A Study of the Impact of Penicillin Allergy on Antimicrobial Resistance and ouTcomes (IMPAART)

Penicillin allergy is one of the commonest reported allergies. The presence of a penicillin allergy record in a patients notes leads to the avoidance of recommended first-line penicillin antibiotics and the use of alternative non-penicillin antibiotics which can be less effective, have more side effects and have a greater propensity to drive antimicrobial resistance (AMR). Most patients with penicillin allergy records do not have a true allergy when they are tested by a specialist, so many patients are denied the best antibiotics because of an incorrect penicillin allergy record.

The study will investigate how having a penicillin allergy impacts on treatment for patients who need antibiotics when they are hospitalised with COVID-19 and how penicillin allergy affects AMR.

Antibiotic use is the main driver of AMR, antibiotic use can also disrupt the bacteria that normally live in our guts and mouths. These bacterial communities also known as the gastrointestinal (GI) and oral microbiome respectively, help us digest food and prevent infections. Antibiotic use can 'kill off' these harmless bacteria and lead to an increase in bacteria which have genes that make them resistant to antibiotics (antibiotic resistance genes). The study investigators believe that patients with penicillin allergy are likely to have a greater number of antibiotic resistance genes in their oral and GI microbiomes, ans that this will make it more likely that they will fail antibiotic treatment and will increase their risk of transmitting resistance to others.

The study objectives are:

1. To determine how penicillin allergy impacts on clinical outcomes in patients admitted with COVID-19
2. To find out if AMR genes in the oral microbiome of people with a penicillin allergy record are different to those without a penicillin allergy record
3. To investigate whether AMR genes are lost in patients who have an incorrect penicillin allergy label removed

Study Overview

• Status: Active, not recruiting
• Conditions: Penicillin Allergy; Antimicrobial Drug Resistance; AMR

Detailed Description

Study hypothesis:

Patients with a penicillin allergy record are more likely to have resistance to non-penicillin antibiotics in their normal flora and that this will increase their risk of treatment failure with non-penicillin antibiotics. In particular, penicillin allergic patients admitted with COVID-19 who have bacterial infections will have an increased risk of treatment failure and poor outcomes.

Study design:

This research will be conducted in three separate but complementary workstreams:

Workstream 1 will include secondary analysis of data collected as a part of the Procalcitonin Evaluation of Antibiotic use in COVID-19 Hospitalised patients (PEACH) study (ISRCTN66682918) to determine how penicillin allergy impacts on antibiotic use and clinical outcomes in patients admitted with COVID-19. The PEACH study was a multi-centre, retrospective, observational, cohort study using patient-level clinical data which investigated whether the use of procalcitonin testing, to guide antibiotic prescribing, safely reduced antibiotic use amongst hospitalised patients with COVID-19 during the first wave of the pandemic using routinely collected patient institutional clinical databases and patient medical records. Data were collected in 11 National Health Service (NHS) acute hospital Trusts and Health Boards in England and Wales, and data in a pseudo-anonymised format was received from the Cardiff Clinical Trials Unit who were the data controllers for the PEACH study.

Workstream 2 will compare the oral resistome of patients with and without penicillin allergy. Metagenomic and metatranscriptomic analysis will be used for resistome assessment.

Workstream 3 will determine the feasibility of investigating if antibiotic resistance genes are lost after removal of an incorrect penicillin allergy record. This workstream will recruit patients enrolled in the Allergy Antibiotics and Microbial Resistance (ALABAMA) trial (NCT04108637), which is a randomised control trial (RCT) designed to assess the effect of removing incorrect penicillin allergy records on health outcomes. Participants are randomised to either usual care or the intervention group where they receive a novel penicillin allergy assessment pathway (PAAP), if patients in the intervention group are found to be not allergic to penicillin, their allergy label is subsequently removed. Patients recruited to this workstream will be followed up as per the ALABAMA protocol but will also be required to provide baseline and follow up (> 6 months after enrolment or allergy testing) saliva +/- stool samples. Metagenomic and metatranscriptomic analysis will be used for resistome assessment.

