Eradication of Antibiotic-resistant Bacteria Through Antibiotics and Fecal Bacteriotherapy
- Conditions
- Intestinal Colonization With Multidrug-resistant Bacteria
- Interventions
- Registration Number
- NCT02472600
- Lead Sponsor
- Stephen Harbarth
- Brief Summary
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
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.
Recruitment & Eligibility
- Status
- UNKNOWN
- Sex
- All
- Target Recruitment
- 39
- 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)
-
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)
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Anatomic contraindication to the placement of a nasogastric tube (only if FMT application via nasogastric tube)
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description colistin + neomycin followed by FMT Fecal microbiota transplantation (FMT) 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) colistin + neomycin followed by FMT Colistin 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) colistin + neomycin followed by FMT Neomycin 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) colistin + neomycin followed by FMT Omeprazole 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)
- Primary Outcome Measures
Name Time Method Intestinal carriage of ESBL-E / CRE 35 to 48 days after randomization 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
- Secondary Outcome Measures
Name Time Method Occurrence of any adverse event 6 months Occurrence of any gastrointestinal adverse event 6 months Occurrence of any serious adverse event 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 Intestinal carriage of ESBL-E / CRE 6 months after randomization Intestinal ESBL-E or CRE carriage (detected / not detected) by stool culture during the other follow-up visits
Occurrence of any adverse drug reaction 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 Assess the stability of the microbiome of donor stools after 3 months of frozen storage 3 months of freezing (donor stools) 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
Assess the stability of the microbiome of donor stools after 6 months of frozen storage 6 months of freezing (donor stools) 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
Use of any antibiotics active against all of the colonizing ESBL-E / CRE strains 6 months Assess the stability of the microbiome of donor stools after 18 months of frozen storage 18 months of freezing (donor stools) 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
Assess the stability of the microbiome of donor stools after 24months of frozen storage 24 months of freezing (donor stools) 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
ESBL-E and CRE infections per 100 patient months at risk (first infection with either) 6 months Use of any antibiotics active against at least one of the colonizing ESBL-E / CRE strains 6 months Assess the stability of the microbiome of donor stools after 12 months of frozen storage 12 months of freezing (donor stools) 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
Trial Locations
- Locations (4)
Assistance Publique-Hôpitaux de Paris, Hôpital Beaujon
🇫🇷Clichy, France
Universitair Medisch Centrum Utrecht,
🇳🇱Utrecht, Netherlands
Geneva University Hospitals
🇨🇭Geneva, Switzerland
Sourasky Medical Center
🇮🇱Tel Aviv, Israel