C. difficile prevention & treatment Probiotics, antibiotics & fecal microbiota transplantation

1. C. difficile prevention & treatment Probiotics, antibiotics & fecal microbiota transplantation The scoop on therapeutic poop Monika Fischer, MD, MSCR Assistant Professor of Clinical Medicine

2. Disclosure • No conflict of interest

3. Clostridium difficile infection (CDI) • Traditional medical school fact: Clostridium difficile pseudomembranous colitis is a Clindamycin aftermath and highly treatable with metronidazole • C. difficile infection (CDI) associated with numerous other antibiotics and often resistant to metronidazole

4. Beginning of 2000 Epidemic strain of C. difficile US rates hospital discharges with CDI doubled between 2000 and 2008 Increased need for ICU stay and prolonged antibiotic courses to clear infection High colectomy rates (10%) High case mortality: 7500/year (10-fold increase since 1999) Refractory disease in low risk populations .

5. BI/NAP1/027 • Linked to widespread fluoroquinolone and cephalosporin use • High-level fluoroquinolone resistance • “Hypervirulent” • 18-fold more toxin A & B • Binary toxin: Improved toxin-binding and translocation into the cells

6. C. difficile infectious inoculum is 10 spores Poutanen SM et al. CMAJ. July 6,2004;171(1).

7. Host factors • Age ≥ 65 year • Immunosuppression • recipients of organ transplants (3-11%), chemotherapy, corticosteroids, HIV, IBD, ESRD, ESLD • PPI use ≥ 3-fold • Hospitalization, long-term care facilities • After 1 week 13%, after 4 weeks > 50% colonization rate • Previous CDI

8. Prevention: infection control • Early detection • High index of suspicion in patients with risk factors • Empiric therapy should be started regardless of laboratory testing • Use of best diagnostic test for toxigenic C. diff. with a rapid turn-around time (PCR) • Repeat stool testing is discouraged • < 5% chance for positive test • Routine screening in hospitalized patients without diarrhea is not recommended

9. Hospital-based infection control program • Antibiotic stewardship • Contact precautions should be maintained at a minimum until the resolution of the diarrhea • Private rooms • Hand hygiene: soap (preferably 4% chlorhexidine) & water. Alcohol based antiseptic does not kill C.diff spores! • Barrier precautions (gloves & gowns)

10. Prevention: infection control • Single use disposable equipment • Environmental disinfection with10% bleach (5,000 p.p.m. chlorine) for at least 10 minutes • Infection control “bundle” decreased CDI hospital rates by 33% (7.2/1000 to 4.8/1000)

11. Prevention: Probiotics • Annals 2012 SER and Meta-analysis of 20 trials: Probiotics given for the duration of the antibiotic therapy or up to 2 weeks after reduced the incidence of CDI by 66% • No difference in outcome • Between species: Bifidobacterium, Lactobacillus, Saccharomyces, or Streptococcus • Single species vs. mixture • Adults vs. children • Lower or higher doses (<10 billion CFU/d vs.≥10 billion CFU/d)

12. Treatment: supportive care • Any inciting antimicrobial agent should be discontinued • Maintain enteral nutrition • Fluid resuscitation, electrolyte replacement • DVT prophylaxis • Anti-motility agents are allowed but only in combination with medical therapy

13. Treatment: antibiotics • Patients with mild-to-moderate CDI should be treated with metronidazole 500 mg po tid for 10 days • Patients with severe CDI should be treated with vancomycin 125 mg po qid for 10 days • Failure to respond to metronidazole therapy within 5-7 days should prompt change to vancomycin ACG guidelines 2013

14. Patients with ileostomy, Hartman’s pouch, or colon diversion • Vancomycin via enema should be included in the treatment • Oral vancomycin can’t reach the disconnected segments • Metronidazole as adjunctive therapy: colonic excretion is high across the inflamed mucosa but drops dramatically once mucosa starts to heal

15. CDI severity • Mild-to-moderate: diarrhea ± any other sign/symptom - not meeting criteria for severe • Severe: serum albumin< 3g/dl plus one of the following • WBC≥ 15,000 • Abdominal tenderness ACG guidelines 2013

16. Severe and complicated CDI • Any of the following attributable to CDI: • Admission to ICU • Hypotension • T≥ 38.5 °C • Ileus or significant abdominal tenderness • Mental status changes • WBC ≥ 35,000 or ≤ 2,000 • Serum lactate level > 2.2 mmol/L • End organ failure ACG guidelines 2013

17. Severe and Complicated CDI • Vancomycin 500 mg po qid plus metronidazole 500 mg iv q 8 hrs, and vancomycin per rectum (500 mg in 500ml saline as enema) qid (patients with ileus) • Consult surgery: colectomy vs. loop ileostomy with lavage and vancomycin flushes • Fidaxomicin po and tigecycline iv. • ((Fecal transplant?)) ACG guidelines 2013

18. Special situations • Pregnancy and breastfeeding: Oral Vancomycin • IBD • All patients with IBD flare need testing for c.diff – empirical therapy • Highest risk with corticosteroid use > 3-fold • Reduced dosing of corticosteroids • Immunosuppression can be maintained but escalation should be avoided • Initiation of anti-TNF 72-hrs after starting therapy for CDI • C. diff can cause enteritis and pouchitis!

