Intestinal Colonization With Multidrug-resistant Bacteria
Conditions
Keywords
extended spectrum beta-lactamase producing enterobacteriaceae, carbapenemase producing enterobacteriaceae, multidrug resistant bacteria
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.
Interventions
DRUGColistin
DRUGNeomycin
DRUGFecal microbiota transplantation (FMT)
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.
DRUGOmeprazole
Administered to inhibit gastric acid secretion before FMT administration if FMT administered via nasogastric tube approach (not used for capsule approach).
Sponsors
European Commission
Stephen Harbarth
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 | — |
| 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 |
| 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 |
| 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 |
| 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 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 | — |
| 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 |
Countries
France, Israel, Netherlands, Switzerland
Outcome results
None listed