Efficacy and Safety of Fecal Microbiota Transplantation for Severe Clostridium Difficile Associated Colitis
Efficacy and Safety of Fecal Microbiota Transplantation for Severe Clostridium Difficile Associated Colitis
Clostridium difficile has become one of the leading causes of hospital acquired infections,
 and is associated with increased mortality. Patients with C. difficile associated disease
 (CDAD) possess deficiencies in 'normal' fecal microbial composition, most likely as a result
 of earlier antibiotic usage. The current standard of care treatment for severe C. difficile,
 which consists of antibiotics, does not restore the microbiota. Restoration of the normal
 colonic microbiota by fecal microbiota transplantation (FMT) may enable reversion colonic
 microbial population to a more 'normal'state and lead to cure.

 A few patients develop severe CDAD which may be complicated by adynamic ileus, or toxic
 megacolon. The management in this context is based on limited data, and for some the only
 available option is sub-total colectomy.

 Although FMT is by no means a new therapeutic modality, there is limited information on its
 use for the treatment of acute CDAD, including severe CDAD. Because of the high morbidity and
 mortality associated with treatment of patients with severe CDAD, and because the evidence
 supporting the current recommendations is weak and based upon the demonstration that FMT is
 an effective strategy to re-establish a balanced intestinal microbiota with resultant cure of
 recurrent CDAD, we propose to study the efficacy and safety of FMT for severe CDAD.

 Patients with severe CDAD can be divided into two operational groups; those that have
 diarrhea and those that suffer from adynamic ileus. We propose to apply FMT through
 colonoscopy for all patients because current data suggest that the overall success rate of
 FMT for recurrent CDAD with lower gastrointestinal tract FMT was higher than FMT through the
 upper gastrointestinal tract. In addition, for patients with adynamic ileus and toxic
 megacolon (i.e., the population with the highest CDAD-associated morbidity and mortality),
 intra-colonic FMT administration is the preferred alternative.
Screening and Consent - Index cases:

 1. Hospitalized patient with the diagnosis of severe CDAD

 2. At screening visit the study investigator(s) will explain the study in detail, answer
 any questions the candidate may have, and give the candidate a consent form to read and
 sign.

 3. After signing the consent form, the candidate subject will be asked to provide a
 complete medical history and undergo a physical examination.

 4. Blood will be drawn for a complete blood count (CBC) and bacterial culture

 5. Stool will be collected and archived for use for further analysis as deemed necessary by
 the principal investigator. All analyses will be performed in an anonymous coded method,
 without any disclosure of the patient identifiers.

 Screening and Consent - Donors:

 1. Identified by recipients, generally an intimate partner or adult family member

 2. Willing to donate stool

 3. Exclusion criteria (per questionnaire):

 1. Had taken antibiotics within 90 days of the planned procedure

 2. Fever, diarrhea, vomiting, or any other symptoms of infection, which occurred
 within the two weeks prior to the day of the procedure.

 3. Known exposure to HIV or viral hepatitis (within the previous 12 months)

 4. High-risk sexual behaviors (examples: sexual contact with anyone with HIV/AIDS or
 hepatitis, men who have sex with men, sex for drugs or money)

 5. Use of illicit drugs

 6. Tattoo or body piercing within 6 months

 7. Incarceration within previous 12 months

 8. Known current communicable disease

 9. Risk factors for variant Creutzfeldt-Jakob disease

 10. Gastrointestinal co-morbidities

 11. History of inflammatory bowel disease

 12. History of irritable bowel syndrome, idiopathic chronic constipation, or chronic
 diarrhea

 13. History of gastrointestinal malignancy

 14. Recent ingestion of a potential allergen (eg, nuts) where recipient has a known
 allergy to this agent

 15. Systemic autoimmunity, for example, multiple sclerosis, connective tissue disease

 4. Exclusion criteria (per laboratory assays):

 1. Positive HIV, hepatitis C virus, hepatitis B virus, Syphilis antibodies

 2. Stool culture positive for the enteropathogenic bacteria Salmonella, Shigella, or
 Campylobacter

 3. Stool stain positive for Ova and Parasites

 4. Stool positive for Giardia- and Entamoeba histolytica-specific antigens

 5. Stool positive for C. difficile toxins

 Fecal Microbiota Transplantation Protocol Donor

 1. Provide informed consent (laxative administration)

 2. Report symptoms of infection, which occur between screening and the day of the procedure

 3. Take a single dose of osmotic laxative (one tablet of "Laxadin") on the evening before
 the procedure

 4. Provide fresh stool, at least 50 grams

 Recipient 1. Provide informed consent

 Fecal solution preparation

 1. Universal precautions (gown, gloves, eye protection) during stool processing

 2. Fresh (<6 h) donor stool specimen

 3. About 50 grams of donor stool, diluted and shaken vigorously in sterile Saline 0.9% to
 homogeneity.

 4. Filter stool through gauze if necessary to remove large debris

 5. Stool suspension drawn up into 50 mL slip-tip syringes

 Procedure

 1. Informed consent for colonoscopy obtained including the additional theoretical risk of
 infection related to fecal transfusion

 2. Document that examination of the colon is not adequate for cancer screening purposes
 (stool infusion interferes with visualization)

 3. Colonoscopy performed aiming to reach the cecum with or without decompression without
 bowel inflation. If the cecum is not reachable the injection will be performed at the
 most distal site.

 4. No biopsies taken

 5. Upon withdrawal, injection of the fecal suspension via the biopsy channel of a
 colonoscope, majority into the right colon. Deliver between 300-500 ml.

 Post procedure

 1. Patient encouraged to retain stool (if possible) for 4 hours

 Clinical and laboratory follow up

 1. A blood culture will be drawn immediately following the procedure

 2. Subjects will be followed during hospitalization and after discharge for at least 30
 days. Data on symptoms of CDAD, on-going medical history review, physical examination,
 and laboratory tests as described in Table 1 will be collected.

 3. Safety will be assessed by monitoring the subjects for adverse events.
Inclusion Criteria:

 1. Both genders are eligible for study

 2. Age 18 years and older

 3. Able to provide written, informed consent

 4. Confirmed diagnosis of severe CDAD as defined above

 Exclusion Criteria:

 (If any of the following apply, the subject MUST NOT enter the study):

 1. Pregnant or lactating women

 2. Need for prolonged antibiotics for other cause

 3. Other known etiology for diarrhea, or clinical infection with other known enteric
 pathogens

 4. Active, chronic conditions such as: Inflammatory bowel disease, Crohn's disease, Short
 bowel syndrome, Ulcerative or ischemic colitis

 5. Laxatives or motility-altering drugs within 12 hours of enrolment

 6. Clinically unstable. Hemodynamic instability defined as hypotension (mean arterial
 pressure < 60) not responsive to fluids.

 7. Any condition that, in the opinion of the investigator, would preclude safe
 participation in the trial or compromise the quality of the data obtained.

 8. Immune suppression, HIV, hematological or solid malignancy (chemotherapy in the past 3
 months).

 9. Prior colon surgery