¡®Faecal microbiota transfusion for decolonization of
multidrug resistant Enterobacteriaceae in renal
transplant recipients (RESET): a pilot study.¡¯

SUMMARY

Rationale: Renal transplant patients are at increased risk of colonization and infection with
multidrug resistant Enterobacteriaceae (MDRE) due to medications that modify their immune
systems, increased healthcare and antibiotic exposure, and surgical alteration of the urinary
tract [Pinheiro 2010]. Innovative strategies for decolonization of MDR bacteria are urgently
needed to reduce hospital admissions, the use of reserve antibiotics and to prevent
transmission. Currently, effective decolonization strategies are lacking and targeted selective
digestive decontamination seems to result in short term benefits only. Successful eradication
of intestinal MDRE colonization by faecal microbiota transfer (FMT) has been reported in
immunocompetent patients [Manges 2016, Davido 2017, Singh R et al, 2014]. FMT appears
to be safe and effective in immunocompromised patients with recurrent Clostridium difficile
infections [van Nood 2013, van Beurden 2016, Kelly 2014] and is a potential eradication
treatment for renal transplant recipients with intestinal MDRE colonization.

Objective: To assess the safety and efficacy of faecal microbiota transfusion to eradicate
intestinal colonization with MDRE in renal transplant patients with a history of infection
caused by these MDR bacteria. Targeted bacteria are extended-spectrum β-lactamase
Enterobacteriaceae (ESBL-E) and carbapenemase producing Enterobacteriaceae (CPE).

Study design: Interventional pilot study, 1:1 randomized controlled trial with 12 participants,
follow up of 6 months.

Study population: Consenting adult female renal transplant recipients (≥18 years), with
intestinal carriage of one of the target MDR organisms by rectal swab or stool culture tests
(at least on two occasions), and a history of at least one documented infection by these
bacteria within 6 months before enrolment.

Exclusion criteria: need for systemic antibiotics at enrolment; ICU admission at enrolment;
creatinine clearance <30 ml/min; (planned) pregnancy during study duration; allergy or other
contraindication to one of the study drugs; recurrent aspirations / chronic dysphagia; recent
intra-abdominal surgery; recent treatment with alemtuzumab or eculizumab; active colitis /
gastro-enteritis or inflammatory bowel disease; severe food allergy.

Intervention:

Intervention group (6 subjects): Oral gut decontamination regimen colistin sulphate
(1.000.000 E 4×/day) and neomycin sulphate (250 mg 4×/day) for 5 days, combined with
nitrofurantoin (100 mg 2×/day) for 5 days if MDRE bacteriuria is present, followed by bowel
lavage on day 6. Patients will receive Omeprazole 20 mg per os 1 dose on the evening of
day 6 and on the morning of day 7. On day 7 200 ml of standardized faecal suspension will
be infused through a nasoduodenal tube. FMT will be matched with regard to donor /
recipient cytomegalovirus and Epstein-Barr virus serology.

Control group (6 subjects): Oral decontamination regimen for 5 days as described above.

Main study parameters/endpoints:

Primary study parameters:

Frequency and magnitude of any adverse events within 1 month of faecal microbiota
transfusion, including infections. The occurrence of renal transplant related adverse events
(graft loss, biopsy-proven acute rejection, doubling of serum creatinine) within 3 months after
FMT.

Secondary / exploratory study parameters:

- Number of participants with intestinal carriage of MDRE after FMT (assessed at 1 and 2
weeks and 1, 3 and 6 months after FMT).

- Number of participants with one or more MDRE infection(s) within 6 months after FMT.

- Change (relative to baseline) in the microbiota composition during 6 months of follow-up.

- Change in microbiome diversity, calculated by Shannon diversity index, during 6 months of
follow-up.

- Prevalence of antibiotic resistance genes in faecal samples during 6 months of follow up as
determined by metagenomics.

- Magnitude of intra-patient variability in immunosuppressive drug exposure.

Renal transplant patients are at increased risk of colonization and infection with
multidrug resistant Enterobacteriaceae (MDRE) due to medications that modify their immune
systems, increased healthcare and antibiotic exposure, and surgical alteration of the urinary
tract. Innovative strategies for decolonization of MDR bacteria are urgently
needed to reduce hospital admissions, the use of reserve antibiotics and to prevent
transmission. Currently, effective decolonization strategies are lacking and targeted selective
digestive decontamination seems to result in short term benefits only. Successful eradication
of intestinal MDRE colonization by faecal microbiota transfer (FMT) has been reported in
immunocompetent patients. FMT appears
to be safe and effective in immunocompromised patients with recurrent Clostridium difficile
infections and is a potential eradication
treatment for renal transplant recipients with intestinal MDRE colonization.

Screening visit

Intervention period with 5 days of SDD (with or without FMT)

Follow up 1,2,4,12 and 24 weeks after the intervention

Intervention:

Intervention group (6 subjects): Oral gut decontamination regimen colistin sulphate
(1.000.000 E 4¡Á/day) and neomycin sulphate (250 mg 4¡Á/day) for 5 days, combined with
nitrofurantoin (100 mg 2¡Á/day) for 5 days if MDRE bacteriuria is present, followed by bowel
Version 1.0, 14-06-2017 9 of 45
lavage on day 6. Patients will receive Omeprazole 20 mg per os 1 dose on the evening of
day 6 and on the morning of day 7. On day 7 200 ml of standardized faecal suspension will
be infused through a nasoduodenal tube. FMT will be matched with regard to donor /
recipient cytomegalovirus and Epstein-Barr virus serology.

Control group (6 subjects): Oral decontamination regimen for 5 days as described above.