Stool Biobanking and Impact of Antimicrobials on the Gut Microbiota in Patients With Bone and Joint Infection (GUMIBONE)

Bone and joint infections (BJI) is a public health issue in industrialized countries.

Implant-associated BJI, are complex hospital-acquired infections and eradication of the pathogen is challenging in such patients.

A prolonged antimicrobial therapy is usually required from 6 weeks to 3 months, but some patients are eligible to several years of treatment and most of patients report gastrointestinal troubles, such as nausea and mild to severe diarrhea (but very few developed C. difficile diarrhea).

Moreover, the host gut microbiota is probably largely affected in abundance, richness and diversity. Indeed, it is known, that few days of antibiotics are sufficient to induce significant alterations of the gut microbiota, also called dysbiosis.

Severe dysbiosis, which is potentially irreversible and associated with a definitive shift in the gut microbiota metabolism and host homeostasis, may lead to and/or promote a large panel of severe diseases such as Clostridium difficile infection, diabetes mellitus, obesity, inflammatory bowel disease (IBD), cirrhosis, neurological disorders and cancer. It may also be associated with BJI recurrence and then impact global health costs.

The main objective of this study is to constitute biobanking of stools and perform DNA sequencing of the gut microbiota in patients with acute or sub-acute implant-related Bone and Joint Infection (BJI), caused by Staphylococcus aureus.

Study Overview

• Status: Terminated
• Conditions: Infection, Bacterial
• Intervention / Treatment: Biological: Patients treated by antibiotherapy

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Lyon, France, 69004
    • Hôpital de la Croix Rousse-Service de chirurgie orthopédique
  • Lyon, France, 69004
    • Hôpital de la Croix Rousse-Service des Maladies Infectieuses et Tropicales
  • Pierre Benite, France, 69310
    • Centre Hospitalier Lyon Sud-Service de Chirurgie Orthopédique
  • Pierre Bénite, France, 69310
    • Centre Hospitalier Lyon Sud-Service des maladies infectieuses

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. The subject is willing, able to understand and comply to the protocol requirement
2. More than 18-years-old
3. Subject with suspicion of implant-related BJI within 3 months after surgery and treated by antibiotherapy for a maximal duration of six months
4. Subject signed Inform Consent Form
5. Contraception for women of childbearing age

Exclusion Criteria:

1. Pregnancy
2. Severe disease with a life expectancy < 3months
3. Any antibiotherapy treated all diseases in the 14 days before inclusion
4. Guardianship, curatorship patients
5. Patient non-affiliated to health care system
6. Patient under the power of law

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Patients treated by antibiotherapy; 35 Patients treated by antibiotherapy for acute and subacute post-operative implant-associated BJI infections and among them 10 patients with Staphylococcus. aureus treated with antibiotics as part of their standard treatment procedure for metagenomic procedure.

Biological: Patients treated by antibiotherapy; Biological samples (stool, blood, swabs) will be collected : Blood sampling (12 ml) at baseline (week 0) at the end of treatment (W6/W24),and 15 days after antibiotherapy stop (optional) (W8/W26),; Feces collection at baseline (week 0) during antibiotic treatment (W2), at the end of treatment (W6/W24),15 days after antibiotherapy stop (W8/W26), and W26 after baseline; Swab samples (nasal and rectal) at baseline at week 0 and at the end of treatment (W6/W24),

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
change in the gut microbiota after treatment	stools will be collected to perform DNA sequencing of the gut microbiota in patients with acute or sub-acute implant-related Bone and Joint Infection (BJI), caused by Staphylococcus aureus. Stools will be collected at baseline, during antibiotic treatment (Week 2), at the end of treatment (Week 6 or Week 24),15 days after antibiotherapy stop (Week 8 or Week 26), and W26 after baseline.	from baseline to week 26

