A number of low-risk patients with a penicillin allergy were able to have their allergy label removed through a simple procedure known as “direct oral challenge” as part of the world-first Penicillin Allergy Clinical Decision Rule (PALACE) study, researchers have reported.
Penicillin allergy has been shown to lead to particularly poor health outcomes in pregnant women and surgical patients. It is also a public health threat, leading to antibiotic resistance and infections in hospitalised patients that can be life-threatening, according to a JAMA Internal Medicine report.
At least 75% of penicillin allergy labels are given to people by the age of three, due to, for example, confusion with a viral rash. Most of these rashes were never allergic, but the labels stick into adulthood and carry many adverse consequences.
In the multicentre control trial – the PALACE study – investigators randomised low-risk penicillin allergic patients to two different approaches to remove their allergy label.
They either underwent the current standard of care to have skin testing followed, if negative, by oral challenge with a penicillin, or went straight to oral challenge (“direct oral challenge”) without the preceding skin testing.
“Most of the patients labelled as penicillin allergic – more than 90% – have low-risk histories, meaning they did not have a history to suggest a severe or more recent reaction to a penicillin,” said PALACE study protocol member and Vanderbilt University Medical Centre principal investigator Dr Elizabeth Phillips, the John Oates Professor of Clinical Research.
“We would expect more than 95% of these patients to have negative testing and be able to take penicillin in the future.”
The study, by researchers from specialised centres in North America and Australia, enrolled 382 adults who were assessed using a specialised risk assessment tool called PEN-FAST.
Participants were randomly assigned to receive either a direct oral penicillin challenge or the standard approach (penicillin skin testing followed by an oral challenge).
The primary goal was to determine if the direct oral penicillin challenge were no worse than the standard method of skin testing followed by oral challenge, which needs to be performed in an allergist’s office.
Only one patient (0.5%) in each group experienced a positive reaction to the penicillin challenge, demonstrating that the direct oral penicillin challenge performs just as well as the standard method.
Importantly, there were no significant differences in adverse events between the two groups, and no serious adverse events reported.
The findings have wide-ranging implications for patients. By accurately identifying low-risk penicillin allergy patients, healthcare providers can ensure appropriate antibiotic prescriptions.
Patients with a documented penicillin allergy are more likely to be prescribed alternative antibiotics, known as second-line antibiotics, which are often not as effective against certain infections and may have more side effects.
“Patients with penicillin allergy are more likely to get second-line or broader spectrum antibiotics that lead to risk of antibiotic resistance and serious infections such as antibiotic-associated diarrhoea due to Clostridioides difficile, which can spread through hospitals and become a major public health problem,” said Phillips.
“In the US, increasingly, we also have a major problem with other antibiotic-resistant superbugs such as multi-resistant gram-negative infections, Candida auris and even a resurgence of syphilis, for which penicillin is the best treatment and the only one that should be used in pregnancy to prevent transmission to an unborn child.
“The evidence provided by the PALACE study will change clinical practice. Many people do not have direct access to an allergist who can provide specialist skin testing, for example. So being able to go to direct oral challenge that can be carried out in any observed setting will make it easier to safely remove the penicillin allergy label.”
Study details
Efficacy of a clinical decision rule to enable direct oral challenge in patients with low-risk penicillin allergy – the PALACE Randomised Clinical Trial
Ana Maria Copaescu, Sara Vogrin, Jason Trubiano, et al.
Published in JAMA Internal Medicine on 17 July 2023.
Key Points
Question Is direct oral penicillin challenge in adults with a low-risk penicillin allergy, defined as a PEN-FAST score less than 3, safe and effective compared with the standard-of-care penicillin skin testing followed by an oral penicillin challenge?
Findings In this randomised clinical trial of 382 patients across 6 centres in 3 countries, a positive penicillin oral challenge consistent with an immune-mediated reaction occurred in 0.5% of both the direct oral challenge intervention group and the control group, with an upper 1-sided confidence interval below the non-inferiority margin of 5 percentage points.
Meaning In adult patients with a low-risk penicillin allergy, direct oral penicillin challenge is a safe and effective procedure that may facilitate the removal of a larger number of penicillin allergy labels.
Abstract
Importance
Fewer than 5% of patients labelled with a penicillin allergy are truly allergic. The standard of care to remove the penicillin allergy label in adults is specialised testing involving prick and intradermal skin testing followed by an oral challenge with penicillin. Skin testing is resource intensive, limits practice to specialist-trained physicians, and restricts the global population who could undergo penicillin allergy delabelling.
Objective
To determine whether a direct oral penicillin challenge is non-inferior to the standard of care of penicillin skin testing followed by an oral challenge in patients with a low-risk penicillin allergy.
Design, Setting, and Participants
This parallel, 2-arm, non-inferiority, open-label, multicentre, international randomised clinical trial occurred in six specialised centres, 3 in North America (US and Canada) and 3 in Australia, from June 18, 2021, to December 2, 2022. Eligible adults had a PEN-FAST score lower than 3. PEN-FAST is a prospectively derived and internationally validated clinical decision rule that enables point-of-care risk assessment for adults reporting penicillin allergies.
Interventions
Patients were randomly assigned to either direct oral challenge with penicillin (intervention arm) or a standard-of-care arm of penicillin skin testing followed by oral challenge with penicillin (control arm).
Main Outcome and Measure
The primary outcome was a physician-verified positive immune-mediated oral penicillin challenge within one-hour post-intervention in the intention-to-treat population. Non-inferiority was achieved if a 1-sided 95% CI of the risk difference (RD) did not exceed 5 percentage points (pp).
Results
A total of 382 adults were randomised, with 377 patients (median [IQR] age, 51 [35-65] years; 247 [65.5%] female) included in the analysis: 187 in the intervention group and 190 in the control group. Most patients had a PEN-FAST score of 0 or 1. The primary outcome occurred in 1 patient (0.5%) in the intervention group and 1 patient (0.5%) in the control group, with an RD of 0.0084 pp (90% CI, −1.22 to 1.24 pp). The 1-sided 95% CI was below the non-inferiority margin of 5 pp. In the 5 days following the oral penicillin challenge, 9 immune-mediated adverse events were recorded in the intervention group and 10 in the control group (RD, −0.45 pp; 95% CI, −4.87 to 3.96 pp). No serious adverse events occurred.
Conclusions and Relevance
In this randomised clinical trial, direct oral penicillin challenge in patients with a low-risk penicillin allergy was non-inferior compared with standard-of-care skin testing followed by oral challenge. In patients with a low-risk history, direct oral penicillin challenge is a safe procedure to facilitate the removal of a penicillin allergy label.
See more from MedicalBrief archives:
Penicillin allergy cases on the decline
Misconceptions over penicillin allergy deprive patients of best treatment
All children with possible penicillin allergy test negative – small study