Star Articles in Review

Christina M. Surawicz, MD MACGProfessor of Medicine

Division of GastroenterologyDepartment of Medicine

University of Washington

CDDW/CASL MeetingToronto, February 10, 2014

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.

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

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)

Recurrent C. difficile infection (RCDI) – Background• Result of disturbed microbiome

• Less diversity• Fecal microbiota transplant (FMT)

“stool transplant”- 90% effective in small series + meta-

analysis- Better than other therapies

Pulsed vancomycinAdjunct probiotics

- No prior RCT

RCDI – Evidence of the Altered Microbiome

Evaluated microbiome in 7 pts with CDI and 3 controls

Bacteroidetes and Firmicutes = majority3 developed RCDI

Microbiota was less diverseMore other bacteria

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

Colon Microbiota

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

Patient Population• Adults with life expectancy > 3 months• Recurrent CDI -

One or more episodesFailed standard therapy

• Diarrhea> 3 loose or watery / 24 hour x 2 days

OR> 8 in 48 hours

PLUSC. difficile toxin by PCR

Patient Population

Elderly (66 – 73 mean age)Men and womenMedian recurrences 2 – 3

Most had 4 episodesHospital acquired 46 (77%)Normal labs

WBC, albumin, creatinine

Exclusions

Immune compromise – risk

Pregnancy

Intercurrent antibiotics – recurrence

ICU or on pressors - too sick – refractory not recurrence

Donors (15) – Extensive Screening

Repeated every 4 monthsStool: Parasites, bacteria

Blood: HIV, HTLV 1 + 2,Hepatitis A, B, C, CMVEBV, syphilis, strongyloides,Entamoeba histolytica

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

13

Vancomycin 2 gm/day for 4 days with gut lavage and donor feces via nasoduodenal tube

16

Method

• Fresh stool – passed within 6 hours

• Infused via nasoduodenal tube after gut lavage

Outcome 1 - Recurrence10 week follow up

If recurred, 2nd infusion, different donor10 week follow up extended

Recurrence definedDiarrhea + positive C. difficile toxinNo other cause of diarrheaStools tested

Days 14, 21, 35, 70, and if diarrhea

Outcome 2 - Microbiota Analysis of Stool

16 S ribosomal RNA

Diversity scale

Enrollment and Outcomes

van Nood E et al. N Engl J Med 2013;368:407-415.

Results• 43 patients randomized

2 patients dropped: One stopped meds at homeOne needed steroids for unrelated problem

Results Vancomycin Resolution of RCDI

Regimen Response Notes

Vancomycin alone 4/13 (31%)Vancomycin and gut lavage

3/13 (23%)

Vancomycin and gut lavage and donor stool

13/16 (81%) 2/3 responded to second infusion (94%)

Results

• Trial terminated early

Planned 40/each group

Time to recurrence23 – 25 days

Off protocol treatment – 1 or 2 infusions15/18 83% response

Adverse Events

Immediate 3 hours – resolvedDiarrhea 94%Cramps 31Belching 19

Follow upConstipation 19%

Stool Microbiota – 9 Patients• Pre FMT

- Low diversity• Post FMT

- diversity - Similar to donor

• Bacterioidetes• Clostridium clusters IV, XIVa• Proteobacteria

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;368:407-415.

Critique 1 – Study Stopped Early

- But did wait until evaluation of the33% had reached their primary outcome

Critique 2 - Unblinded

But data points collected at regular intervals in all 3 groups

Also diarrhea and C. difficile testing are objective outcomes

Conclusion

FMT effective for RCDI

Nasoduodenal routeSafe Effective

Unanswered Questions for Future of FMT

• Protocol• Screening of donor and recipient• Route• Amount of stool • Safety – need database

Short term and long term

Long Term Follow Up of Colonoscopic FMT for RCDI

Lawrence Brandt – Bronx, NYColleen Kelly – Providence, RIMark Mellow – Oklahoma City, OKNeil Stollman – Oakland, CAChristina Surawicz – Seattle, WA

(Brandt et al, Am J Gastro, March 27, 2012)

Results77 patients - 56 women

Duration - 11 months averageAge 22 - 88 (65 mean)

Resolution – within 6 days commonly91% immediate cure, 98% secondary cureOf 7 failures

2 retransplanted4 retreated

53% would have it as a 1st treatment if it recurred

Long Term Safety

• 4 had a new medical conditionPeripheral neuropathySjögren syndromeITPRheumatoid arthritis

• No infections or deaths related1 sepsis – 6 months later in Crohn’s pt.1 pneumonia

Safety of FMT in RCDIReports

Norovirus2 casesDonor Asymptomatic

(Gluck et al, Am J Gastroenterol 2013; 108:1367)

Flare of IBD1 case

(deLeon et al, Clin Gastro Hep 2013; 11:1036-8)

ConclusionFMT effective for RCDI – first RCT

Colonoscopic RCT – in progress (Colleen Kelly)

Needs more studyNeed long-term follow up – Data baseSafetyEfficacy