Are You Sure You’re Allergic to Penicillin? How Sure?

Millions of people falsely believe they have a penicillin allergy, but disproving their allergy has been costly and cumbersome... until now.


When penicillin was discovered in 1928, it became one of the world’s first antibiotics, offering a cure for deadly infectious diseases. It remains one of our most effective and commonly prescribed tools to fight bacteria, but many people are needlessly prescribed less effective or more toxic alternatives because they falsely believe they have a penicillin allergy.

One in 10 patients are documented as having a penicillin allergy, ruling out a long list of potential antibiotics in its class. This exclusion leads to higher risk of treatment failure and development of antibiotic-resistant superbugs.

True penicillin allergies can be dangerous; the first exposure can trigger the body to produce antibodies, and a second exposure can then trigger anaphylaxis. But the symptoms of an adverse reaction may not lead to an allergy, and an allergy can also disappear on its own if there are no further exposures for a certain period of time — usually around 10 years.

As a result, many people who had an adverse reaction as a child are not allergic to penicillin into adulthood. It is estimated that fewer than 5 percent of patients labeled with a penicillin allergy actually have one. That adds up to millions of people with documented allergies who could be prescribed penicillins safely if there was a simple way to know for sure.

The trouble is that the standard to find out today is not simple. Traditional skin testing is the first step to rule out a penicillin allergy. It’s a process that is resource intensive, time consuming, and painful for patients. It also requires specialist-trained allergists to perform with specialized testing reagents, further limiting global access.

If a patient passes, the second step to confirm is a supervised oral challenge with penicillin. This second test is much simpler to administer, but it was not clear whether the skin test could be safely skipped for patients with at low risk of true penicillin allergies, or whether the oral challenge alone would find all true cases.

The PALACE study sought to answer that question with an international clinical trial, led by researchers from six specialized centres in Canada, the United States, and Australia. Their study was published in JAMA Internal Medicine.

The team recruited 382 patients with a low risk of penicillin allergy; their risk was assessed using a question-based tool called PEN-FAST, scoring patients based on the severity of their symptoms after being given penicillin, and how recent their last exposure was. The participants were randomly assigned to one of two groups: one to be evaluated with the conventional two-step test, and another to proceed directly to an oral challenge test.

The groups reported one patient each (0.5 percent) who experienced a positive reaction to the oral challenge, showing equal effectiveness in identifying people with true penicillin allergies. The authors also didn’t observe any significant differences in adverse events between the two groups, and no serious adverse events were reported. The result is known one hour after initiating the test.

“The biggest takeaway from the PALACE study is that patients with a low-risk penicillin allergy, like a childhood rash, can safely have a test dose of penicillin to determine if they are still allergic,” said first author Ana-Maria Copaescu, associate investigator at the Research Institute of the McGill University Health Centre, in a press release.

“This will change the way doctors test for penicillin allergy in the future. Millions of patients worldwide, including millions of Canadians, will be able to have their penicillin allergy disproved by a safe single oral test dose following a carefully risk-validated risk assessment.”

In combination with the PEN-FAST tool, a direct oral challenge is a simple way that infectious disease specialists, general internists, or general practitioners can safely test low-risk patients. Adopting this protocol to quickly disprove a penicillin allergy at the point of care will restore the ability to prescribe this important antibiotic to millions of people.

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Karyn Ho is a science animator and engineer who thrives at the interface between science, engineering, medicine, and art. She earned her MScBMC (biomedical communications) and PhD (chemical engineering and biomedical engineering) at the University of Toronto. Karyn is passionate about using cutting edge discoveries to create dynamic stories as a way of supporting innovation, collaboration, education, and informed decision making. By translating knowledge into narratives, her vision is to captivate people, spark their curiosity, and motivate them to share what they learned.