Direct Oral Challenge for Penicillin Allergy: The International Network of Antibiotic Allergy Nations (iNAAN) Study
Abstract
Background Approximately 10% of hospitalized patients globally report a penicillin allergy, leading to inappropriate antibiotic prescribing and inferior healthcare outcomes. Evidence supporting the effectiveness and widespread implementation of inpatient penicillin direct oral challenge (DOC) is limited. Methods A prospective, multicenter, international type 2 hybrid effectiveness-implementation study was conducted in 40 hospitals across 8 countries between November 2022 and May 2025. Adult inpatients with a penicillin allergy underwent assessment using a digital penicillin allergy toolkit (National Antibiotic Allergy Network [NAAN] App). According to site clinical practice, participants received penicillin DOC (effectiveness intervention) or assessment only. Participating sites received bimonthly audit and feedback at least 3 months after site activation (implementation strategy). Observational data were used to emulate a target trial to examine secondary effectiveness outcomes, including antibiotic prescribing at 90 days in DOC versus non-DOC participants. The primary implementation outcome was adoption of the NAAN App within 6 months of site activation. Results Among 5121 participants assessed, 1573 (30.7%) underwent DOC, of which 1502 (95.5%) were delabeled. Of 71 (4.5%) participants with a positive DOC, 6 (0.4%) had a serious adverse event. Of 1852 inpatients in the target trial analysis, 892 underwent DOC and 960 underwent assessment only. Participants who underwent DOC were more likely to be prescribed penicillin (risk ratio [RR], 13.25 [95% confidence interval {CI}, 7.82–22.46]), and less likely to be prescribed World Health Organization (WHO) “Watch” or “Reserve” antibiotics (RR, 0.73 [95% CI, .60–.89]) at 90 days post evaluation. Within 6 months of site activation, 77 clinicians adopted the NAAN App. Conclusions Multidisciplinary adoption of inpatient penicillin DOC was safe and significantly improved penicillin prescribing and reduced use of WHO restricted antibiotics.
Related
- Direct Oral Challenge for Penicillin Allergy: A Hospital Implementation Evaluation Via the International Network of Antibiotic Allergy Nations (iNAAN) Study
- Commentary on “Reported Penicillin Allergy Affects the Length of Hospital Stay in Patients with Erysipelas”
- Guidelines for the management of adult penicillin allergy in community and specialist settings in Australia and New Zealand: An AGREE II and Delphi-based approach.
- Beyond delabeling: long-term penicillin use and avoidance following negative penicillin challenge in children.
- Dental antibiotic stewardship: study protocol for developing international consensus on a core outcome set
BibTeX
@article{mitri2026direct,
title = {{Direct Oral Challenge for Penicillin Allergy: The International Network of Antibiotic Allergy Nations (iNAAN) Study}},
author = {Elise Mitri and Luke Fletcher and Sara Vogrin and Sara Barnes and Neil Powell and Jonny Peter and Philip Kam-Tao Li and Ana Maria Copaescu and Nicholas Turner and Fiona James and Camille Paynter and Richard Sullivan and Maryam Sherkat Masoum and Matthew Rawlins and Geoff Mackay and Benjamin Smith and Patricia Kilfoyle and Daniel Forster and Morgan Rose and Raquel Cowan and Kylie Alcorn and Anna Brischetto and Andrew Mahony and Andrew Redmond and Arindam Chakravorty and Zaal Meher-Homji and Chino Yuson and Simeon Crawford and Greg Weeks and Sasheela Sri La Sri Ponnampalavanar and Constance Katelaris and Priscilla Tran and Jennifer O'Hern and Jack Godsell and Trisha Peel and Indy Sandaradura and David New and Candice Holland and Tim Cutfield and Sarah Coghill and Caitlin Hand and Jacob Williams and Jaclyn Bishop and Belinda Lambros and Cascia Day and Courtney Ierano and Jason A. Roberts and Natasha Holmes and Marlena Klaic and Suran Fernando and Jason Trubiano},
