Studies Confirm Direct Oral Challenge Safely Delabels Penicillin Allergies in Hospitals

Researchers at Duke University Hospital and six international centers confirmed in studies published in 2023 that direct oral challenge (DOC) safely delabeled penicillin allergies in hospitalized patients. The method demonstrated comparable safety to standard skin testing and increased penicillin prescriptions by 13 times within 90 days, according to trial results and hospital officials.

The studies, including a randomized clinical trial involving 382 patients across six centers in three countries, demonstrated that direct oral challenge (DOC) is a safe and effective method for delabeling penicillin allergies in hospitalized patients, according to published trial results and hospital officials.

The PALACE trial and Duke University Hospital’s pilot program, which began in August 2023, both supported these findings, showing that 96% of patients with low-risk penicillin allergies were successfully delabeled following DOC.

Safety data from the studies indicated that immediate immune-mediated reactions occurred in only 0.5% of participants in both the DOC intervention group and control group, according to the PALACE trial results. In Duke University Hospital’s cohort, one patient (1.1%) experienced an immediate reaction within one hour of receiving DOC, but no serious adverse events were reported across any study groups. The upper one-sided confidence interval for positive reactions remained below the noninferiority margin of 5 percentage points, confirming DOC’s safety profile as comparable to standard penicillin skin testing followed by oral challenge, sources said.

Researchers employed the PEN-FAST clinical decision tool to identify patients eligible for DOC. The PEN-FAST scoring system, which was externally validated using mixed prospective derivation and retrospective validation cohorts from Australia and the United States, helped stratify risk and determine that patients with a score less than 3 and no history of anaphylaxis qualified for the oral challenge without prior skin testing, according to the International Network of Antibiotic Allergy Nations (iNAAN) study. The NAAN smartphone application enabled clinicians, nurses, nurse practitioners, and pharmacists to perform point-of-care risk assessments, which facilitated patient selection for DOC across 34 hospital sites.

The DOC approach also demonstrated positive impacts on antibiotic prescribing patterns. Patients who underwent DOC were 13 times more likely to receive penicillin prescriptions within 90 days post-evaluation compared to those who received assessment only, according to data presented by Duke University officials. Additionally, these patients were 22% less likely to be prescribed restricted antibiotics and 27% less likely to receive broad-spectrum antibiotics during the same period. Researchers and hospital officials cited these findings as evidence that removing incorrect penicillin allergy labels leads to more appropriate antibiotic use, reducing reliance on second-line agents that may be less effective and contribute to antimicrobial resistance.

The studies also addressed delayed adverse reactions. The PALACE trial reported that 11.6% of participants experienced any delayed adverse effect, with 4.7% being immune-mediated, occurring at a median of four days after DOC. Duke University’s cohort observed a similar delayed reaction rate of 4.3%, with reactions occurring at a median of seven days post-challenge. Extended monitoring periods at Duke University went beyond those reported in previous literature, confirming the long-term safety of DOC in low-risk patients, hospital officials said.

From an operational standpoint, DOC was associated with greater clinic efficiency and resource savings compared to traditional skin testing. The procedure required less time in clinic and avoided minor skin reactions commonly associated with positive skin tests, according to the PALACE trial findings. Specialized allergy skin testing is not universally accessible and can be labor-intensive and costly, researchers noted. The studies found that two-stage skin testing preceding oral challenge provided no additional safety benefit in well-defined low-risk cohorts, further supporting DOC as a streamlined alternative.

The iNAAN study demonstrated the feasibility of implementing DOC protocols across a large number of inpatient settings using a digital toolkit that supported local adaptation of heterogeneous protocols while maintaining safety. Audit and feedback mechanisms increased penicillin allergy assessments from baseline to an average of 31 assessments per week and 11 direct oral challenges per week across participating sites, according to the network’s published data.

Background context highlights that over 90% of hospitalized patients with documented penicillin allergies are believed to be mislabeled, according to Duke University Hospital officials. This mislabeling often results in suboptimal antibiotic prescribing and increased healthcare costs. The direct oral challenge method offers a pragmatic, scalable approach to address this issue by safely confirming penicillin tolerance in low-risk patients without the need for extensive skin testing.

Future directions include ongoing monitoring of DOC protocols and further integration of digital tools such as the NAAN smartphone application to enhance risk stratification and clinical decision-making. The international collaboration among research centers and hospital systems underscores the growing acceptance of DOC as a standard practice to improve antimicrobial stewardship and patient outcomes in hospital settings.