Star Articles in Review

Transcription

1 Star Articles in Review CDDW/CASL Meeting Toronto, February 10, 2014 Christina M. Surawicz, MD MACG Professor of Medicine Division of Gastroenterology Department of Medicine University of Washington

2 Disclosure of Financial Relationships Christina M. Surawicz, MD Has no relationships with any entity producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients.

3 Duodenal infusion of donor feces for recurrent Clostridium difficile. van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal ED, de Vos WM, Visser CE, Kuijper Ejk Bartelsman JF, Tijssen JG, Speelman P, Dijkgraaf MG, Keller JJ. N Engl J Med 2013, Jan 31; 368(5):407-15

4 Treating Infectious Diarrhea with Human Stool 1700 years ago in China (Dong-Jin Dynasty) Human feces given to treat food poisoning and severe diarrhea (Zhang, Am J Gastroenterol 2012; 107:1755)

5 Recurrent C. difficile infection (RCDI) Background Result of disturbed microbiome Less diversity Fecal microbiota transplant (FMT) stool transplant - 90% effective in small series + metaanalysis - Better than other therapies Pulsed vancomycin Adjunct probiotics - No prior RCT

6 RCDI Evidence of the Altered Microbiome Evaluated microbiome in 7 pts with CDI and 3 controls Bacteroidetes and Firmicutes = majority 3 developed RCDI Microbiota was less diverse More other bacteria Chang JY, et al, J Infect Dis. 2008;197:435-8.

7 Colon Microbiota Chang JY, et al, J Infect Dis. 2008;197:435-8.

8 Patient Population Adults with life expectancy > 3 months Recurrent CDI - One or more episodes Failed standard therapy Diarrhea > 3 loose or watery / 24 hour x 2 days OR > 8 in 48 hours PLUS C. difficile toxin by PCR

9 Patient Population Elderly (66 73 mean age) Men and women Median recurrences 2 3 Most had 4 episodes Hospital acquired 46 (77%) Normal labs WBC, albumin, creatinine

10 Exclusions Immune compromise risk Pregnancy Intercurrent antibiotics recurrence ICU or on pressors - too sick refractory not recurrence

11 Donors (15) Extensive Screening Repeated every 4 months Stool: Parasites, bacteria Blood: HIV, HTLV 1 + 2, Hepatitis A, B, C, CMV EBV, syphilis, strongyloides, Entamoeba histolytica

12 3 Groups Regimen Number of patients Vancomycin 2 gm/day for 14 days 13 Vancomycin 2 gm/day for 4 days with gut lavage but no donor feces infusion Vancomycin 2 gm/day for 4 days with gut lavage and donor feces via nasoduodenal tube 13 16

13 Method Fresh stool passed within 6 hours Infused via nasoduodenal tube after gut lavage

14 Outcome 1 - Recurrence 10 week follow up If recurred, 2 nd infusion, different donor 10 week follow up extended Recurrence defined Diarrhea + positive C. difficile toxin No other cause of diarrhea Stools tested Days 14, 21, 35, 70, and if diarrhea

15 Outcome 2 - Microbiota Analysis of Stool 16 S ribosomal RNA Diversity scale

16 Enrollment and Outcomes van Nood E et al. N Engl J Med 2013;368:

17 Results 43 patients randomized 2 patients dropped: One stopped meds at home One needed steroids for unrelated problem

18 Results Vancomycin Resolution of RCDI Regimen Response Notes Vancomycin alone 4/13 (31%) Vancomycin and 3/13 (23%) gut lavage Vancomycin and gut lavage and donor stool 13/16 (81%) 2/3 responded to second infusion (94%)

19 Results Trial terminated early Planned 40/each group

20 Time to recurrence days Off protocol treatment 1 or 2 infusions 15/18 83% response

21 Adverse Events Immediate 3 hours resolved Diarrhea 94% Cramps 31 Belching 19 Follow up Constipation 19%

22 Stool Microbiota 9 Patients Pre FMT - Low diversity Post FMT - diversity - Similar to donor Bacterioidetes Clostridium clusters IV, XIVa Proteobacteria

23 Microbiota Diversity in Patients before and after Infusion of Donor Feces, as Compared with Diversity in Healthy Donors. van Nood E et al. N Engl J Med 2013;368:

24 Critique 1 Study Stopped Early - But did wait until evaluation of the 33% had reached their primary outcome

25 Critique 2 - Unblinded But data points collected at regular intervals in all 3 groups Also diarrhea and C. difficile testing are objective outcomes

26 Conclusion FMT effective for RCDI Nasoduodenal route Safe Effective

27 Unanswered Questions for Future of FMT Protocol Screening of donor and recipient Route Amount of stool Safety need database Short term and long term

28 Long Term Follow Up of Colonoscopic FMT for RCDI Lawrence Brandt Bronx, NY Colleen Kelly Providence, RI Mark Mellow Oklahoma City, OK Neil Stollman Oakland, CA Christina Surawicz Seattle, WA (Brandt et al, Am J Gastro, March 27, 2012)

29 Results 77 patients - 56 women Duration - 11 months average Age (65 mean) Resolution within 6 days commonly 91% immediate cure, 98% secondary cure Of 7 failures 2 retransplanted 4 retreated 53% would have it as a 1 st treatment if it recurred

30 Long Term Safety 4 had a new medical condition Peripheral neuropathy Sjögren syndrome ITP Rheumatoid arthritis No infections or deaths related 1 sepsis 6 months later in Crohn s pt. 1 pneumonia

31 Safety of FMT in RCDI Reports Norovirus 2 cases Donor Asymptomatic (Gluck et al, Am J Gastroenterol 2013; 108:1367) Flare of IBD 1 case (deleon et al, Clin Gastro Hep 2013; 11:1036-8)

32 Conclusion FMT effective for RCDI first RCT Colonoscopic RCT in progress (Colleen Kelly) Needs more study Need long-term follow up Data base Safety Efficacy