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assessment of the evolution of intensity of Diarrheic Symptoms	intensity of diarrheic symptoms will be collected at baseline, at the end of treatment (Week 6 or Week 24) and 15 days after antibiotic stop (Week 8 or Week 26)	from baseline to week 8 or week 26
Assessment of the evolution of frequency of Diarrheic Symptoms	frequency of diarrheic symptoms will be collected at baseline, at the end of treatment (Week 6 or Week 24) and 15 days after antibiotic stop (Week 8 or Week 26)	from baseline to week 8 or week 26
Quantity of rectal acquisition of Multi Drug Resistance (MDR) bacteria under antibiotics measured by classic culture and quantification culture methods	classic culture and quantification culture methods determined by microbiology analysis of the feces. Feces will be collected at baseline and at the end of treatment	at week 6 or week 24
gut dysbiosis measured by Next Generation Sequencing (NGS)	Stools will be collected at baseline, during antibiotic treatment (Week 2), at the end of treatment (Week 6 or Week 24),15 days after antibiotherapy stop (Week 8 or Week 26), and W26 after baseline. Microbiota sequencing will be done after DNA extraction. Composition of the microbiota will be screened in feces samples using the shotgun sequencing method to establish a total picture of the gut composition and diversity as well as evolution of the microbiome.	from baseline to week 26
severe post-antibiotic dysbiosis (SPAD) measured by Next Generation Sequencing (NGS)	Severe Post-Antibiotic Dysbiosis lead to irreversible change in gut microbiota status and systemic consequences for the host. Stools will be collected at baseline, during antibiotic treatment (Week 2), at the end of treatment (Week 6 or Week 24),15 days after antibiotherapy stop (Week 8 or Week 26), and W26 after baseline.	from baseline to week 26
Identification of markers of the gut dysbiosis (inflammatory proteins) measured by Elisa techniques	ELISA techniques will be used to determine the concentration of 3 specific inflammatory stool epithelium proteins: zonulin, calprotectin and neopterin. Stools will be collected at baseline, during antibiotic treatment (Week 2), at the end of treatment (Week 6 or Week 24),15 days after antibiotherapy stop (Week 8 or Week 26), and W26 after baseline.	from baseline to week 26
Analysis of impact of Bone and Joint Infection on health-related quality of life in patients by EQ5D5L questionnaires	EQ-5D questionnaire has 5 dimensions: "Mobility", "Human Autonomy," "Current Activities", "Pain / Discomfort", "Anxiety / Depression". All dimensions are described by 5 (EQ-5D-5L) problem levels corresponding to patient response choices. Questionnaire will be completed at baseline, during antibiotic treatment (Week 2), at the end of treatment (Week 6 or Week 24),15 days after antibiotherapy stop (Week 8 or Week 26), and W26 after baseline.	from baseline to week 26
Analysis of impact of Bone and Joint Infection on health-related quality of life in patients by EQ5D3L questionnaire	EQ-5D questionnaire has 5 dimensions: "Mobility", "Human Autonomy," "Current Activities", "Pain / Discomfort", "Anxiety / Depression". All dimensions are described by 3 (EQ-5D-3L) problem levels corresponding to patient response choices. In France, only the EQ-5D-3L has been validated, not yet the EQ-5D-5L which has only been translated. Questionnaire will be completed at baseline, during antibiotic treatment (Week 2), at the end of treatment (Week 6 or Week 24),15 days after antibiotherapy stop (Week 8 or Week 26), and W26 after baseline.	from baseline to week 26

Collaborators and Investigators

• Sponsor: Hospices Civils de Lyon
• Collaborators: University of Lyon
• Investigators: Principal Investigator: Tristan FERRY, Pr, Hospices Civils de Lyon

Study record dates

Study Major Dates

• Study Start (Actual): July 19, 2018
• Primary Completion (Actual): August 28, 2020
• Study Completion (Actual): August 28, 2020

Study Registration Dates

• First Submitted: July 17, 2018
• First Submitted That Met QC Criteria: August 13, 2018
• First Posted (Actual): August 16, 2018

Study Record Updates

• Last Update Posted (Actual): February 5, 2021
• Last Update Submitted That Met QC Criteria: February 2, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: gut dysbiosis; antimicrobial resistance; Bone and Joint Infections (BJI); antibiotic resistance gene; mobile genetic elements
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Bacterial Infections and Mycoses; Infections; Communicable Diseases; Bacterial Infections
• Other Study ID Numbers: 69HCL17_0652; 2017-A02813-50 (Other Identifier: ANSM)

Drug and device information, study documents

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