The challenge of de-labeling penicillin allergy

Abstract

Background: Even though 8%-25% of most populations studied globally are labeled as penicillin allergic, most diagnoses of penicillin allergy are made in childhood and relate to events that are either not allergic in nature, are low risk for immediate hypersensitivity, or are a potential true allergy that has waned over time. Penicillin allergy labels directly impact antimicrobial stewardship by leading to use of less effective and broader spectrum antimicrobials and are associated with antimicrobial resistance. They may also delay appropriate antimicrobial therapy and lead to increased risk of specific adverse healthcare outcomes. Operationalizing penicillin allergy de-labeling into a new arm of antimicrobial stewardship programs (ASPs) has become an increasing global focus.

Methods: We performed an evidence-based narrative review of the literature of penicillin allergy label carriage, the adverse effects of penicillin allergy labels, and current approaches and barriers to penicillin allergy de-labeling. Over the period 1928-2018 in Pubmed and Medline, search terms used included "penicillin allergy" or "penicillin hypersensitivity" alone or in combination with "adverse events," "testing," "evaluation," "effects," "label," "de-labeling," "prick or epicutaneous," and "intradermal" skin testing, "oral challenge or provocation," "cross-reactivity," and "antimicrobial stewardship".

Results: Penicillin allergy labels are highly prevalent, largely inaccurate and their carriage may lead to unnecessary treatment and inferior outcomes with alternative agents as well as adverse public health outcomes such as antibiotic resistance.

Conclusions: Operationalizing penicillin allergy de-labeling as an aspect of ASP has become an increasing global focus. There is a need for validated approaches that optimally combine the use of history and ingestion challenge with or without proceeding formal skin testing to tackle penicillin allergy efficiently within complex healthcare systems. At the same time, there is great promise for penicillin allergy evaluation and de-labeling as an individual and public health strategy to reduce adverse healthcare outcomes, improve antimicrobial stewardship, and decrease healthcare costs.

Keywords: allergy; de-labeling; label; penicillin; testing.

Figure 1:. Events that Lead to Application of a Penicillin Allergy Label.

The application of penicillin allergy labels results from events that are low risk for allergy in the vast majority of cases.^,–,,,

Figure 2:. A Penicillin Allergy Label is like a Tree Planted Too Close to Your House in Childhood.

Most penicillin allergy labels are applied in childhood, like a seed that grows up into a tree too close to the house (Label Acquisition). In adulthood, the justification for leaving such a tree next to the house is shaky (Labels Persist and Grow in Significance), as they can contribute to worsened outcomes during the storm of a healthcare encounter requiring antimicrobial treatment (Consequences of a Label). Removal of unnecessary penicillin allergy labels is likely to provide protection against adverse outcomes associated with its carriage (Testing/Removal of Unnecessary Labels).

Figure 3:. Understanding Cross Reactivity Amongst Beta Lactams Based Upon R1, R2 Side Chains or Shared Methoxyimino (MI) Grouping is Important to De-labeling Efforts.

For example, consider a patient with two allergy labels, one to penicillin and the other to ceftriaxone. Tolerance of an oral challenge with amoxicillin would prove the safety of all penicillins in this patient by challenging the patient with both the basic penicillin structure and the aminopenicillin side chain. This challenge would not effectively determine the safety of ceftriaxone in a patient labeled allergic to ceftriaxone, however, due to differing side chains and basic structure. Hence, the penicillin allergy label could be removed, but additional basic cephalosporin and ceftriaxone specific side chain specific testing would be needed to determine the safety of ceftriaxone prior to ceftriaxone label removal. ^,,,

Figure 4:. Roadmap for Future Directions in Penicillin De-labeling Research.

An additional important milestone includes research to identify factors that lead to reintroduction of penicillin allergy labels into a patient’s chart.