RESET-MDR

To assess the efficacy of an antibiotic induction regimen in combination with high- dose individualized oral encapsulated fecal microbiota transfer (FMT) in achieving eradication of multidrug resistant Enterobacteriaceae (MDR-E) at day 30

• To assess the safety and tolerability of an antibiotic induction regimen in combination with encapsulated individualized FMT
• To assess the potential added value of an FMT dose intensification from single to double FMT administration
• To assess the potential benefits of an individualized FMT compared to standard FMT
• To assess the potential of FMT in preventing bacterial infections
• To assess the potential of FMT in preventing any type of infection (bacteria, viruses, fungi, parasites)
• To assess the potential of FMT to prevent further infection episodes in patients with recurrent MDR-E infections
• To assess the potential of FMT in preventing hospitalizations due to any kind of complication
• To assess the effect of FMT on all-cause mortality

• Patients aged ≥ 18 years
•  Fecal colonization with an MDR-E, fulfilling the criteria for classification as 3MRGN or 4MRGN (as defined by the Robert-Koch-Institute) confirmed by a positive sample (rectal swab or stool sample) obtained within 14 days prior to study enrolment
• Patients at risk of infection with the colonizing strain referred to in criterion 2 (based on cultural resistance testing) who already experienced at least two infections within the last 6 months or three infections within the last 12 months prior to enrolment.

AND/OR

• Patients under mid- or long-term immunosuppression, defined by ≥ 1 of the following criteria:
  •  solid organ transplant recipients receiving ≥ 2 immunosuppressants
  • recipients of CAR-T-cell therapy or hematopoietic stem cell transplantation either within 100 days and 2 years of transplantation or who are receiving ≥ 2 immunosuppressants after 2 years of therapy/transplantation
  • moderate or severe primary immunodeficiency (eg, DiGeorge syndrome, Wiskott-Aldrich syndrome)
  • Use of at least 1 of the following medications:
    • Recent treatment with corticosteroids equivalent to prednisone ≥20 mg daily for at least 14 consecutive days, all of which must have been within the last 30 days prior to study entry OR are currently receiving ≥20 mg daily that must have been administered for at least 14 consecutive days at the time of study entry.
    • Active treatment causing significant immunosuppression, including alkylating agents, antimetabolites, transplant- related immunosuppressive drugs, cancer chemotherapeutic agents, TNF blockers, or other highly immunosuppressive drugs such as biologics (eg, ustekinumab, anti-CD20).
  • chronic kidney diseases stage (CKD-EPI stage 4 or 5) requiring chronic hemodialysis for at least 6 months
  • HIV infection with CD4+ cell count <200/mm³ from known medical history within the past 6 months of screening.

• Resistance to colistin according to EUCAST breakpoints v.12 (MIC > 2 mg/L) of the MDR-E isolate at baseline
•  Foreseeable inability to swallow 30 FMT capsules over two days
•  Active inflammatory bowel disease (e.g. ulcerative colitis or Crohn’s disease)
• Severe immunosuppression defined as:
  • patients with current or foreseeable neutropenia within the 14 days of study treatment (defined as <500 neutrophils/µl)
  • patients scheduled for allogeneic stem cell transplantation (SCT) or having received allogeneic SCT within 100 days of study treatment
  • patients with active graft versus host disease or allograft rejection requiring intensified immunosuppressive treatment
•  Active infection with the MDR-E organism to be eradicated
•  Current or scheduled administration of antibiotic treatment active against the MDR-E organism to be eradicated
• Planned selective digestive tract decolonization within 30 days following randomization
• Known hypersensitivity or allergy to any of the components of the study treatment
• Current pregnancy or nursing period
•  Failure to use highly-effective contraceptive methods
•  Inability to give written informed consent
• Concurrent participation in another clinical trial with an investigational drug is not permitted, unless the drug under study is related to the treatment of the underlying condition or a transplantation

Treatment Arm 1:

No intervention

Treatment Arm 2:

Antibiotic induction followed by 2 high-dose individualized FMTs

• d0 to d3: Vancomycin 250 mg 4x/day
• d0 to d3: Colistin 2x 106 IU 4x/day
•  d5 and d6: 1st individualized FMT (15 capsules each day)
• d12 and d13: 2nd individualized FMT (15 capsules each day)

Treatment Arm 3:

Antibiotic induction followed by 1 individualized FMT

• d0 to d3: Vancomycin 250 mg 4x/day
• d0 to d3: Colistin 2x 106 IU 4x/day
• d5 and d6: individualized FMT (15 capsules each day)

Treatment Arm 4:

Antibiotic induction followed by 1 conventional FMT

•  d0 to d3: Vancomycin 250 mg 4x/day
•   d0 to d3: Colistin 2x 106 IU 4x/day
• d5 and d6: conventional FMT (15 capsules each day)