• Study Type: Observational
• Enrollment (Actual): 214

Contacts and Locations

Study Locations

• United Kingdom
  • Leeds, United Kingdom
    • Leeds Teaching Hospitals NHS Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Probability Sample

Study Population

- Workstream 1 population: Participants included in the Procalcitonin Evaluation of Antibiotic use in COVID-19 Hospitalised patients (PEACH) study (ISRCTN66682918)

- Workstream 2 population: Participants will be recruited from patients attending outpatient clinics at Leeds Teaching Hospitals NHS Trust, United Kingdom.

- Workstream 3 population: Participants will be recruited from the population of patients participating in the he Allergy Antibiotics and Microbial Resistance (ALABAMA) trial (NCT04108637).

Description

Inclusion Criteria:

• Workstream 1

  1. Adult (>16 years) with confirmed COVID-19 (positive PCR test)
  2. Admitted to participating NHS Trusts/hospitals between 01/02/2020 to 30/06/2020

• Workstream 2

  1. Adult (≥18 years) patients with a penicillin allergy or a matched patients (by age and sex) without a penicillin allergy
  2. Received antibiotics in the 24 months prior to recruitment
  3. Willing to provide saliva +/- stool samples

• Workstream 3

  1. Patients enrolled into the ALABAMA trial

Exclusion Criteria:

• Workstream 1

  a. Patients with their allergy status missing will be excluded.

• Workstream 2

  1. Patients unable to give informed consent or who are unwilling/unable to provide saliva samples
  2. Unwilling/unable to provide saliva samples

• Workstream 3

  1. Patients unable to give informed consent or who are unwilling/unable to provide saliva samples
  2. Unwilling/unable to provide saliva samples

Study Plan

How is the study designed?

