Eradication of Antibiotic-resistant Bacteria Through Antibiotics and Fecal Bacteriotherapy

Study Overview
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Brief Summary
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This investigator initiated,international, multicenter open-label, randomized controlled trial aims to assess whether a 5 day course of oral nonabsorbable antibiotics (colistin sulfate 2 million IU per os 4x/day and neomycin sulfate 500 mg (salt) per os 4x/day ) followed by fecal microbiota transplantation (administered either via nasogastric administration or via capsules) is effective at eradicating intestinal carriage of beta-lactamase producing Enterobacteriaceae (ESBL-E) and carbapenemase producing Enterobacteriaceae (CPE). compared to no intervention (current standard of care) in adult non-immunosuppressed patients .

Detailed Description
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In recent years a certain family of bacteria (Enterobacteriaceae) that colonizes the human gastrointestinal tract but can also cause severe infections has increasingly become resistant to antibiotics by acquiring enzymes that can inactivate a wide array of these valuable drugs. Depending on the class of beta-lactam antibiotics that these enzymes can inactivate, these bacteria are either designated as extended spectrum beta-lactamase producing Enterobacteriaceae (ESBL-E) or carbapenemase producing Enterobacteriaceae (CPE). The R-GNOSIS project which is financed by the European Commission combines five separate international clinical studies (work packages 2 to 6) that examine intervention strategies to reduce carriage, infection and spread of these bacteria. This study (work package 3 of R-GNOSIS) will be conducted in 4 centers in 3 European countries (Switzerland, France, The Netherlands) and Israel. The study will examine whether it is possible to eradicate intestinal carriage with ESBL-E and CPE by administering a 5 day course of oral nonabsorbable antibiotics (colistin sulfate and neomycin sulfate) followed by administration of healthy stool flora obtained from a healthy volunteer donor (fecal microbiota transplantation or FMT). The healthy stool flora for this procedure will be obtained from carefully selected healthy volunteers that have been tested for a wide variety of infectious diseases and do not show any risk factors or risky behavior for transmittable diseases. Once the fecal material has been processed it will be frozen at -80°C for up to six months until administration to patients (via capsules or via a nasogastric tube). FMT has been successfully used to treat recurrent infections with a specific pathogen (Clostridium difficile) and has proven safe and effective for this indication but has never been studied with the aim of eradicating multidrug-resistant organisms.

Official Title
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A Randomized Controlled Multicenter Trial of a Five Day Course of Oral Colistin and Neomycin Followed by Restoration of the Gut Microbiota Using Fecal Transplantation to Eradicate Intestinal Carriage of Extended Spectrum Beta-lactamase or Carbapenemase-producing Enterobacteriaceae in High-risk Patients

Conditions
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Intestinal Colonization With Multidrug-resistant Bacteria

Intervention / Treatment
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* Drug: Colistin
* Drug: Neomycin
* Drug: Fecal microbiota transplantation (FMT)
* Drug: Omeprazole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients (>= 18 years at date of inclusion) Ability to provide informed consent Documented intestinal carriage of ESBL-E and / or CPE by stool culture at baseline (visit 0) IF COLONIZED WITH ESBL-E ONLY (WITHOUT CPE): At least one episode of symptomatic infection with ESBL-E requiring systemic antibiotic therapy within the last 180 days before date of inclusion (based on the last day of antibiotic therapy for that infection) Exclusion Criteria: Pregnancy or planned pregnancy Breastfeeding Difficult / impossible follow-up Allergy or other contraindication to one of the study drugs Recurrent aspirations / chronic dysphagia Resistance to colistin (defined as MIC> 2 mg/l) of any of the ESBL-E or CPE strains isolated at baseline Estimated life expectancy < 6 months Treatment with any systemic antibiotic on the day of inclusion Severe immunodeficiency Systemic chemotherapy ≤30 days from baseline or planned chemotherapy within the next 6 months Human Immunodeficiency Virus (HIV) with CD4 count < 250/mcl Prolonged use of steroids (prednisone equivalent ≥ 60 mg per day for >= 30 days) or other immunosuppressive medications neutropenia with absolute neutrophil count <1000/μL, Solid organ transplant Hematopoeitic stem cell transplant recipients Other causes of severe immunodeficiency Current hospitalization in an Intensive Care Unit Estimated glomerular filtration rate (CKD-EPI) < 15 ml/min/1.73m2 Severe food allergy (anaphylaxis, urticaria) Unavailability of compatible FMT preparation (with regard to donor / recipient cytomegalovirus, Epstein-Barr virus and toxoplasma serology) Anatomic contraindication to the placement of a nasogastric tube (only if FMT application via nasogastric tube)

