Project

RESET-MDR: Randomized trial assessing individualized microbiota-based prevention of healthcare-associated infections with multidrug-resistant Enterobacteriaceae

Short description

Infections caused by multidrug-resistant Gram-negative organisms are a major contributor to severe disease and mortality worldwide. Infection is often preceded by colonization of the intestine with these organisms, which cannot be controlled by oral antibiotic therapy. Fecal Microbiota Transfer (FMT) is a promising alternative for achieving long-term decolonization of the intestine. Within the RESET-MDR study we are testing oral FMT products tailored to the individual patient. In addition, this project aims to elucidate the underlying mechanisms of action. The long-term goal is the development of defined bacterial consortia as an innovative and safe microbiota-based therapy.

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Infection with multidrug-resistant Gram-negative organisms (GN-MDROs) is often preceded by colonization of the intestine with these organisms. However, previous attempts to decolonize the intestine using oral antibiotics have not achieved lasting success.

Presumably, antibiotic exposure only temporarily suppresses the density of GN-MDRO colonization. After the end of antibiotic therapy, the intestinal environment continues to favor their renewed spread. As a consequence, long-term treatment success is often not achieved.

Fecal Microbiota Transfer (FMT) is a promising alternative for achieving decolonization of GN-MDROs, especially in cases of colonization with multidrug-resistant Enterobacteriaceae (MDR-E). The transferred microbiota may reduce the density of MDR-E by restoring the intestinal microbial community through competition for nutrients and ecological niches.

Encapsulated, orally administered FMT preparations have already proven to be safe and effective in the treatment of recurrent Clostridioides difficile infections. Initial results from a clinical study and several case series aimed at GN-MDRO decolonization have shown promising results. 

Schematic overview of the RESET-MDR platform for the development of individualized Fecal Microbiota Transfer (FMT) approaches targeting patients colonized with multidrug-resistant organisms (MDR-E). The platform integrates characterization of patient-specific MDR-E and microbiome profiles, identification of donor microbiomes with high colonization resistance, and GMP-compliant manufacturing of personalized FMT investigational products for use within the RESET-MDR study.

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Within the RESET-MDR study, we are investigating which factors may improve the response rate, including:

  • Antibiotic induction therapy as preparation for optimal integration of the transferred microbiota after FMT
  • Personalized donor-recipient matching based on prior laboratory analyses
  • Intensified FMT dosing 

The study includes in-depth microbiota analyses to elucidate the underlying mechanisms of action of FMT and thus provide a foundation for the development of defined bacterial consortia.