journal = {Clinical Infectious Diseases},
year = {2026},
month = jun,
doi = {10.1093/cid/ciag082},
url = {https://hal.science/hal-05834749v1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Direct Oral Challenge for Penicillin Allergy: The International Network of Antibiotic Allergy Nations (iNAAN) Study
AU - Elise Mitri
AU - Luke Fletcher
AU - Sara Vogrin
AU - Sara Barnes
AU - Neil Powell
AU - Jonny Peter
AU - Philip Kam-Tao Li
AU - Ana Maria Copaescu
AU - Nicholas Turner
AU - Fiona James
AU - Camille Paynter
AU - Richard Sullivan
AU - Maryam Sherkat Masoum
AU - Matthew Rawlins
AU - Geoff Mackay
AU - Benjamin Smith
AU - Patricia Kilfoyle
AU - Daniel Forster
AU - Morgan Rose
AU - Raquel Cowan
AU - Kylie Alcorn
AU - Anna Brischetto
AU - Andrew Mahony
AU - Andrew Redmond
AU - Arindam Chakravorty
AU - Zaal Meher-Homji
AU - Chino Yuson
AU - Simeon Crawford
AU - Greg Weeks
AU - Sasheela Sri La Sri Ponnampalavanar
AU - Constance Katelaris
AU - Priscilla Tran
AU - Jennifer O'Hern
AU - Jack Godsell
AU - Trisha Peel
AU - Indy Sandaradura
AU - David New
AU - Candice Holland
AU - Tim Cutfield
AU - Sarah Coghill
AU - Caitlin Hand
AU - Jacob Williams
AU - Jaclyn Bishop
AU - Belinda Lambros
AU - Cascia Day
AU - Courtney Ierano
AU - Jason A. Roberts
AU - Natasha Holmes
AU - Marlena Klaic
AU - Suran Fernando
AU - Jason Trubiano
PY - 2026
DA - 2026/06/15
JO - Clinical Infectious Diseases
DO - 10.1093/cid/ciag082
UR - https://hal.science/hal-05834749v1
AB - Background Approximately 10% of hospitalized patients globally report a penicillin allergy, leading to inappropriate antibiotic prescribing and inferior healthcare outcomes. Evidence supporting the effectiveness and widespread implementation of inpatient penicillin direct oral challenge (DOC) is limited. Methods A prospective, multicenter, international type 2 hybrid effectiveness-implementation study was conducted in 40 hospitals across 8 countries between November 2022 and May 2025. Adult inpatients with a penicillin allergy underwent assessment using a digital penicillin allergy toolkit (National Antibiotic Allergy Network [NAAN] App). According to site clinical practice, participants received penicillin DOC (effectiveness intervention) or assessment only. Participating sites received bimonthly audit and feedback at least 3 months after site activation (implementation strategy). Observational data were used to emulate a target trial to examine secondary effectiveness outcomes, including antibiotic prescribing at 90 days in DOC versus non-DOC participants. The primary implementation outcome was adoption of the NAAN App within 6 months of site activation. Results Among 5121 participants assessed, 1573 (30.7%) underwent DOC, of which 1502 (95.5%) were delabeled. Of 71 (4.5%) participants with a positive DOC, 6 (0.4%) had a serious adverse event. Of 1852 inpatients in the target trial analysis, 892 underwent DOC and 960 underwent assessment only. Participants who underwent DOC were more likely to be prescribed penicillin (risk ratio [RR], 13.25 [95% confidence interval {CI}, 7.82–22.46]), and less likely to be prescribed World Health Organization (WHO) “Watch” or “Reserve” antibiotics (RR, 0.73 [95% CI, .60–.89]) at 90 days post evaluation. Within 6 months of site activation, 77 clinicians adopted the NAAN App. Conclusions Multidisciplinary adoption of inpatient penicillin DOC was safe and significantly improved penicillin prescribing and reduced use of WHO restricted antibiotics.
SN - 1058-4838
SN - 1537-6591
ER -