penicillin Molecules

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. Skin Testing • Tests are read at 15 minutes and scored from negative to 4+ based on erythema and wheal size.

  18. 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.

  19. 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.

  20. 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.

  21. Outpatient STD Clinic • Methods: 5063 consecutive patients in Baltimore STD clinic. 66% male, 90% African-American. Follow-up was 94% complete.

  22. 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%)

  23. 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).

  24. 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.

  25. 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.

  26. 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.

  27. 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.

  28. 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.

  29. 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

  30. 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.

  31. 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.

  32. 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.

  33. 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.

  34. 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.

  35. 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.

  36. 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%

  37. 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.

  38. 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.

  39. 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.

  40. 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).

  41. 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%

  42. 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%

  43. 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).

  44. 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.

  45. 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. (+/-)

  46. 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.

  47. 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

  48. 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.

  49. 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

  50. 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

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