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

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ClinicalTrials.gov Identifier: NCT04062344
Recruitment Status : Not yet recruiting
First Posted : August 20, 2019
Last Update Posted : August 20, 2019
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Brief Summary:

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.


Condition or disease Intervention/treatment
Betalactams Hypersensitivity 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.


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Study Type : Observational
Estimated Enrollment : 300 participants
Observational Model: Case-Control
Time Perspective: Prospective
Official Title: Acquisition of Resistant Enterobacteria During Oral Drug Challenge for Betalactams in Children
Estimated Study Start Date : November 2019
Estimated Primary Completion Date : May 2021
Estimated Study Completion Date : May 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Allergy

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 Name: 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 Name: Rectal swab




Primary Outcome Measures :
  1. Acquisition of at least one strain of extended-spectrum betalactamase-producing enterobacteria [ Time Frame: 18 months ]

    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.



Secondary Outcome Measures :
  1. Acquisition of at least one strain of third generation cephalosporin-resistant gram-negative bacteria [ Time Frame: 18 months ]

    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.


  2. Metagenomic analysis of intestinal microbiota [ Time Frame: 18 months ]
    Metagenomic analysis will be performed by high-throughout sequencing using next-generation high-throughout DNA sequencing technologies.


Biospecimen Retention:   Samples Without DNA
Faeces


Information from the National Library of Medicine

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Ages Eligible for Study:   up to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Minors in consultation at Necker Hospital
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04062344


Contacts
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Contact: Guillaume Lezmi, Doctor (PHU) +33 1 44 49 48 38 guillaume.lezmi@aphp.fr
Contact: Hélène Morel + 33 1 71 19 63 46 helene.morel@aphp.fr

Locations
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France
Hôpital Necker-Enfants Malades Not yet recruiting
Paris, France, 75015
Contact: Guillaume Lezmi, Doctor (PHU)    +33 1 44 49 48 38    guillaume.lezmi@aphp.fr   
Contact: Hélène Morel    +33 1 71 19 63 46    helene.morel@aphp.fr   
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Investigators
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Principal Investigator: Guillaume Lezmi, Doctor (PHU) Assistance Publique - Hôpitaux de Paris

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Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT04062344     History of Changes
Other Study ID Numbers: APHP190252
2019-A00755-52 ( Other Identifier: IDRCB number )
First Posted: August 20, 2019    Key Record Dates
Last Update Posted: August 20, 2019
Last Verified: August 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Assistance Publique - Hôpitaux de Paris:
Betalactams hypersensitivity
Children
Drug provocation testing
Bacterial resistances
Additional relevant MeSH terms:
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Hypersensitivity
Immune System Diseases
beta-Lactams
Anti-Bacterial Agents
Anti-Infective Agents