Most Penicillin Allergy Labels Are Wrong, Blumenthal Says

Most patients carrying a penicillin allergy label are not actually allergic, and clinicians should treat that label as a diagnosis in need of revisiting rather than a permanent fixture in the chart, according to Kimberly Blumenthal, MD, MSc, professor of medicine at Mayo Clinic College of Medicine and Science.¹ In an interview with HCPLive, Blumenthal said the label itself carries measurable harm, including greater rates of Clostridioides difficile infection, MRSA, and surgical site infections within 5 years of documentation.

Blumenthal said the strength of the recommendation for testing or delabeling depends heavily on how recently the reaction occurred. Patients reporting a reaction within the past few years may warrant confirmatory testing. Those citing a childhood reaction relayed secondhand, often decades old, are typically strong candidates for direct delabeling with little to no testing.

“We're talking 50, 60, 70 years ago,” Blumenthal said. “With all of that time that has passed, the likelihood of them being allergic is quite low.”

Risk Stratification Now Drives the Testing Pathway

The approach to confirming or removing a penicillin allergy label has shifted substantially since the 2009 FDA approval of the major determinant skin test reagent, Blumenthal said. Early widespread skin testing revealed that the test performs poorly in low-risk patients, generating false positives, while emerging safety data showed that direct drug challenges work well in that same low-risk group. Pooled data across thousands of pediatric challenges have shown reaction rates of roughly 3.5% to 6%, supporting direct challenge as the preferred pathway for lower-risk patients while reserving skin testing for higher-risk cases.²

“If you are a lower-risk patient, direct drug challenge is the most effective way of getting that penicillin allergy label safely removed,” Blumenthal said. “If you're a higher-risk person, you should be focusing on skin testing.”

That shift toward direct oral challenge in low-risk patients is reflected in a 2024 systematic review and meta-analysis, which pooled 12 studies and found that direct drug challenge safely delabeled 97.13% of previously labeled patients, with no critical adverse events.³ Only 10 of 1070 participants developed mild immediate reactions.

Some Labels Stay in Modified Form, Even After Negative Testing

Blumenthal said a negative workup does not always mean the allergy label disappears entirely. When patients report symptoms like isolated itching or a headache without objective signs of an allergic reaction, she often revises the label to specify the milder concern rather than removing it outright.

“I would feel comfortable removing the allergy, but the patient doesn't,” she said. “In those cases, I revise the allergy label to say itching only—not a full contraindication to taking this medication again. I tried to specify in the comments to communicate to future doctors that I wasn't concerned that this patient was going to have a significant reaction.”

Check out parts 1 and 2 of our interview with Blumenthal here: What's Behind Perioperative Anaphylaxis? Cefazolin Tops the List and Hidden Operating Room Allergens: Dyes, Implants, Chlorhexidine Overwash.

Blumenthal has no reported disclosures.

References

1. Blumenthal KG, et al. Penicillin allergy delabeling: a multidisciplinary opportunity. J Allergy Clin Immunol Pract. 2021. https://pmc.ncbi.nlm.nih.gov/articles/PMC8019188/

2. Blumenthal KG, Smith LR, Mann JTS, et al. Reaction Risk to Direct Penicillin Challenges: A Systematic Review and Meta-Analysis. JAMA Intern Med. 2024;184(11):1374-1383. doi:10.1001/jamainternmed.2024.4606

3. Safe penicillin allergy delabeling in primary care: a systematic review and meta-analysis. J Allergy Clin Immunol Pract. 2024. https://www.jaci-inpractice.org/article/S2213-2198(24)00640-8/abstract