Eradication of Antibiotic-resistant Bacteria Through Antibiotics and Fecal Bacteriotherapy

Condition(s) targeted: Intestinal Colonization With Multidrug-resistant Bacteria

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

Phase: Phase 2

Status: Not yet recruiting

Sponsored by: Stephen Harbarth

Official(s) and/or principal investigator(s):
Stephan J Harbarth, MD, MS, Principal Investigator, Affiliation: Geneva University Hospitals and University of Geneva

Overall contact:
Stephan J Harbarth, MD, MS, Phone: +41 79 55 33 633, Email: stephan.harbarth@hcuge.ch

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 .

Official title: 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

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Intestinal carriage of ESBL-E / CRE

Secondary outcome:

Intestinal carriage of ESBL-E / CRE

Occurrence of any adverse drug reaction

Occurrence of any adverse event

Occurrence of any serious adverse event

Occurrence of any gastrointestinal adverse event

Isolation of any not intrinsically colistin resistant strain of Enterobacteriaceae during follow-up (MIC> 2mg/l)

Comparison between treatment groups of the change (relative to baseline) in the proportion of bacterial taxa and antibiotic resistance genes over time

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

Assess the stability of the microbiome of donor stools after 3 months of frozen storage

Assess the stability of the microbiome of donor stools after 6 months of frozen storage

Assess the stability of the microbiome of donor stools after 12 months of frozen storage

Assess the stability of the microbiome of donor stools after 18 months of frozen storage

Assess the stability of the microbiome of donor stools after 24months of frozen storage

ESBL-E and CRE infections per 100 patient months at risk (first infection with either)

Use of any antibiotics active against all of the colonizing ESBL-E / CRE strains

Use of any antibiotics active against at least one of the colonizing ESBL-E / CRE strains

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.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

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)

Stephan J Harbarth, MD, MS, Phone: +41 79 55 33 633, Email: stephan.harbarth@hcuge.ch

Assistance Publique-Hôpitaux de Paris, Hôpital Beaujon, Clichy 92110, France; Not yet recruiting
Bruno Fantin, MD, Email: bruno.fantin@bjn.aphp.fr
Victoire de Lastours, MD, Phone: +33 (1) 71 11 46 20, Email: victoire.de-lastours@aphp.fr

Sourasky Medical Center, Tel Aviv, Israel; Not yet recruiting
Yehuda Carmeli, Email: yehudac@tlvmc.gov.il

Universitair Medisch Centrum Utrecht,, Utrecht, Netherlands; Not yet recruiting
Marc Bonten, Email: M.J.M.Bonten@umcutrecht.nl

Geneva University Hospitals, Geneva, Switzerland; Not yet recruiting
Stephan Harbarth, MD, MS, Email: stephan.harbarth@hcuge.ch

Official website of the R-GNOSIS project

Related publications:

Huttner B, Haustein T, Uçkay I, Renzi G, Stewardson A, Schaerrer D, Agostinho A, Andremont A, Schrenzel J, Pittet D, Harbarth S. Decolonization of intestinal carriage of extended-spectrum β-lactamase-producing Enterobacteriaceae with oral colistin and neomycin: a randomized, double-blind, placebo-controlled trial. J Antimicrob Chemother. 2013 Oct;68(10):2375-82. doi: 10.1093/jac/dkt174. Epub 2013 May 29.

Youngster I, Russell GH, Pindar C, Ziv-Baran T, Sauk J, Hohmann EL. Oral, capsulized, frozen fecal microbiota transplantation for relapsing Clostridium difficile infection. JAMA. 2014 Nov 5;312(17):1772-8. doi: 10.1001/jama.2014.13875. Erratum in: JAMA. 2015 Feb 17;313(7):729.

Starting date: June 2015
Last updated: June 15, 2015