Acquisition of Resistant Enterobacteria During Oral Drug Challenge for Betalactams in Children (ARET)

Direct drug provocation testing, without prior skin or in vitro testing, is the reference standard for confirming the diagnosis of drug hypersensitivity reactions in children reporting mild and delayed-onset reactions. However, optimal protocol(s) have not been standardized. Although a 2-days' provocation testing protocol is effective, increasing its duration (up to 14 days) may improve its diagnosis performance without increasing the risk of severe reactions. However, a prolonged provocation testing could increase the risk of emergence of bacterial resistances in the digestive flora. Longer duration could be associated with the emergence of extended-spectrum betalactamase producing enterobacteria. However, this point has never been confirmed.

The study will include children (0-18 years); referring for histories of mild and delayed-onset reactions to betalactams. drug provocation testing will be performed with the suspected BLs in our department, as in clinical practice. Two groups of patients will be compared: a group performing short provocation testing (arbitrary defined as lasting 1 to 4 days) and a group with prolonged drug provocation testing (arbitrary defined as lasting 5-8 days). A rectal swab will be collected for each patient before the provocation testing, a second one at the end of the provocation testing. Each sample will be analyzed to detect the presence extended-spectrum betalactamase -producing enterobacteria.

Study Overview

• Status: Recruiting
• Conditions: Betalactams Hypersensitivity
• Intervention / Treatment: Other: Swab

Detailed Description

Drug hypersentivity in children is suspected in up to 10% of parents. However, drug hypersensitivity is rarely confirmed: its prevalence in children is estimated to be less than 0.5%. The most frequently suspected drugs are betalactams such as amoxicillin and oral cephalosporins (cefpodoxime, cefixime, cefuroxime). Most reported drug hypersensitivity reactions to betalactams in children are mild and delayed-onset, typically starting more than one hour after the first dose. These reactions often include urticaria, maculo-papular rashes, and/or edema. Amoxicillin is indicated as a first-line therapy in the majority of common infections in children. Suspicion of betalactams hypersensitivity is associated with the prescription of alternate antibiotics often less effective and that may increase the risk of bacterial resistance, morbidity and health costs. Therefore it is necessary to confirm or exclude a true betalactams hypersensitivity.

Direct drug provocation testing without prior skin or in vitro testing, is the reference standard for confirming the diagnosis of drug hypersensitivity reactions in children reporting mild and delayed-onset reactions. However, optimal protocol(s) have not been standardized. Although a 2-days' drug provocation testing protocol is effective, increasing its duration (up to 14 days) may improve its diagnosis performance without increasing the risk of severe reactions. However, a prolonged drug provocation testing could increase the risk of emergence of bacterial resistances in the digestive flora. Longer duration could be associated with the emergence of extended-spectrum betalactamase producing enterobacteria. However, this point has never been confirmed.

The aim of this study is to determine whether the risk of emergence of ESBL-producing bacteria in the digestive flora is higher in case of prolonged drug provocation testing.

Our hypothesis is that the acquisition rate of extended-spectrum betalactamase -producing enterobacteria will be higher in prolonged drug provocation testing.

As previously published, in the Pediatric Pulmonology and Allergy Department of the Necker Hospital, we perform direct drug provocation testing with the culprit drug in children with histories of mild delayed-onset reactions. Drug provocation testing is prolonged at home at normal therapeutic doses. The duration of the drug provocation testing is 1-2 days more than the chronology of the index reactions, with a maximum of eight days.

The study will include children (0-18 years), referring for histories of mild and delayed-onset reactions to betalactams. drug provocation testing will be performed with the suspected betalactam in our department, as in clinical practice. Two groups of patients will be compared: a group performing short drug provocation testing (arbitrary defined as lasting 1 to 4 days) and a group with prolonged drug provocation testing (arbitrary defined as lasting 5-8 days). A rectal swab will be collected for each patient before the drug provocation testing, a second one at the end of the drug provocation testing. Each sample will be analyzed to detect the presence extended-spectrum betalactamase -producing enterobacteria.