Number of groups / cohorts

5

Cohorts and Interventions

Group / Cohort
Workstream 1: PEACH Study participants; Adults and adolescents 16 years old and older, admitted to hospital between 1/2/20 and 30/06/20 with a positive SARS-CoV-2 test.
Workstream 2 exposure group; Adult patients with a penicillin allergy attending immunology clinics at Leeds Teaching Hospitals, UK
Workstream 2 comparator group; Adult patients without a penicillin allergy attending immunology clinics at Leeds Teaching Hospitals, UK
Workstream 3 exposure group; Participants enrolled in the ALABAMA trial who underwent penicillin allergy testing
Workstream 3 comparator group; Participants enrolled in the ALABAMA trial who had usual care only (i.e. did not undergo penicillin allergy testing)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Workstream 1: 60 day mortality in patients with and without penicillin allergy	This outcome will measure mortality within 60 days of positive COVID-19 test. Comparative analysis will be conducted between patients with and without a documented penicillin allergy.	60 days from the date of positive COVID 19 test
Workstream 2: The prevalence of antibiotic resistance genes (ARGs) in the mouth of patients with and without a penicillin allergy record.	The prevalence of ARGs will be assessed using shotgun metagenomic sequencing of saliva samples. Comparative analysis will be conducted between patients with and without a documented penicillin allergy.	At enrolment
Workstream 3: Change in abundance of antibiotic resistance genes in saliva samples collected from participants enrolled in the ALABAMA trial	This outcome will determine the change in antibiotic resistance gene (ARG) abundance over time in patients who received the ALABAMA trial intervention (penicillin allergy assessment) compared to those in the control group (no penicillin allergy assessment). This analysis will focus on the subset of ALABAMA trial patients with at least one antibiotic prescription prior to their second saliva sampling. Comparative analysis will be conducted between the penicillin allergy assessment group and the no penicillin allergy assessment group.	At enrolment (first sample collection) and 6 to 12 months post-enrolment (second sample collection)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Workstream 1: Length of hospital stay in patients with and without a penicillin allergy.	This will be determined by a retrospective measurement of total hospital stay (day 0 = date of admission), calculated as days from admission date to the date of discharge or inpatient death (whichever occurred first). Comparative analysis will be conducted between patients with and without a documented penicillin allergy.	Time of hospital admission to discharge or inpatient death for each patient, assessed up to 600 days
Workstream 1: Number of AMR bacterial infections in patients with and without a penicillin allergy.	This will be determined by blood cultures and deep respiratory culture positivity, and a infection will be considered to be a AMR/resistant infection if the isolated pathogen is resistant to ≥1 antibiotic agent in 3 or more antibiotic classes. Comparative analysis will be conducted between patients with and without a documented penicillin allergy.	Time of hospital admission to discharge or inpatient death for each patient, assessed up to 600 days
Workstream 1: Total antibiotic usage in patients with and without a penicillin allergy.	This outcome will assess inpatient antibiotic use including antibiotic agent, route of administration and duration following COVID-19 diagnosis in hospital from day 1 of COVID-19 diagnosis to date of discharge or death (inclusive of day 1 and last day). Comparative analysis will be conducted between patients with and without a documented penicillin allergy.	Time of hospital admission to discharge or inpatient death for each patient, assessed up to 600 days
Workstream 1: Rates of treatment failure in patients with and without a penicillin allergy.	This will be defined as re-prescription of an antibiotic within 30 days of index antibiotic prescription. Comparative analysis will be conducted between patients with and without a documented penicillin allergy.	Time of hospital admission to discharge or inpatient death for each patient, assessed up to 600 days
Workstream 1: ICU admission rates in patients with and without a penicillin allergy.	The number of admission to intensive care units (ICU) will be counted. Comparative analysis will be conducted between patients with and without a documented penicillin allergy.	Time of hospital admission to discharge or inpatient death for each patient, assessed up to 600 days
Workstream 1: Rate of Clostridioides difficile infection in patients with and without a penicillin allergy.	This will be determined by a toxin positive result from day 1 of COVID-19 diagnosis. Comparative analysis will be conducted between patients with and without a documented penicillin allergy.	Time of hospital admission to discharge or inpatient death for each patient, assessed up to 600 days
Workstream 1: 30 day mortality in patients with and without a penicillin allergy	This outcome will measure mortality within 30 days of COVID-19 diagnosis in patients with and without penicillin allergy.	30 days from COVID-19 diagnosis
Workstream 2: The difference in diversity of antibiotic resistance genes (ARGs) in oral microbiome of patients with and without a penicillin allergy record.	This outcome will assess the diversity of ARGs using shotgun metagenomic and metatranscriptomic sequencing of saliva samples collected at the time of enrolment. Bioinformatic analysis will be performed to quantify the overall counts, relative abundance, and diversity indices (e.g., Shannon and Simpson diversity) of ARGs. Comparative analysis will be conducted between patients with and without penicillin allergy to determine differences in ARG diversity.	Enrolment
Workstream 2: The number of resistance genes to specific antibiotic classes present in the oral microbiome of patients with and without a penicillin allergy record.	This outcome will assess the number antibiotic resistance genes (ARGs) associated with specific antibiotic classes using shotgun metagenomic sequencing of saliva samples. A comparative analysis will be conducted between patients with and without a documented penicillin allergy.	Enrolment
Workstream 2: To determine whether a metagenomic or transcriptomic approach could be used to predict phenotypic antibiotic susceptibility	This outcome will evaluate whether of shotgun metagenomic and metatranscriptomic sequencing of saliva samples can be used to predict phenotypic antibiotic susceptibility. Saliva samples taken at enrolment will undergo metagenomic and transcriptomic sequencing analysis to identify antibiotic resistance genes and their expression as well as antimicrobial susceptibility testing (AST) on cultured bacterial isolates from the same samples to determine actual resistance profiles.	Enrolment
Workstream 3: The change in the abundance and richness of antibiotic resistance genes (ARGs) over time between patients who had the ALABAMA trial intervention and those in the control group	This outcome will assess the change over time in the abundance and richness of ARGs in the oral microbiome, and where available, the gut microbiome. Samples will be analysed using shotgun metagenomic sequencing of saliva and optional stool samples. Bioinformatic analysis will include overall ARG counts, relative abundance and diversity indices (e.g., Shannon and Simpson diversity). Comparative analysis will be conducted between patients who received the intervention (penicillin allergy assessment) and those in the control group (no penicillin allergy assessment) to evaluate differences in ARG dynamics over time.	At enrolment (first sample collection) and 6 to 12 months post-enrolment (second sample collection).
Workstream 3: The number and abundance of 'non-penicillin' antibiotic resistance genes in patients who had the ALABAMA trial intervention (penicillin allergy assessment) and those in the control group (no penicillin allergy assessment).	This outcome will assess the number and abundance of ARGs associated with non-penicillin antibiotic classes (e.g., macrolides, tetracyclines, fluoroquinolones, aminoglycosides) in the oral microbiome, and where available, the gut microbiome. Comparative analysis will be conducted between patients who received the intervention and those in the control group to evaluate differences in ARG dynamics over time.	At enrolment (first sample collection) and 6 to 12 months post-enrolment (second sample collection)
Workstream 3: The number and abundance of 'penicillin' antibiotic resistance genes (ARGs) in patients who had the ALABAMA trial intervention (penicillin allergy assessment) and those in the control group (no penicillin allergy assessment).	This outcome will assess the number and abundance of ARGs specifically associated with penicillin-class antibiotics in the oral microbiome, and where available, the gut microbiome. Comparative analysis will be conducted between patients who received the intervention and those in the control group to evaluate differences in ARG dynamics over time.	At enrolment (first sample collection) and 6 to 12 months post-enrolment (second sample collection).

