Results from a multinational study indicate that direct oral challenge (DOC) is a safe and effective strategy for identifying hospital patients who truly have a penicillin allergy, researchers reported last week in Clinical Infectious Diseases.
The study, conducted in 40 hospitals in eight countries by researchers with the International Network of Antibiotic Allergy Nations (iNAAN) Study Group, aimed to prospectively evaluate the safety and effectiveness of inpatient penicillin DOC in hospitals with an existing penicillin allergy delabeling program. While approximately 10% of people globally have a penicillin allergy label, previous research suggests that less than 5% of those with the label are truly allergic.
Determining which patients have a penicillin allergy has become an important element of antimicrobial stewardship programs, because incorrect penicillin allergy labels can result in patients receiving antibiotics that aren't as effective, have side effects, and promote the development of antimicrobial resistance [AMR].
"The downstream effects of self-reported penicillin allergy include an increased risk of suboptimal antibiotic prescribing, multidrug-resistant infections, extended hospital length of stay (LOS), and hospital readmission," the study authors wrote.
While a skin test has been the standard for assessing penicillin allergies, the practice is resource intensive, and several smaller studies have found penicillin DOC is effective in limited settings. But the authors note that broader use of the strategy, particularly in rural and remote settings and areas where allergists aren't available, needs to be evaluated. Their study included a mix of low-, middle-, and high-income countries (Australia, Canada, Hong Kong, Malaysia, New Zealand, South Africa, the United Kingdom, and the United States) and hospitals with varied approaches to penicillin allergy evaluation.
96% of patients delabeled after DOC
Using a smartphone application (the NAAN app) that can be used at the point of care, clinicians, nurses, nurse practitioners, and pharmacists at the participating hospitals first assessed patients' level of risk based on their penicillin allergy history and hospital protocols. Those deemed to have a low-risk penicillin allergy were then further assessed or offered DOC, which involves taking a single oral dose of a penicillin antibiotic and being observed for a possible reaction. The primary outcome was the proportion of participants with low-risk allergy who were delabeled following DOC.
The study also assessed implementation strategy and adoption of the NAAN app. Observational data gathered in the three months after penicillin allergy evaluation began at the study sites were used to emulate a target trial to evaluate the downstream outcomes, including prescribing of penicillin and restricted antibiotics post-evaluation.
Of the 5,121 patients (median age 68 years; 60.7% female) assessed from November 2022 through May 2025, 1,573 (30.7%) underwent penicillin DOC. Of those patients, 1,502 (95.5%) were subsequently delabeled. Of the 71 patients who had a positive DOC, six (0.4%) had a serious adverse event, but none experienced a rapid, life-threatening reaction known as anaphylaxis. The majority of DOC's (61.3%) were performed by non-allergists.
The downstream effects of self-reported penicillin allergy include an increased risk of suboptimal antibiotic prescribing, multidrug-resistant infections, extended hospital length of stay (LOS), and hospital readmission.
Among the 1,852 patients identified for the target trial emulation, 892 had undergone DOC and 960 underwent assessment only. Analysis of antibiotic prescribing among these patients showed that those who underwent DOC were 13 times more likely to be prescribed penicillin (risk ratio [RR], 13.25) at 90 days post evaluation than those who underwent assessment only, 22% less likely to receive restricted antibiotics (RR, 0.78), and 27% less likely to be prescribed broad-spectrum antibiotics (RR, 0.73). Penicillin DOC was also associated with a lower risk of acquiring multidrug-resistant bacteria.
Within six months of site activation, 77 of 126 clinicians (61%) adopted the NAAN app.
The study authors say that, in addition to providing the largest body of evidence yet for the safety of inpatient penicillin DOC across a wide range of settings, the study reveals the positive impact the intervention can have on antibiotic prescribing.
"Beyond just confirming safety, iNAAN also demonstrated how penicillin DOC can influence antibiotic prescribing including globally recognized antibiotics known to drive AMR," they wrote.
Audit and feedback boosts uptake of DOC
In a separate paper published in the same journal, the same team of researchers reported on the effectiveness of using a digital audit and feedback (A&F) strategy to implement penicillin DOC at study sites. The A&F, which was initiated at all hospitals in the study at least six weeks after the intervention was initiated, involved bimonthly emails to all registered NAAN app users detailing the outcomes of penicillin allergy assessment and DOC.
Analysis of 142 NAAN app users (roughly three per hospital) found that the A&F strategy was associated with significant increases in penicillin DOCs and penicillin allergy assessments at all sites, and also with increased fidelity to hospital protocols for penicillin allergy delabeling. Use of the NAAN app also increased over time, suggesting the strategy is sustainable.
"We demonstrated that digital A&F is a viable strategy for initially implementing penicillin allergy delabeling programs internationally, including in resource-limited settings, and that it notably produces sustained improvements in protocol fidelity over time," the authors wrote.