• Study Type: Observational
• Enrollment (Estimated): 300

Contacts and Locations

• Study Contact: Name: Guillaume Lezmi, Doctor (PHU); Phone Number: +33 1 44 49 48 38; Email: guillaume.lezmi@aphp.fr
• Study Contact Backup: Name: Hélène Morel; Phone Number: + 33 1 71 19 63 46; Email: helene.morel@aphp.fr

Study Locations

• France
  • Paris, France, 75015
    • Recruiting
    • Hopital Necker-Enfants Malades
    • Contact: Guillaume Lezmi, Doctor (PHU); Phone Number: +33 1 44 49 48 38; Email: guillaume.lezmi@aphp.fr
    • Contact: Hélène Morel; Phone Number: +33 1 71 19 63 46; Email: helene.morel@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 second to 17 years (Child)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Minors in consultation at Necker Hospital

Description

Inclusion Criteria :

• Minors aged 0 to 18
• Consultation in Necker for an oral drug provocation test to explore mild (urticaria, edema, maculo-papulous exanthema) delayed-onset reaction (1 hour after initiation of treatment) to betalactams (amoxicillin +/-clavulanic acid, cefpodoxime, cefixime, cefuroxime)

Exclusion Criteria :

• Minors with potentially severe delayed-onset reactions (painful skin lesions, atypical target lesions, erosions of mucosa, centro facial oedema, purpuric infiltrated papules) or severe (Lyell/Stevens Johnson Syndrome, fixed drug eruption, acute generalized exanthematous pustulosis, skin rash with systemic and hypereosinophilic disorders)
• Antibiotic treatment within the past month before the drug provocation test
• Travel abroad within the past 6 months before the drug provocation test
• Cardio-respiratory failure, renal failure, hepatic impairment or any other severe chronic pathology

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Short oral drug provocation test; Minors performing a short (1-4 days) drug provocation test	Other: Swab; Rectal swab before and after the drug provocation testing; Other Names: Rectal swab
Prolonged oral drug provocation test; Minors performing a prolonged (5-8 days)drug provocation test	Other: Swab; Rectal swab before and after the drug provocation testing; Other Names: Rectal swab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Acquisition of at least one strain of extended-spectrum betalactamase-producing enterobacteria	Bacteriological culture with gram-negative bacteria-specific agar. Bacterial colonies will be identified by mass spectrometry (Matrix Assisted Laser Desorption Ionization technique - Time of Flight, MALDI-TOF). Antibiogram.	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Acquisition of at least one strain of third generation cephalosporin-resistant gram-negative bacteria	Bacteriological culture with gram-negative bacteria-specific agar supplemented with third-generation cephalosporins. Bacterial colonies will be identified by mass spectrometry (Matrix Assisted Laser Desorption Ionization technique - Time of Flight, MALDI-TOF). Antibiogram.	24 months
Metagenomic analysis of intestinal microbiota	Metagenomic analysis will be performed by high-throughout sequencing using next-generation high-throughout DNA sequencing technologies.	24 months

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Guillaume Lezmi, Doctor (PHU), Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Actual): March 23, 2021
• Primary Completion (Estimated): March 1, 2025
• Study Completion (Estimated): March 1, 2025

Study Registration Dates

• First Submitted: August 19, 2019
• First Submitted That Met QC Criteria: August 19, 2019
• First Posted (Actual): August 20, 2019

Study Record Updates

• Last Update Posted (Actual): July 3, 2023
• Last Update Submitted That Met QC Criteria: June 30, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Children; Betalactams hypersensitivity; Drug provocation testing; Bacterial resistances
• Additional Relevant MeSH Terms: Immune System Diseases; Hypersensitivity
• Other Study ID Numbers: APHP190252; 2019-A00755-52 (Other Identifier: IDRCB number)

Drug and device information, study documents

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