RESET-MDR: Randomized trial assessing individualized microbiota-based prevention of healthcare-associated infections with multidrug-resistant Enterobacteriaceae
Infections caused by Gram-negative multidrug-resistant organisms are one of the leading causes of morbidity 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 transplantation (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 intestinal microbiota of patients. In addition, this project aims to elucidate the underlying mechanisms of action. This research project is expected to yield initial results for the development of defined bacterial consortia as an advanced and safe microbiota-based therapeutic agent.
Infection with Gram-negative multidrug-resistant organisms (GN-MDROs) is often preceded by colonization of the intestine with these organisms. However, previous attempts to decolonize the intestine by administering oral antibiotics have failed.
Presumably, antibiotic exposure achieves only temporary suppression of the colonization density of GN-MDROs and after the end of antibiotic therapy, the intestinal environment continues to favor their renewed spread. As a consequence, medium- or long-term decolonization success is not achieved.
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 in the intestine through direct competition for nutrients and ecological niches between transplanted and resident bacteria.
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 transplantation (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.
Within the RESET-MDR study, we are specifically investigating whether the following aspects can improve the response rate by
- Antibiotic induction therapy as preparation for optimal integration of the transferred microbiota after FMT
- Personalized donor–recipient matching based on prior microbiome screening
- Intensified FMT dosing
The study includes in-depth microbiota analyzes to elucidate the underlying mechanisms of action of FMT and thus provide a foundation for the development of defined bacterial consortia.
