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Evaluation and Management of Penicillin AllergyA Review

Educational Objective
To review the clinical management of patients who report penicillin allergy.
1 Credit CME

Importance  β-Lactam antibiotics are among the safest and most effective antibiotics. Many patients report allergies to these drugs that limit their use, resulting in the use of broad-spectrum antibiotics that increase the risk for antimicrobial resistance and adverse events.

Observations  Approximately 10% of the US population has reported allergies to the β-lactam agent penicillin, with higher rates reported by older and hospitalized patients. Although many patients report that they are allergic to penicillin, clinically significant IgE-mediated or T lymphocyte–mediated penicillin hypersensitivity is uncommon (<5%). Currently, the rate of IgE-mediated penicillin allergies is decreasing, potentially due to a decreased use of parenteral penicillins, and because severe anaphylactic reactions to oral amoxicillin are rare. IgE-mediated penicillin allergy wanes over time, with 80% of patients becoming tolerant after a decade. Cross-reactivity between penicillin and cephalosporin drugs occurs in about 2% of cases, less than the 8% reported previously. Some patients have a medical history that suggests they are at a low risk for developing an allergic reaction to penicillin. Low-risk histories include patients having isolated nonallergic symptoms, such as gastrointestinal symptoms, or patients solely with a family history of a penicillin allergy, symptoms of pruritus without rash, or remote (>10 years) unknown reactions without features suggestive of an IgE-mediated reaction. A moderate-risk history includes urticaria or other pruritic rashes and reactions with features of IgE-mediated reactions. A high-risk history includes patients who have had anaphylaxis, positive penicillin skin testing, recurrent penicillin reactions, or hypersensitivities to multiple β-lactam antibiotics. The goals of antimicrobial stewardship are undermined when reported allergy to penicillin leads to the use of broad-spectrum antibiotics that increase the risk for antimicrobial resistance, including increased risk of methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus. Broad-spectrum antimicrobial agents also increase the risk of developing Clostridium difficile (also known as Clostridioides difficile) infection. Direct amoxicillin challenge is appropriate for patients with low-risk allergy histories. Moderate-risk patients can be evaluated with penicillin skin testing, which carries a negative predictive value that exceeds 95% and approaches 100% when combined with amoxicillin challenge. Clinicians performing penicillin allergy evaluation need to identify what methods are supported by their available resources.

Conclusions and Relevance  Many patients report they are allergic to penicillin but few have clinically significant reactions. Evaluation of penicillin allergy before deciding not to use penicillin or other β-lactam antibiotics is an important tool for antimicrobial stewardship.

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Article Information

Accepted for Publication: November 26, 2018.

Corresponding Author: Erica S. Shenoy, MD, PhD, Infection Control Unit, Massachusetts General Hospital, 55 Fruit St, Bulfinch 332, Boston, MA 02114 (eshenoy@mgh.harvard.edu).

Author Contributions: Drs Shenoy and Blumenthal had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: All authors.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: All authors.

Critical revision of the manuscript for important intellectual content: All authors.

Administrative, technical, or material support: Shenoy, Macy, Blumenthal.

Supervision: All authors.

Conflict of Interest Disclosures: Dr Macy is a partner in the Southern California Permanente Medical Group. Dr Macy has received research grants from ALK Abello, Inc. to study adverse drug reactions and has served on clinical trial safety and monitoring committees for BioMarin, Ultragenyx, and Audentes. Dr Macy reported grants from ALK during the conduct of the study. Drs Blumenthal and Shenoy report copyright on a clinical decision support tool for penicillin allergy evaluation. No other disclosures were reported.

Additional Contributions: The authors thank Erin Ryan, MPH; Yu Li, MS; Lisa L. Philpotts, BSN, MSLS; Lauren R. West, MPH; and Ronak G. Gandhi, PharmD, BCPS, for their assistance in manuscript preparation and Sheila Heitzig, JD, MNM, CAE, of the American Academy of Allergy, Asthma and Immunology, Amanda Jezek, BA, of the Infectious Diseases Society of America, and Valerie Deloney, MBA, and Kristy Weinshel, MBA, of the Society for Healthcare Epidemiology of America for their support.

Additional Information: This review, which was approved by The American Academy of Allergy, Asthma, and Immunology (AAAAI), the Infectious Diseases Society of America (IDSA), and the Society for Healthcare Epidemiology of America (SHEA), summarizes the evidence regarding the epidemiology, clinical consequences, and evaluation of patients with reported penicillin allergy.

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