FMT for the Decolonization of Carbapenem-resistant Enterobacteriaceae

Study Overview
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Brief Summary
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Rates of antimicrobial resistance are increasing worldwide. There is increasing evidence that physiological gut microbiota is a large reservoir of antibiotic-resistance genes. Healthy gut microbiota is known to prevent the colonization of the gastrointestinal tract by pathogens, the so-called mechanism of colonization resistance, but this protective mechanism can be altered by therapies that impair gut microbiota, including antibiotics or chemotherapeutics, with consequent colonisation of gut pathogens, including multi-drug resistant bacteria (MDRB). MDRB carriers represent an epidemiological threat to other hospitalized patients and to the whole community, but are also at risk of developing clinical consequences of this colonization, including bloodstream infections from these pathogens. Fecal microbiota transplantation (FMT) has shown high efficacy in the eradication of recurrent C. difficile infection, and initial evidence suggests that this procedure could be useful in eradicating also MDRB, mainly carbapenem-resistant Enterobacteriaceae. However, current evidence is mostly limited to case reports and case series, and to a single randomised trial, which was stopped early and did not draw clear conclusion. In a systematic review of 21 studies and 192 patients, eradication rates ranged from 0% to 100%, and authors concluded that larger, well designed randomised controlled trials are needed to further explore this therapy. The aim of this study is to investigate the efficacy of FMT, compared with placebo FMT, in eradicating gut colonisation from MDRB, focusing on CRE. The investigators will randomize patients colonized by CRE (diagnosed by rectal swab) to FMT from healthy donors or placebo, by colonoscopy. Then, patients will be followed up, rectal swabs will be repeated, and stool samples for culture and microbiome analysis will be collected, up to 3 months after FMT.

Detailed Description
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Rates of antimicrobial resistance are increasing worldwide. There is increasing evidence that physiological gut microbiota is a large reservoir of antibiotic-resistance genes. Healthy gut microbiota is known to prevent the colonization of the gastrointestinal tract by pathogens, the so-called mechanism of colonization resistance, but this protective mechanism can be altered by therapies that impair gut microbiota, including antibiotics or chemotherapeutics, with consequent colonisation of gut pathogens, including multi-drug resistant bacteria (MDRB). MDRB carriers represent an epidemiological threat to other hospitalized patients and to the whole community, but are also at risk of developing clinical consequences of this colonization, including bloodstream infections from these pathogens. Fecal microbiota transplantation (FMT) has shown high efficacy in the eradication of recurrent C. difficile infection, and initial evidence suggests that this procedure could be useful in eradicating also MDRB, mainly carbapenem-resistant Enterobacteriaceae. However, current evidence is mostly limited to case reports and case series, and to a single randomised trial, which was stopped early and did not draw clear conclusion. In a systematic review of 21 studies and 192 patients, eradication rates ranged from 0% to 100%, and authors concluded that larger, well designed randomised controlled trials are needed to further explore this therapy. The extended aims of this study are: To compare the efficacy of donor FMT and placebo FMT in eradicating gut colonisation from CRE To compare the efficacy of donor FMT and placebo FMT in preventing clinical manifestations of gut colonisation from CRE To investigate changes in gut microbiome after treatments The investigators will carry out a single-centre placebo-controlled, double blind randomised clinical trial of donor FMT vs placebo FMT in carriers of CRE Patients will be recruited among those referred to the infectious disease outpatient clinic of the Fondazione Policlinico Universitario A. Gemelli. Patients with all inclusion criteria and none of the exclusion criteria (detailed in the specific section of this website) will be considered for this study. Before randomisation, demographic data will be collected by the infectious disease staff. Moreover, patients will repeat rectal swab and stool culture. Additionally, patients will be requested to give stool samples to be collected in a sterile, sealed container and stored at -80°C for metagenomic assessment of gut microbiome and meta-transcriptome assessment by the microbiology staff. After baseline assessments, patients will be randomly assigned to one of the following treatment arms: Donor FMT (D-FMT) Placebo FMT (P-FMT) Patients in both groups will undergo a single FMT procedure by colonoscopy. Each patient in the donor FMT group will receive faeces from one single donor. Placebo FMT will be made of 250 mL water. The selection of stool donors will be performed by the gastroenterology staff following protocols previously recommended by international guidelines and according the new recommendation imposed by the reorganisation of faecal microbiota transplant during the COVID-19 pandemic (Ianiro et al. - Gut 2020) The assignment of faecal infusates from healthy donors to patients will be done randomly, without any specific recipient-donor match, as this is not recommended by international guidelines All faecal infusates will be manufactured in the microbiology unit of our hospital. Only frozen faeces will be used. Preparation of frozen faeces will follow protocols from international guidelines. Follow-up visits will be performed by physicians from the gastroenterology and the infectious disease unit. All patients will be followed up for 3 months after the end of treatments. Follow-up visits will be scheduled at week 1, week 2, week 4, and week 12, after the end of treatments, respectively. At each visit the following assessments will be performed: 1) rectal swab for MDRB; 2) collection of stool samples for stool culture ; 3) collection of stool samples for microbiome analysis; 4) record of adverse events. Unscheduled follow-up visits will be offered if requested by the patients. Study Outcomes are detailed in the specific section of this website. The statistical analysis will be performed both on an intention-to-treat and per-protocol basis. Differences among groups will be assessed with a two-tailed Wilcoxon-rank sum test for continuous data and with Fisher's exact probability test (using two-tailed P-values) for categorical data. Differences in cure percentages will be determined with Fisher's exact test (with two-tailed P values). For microbiome analysis, statistical differences between group means will be calculated using a two-tailed Wilcoxon-Rank Sum Test, through the R statistical software package (R Core Team, Vienna, Austria).

