C. Difficile and Fecal Microbiota Therapy Niraj Jani, M.D. Greater Baltimore Medical Center 1/30/15

C. Difficile Most common hospital acquired infection. Incidence has risen from 3-12/1000 people in the 1990’s to 25-40/1000 people in the 2000’s. Hypervirulent strain NAP1/B1/027- produces larger quantities of Toxin A, B. Resistant to fluoroquinolones.

Treatment Current guidelines for initial disease: Mild/Moderate Dz: Metronidazole 500 mg tid x 10 days. Severe Dz: Vanco 125 mg qid x 10 days. If not responding Vanco plus Metronidazole for 14-21 days. If toxic, consider colectomy. Fidaxomicin has statistically better cure rate and less recurrence rate at 28 days.

Treatment Recurrent C. Difficile First Episode: repeat treatment as for initial infection. Second Episode: Pulsed Vanco. Third Episode: Pulsed tapered Vanco vs Fecal Transplant. IVIG may be helpful in patients with hypo-gammaglobulinemia. Rifaximin has been studied and may have a role as a “chaser” for recurrent C. Diff.

Treatment Vaccine- Still in development. Antibodies- In development fully human monoclonal Ab against C. Diff toxins A, B. One course of treatment with Vancomycin is $1500.00. Fidaxomicin treatment is $2500.00 and obtaining insurance approval is a struggle.

Recurrent C. Difficile 15-20% of patients either have relapse, re-infection, or post-CDI IBS. Due to impaired host response and altered intestinal microbiome. Also decreased phylogenetic richness (Bacteroides, Firmicutes). 2nd recurrence- 30-45%. 3rd recurrence 45-60%. Treatment failure in up to 20% of cases.

Fecal Microbiota Therapy (FMT) As old as the 4th century and has been used in horses and cows for severe diarrhea. 1958 First description of FMT for pseudomembranous colitis in 4 patients. C. Diff infection occurs due to a breakdown in the intestinal barrier and then toxin invasion. Recurrent C. Diff occurs due to a perturbation or imbalance in intestinal bacteria (dysbiosis).

Protocol for FMT Test affected patient for HIV 1, 2, Hep A, BsAg, Bs Ab, HBc Ab, Hep C Ab, RPR. Stool for culture, O + P. Patient also has to stop antibiotics for up to 5 days prior to the procedure. (debateable)

Donor Screening Donor Selection- spouse, first degree relative, friend, stool bank. Excluded if they have had antibiotics within 3 months, active GI symptoms, IBS, IBD, CRC, or high risk behaviors. Donor’s blood is tested for HIV 1, 2, Hep A, BsAg, Bs Ab, HBc Ab, Hep C Ab, and RPR. Stool is tested for C. Diff, Giardia, O + P and culture.

Protocol for FMT Patient performs a colonoscopy prep prior to the procedure. Donor uses a gentle laxative the night before the procedure and brings stool the morning of the procedure. Stool is kept on ice until ready to mix.

Protocol for FMT Need 50 g/250 cc of diluent. Stool is mixed with non-bacteriostatic saline either by hand or blender and then filtered through gauze pad. Five 60 cc syringes are filled with stool for a total of 300 cc. 60 cc are placed with enteroscopy in the distal duodenum and 240 cc are placed through colonoscopy in the ascending colon.

Fecal Microbiota Therapy (FMT) Other routes of administration: Enema NG/NJ tube Oral FMT capsules All effective, but not as effective as delivery via enteroscopy/colonoscopy

Efficacy of FMT In a MCT study looking at 77 pts with recurrent CDI, primary cure rate was 91%. Symptoms resolved within 3-6 days. Secondary cure rate was 99% and late recurrences were due to repeated exposure to antibiotics. No adverse events reported. Another study looking at 70 patients, found all 38 patients with conventional CDI has resolution with FMT. 32/36 pts with 027 strain had resolution. Brandt LJ, et al. Am J Gastro 2012; 107(7):1079-87. Mattila E, et al. Gastro 2012; 142(3):490

Adverse Events with FMT Bloating, gas, cramping has been reported. Fever may develop first night due to an immune response. Overall extremely safe with no long-term side effects.

FMT and FDA FMT is not yet approved by the FDA and therefore this is considered an investigational drug (IND). FDA issued a guidance statement that informed consent must state that the use of FMT products to treat C. Difficile is investigational and its potential risks should be discussed. At GBMC, approval was required from the IRB and medical board. All data is being collected for every patient and adverse events are reported to the medical board.

FMT Summary Argument can be made for FMT for patient with recurrent refractory disease, severe initial episode, and maybe even post C. Diff IBS. Future will likely be either utilization of stool banks consisting of stool from multiple donors or synthetic stool with the correct strains.