Eradication of Antibiotic-resistant Bacteria Through Antibiotics and Fecal Bacteriotherapy (R-GNOSIS WP3)

Stephen Harbarth

Status and phase: Unknown; Phase 2

Conditions: Intestinal Colonization With Multidrug-resistant Bacteria

Treatments: Drug: Neomycin; Drug: Colistin; Drug: Omeprazole; Drug: Fecal microbiota transplantation (FMT)

Study type: Interventional

Funder types: Other

Identifiers

NCT02472600

2014-003727-22 (EudraCT Number)

13-266

Details and patient eligibility

About

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 .

Full 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.

Enrollment: 39 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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)

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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39 participants in 2 patient groups

colistin + neomycin followed by FMT

Active Comparator group

Description:

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)

Treatment:

Drug: Fecal microbiota transplantation (FMT)

Drug: Omeprazole

Drug: Colistin

Drug: Neomycin

No intervention

No Intervention group

Description:

Control arm without any intervention