Direct penicillin challenges carry a low risk of adverse reactions for individuals with a history of penicillin allergy, with a reaction frequency of only 3.5%.
Kimberly Blumenthal, MD, MSc
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A systematic review and meta-analysis found that direct penicillin challenges pose a low risk of reaction for patients with a history of penicillin allergy. The analysis encompassed 56 studies involving 9,225 participants and revealed an overall reaction frequency of just 3.5%. Key risk factors for positive reactions included challenges conducted outside North America, in children, in outpatient settings, and those involving multiple dosing (graded or prolonged).
Among the participants, 438 experienced reactions, reflecting the 3.5% meta-analytic frequency (95% credible interval: 2.5%-4.6%). Notably, reactions were less common in studies conducted in North America (odds ratio (OR), 0.36), while children (OR, 3.37), outpatient settings (OR, 2.19), and graded (OR, 3.24) or prolonged challenges (OR, 5.45) showed higher rates. Only five severe reactions were documented, including three cases of anaphylaxis, with none resulting in fatalities.
In our discussion of the long-term implications of direct penicillin challenges with Kimberly Blumenthal, MD, MSc, she noted, “The long-term effects of direct penicillin challenges are related to the fact that most direct penicillin challenges result in delabeling (removal of inaccurate penicillin allergies in the record), allowing patients to take penicillins moving forward when needed to prevent and treat infections. The ability to take penicillins and related beta lactam antibiotics, first-line treatments for many infections, improves care quality and aligns with antimicrobial stewardship.”
Blumenthal added, “This study had limited follow-up data, but the rate of reaction to penicillin in follow up when taken following direct penicillin challenges is similar to the rate of reaction to penicillin in general. This suggests that completing direct penicillin challenges does not influence future allergy development.Of course, allergies can always occur in the future and so a best practice is to let patients know that new allergy can always occur but the best available evidence suggests the delabeled person has the same risk of reacting as someone never labeled.”
The objective was to evaluate the safety and frequency of reactions to direct penicillin challenges and identify associated risk factors. The data sources included MEDLINE, Web of Science, and Scopus, with searches conducted up to July 19, 2023. Two reviewers independently selected original studies and assessed their quality using a risk-of-bias tool.
When asked about the applicability of the findings to diverse populations, Blumenthal stated, “Our findings are generalizable to a multitude of racially and ethnically diverse populations, given that the studies included in our analysis come from North America (25 studies), Europe (18 studies), Oceania (7 studies), Asia (5 studies), and South America (1 study). To date, differences in penicillin allergy across racial and ethnic groups appear more related to systemic inequities rather than any biological or genetic factors. For these reasons, we anticipate that our results to be applicable across all populations.”
Although, she cautioned that recommendations may vary for patients with a recent history of severe reactions, such as anaphylaxis, stating, “In terms of patients with different allergy histories, the recommendations for direct penicillin challenges may differ, especially regarding those with a recent history of severe reactions to penicillin. For example, patients who have had a severe immediate reaction, such as an anaphylactic reaction, to penicillin should not undergo direct penicillin challenges. These higher risk individuals were not included in the primary studies we meta-analyzed.The same is true for those with a history of delayed severe reactions, such as severe cutaneous adverse reactions, serum sickness, organ injuries or other reactions requiring hospitalization related to ingestion of penicillin.”
In conclusion, the findings suggest that reactions to direct penicillin challenges are infrequent and comparable in risk to indirect challenges following allergy testing. This supports the safe incorporation of direct challenges into penicillin allergy evaluations across various age groups and clinical contexts, potentially addressing barriers related to perceived risks.
Blumenthal also provided practical guidelines for implementing direct penicillin challenges in clinical practice, especially in resource-limited settings “We recommend implementing single-dose or graded (2-step) challenges to penicillin for individuals who present with low risk penicillin allergy histories. Patients should be observed for a minimum of 60 minutes. Direct challenges only require one visit, and the only materials needed are doses of penicillin (typically amoxicillin solution) and rescue medications (such as epinephrine and antihistamines). For these reasons, direct penicillin challenges are actually the most affordable and applicable penicillin allergy evaluation method for resource-limited settings. While direct penicillin challenges do not require the same level of formal training as penicillin skin testing, clinicians performing direct penicillin challenges should be sufficiently trained in diagnosis and management of allergy/anaphylaxis, particularly in resource-limited settings.”
This research underscores the importance of reevaluating penicillin allergies, which could lead to better antibiotic stewardship and improved patient outcomes.