Official Title
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Faecal Microbiota Transplantation to Eradicate Gut Colonisation From Carbapenem-resistant Enterobacteriaceae: a Randomised Controlled Trial

Conditions
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Enterobacteriaceae Infections, Multi-antibiotic Resistance

Intervention / Treatment
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* Biological: Donor FMT
* Other: Placebo FMT


Participation Criteria
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Eligibility Criteria
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Inclusion criteria 18 years old or older Current evidence of gut colonisation (diagnosed with rectal swab) by CRE Ability to give their consent to be included in the study. Exclusion criteria Another known gastrointestinal infection apart from C. difficile infection Known active gastrointestinal disorders (e.g. infectious gastroenteritis, coeliac disease, inflammatory bowel disease, irritable bowel syndrome, chronic pancreatitis, biliary salt diarrhoea) Previous colorectal surgery or cutaneous stoma Food allergies Current or recent (<2 weeks) therapy with drugs that could possibly alter gut microbiota (e.g. antimicrobials, probiotics, proton pump inhibitors, immunosuppressants, metformin) Decompensated heart failure or heart disease with ejection fraction lower than 30% Severe respiratory insufficiency Psychiatric disorders Pregnancy Unable to give informed consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized controlled trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Donor FMT<br>Patients enrolled in this arm will receive donor FMT | Biological: Donor FMT<br>* This intervention is represented by the administration, in the recipients' gut, of donor microbiota through FMT<br>|
| Placebo Comparator: Placebo FMT<br>Patients enrolled in this arm will receive placebo FMT (that will be made of water) | Other: Placebo FMT<br>* This intervention is represented by the administration, in the recipients' gut, of a placebo through FMT<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants who will obtain an eradication of CRE carriage after treatments | The investigators will evaluate the number of participants who will obtain eradication of CRE carriage after treatments, at 4 weeks-follow-up, evaluated through rectal swab for CRE | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants who will obtain an eradication of CRE carriage after treatments | The investigators will evaluate the number of participants who will obtain eradication of CRE carriage after treatments, at 1,2 and 12 weeks-follow-up, evaluated through rectal swab for CRE | 12 weeks | 
| Number of participants with significant increase in alpha-diversity and beta-diversity of their gut microbiota after treatments | Throughout the study period (12 weeks) the investigators will evaluate the number of participants with significant increase in alpha-diversity (assessed by Shannon index) and beta-diversity (assessed by Bray-Curtis dissimilarity) of their gut microbiota after treatments, compared with baseline | 12 weeks | 
| Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | The number of participants with treatment-related adverse events (assessed by CTCAE v4.0) will be recorded throughout the study period (12 weeks) | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fecal microbiota transplantation, Enterobacteriaceae, Multi-drug resistant bacteria