Efficacy and Mechanisms of Fecal Microbiota Transplantation to Eradicate Intestinal Colonization by Carbapenem-resistant Enterobacteriaceae

Antibiotic resistance (AR) is a critical public health threat and one of the greatest challenges of the 21st century. In an estimate of 2019, nearly 700.000 infections and 33.000 attributable deaths from multi-drug-resistant bacteria (MDRB) have occurred in Europe in 2015. Despite specific interventions, including antibiotic stewardship measures and AR surveillance programs, this burden has nearly doubled since 2007 and is highest for infections caused by intestinal bacteria. The gastrointestinal tract is a large reservoir for MDRB, and the gut microbiota can harbor a collection of AR genes, called gut resistome. There is increasing evidence that healthy gut microbiota can prevent the colonization of MDRB through mechanisms of colonization resistance, including competition, production of antimicrobial peptides, immune regulation. However, this protective mechanism can be impaired by therapies that alter gut microbiota (e.g. antibiotics). The restoration of healthy gut microbiota by fecal microbiota transplantation (FMT) may lead to the eradication of antibiotic-resistant bacteria. After becoming a standard treatment for Clostridioides difficile infection, FMT has been investigated in several disorders, and preliminary nonrandomized reports suggest that it could be a promising treatment option to eradicate MDRB, but established evidence, as well as mechanisms that underpin this therapeutic pathway, are still unavailable. We hypothesize that 1) FMT from donors with limited presence of AR genes can be more effective than placebo in eradicating intestinal MDRB (focusing on carbapenem-resistant Enterobacteriaceae) and 2) microbial features of donors and patients can be reproducibly associated with clinical efficacy and clearance of AR genes. Our results will pave the way for the development of effective, targeted microbiome-based therapies against MDRB, alleviating the burden of AR, with considerable benefits for healthcare systems.

The extended aims of this study are:

• To identify FMT donors with limited presence of AR genes and store feces for FMT
• To assess the efficacy of FMT in eradicating intestinal MDRB (carbapenem-resistant Enterobacteriaceae) and collect stool samples for multi-omics analysis
• To characterize the fecal microbiome (bacteriome, virome, mycobiome), resistome, of donors and patients before and after FMT, to associate microbial profiles with clearance of AR genes and clinical efficacy, and identify the microbial features that influence it

The investigators will carry out a single-centre placebo-controlled, double blind randomised clinical trial of donor FMT vs placebo FMT in carriers of CRE Patients will be recruited among those referred to the infectious disease outpatient clinic of the Fondazione Policlinico Universitario "A. Gemelli". Patients with all inclusion criteria and none of the exclusion criteria (detailed in the specific section of this website) will be considered for this study.

Before randomisation, demographic data will be collected by the infectious disease staff. Moreover, patients will repeat rectal swab and stool culture.