Fecal Microbiota Transplantation for Severe Clostridium Difficile Infection
Fecal Microbiota Transplantation for Severe Clostridium Difficile Infection
Fecal microbiota transplantation (FMT) is acknowledged as a highly effective treatment for
 recurrent Clostridium difficile infection (CDI). Usually single fecal infusion achieves
 satisfactory cure rates of recurrent CDI). However, several retrospective studies show that
 severe clinical picture of recurrent CDI is a risk factor for the failure of single-infusion
 FMT, suggesting that multiple fecal infusions are required to cure this condition.

 This is an open-label randomized clinical trial aiming to assess if multiple-infusion FMT is
 more effective than single-infusion FMT in curing severe CDI
Fecal microbiota transplantation (FMT) is acknowledged as a highly effective treatment for
 recurrent Clostridium difficile infection (CDI). Usually single fecal infusion achieves
 satisfactory cure rates of recurrent CDI). However, several retrospective studies show that
 severe clinical picture of recurrent CDI is a risk factor for the failure of single-infusion
 FMT, suggesting that multiple fecal infusions are required to cure this condition.

 This is an open-label randomized clinical trial aiming to assess if multiple-infusion FMT is
 more effective than single-infusion FMT in curing severe CDI

 The investigators' study is an open-label randomized controlled trial, enrolling patients
 with recurrent and refractory C. difficile infection with a severe clinical picture of the
 disease.

 At enrollment, C. difficile infection is defined as diarrhoea (at least 3 loose or watery
 stools per day for 2 or more consecutive days, or at least 8 loose stools in 48 hours) and
 positivity in the C. difficile toxin stool test.

 Recurrent C. difficile infection is meant as the reappearance of clinical symptoms and
 positivity of C. difficile toxin test within 8 weeks after the end of the previous therapy.

 Refractory CDI is defined as CDI unresponsive to the antimicrobial treatment, namely
 persistence of diarrhoea with CD toxin positive or persistent diarrhoea with toxin negative
 in the absence of other possible causes of diarrhoea (e.g. IBS, IBD, non-CDI
 antibiotic-associated diarrhea) Severe CDI is defined, according to the latest ESCMID
 guidelines, as: Episode of CDI with one or more specific clinical (fever, haemodynamic
 instability, respiratory failure which needs mechanical ventilation, signs and symptoms of
 peritonitis, signs and symptoms of colonic ileus), laboratory (marked leukocytosis, rise in
 serum creatinine and lactate, marked decrease of serum albumin), radiological (colon
 distension, colonic wall thickening) or endoscopic (pseudomembranous colitis), symptoms and
 signs of severe colitis or complicated course of disease.

 Patients' stool are screened for detection of parasites and enteric bacterial pathogens to
 exclude other infective pathogens. Patients with former colectomy, inflammatory bowel
 diseases (IBD), irritable bowel syndrome (IBS), viral hepatitis, AIDS or syphilis will be
 excluded.

 Patients are instructed and invited to signal recurrent symptoms and diarrhea after
 treatment. Monthly clinical and lab checks are performed for a period of 2 months after the
 treatment.

 Treatment procedures:

 All patients start therapy with vancomycin for 3 days before of stratification, with random
 allocation (1 to 1, through statistical software) to one of the two treatment schemes: 1)
 single-infusion FMT by colonoscopy, with the infusion in the cecum - through the biopsy
 channel - of 60-120 gr (depending on production) of donated feces, obtained from the donor
 within 6 hours from transplantation, and manually homogenized in 100/200 ml of physiological
 solution; colonoscopy will be performed by an expert endoscopist; preparation for colonoscopy
 (four liters of a solution with saline laxatives) will be provided 2) multiple-infusion FMT
 (with the same protocol of the other arm, but with repeated fecal infusions).

 All patient will be instructed on hygiene rules to be followed at the patient's domicile to
 avoid re-infections at home. Stool donors will be selected following recommendations from the
 European FMT Working Group Consensus Conference.
Inclusion criteria:

 -  Recurrent C. difficile infection (identified by positivity of C. difficile toxin in
 stools) with severe clinical picture (defined by the ESCMID Guidelines published in
 2014 - Debast et al, Clin Microbiol Infect 2014)

 -  Possibility to undergo standard antimicrobial therapy for recurrent C. difficile
 infection Approval of informed consent

 -  Possibility to undergo protocol diagnostic and therapeutic procedures

 -  Stool negativity for parasites

 -  Stool negativity for Salmonella spp., Shigella spp., Yersinia enterocolitica,
 Campylobacter, Streptococcus agalactiae, Staphylococcus aureus, enteropathogenic
 Escherichia coli and other microorganisms except for C. difficile

 -  Blood negativity for: Hepatitis A virus-Immunoglobulin M, HBsAg, Anti-Hepatitis C
 Virus, Anti-Human Immunodeficiency Virus1-2, venereal disease reaction level (VDRL).

 Exclusion Criteria:

 -  Subjects <18 years old

 -  Prior colectomy

 -  Negativity of C. difficile toxin in stools

 -  Mild clinical picture of C. difficile infection

 -  High risk of post-colonoscopy complications

 -  Other main gastrointestinal diseases (es. Crohn's disease or ulcerative colitis)

 -  Stool positivity for parasites

 -  Stool positivity for Salmonella spp., Shigella spp., Yersinia enterocolitica,
 Campylobacter, Streptococcus agalactiae, Staphylococcus aureus, enteropathogenic
 Escherichia coli and other microorganisms except for C. difficile

 -  Blood positivity for: Hepatitis A virus-Immunoglobulin M, HBsAg, Anti-Hepatitis C
 Virus, Anti-Human Immunodeficiency Virus1-2, venereal disease reaction level (VDRL).

 -  Pregnancy or breastfeeding.

 -  Inability to follow protocol procedures