Clinical trial NCT02472600: Eradication of Antibiotic-resistant Bacteria Through Antibiotics and Fecal Bacteriotherapy
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 type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Intestinal Colonization With Multidrug-resistant Bacteria
Keywords: extended spectrum beta-lactamase producing enterobacteriaceae
carbapenemase producing enterobacteriaceae
multidrug resistant bacteria
Lead sponsor: University Hospital, Geneva
Sponsor class: OTHER
Collaborators: name: European Commission
First posted: 2015-06-16
Enrollment: 39
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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)

Primary outcomes:
measure: Intestinal carriage of ESBL-E / CRE
timeFrame: 35 to 48 days after randomization
Secondary outcomes:
measure: Intestinal carriage of ESBL-E / CRE
timeFrame: 6 months after randomization
measure: Occurrence of any adverse drug reaction
timeFrame: 6 months
measure: Occurrence of any adverse event
timeFrame: 6 months
measure: Occurrence of any serious adverse event
timeFrame: 6 months
measure: Occurrence of any gastrointestinal adverse event
timeFrame: 6 months
measure: Isolation of any not intrinsically colistin resistant strain of Enterobacteriaceae during follow-up (MIC> 2mg/l)
timeFrame: 6 months
measure: Comparison between treatment groups of the change (relative to baseline) in the proportion of bacterial taxa and antibiotic resistance genes over time
timeFrame: 6 months
measure: 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
timeFrame: 6 months
measure: Assess the stability of the microbiome of donor stools after 3 months of frozen storage
timeFrame: 3 months of freezing (donor stools)
measure: Assess the stability of the microbiome of donor stools after 6 months of frozen storage
timeFrame: 6 months of freezing (donor stools)
measure: Assess the stability of the microbiome of donor stools after 12 months of frozen storage
timeFrame: 12 months of freezing (donor stools)
measure: Assess the stability of the microbiome of donor stools after 18 months of frozen storage
timeFrame: 18 months of freezing (donor stools)
measure: Assess the stability of the microbiome of donor stools after 24months of frozen storage
timeFrame: 24 months of freezing (donor stools)
measure: ESBL-E and CRE infections per 100 patient months at risk (first infection with either)
timeFrame: 6 months
measure: Use of any antibiotics active against all of the colonizing ESBL-E / CRE strains
timeFrame: 6 months
measure: Use of any antibiotics active against at least one of the colonizing ESBL-E / CRE strains
timeFrame: 6 months
Other outcomes:
Locations:
city: Clichy
country: France
facility: Assistance Publique-Hôpitaux de Paris, Hôpital Beaujon
city: Tel Aviv
country: Israel
facility: Sourasky Medical Center
city: Utrecht
country: Netherlands
facility: Universitair Medisch Centrum Utrecht,
city: Geneva
country: Switzerland
facility: Geneva University Hospitals
Study officials:
affiliation: Geneva University Hospitals and University of Geneva
name: Stephan J Harbarth, MD, MS
role: PRINCIPAL_INVESTIGATOR
References:
citation: Huttner B, Haustein T, Uckay I, Renzi G, Stewardson A, Schaerrer D, Agostinho A, Andremont A, Schrenzel J, Pittet D, Harbarth S. Decolonization of intestinal carriage of extended-spectrum beta-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.
citation: 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.
citation: de Lastours V, Poirel L, Huttner B, Harbarth S, Denamur E, Nordmann P. Emergence of colistin-resistant Gram-negative Enterobacterales in the gut of patients receiving oral colistin and neomycin decontamination. J Infect. 2020 May;80(5):578-606. doi: 10.1016/j.jinf.2020.01.003. Epub 2020 Jan 15. No abstract available.
citation: Huttner BD, de Lastours V, Wassenberg M, Maharshak N, Mauris A, Galperine T, Zanichelli V, Kapel N, Bellanger A, Olearo F, Duval X, Armand-Lefevre L, Carmeli Y, Bonten M, Fantin B, Harbarth S; R-Gnosis WP3 study group. A 5-day course of oral antibiotics followed by faecal transplantation to eradicate carriage of multidrug-resistant Enterobacteriaceae: a randomized clinical trial. Clin Microbiol Infect. 2019 Jul;25(7):830-838. doi: 10.1016/j.cmi.2018.12.009. Epub 2019 Jan 4.