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Workstream 3: To determine the number of patients from the ALABAMA trial who consented to participate in this sub-study.	Feasibility outcome to evaluate the feasibility of conducting the ARG sub-study by reporting the number and percentage of ALABAMA trial participants who provided consent to join the sub-study.	From the start of recruitment until the end of the recruitment period, estimated to last up to 5 years
Workstream 3: To determine the number of patients who provide baseline samples	Feasibility outcome to evaluate the feasibility of conducting the ARG sub-study by reporting the number and percentage of participants who provide a sample at baseline (enrolment).	At enrolment
Workstream 3: To determine the number of patients who provide a second sample	Feasibility outcome to evaluate the feasibility of conducting the ARG sub-study by reporting the number and percentage of participants who provide a second sample 6 to 12 months post-enrolment.	Six to twelve months post-enrolment
Workstream 3: Explore the relationship between antibiotic resistance gene (ARG) abundance and treatment response failure	This feasibility outcome aims to generate initial data to inform the design of future research studies. Measures will include relative abundance of ARGs.	Up to 12 months post-enrolment
Workstream 3: Explore the relationship between antibiotic resistance gene (ARG) richness and treatment response failure	This feasibility outcome aims to generate initial data to inform the design of future research studies. Measures will include overall counts of unique ARGs and diversity indices to assess ARG richness.	Up to 12 months post-enrolment

Collaborators and Investigators

• Sponsor: University of Leeds
• Investigators: Principal Investigator: Shadia Ahmed, MBChB, Univeristy of Leeds

Study record dates

Study Major Dates

• Study Start (Actual): November 30, 2021
• Primary Completion (Actual): April 24, 2024
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: July 22, 2025
• First Submitted That Met QC Criteria: September 10, 2025
• First Posted (Estimated): September 17, 2025

Study Record Updates

• Last Update Posted (Estimated): September 17, 2025
• Last Update Submitted That Met QC Criteria: September 10, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: Antimicrobial resistance; AMR; penicillin allergy
• Other Study ID Numbers: Version 1. 3 25/01/2022

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No