95 Percent of Penicillin Allergies Are Wrong. A New Test Could Help

If you’ve been told your whole life that you have a penicillin allergy, you’d be forgiven for not giving it a second thought. About one in 10 people in the U.S. report having this condition, making it the most common drug allergy in the country—and seemingly ordinary. In reality, 95 percent of those diagnosed with a penicillin allergy aren’t actually allergic. The impact of the sheer number of misdiagnoses is worthy of attention. When treating patients who have an allergy to the antibiotic on their medical record, doctors must turn to other antibiotics that are less effective and more expensive and can lead to serious health complications.

A small contingent of health care professionals is working to remove the millions of false penicillin allergy diagnoses from individuals’ medical records. Experts say that educating their medical colleagues and the public about the rampant number of falsely diagnosed penicillin allergies and using an easier new test could curb the issue. But removing so many diagnoses from the health record and changing the larger public concern around penicillin allergy may be challenging. Shaking an incorrect penicillin allergy diagnosis has proved difficult among people who have held onto one “longer than a pet, even longer than a student loan,” says Christopher Bland, an associate professor in the College of Pharmacy at the University of Georgia. “It almost becomes a part of them.”

A Commonly Misunderstood Allergy

Penicillin is not just the name of a single antibiotic—it is also a blanket term for the family of drugs containing chemical relatives of penicillin such as amoxicillin or methicillin. Penicillin antibiotics, which kill bacteria by preventing them from building a cell wall, are used to treat various illnesses such as pneumonia, meningitis, skin infections and dental abscesses. They are also the first-choice treatment for common childhood infections.

When doctors ramped up penicillin treatments in the early 1940s, reports of adverse reactions, such as hives, soon emerged. In 1949 doctors reported the first case of penicillin-caused death from anaphylaxis, a severe allergic reaction that lowers blood pressure and impairs breathing. “That was a shock that both the public and health care workers of all types never really forgot,” says Richard Olans, an infectious disease expert at MelroseWakefield Hospital in Massachusetts. Hives and anaphylaxis are true allergic reactions that result from the immune system producing antibodies that target penicillin like it would if it were fighting a pathogen such as a cold or flu virus. These reactions are rare.

Most people are misdiagnosed with a penicillin allergy in childhood when they take the drug to treat illnesses such as ear infections. Many kids develop a rash, which can appear like an allergic reaction to penicillin but is actually related to viral infections that often occur alongside bacterial ones. “Now we have so many studies that show that these kids are not ever truly allergic when they get these small rashes,” says Ana-Maria Copaescu, an allergy and immunology specialist at McGill University Health Center in Quebec.

Additionally, common side effects of penicillin, such as headaches, diarrhea and nausea, are often mistaken as an allergic response, Bland explains. “Most of the time, the patient has the reaction in their mind,” he says. “Then they just report it as an allergy.” People may also falsely get a penicillin allergy diagnosis because a parent or other relative was allergic.

“There are a lot of myths about drug allergy that stem back to the discovery of penicillin,” says Elizabeth Phillips, an immunology specialist at Vanderbilt University Medical Center.

Why Testing Matters

Penicillin allergy testing has helped untangle real allergies from misdiagnoses. The current gold standard test—only conducted in specialized allergy clinics—involves pricking the skin and injecting a small amount of penicillin. If the person doesn’t react to the skin prick, they are given a small oral dose of an antibiotic in the penicillin family, usually amoxicillin. Should they tolerate the oral dose, the penicillin allergy can be removed from their medical record.

Testing has helped doctors realize how few people are truly allergic. Studies have shown that even among individuals who’ve experienced anaphylaxis, 80 percent lose penicillin antibodies after a decade. This is a huge deal for the long-term health and future antibiotic treatment of potentially millions of people who could take the drug safely. “I think one of the worst things to have on your profile as a patient is a penicillin allergy,” Bland says.

The alternative medications doctors prescribe to people with a penicillin allergy have more side effects and are less effective. They are usually less targeted, so using them is like casting a net to catch a pathogen rather than shooting an arrow at it. That means they can kill off good bacteria and lead to the overgrowth of potentially dangerous ones such as Clostridium difficile or methicillin-resistant Staphylococcus aureus. Less-targeted antibiotics also give more bacteria the chance to evolve ways to survive, spurring new antibiotic-resistant strains that can have a wider impact on the human population.

In addition to the health burdens, there’s also a financial one. A 2018 study found that hospitalized people in several countries, including the U.S., with a documented penicillin allergy paid up to $4,250 more for their visit. Kimberly Blumenthal, an allergist and immunologist at Massachusetts General Hospital, co-authored a 2021 study showing that the cost of having a penicillin allergy overwhelmingly outweighed the cost of running a penicillin allergy test because the alternative antibiotics are more expensive.

But even after correcting the penicillin allergy label with the test, it can persist on many people’s health record. Getting rid of an erroneous penicillin allergy diagnosis is a multifaceted issue: “It’s electronic. It’s culture. It’s fear,” says Rita Olans, a nurse practitioner and an associate professor at the Massachusetts General Hospital Institute of Health Professions. Incompletely clearing a penicillin allergy from a person’s electronic health record can cause it to follow them from doctor to doctor. Bland and Copaescu both give people a physical card to show other doctors they tested negative for a penicillin allergy in case it wasn’t completely cleared from the electronic health record. Many people are still afraid to use the drug even after they’ve been cleared, however. One study found that 41 percent of people who had been told they had a penicillin allergy but later tested negative still avoided penicillin.

Many doctors agree that educating enough people on how to identify potentially incorrect penicillin allergy diagnoses and perform tests is a significant issue. Olans is teaching her nursing students to take more complete allergy histories that could help root out potentially erroneous ones. But even then, allergy tests must be carried out in specialized allergy clinics that are inaccessible to much of the population. “I think the challenges right now are really related to the bottleneck of the process occurring in our specialty clinics,” Phillips says.

Searching for Solutions

To try and address the testing bottleneck, Blumenthal developed an algorithm that evaluates patient histories and guides health care workers on the best antibiotics to use so that they can triage the patients that should be sent for allergy testing. The algorithm is now integrated with the electronic health record across all hospital sites in her health system.

In people who are unlikely to have a severe penicillin allergy, doctors may streamline the testing process by skipping the skin test and using just the oral dose. People in this low-risk group, which includes approximately 98 percent of penicillin allergies, experienced only mild reactions or unrelated symptoms when given the drug. Oral tests were previously considered riskier because they could cause a severe reaction, but a recent large randomized controlled trial led by Copaescu showed for the first time that oral doses are as effective and safe as skin tests for people who have never had a severe allergic reaction. “More and more, colleagues and allergists that work in a hospital setting are using this direct oral [test] based on studies like ours,” says Copaescu, who published the results of the trial in July.

Copaescu says that the oral test alone is cheaper and less painful for patients and doesn’t require specialized training. “It expanded who was doing direct [oral tests] in low-risk patients,” says Blumenthal, who wasn’t involved in the trial. With the simplified test, more people could theoretically be freed of their incorrectly diagnosed drug allergy. Blumenthal’s next step is to work with primary care doctors and their patients to use this type of testing in primary care clinics and verify penicillin allergies proactively rather than at the time people need the drugs most.

Bland sees performing proactive testing as a part of routine care, like vaccination, as the ultimate goal. This way, people can have penicillin on standby if they need it. Many people will encounter a bacterial infection in their lives, Bland says. “You’re going to need an antibiotic,” he adds. “It’s very, very likely. And it could be the one that saves your life.”


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