Disclosures: Stone reports receiving funding from AHRQ/PCORI 1K12HS026395-01 for this project and receiving an American Academy of Allergy, Asthma & Immunology Foundation Faculty Development Award. The other authors report no relevant financial disclosures.

February 23, 2022
5 min read

Direct oral challenge delabels nearly all ICU patients who report penicillin allergy

Disclosures: Stone reports receiving funding from AHRQ/PCORI 1K12HS026395-01 for this project and receiving an American Academy of Allergy, Asthma & Immunology Foundation Faculty Development Award. The other authors report no relevant financial disclosures.

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Medical ICU patients with low-risk penicillin allergy labels would benefit from point-of-care delabeling, according to a study published in The Journal of Allergy and Clinical Immunology: In Practice.

Patients admitted to medical ICUs (MICUs) frequently are predisposed to infections, increasing their need for antibiotics, the researchers wrote, noting that critically ill, immunocompromised patients with multiple drug allergy labels (MDALs) would disproportionately benefit from penicillin and from penicillin allergy delabeling.

Inaccurate allergy labeling

“Under current testing, up to 95% of the penicillin allergies or labels reported by 10% to 15% of the U.S. population may be inaccurate. They don’t test positive for allergy,” author Cosby A. Stone Jr., MD, MPH, assistant professor in the division of allergy, pulmonary and critical medicine in the department of medicine at Vanderbilt University Medical Center, told Healio.

“Unnecessary penicillin allergies are often a barrier to giving the right antibiotic at the right time,” Stone said.

When a penicillin drug is the first-line antibiotic of choice to treat a patient but doctors avoid using it because of an inaccurate or outdated allergy diagnosis, Stone said, it can result in treatment failures and prolonged hospitalizations, while increasing the chance of surgical infections and multidrug-resistant infections.

Cosby A. Stone Jr.

“The second-line antibiotics are often less effective. You can imagine how this is bad for the patient, their doctors, hospitals and the health care system overall in terms of bad outcomes, drug resistance and increased costs,” he said.

The researchers previously had identified a group of patients who, based on their recall of how they had been diagnosed with a penicillin allergy, had less than a 1% chance of testing positive for a penicillin allergy.

“This group comprises between 60% and 70% of all patients reporting a label of penicillin allergy,” Stone said. “Hence, we sought to apply that knowledge prospectively in the ICU setting, where patients were simultaneously in a safe environment in the event of a reaction and also at a higher need for antibiotics.”

The study’s results

Between March 2019 and March 2021, 839 of the 5,203 patients (16.1%) admitted to the MICU at Vanderbilt University Medical Center had a penicillin allergy label (PAL), and 240 (28.6%; 46.7% women; median age, 58 years) of them had low-risk PALs.

Low-risk PALs were defined as having chronic urticaria more than 5 years ago; a past self-limited cutaneous rash that did not involve organs or a severe delayed rash; gastrointestinal symptoms exclusively; a remote reaction during childhood with few details; family history exclusively; fear of allergy avoidance; known penicillin tolerance; or nonallergy symptoms.

All 240 were offered an oral challenge, and all 205 who agreed to the oral challenge passed it after an hour of observation and had their PAL delabeled. Two patients experienced subsequent rashes attributable to penicillin, however, and were relabeled.

“We offered those low-risk penicillin allergy patients the opportunity to take a dose of amoxicillin to disprove their allergy without a penicillin allergy skin test,” Stone said.

Also, 156 of the 240 patients were immunocompromised, with diagnoses including type 1 or 2 diabetes ( 31.3%); end-organ disease including end-stage renal disease, cirrhosis and end-stage lung disease (22.9%); use of immunosuppressive medications (18.3%); active solid organ or hematologic malignancy (17.1%); and autoimmune disorders (11.3%).

According to the researchers, 131 of the immunocompromised patients (84%) agreed to the direct oral amoxicillin challenge, all of whom had their PAL removed. Within a median of 13 days (interquartile range [IQR], 0-49) later, 37 of them received at least one course of penicillin, with 36 of them tolerating 64 separate doses.

“We found that not only are ICU patients at a higher need for antibiotics, but that patients who were being interviewed about their penicillin allergy label were also very likely to be immune compromised or to have other antibiotic allergy labels that were limiting their providers’ treatment options,” Stone said.

“By testing and removing these unnecessary low-risk penicillin allergy labels when the patient and their doctor agreed, we got rid of a barrier to giving them highly effective antibiotic treatments. Around 30% have already taken advantage of penicillin treatments since we tested them in the ICU,” he continued.

Common nonpenicillin antibiotic allergy labels among the 141 patients with MDALs included cephalosporin (17.7%), sulfonamide (24.1%) and fluoroquinolones (12.1%), with 34 (24.1%) reporting allergies to others.

The researchers said that all 114 (80.9%) patients with MDALs who agreed to an amoxicillin challenge passed it and had their PAL removed, with 38 (27%) tolerating 77 total courses of penicillin a median of 8 days (IQR, 0-53.5) later and only one treatment not tolerated.

Further, 73 of the 93 patients (78.5%) who were immunocompromised and had MDALs and who agreed to an oral challenge were initially delabeled, with 24 (32.9%) tolerating 49 subsequent penicillin treatments a median of 13 days (IQR, 0-49) after PAL removal.

“I was surprised by how limited many patients in the ICU are in their antibiotic choices, as around 60% reported having reacted to multiple antibiotics in the past, and by how many had immune compromise — again, around 60% — in the presence of a low-risk penicillin allergy label,” Stone said. “The most significant finding was that things worked out as we had hoped they would.”

Only one of the 205 low-risk patients who agreed to be tested had a rash, and only one experienced a rash during subsequent treatment, Stone noted, although a few patients did report upset stomachs.

“Over 2 years, our testing program has already enabled 100 penicillin treatments for these patients that would not have happened otherwise,” he said.

The MICU, the researchers concluded, represents an opportunity to target interventions in a population of patients with MDALs who are at highest risk for the negative consequences of inaccurate allergy labels.

What’s next in testing

Point-of-care direct oral challenges with amoxicillin are safe and effective means of delabeling patients with low-risk PALs — and they can be used beyond the MICU, Stone added.

“Low-risk penicillin allergy labels can be safely identified and challenged to disprove them in a lot of different health care settings. Around 50 million Americans report a penicillin allergy, and very few of them have ever been tested to confirm or disprove that diagnosis,” he said.

“With 60% to 70% of all those penicillin allergies being simultaneously unnecessary and low risk for a reaction, I think we could make a huge impact on our antibiotic care and stewardship if we implemented programs to tackle them at a national scale. This is the lowest hanging fruit,” he continued.

The researchers also have completed the active phase of a stepped wedge randomized controlled trial within the inpatient internal medicine units at Vanderbilt University Medical Center.

Known as the PROPEL trial, this study aims to show in a randomized fashion that the researchers’ approach is effective in increasing the removal of unnecessary penicillin allergies in the inpatient setting and in improving subsequent patterns of antibiotic use.

“We are now gathering the data from this trial and preparing for analysis,” Stone said.

Future research will focus on other settings where this approach to low-risk penicillin allergies could be applied and on special patient populations who could particularly benefit.

“We also have plans to bring similar approaches to bear for other key first-line antibiotic allergies such as cephalosporins and sulfonamides,” Stone said.

For more information:

Cosby A. Stone Jr., MD, MPH, can be reached at cosby.a.stone@vumc.org.