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Penicillin Allergy: Fake News?

Neda Frayha, MD and Torie Grant, MD MHS
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We see “ALL: PCN” all the time. But how often is it true? And why does it matter? Neda sits down with Dr. Torie Grant, a Med/Peds Allergist and Immunologist at Johns Hopkins, to learn all about the risks attached to a penicillin allergy label and some easy approaches to debunking this allergy in the primary care setting. 

Pearls:

  • Up to 90-95% of people labeled with a penicillin allergy are not allergic and can tolerate penicillin. For the people who were truly allergic (ie: had an IgE-mediated reaction to penicillin/amoxicillin), 80% will no longer be allergic 10 years later. Even 5 years out, 50% of people have lost their allergy.

  • A penicillin allergy is associated with a higher risk of VRE, MRSA and C. diff infections as well as increased costs across both the inpatient and outpatient setting.

  • Allergy testing is simple and has almost 99% negative predictive value. It can be done in a primary care office with the right training and equipment.

 

  • Background:

    • Roughly 10% of people (32 million people) in the US carry a diagnosis of penicillin allergy and up to 15% in higher risk patients like those who are elderly, hospitalized or were diagnosed with an STI

    • Two reactions:

      • 1. Class 1 Hypersensitivity - acute IgE-mediated to either the beta-lactam itself or one of the side chains. Pre-formed antibody on the basophil or mast cell that degranulates when exposed to penicillin releasing histamines, leukotrienes, prostaglandins, bradykinins

        • Symptoms - hives or urticaria, lip swelling, angioedema, wheezing, bronchospasm → vasodilation leading to loss of blood pressure and even cardiovascular compromise

      • 2. Class 4 or T-cell mediated - Cytotoxic T-cells or CD8 cells. Delayed reaction (hours to weeks) that can lead to more severe reactions

        • Symptoms - Stevens Johnson Syndrome, TEN, DRESS (drug-related eosinophilia with systemic symptoms) with a delay in onset

    • Most common presentation:

      • Rash (flat, morbilliform, slightly raised pinpoint macules or papules, hives)

      • Unknown (“My mom's always told me that I'm allergic to penicillin. I have no idea what happened”)

  • Pearl: Up to 90-95% of people labeled with a penicillin allergy are not allergic and can tolerate penicillin

    • Reasons for such a discrepancy

      • 1. Often not a true allergy but many people have access to the allergy tab in a medical record

        • Diarrhea is a side effect of amoxillin and not an IgE-mediated process

        • Headaches can also be a side effect

      • 2. Penicillins are often prescribed when children are sick and were prescribed for a viral illness, which often causes a viral exanthem that gets labeled as a penicillin allergy

      • 3. For the people who were truly allergic (ie: had an IgE-mediated reaction to penicillin/amoxicillin), 80% will no longer be allergic 10 years later. Even 5 years out, 50% of people have lost their allergy 

  • Morbidity and costs related to penicillin allergy:

    • Higher risk of VRE, MRSA and C. diff in the ICU setting

    • Patients given vancomycin instead of cefazolin for perioperative period because of penicillin allergy have higher risk of surgical site infection

    • Penicillins have the most benign side effect profile compared to other antibiotics potentially used in its place

    • Costs for PCN-allergic patients is also higher in both the outpatient and inpatient setting

  • Cross-reactivity with cephalosporins:

    • The beta-lactam ring is shared by both antibiotic classes as well as with carbapenems and the monobactams. However, most patients are allergic to the R1 side chain which are distinct to penicillins

    • Only 2% of patients with a penicillin allergy were actually cross-reactive and allergic to cephalosporins

  • Evaluating a penicillin allergy:

    • Assess the history of allergy:

      • Rash - were there symptoms of a more severe cutaneous reaction like skin falling off or mucosal involvement (mouth, eyes, vagina)?

      • Severity -  did you seek additional treatment

    • Testing: only tests for IgE-mediated allergy but you cannot desensitize or test for the T-cell mediated allergy

      • Prioritize testing for those most at risk: high health care utilization, elderly, cancer, severe COPD/asthma

      • Penicillin skin testing - 99% negative-predictive value, cost mean $220, usually covered by insurance

        • Histamine is placed on the skin to make sure your skin reacts.

          • Cannot be on antihistamine for several days prior to testing

        • Saline control is placed to make sure they don’t just have hives from the irritation prick itself

        • Skin is tested with the major determinant of penicillin allergy (Pre-Pen) and then the minor determinant (penicillin G)

        • Wait 15 minutes to see what happens after skin-prick testing

        • If no hive at allergen site, do intradermal duplicates of the prior testing (like placing a PPD)

        • If not raised and therefore negative, proceed with oral amoxicillin challenge = amoxicillin 250mg and observation for one hour

  • In-office testing:

    • Can be done if you are trained to read the test and have the necessary equipment/staffing to do it (ie: medication for a true anaphylactic reaction)

      • You may just do the skin testing in-office and if positive be prepared to do the oral penicillin challenge in a setting where it can be managed appropriately

 

REFERENCES:

  1. Blanca M, Torres MJ, Garcia JJ, Romano A, Mayorga C, de Ramon E et al. Natural evolution of skin test sensitivity in patients allergic to beta-lactam antibiotics. J Allergy Clin Immunol 1999; 103(5): 918-924.

  2. Blumenthal KG, Li Y, Banerji A, Yun BJ, Long AA, Wolensky RP. The cost of penicillin allergy evaluation. J Allergy Clin Immunol 2018;6(3):1019-1027.

  3. Blumenthal KG, Lu N, Zhang Y, Li Y, Walensky RP, Choi HK et al. Risk of meticillin resistant Staphylococcus aureus and Clostridium difficile in patients with a documented penicillin allergy: population based matched cohort study. BMJ 2018; 361:k2400.

  4. Blumenthal KG, Shenoy ES, Huang M et al. The impact of reporting a prior penicillin allergy on the treatment of methicillin-sensitive Staphylococcus aureus bacteremia. PLoS One 2016;11(7):e0159406. doi:10.1371/journal.pone.0159406 

  5. Joint Task Force on Practice Parameters; American Academy of Allergy, Asthma and Immunology; American College of Allergy, Asthma and Immunology. Drug allergy: an updated practice parameter. Ann Allergy Asthma Immunol 2010;105:259-273.

  6. Macy E, Contreras R. Health care use and serious infection prevalence associated with penicillin “allergy” in hospitalized patients: a cohort study. J Allergy Clin Immunol 2014;133(3):790-796. doi:10.1016/j.jaci.2013.09.021 

  7. Macy E, Khan DA, Castells MC, Lang DM. Penicillin allergy testing: a key component of antibiotic stewardship. Clinical Infectious Diseases 2014;64(4):531-532.

  8. Mattingly TJ II, Fulton A, Lumish RA, et al. The cost of self-reported penicillin allergy: a systematic review. J Allergy Clin Immunol Pract 2018;6(5):1649-1654. doi:10.1016/j.jaip.2017.12.033

  9. McCullagh DJ, Chu DK. Penicillin allergy. CMAJ 2019; 191(8): E231. 

  10. Sacco, KA,  Bates, A, Brigham, TJ,  Imam, JS, Burton, MC. Clinical outcomes following inpatient penicillin allergy testing: A systematic review and meta‐analysis. Allergy 2017; 72: 1288-1296. https://doi.org/10.1111/all.13168

Shenoy ES, Macy E, Rowe T, Blumenthal KG. Evaluation and Management of Penicillin Allergy: A Review. JAMA. 2019;321(2): 188-199. doi:10.1001/jama.2018.19283

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