Ages Eligible for Study
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Minimum Age: 18 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: colistin + neomycin followed by FMT<br>CAPSULE APPROACH: Treatment days 1-5 Colistin sulphate 2 million IU per os 4x/day (for 5 days) Neomycin sulphate 500 mg (salt) per os 4x/day (for 5 days) Treatment day 6: no treatment Treatment days 7 and 8: -15 capsules of capsulized Fecal microbiota transplantation (FMT) per os per day NASOGASTRIC TUBE APPROACH: Treatment days 1-5 Colistin sulphate 2 million IU per os 4x/day (for 5 days) Neomycin sulphate 500 mg (salt) per os 4x/day (for 5 days) Treatment day 6 and 7: - Omeprazole 20 mg per os 1 dose on the evening of day 6 and on the morning of day 7 Treatment day 7: - Infusion of 80 ml of a standardized stool suspension through a nasogastric tube - Fecal microbiota transplantation (FMT) | Drug: Colistin<br> <br> * Other names: A07AA10;Drug: Neomycin<br> <br> * Other names: A01AB08;Drug: Fecal microbiota transplantation (FMT)<br>* FMT consist in the administration of fecal material obtained from healthy donors that has been diluted, homogenized, filtered and reconcentrated. In this study the processed fecal material will be frozen at -80°C after processing and will be administered to patients for up to six months after freezing via a nasogastric tube or via capsules.<br>* Other names: Feces transplantation;Drug: Omeprazole<br>* Administered to inhibit gastric acid secretion before FMT administration if FMT administered via nasogastric tube approach (not used for capsule approach).<br>* Other names: A02BC01;|
| No Intervention: No intervention<br>Control arm without any intervention | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intestinal carriage of ESBL-E / CRE | Intestinal carriage of ESBL-E / CRE (absence / presence by stool culture of any ESBL-E and / or CRE with enrichment independent of type of carriage at baseline) 35 to 48 days after randomization | 35 to 48 days after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intestinal carriage of ESBL-E / CRE | Intestinal ESBL-E or CRE carriage (detected / not detected) by stool culture during the other follow-up visits | 6 months after randomization | 
| Occurrence of any adverse drug reaction |  | 6 months | 
| Occurrence of any adverse event |  | 6 months | 
| Occurrence of any serious adverse event |  | 6 months | 
| Occurrence of any gastrointestinal adverse event |  | 6 months | 
| Isolation of any not intrinsically colistin resistant strain of Enterobacteriaceae during follow-up (MIC> 2mg/l) |  | 6 months | 
| Comparison between treatment groups of the change (relative to baseline) in the proportion of bacterial taxa and antibiotic resistance genes over time |  | 6 months | 
| Comparison of the global microbiota composition and diversity between the groups with FMT from the same donor and the groups with FMT from different donors |  | 6 months | 
| Assess the stability of the microbiome of donor stools after 3 months of frozen storage | Aliquots from a random sample of donations will also be taken for metagenomic analysis performed after 3 months of storage at -80°C to assess the long-term impact of freezing on the microbiome | 3 months of freezing (donor stools) | 
| Assess the stability of the microbiome of donor stools after 6 months of frozen storage | Aliquots from a random sample of donations will also be taken for metagenomic analysis performed after 6 months of storage at -80°C to assess the long-term impact of freezing on the microbiome | 6 months of freezing (donor stools) | 
| Assess the stability of the microbiome of donor stools after 12 months of frozen storage | Aliquots from a random sample of donations will also be taken for metagenomic analysis performed after 12 months of storage at -80°C to assess the long-term impact of freezing on the microbiome | 12 months of freezing (donor stools) | 
| Assess the stability of the microbiome of donor stools after 18 months of frozen storage | Aliquots from a random sample of donations will also be taken for metagenomic analysis performed after 18 months of storage at -80°C to assess the long-term impact of freezing on the microbiome | 18 months of freezing (donor stools) | 
| Assess the stability of the microbiome of donor stools after 24months of frozen storage | Aliquots from a random sample of donations will also be taken for metagenomic analysis performed after 24 months of storage at -80°C to assess the long-term impact of freezing on the microbiome | 24 months of freezing (donor stools) | 
| ESBL-E and CRE infections per 100 patient months at risk (first infection with either) |  | 6 months | 
| Use of any antibiotics active against all of the colonizing ESBL-E / CRE strains |  | 6 months | 
| Use of any antibiotics active against at least one of the colonizing ESBL-E / CRE strains |  | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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extended spectrum beta-lactamase producing enterobacteriaceae, carbapenemase producing enterobacteriaceae, multidrug resistant bacteria