Research Spotlight: Reaction Risk to Direct Penicillin Challenges

Kimberly Blumenthal, MD, MSc, director of research in the Center for Drug and Vaccine Allergy at Massachusetts General Hospital and an associate professor of Medicine at Harvard Medical School, is the lead author of a review in JAMA Internal Medicine titled: “Reaction Risk to Direct Penicillin Challenges: A Systematic Review and Meta-Analysis.”

What is the Background of this Study?

Inaccurate penicillin allergy labeling is a growing concern. In the U.S., many people carry false penicillin allergy labels. These patients are more likely to be treated with second-line antibiotics, which can lead to longer hospital stays and higher treatment costs. The increased use of second-line antibiotics also raises concerns about treatment toxicity and increased antimicrobial resistance.

Although more than 95% of patients with penicillin allergy labels are not truly allergic, most of these patients do not receive allergy evaluations. Direct penicillin challenges, in which people with penicillin allergy labels are given penicillin without any prior testing, would support these penicillin allergy evaluation efforts.

Historically, clinicians have used skin testing before drug challenges (indirect challenges) However, a growing body of literature supports the use of direct penicillin challenges, in which patients with low-risk allergy histories are directly challenged with treatment.

Our research team set out to ask the question: Are direct penicillin challenges safe for use in penicillin allergy evaluations across populations and settings?

What did you Find? 

We conducted a systematic review and meta-analysis of eligible studies in which direct penicillin challenges were performed. We were able to synthesize the frequency of reactions to direct penicillin challenges across all relevant studies.

We included 56 studies in our analyses. Across these studies, 9,225 underwent direct penicillin challenges and there were 438 reactions. This corresponds to a meta-analytical reaction rate of 3.5%.  Among the 438 reactions, only five were severe (three were anaphylaxis), and there were no fatal reactions. This 3.5% reaction rate is comparable to the rate of reactions to indirect penicillin challenges, which another meta-analysis found to be 3.4%.

Indirect challenges are often the current standard for penicillin allergy evaluations, but our results indicate that direct challenges are similarly safe compared to indirect challenges. This indicates that they could be safely incorporated into penicillin allergy evaluation efforts.

What are the implications?

This work could help increase penicillin allergy evaluation efforts across the U.S. and beyond, given that our study demonstrated that direct penicillin challenges are safe.

Additionally, direct penicillin challenges can be performed by generalists, do not require special training, and are less time-intensive than traditional penicillin allergy evaluations. As a result, they could be used to expand penicillin allergy evaluation efforts outside of specialist clinics, allowing more false penicillin allergy labels to be removed. In this way, direct penicillin challenges would help reduce the negative impacts caused by these false penicillin allergy labels, such as increased antimicrobial resistance and mortality.

What are the next steps? 

Future studies and next steps will focus on studying predictors and risk factors for reactions to direct penicillin challenges. Many of the studies that we analyzed in our systematic review did not sufficiently report demographic and allergy history data of participants, limiting our ability to draw conclusions on predictors and risk factors ourselves.

Paper cited: 

Blumenthal KG, Smith LR, Mann JTS, et al. Reaction Risk to Direct Penicillin Challenges: A Systematic Review and Meta-Analysis. JAMA Intern Med. Published online September 16, 2024. doi:10.1001/jamainternmed.2024.4606