Defined Fecal Microbiota Transplantation for Clostridium Difficile Diarrhea

Summary

The study is on indefinite HOLD due to the loss of funding that occurred during the pandemic emergency. Subsequently, a key collaborator left our institution, and as a near-term result, the protocol awaits reactivation. Three patient subjects were enrolled, all 3 patients/subjects were cured of the infection, and there were no adverse events or sequelae observed or reported. The aim of the study continues to confirm and extend the work of Trede and Rask-Madsen (Lancet 1989;1:1156-1160) that administration of a defined fecal microbiota will lead to rapid and sustained resolution of C. difficile-associated chronic relapsing diarrhea. FDA required 4 non-geriatric qualified patients to be studied before including the elderly. However, C. difficile-associated chronic relapsing diarrheal illness is predominantly a disease of the elderly, so this requirement GREATLY impeded timely enrollment. No protocol deviations have occurred.

The current rationale behind FMT for CDI is that the introduction of microbes from a healthy donor should allow for the restoration of a normal microbial community in the diseased host with consequent suppression of C. difficile colonization and disease pathogenesis. The first modern use of FMT was reported in a 1958 case series of 4 patients with pseudomembranous enterocolitis. The first case of confirmed CDI treated with FMT was reported in 1983; treatment was curative. Until 1989, retention enemas were the most common technique for FMT. Alternative methods for delivering FMT have included fecal infusion via duodenal tube (1991), rectal tube (1994), and colonoscopy (1998). FMT for recurrent CDI has been used successfully, whether administered by nasogastric tube, rectal administration by colonoscopy, or rectal tube, including self-administration at home by enema. FMT has proven to be remarkably effective and remarkably safe without any significant problems (see below and attached reviews and meta-analyses).

Increasing interest is emerging regarding the changes in the intestinal microbiota associated with CDI. In 2008 Chang et al. constructed small (\< 200 sequences per subject) 16S rRNA gene libraries from the stools of 4 patients with first-time CDI and 3 patients with recurrent CDI. Based on 16S rRNA gene classification, they found that the fecal microbiomes of patients with an initial episode of CDI were similar at the phylum level to healthy subjects (i.e., the majority of sequences belonged to dominant fecal phyla Bacteroidetes and Firmicutes), while a major reduction or loss of Bacteroidetes was observed in patients with recurrent CDI. The loss of the Bacteroidetes was accompanied by the expansion of other phyla, including Proteobacteria and Verrucomicrobia, which are normally minor constituents of the fecal microbiota. Khoruts et al. (2010) compared the microbiota of a patient with recurrent CDI before and after FMT by using terminal-restriction fragment length polymorphism and clone-based 16S rRNA gene sequencing. Before transplantation, the patient's microbiota was deficient in members of Bacteroides and instead was composed of atypical fecal genera such as Veillonella, Clostridium, Lactobacillus, Streptococcus, and unclassified bacteria similar to Erysipelothrix. Two weeks after the infusion of donor fecal suspension, the bacterial composition of her feces approached normal and was dominated by Bacteroides sp. strains.

In 1989, Tvede and Rask-Madsen used a combination of nine normal fecal organisms to treat 6 patients with chronic relapsing C. difficile diarrhea. These investigators cultivated 10 strains of bacteria, including Enterococcus (Streptococcus) faecalis (1108-2), Clostridium inoculum (A27-24), Clostridium ramosum (A3I-3), Bacteroides ovatus (A40-4), Bacteroides vulgatus (A33-14), Bacteroides thetaiotaomicron (A33-12), Escherichia coli (1109), E. coli (1108-1), Clostridium bifermentans (A27-6), and Blautia producta (Peptostreptococcus productus) (1108-2) in broth for 48 h to a concentration of approximately 10 to the 9th power bacteria/mL. Two mL from each bacterial culture were admixed with 180 mL saline that had been pretreated in an anaerobic chamber for 24 h; the bacterial suspension was then instilled rectally. This procedure was followed promptly by a decline of C. difficile to undetectable levels by culture and the loss of detectable toxin from the stools. Normal bowel function was restored within 24 hours, and abdominal symptoms disappeared. Stool cultures and toxin assays for C. difficile remained negative during a year of follow-up. It is especially important to note that feces from none of the 6 patients contained Bacteroides sp.

Conditions

• Active C. Difficile Colitis

Interventions

BIOLOGICAL

Microbiota Transplantation (FMT)

Active therapy

Sponsors & Collaborators

• Michael E. DeBakey VA Medical Center

  collaborator FED

• Baylor College of Medicine

  lead OTHER

Principal Investigators

• David Y Graham, MD · Baylor College of Medicine

• Antone R Opekun, MS, PA-C · Baylor College of Medicine

Study Design

Allocation

NA

Purpose

TREATMENT

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2013-02-28

Primary Completion

2035-02-28

Completion

2036-02-28

Countries

• United States

Study Locations