19. Treatment of Recurrent CDI ACG guidelines 2013 • Repeat metronidazole if the first epidose was treated with metronidazole • Treat with vancomycin pulse regimen for severe or if the first episode was treated with vanco • Vancomycin 125 mg poqid for 10 days followed by 125 mg every 3 days for 10 doses • Consider FMT for the third recurrence

20. Recurrent C. difficile infection • 25% of patients have a recurrence after the initial treatment • Patient with first recurrence have a 35-45% chance for second recurrence • With subsequent recurrence: risk > 50% • Antibiotics are not very helpful Kelly and Lamont. NEJM 2008

21. After emergence of BI/NAP1/027 high failure rates with metronidazole and high recurrence rates with both metronidazole and vancomycin Aslam S. et al. Lancet Infec.Dis. 2005. 5:549-557 (pooled results from 25 studies)

22. Fidaxomicin • New bacteriocidal antibiotic • Poorly absorbed narrow-spectrum macrolide • FDA approval for CDI in 2011

23. Fidaxomicinvs.Vancomycin Louie TJ. NEJM. 2011;364:422-31

24. Vancomycinvs.fidaxomicin for the first recurrence of CDI 20% recurrence 36% recurrence Cornelly OA. Clin Infect Dis. 2012. 55: 154-61

25. The New Kid on the block: Stool • FMT is placement of suspension of fresh stool harvested from healthy individual into the gastrointestinal tract of an individual with CDI • Through standard colonoscopy • Rectal enema • NJ and NG tube • Alternative therapy, but by no means new…

26. A 1,700-year-old method • 4th century China: human fecal suspension by mouth “yellow soup“ for food poisoning, severe diarrhea

27. Fecal transplantation in veterinary medicine since the 17th century • Transfaunation • Horses with diarrhea per rectum • Cattle per os as rumen

28. Modern history of human fecal transplantation • 1958 Ben Eiseman reported “miraculous cure” with FMT in 4 patients with fulminant pseudomembranous colitis • “re-establish the balance of nature” • “immediate and dramatic” responses • “this simple yet rational therapeutic method should be given more extensive clinical evaluation”

29. Explosion of FMT case studies since 2010 • > 500 cases reported with 92% success rate with the first treatment and up to 98% if a second infusion was necessary • Longest follow up 17 months of 77 pts – zero recurrence without antibiotics (all recurrences related to antibiotic use 8/30) • 97% of patients would undergo another FMT if needed • 57% voted for FMT as their preferred first treatment option Brandt, L. ACG. 2012

30. Duodenal infusion of donor feces after vancomycin for 4 days and bowel lavage • Vancomycin therapy for 14 days plus bowel lavage on day 4-5 • Vancomycin therapy for 14 days

31. 15 13 Nood et al NEJM. Jan. 2013

32. Microbiota diversity increases after stool transplant Nood NEJM 2013

33. Who should be treated with FMT? • After 3 episodes or after failure of vancomycin pulse regimen (ACG guidelines) • L. Brandt recommendations: • First line therapy in severely ill patients • FMT may be preferred for the first episode of CDI because antibiotic perturbs the microbiota and may lead to antibiotic resistance Brandt, L. JCGE. 2011

34. Risks of FMT • Colonoscopic perforation • Transmission of infections and other diseases • Long-term risk? Increased incidence of autoimmune conditions: 4 out of 77 patients developed peripheral neuropathy, Sjӧgren syndrome, RA, ITP within median 17 months f/u Brandt LJ. ACG. 2012;107:1079-1087

35. Donor selection • Intimate contacts, family members to mitigate risk of transmissible diseases • But, results with “standardized” or “universal” donors are similarly excellent with fresh or frozen/thawed preparations

36. Donor screening • Stool • Bacterial culture • Ova & parasites including Giardia, Cryptosporidium, Cyclospora, Isospora • C.difficile • H. pylori • Blood • Hepatitis A, B, C • HIV 1/2 • Syphilis

37. Donor selection • Exclusion criteria • IBD, IBS, functional diarrhea or constipation, h/o GI malignancy • Antibiotic use within 3 months • Systemic chemotherapy or immunosuppression within 1 year • Known HIV, hepatitis B and C, illicit drug use, incarceration, tattoo/piercing within 6 months

38. Donor’s badge

39. Which route of administration is the best? • SER 1: colonoscopy and enema (required repeated infusions) with superior cure rate > 85% vs. 76% upper GI route • SER 2: colonoscopy superior 93% vs. 85% nasogastric tube

40. FMT via colonoscopy at IU

41. FMT at IU Hospital • Patient preps for colonoscopy • Stops vancomycin 36-48 hrs before FMT • Fresh stool (not older than 6 hrs) emulsified in the endo suite and infused into the terminal ileum or right colon • Patient receives Imodium and observed for 2-3 hrs. • Environmental cleaning at home • CPT code 44705 Bakken J, Borody T, Brandt L et al. Treating Clostridium difficile Infection With Fecal Microbiota Transplantation. Clinical Gastroenterology and Hepatology, December 2011, 9(12):1044-1049.

42. Why and how does FMT work?

43. Borody, T. J. & Khoruts, A. (2011) Nat. Rev. Gastroenterol. Hepatol.

44. Mechanism of action • FMT is introduction of a complete, stable community of gut-organisms to repair or replace the disrupted native microbiota • Reestablishment of the host defense against C. difficile • Engraftment of the donor microbiota is durable

45. Bacterial fingerprints of the donor and recipient stool before and after FMT Khoruts A. J Clin Gastroenterol. 2010;44:354-360 Donor Day 0; Patient Day 14; Patient Day 33

46. Probiotics in the treatment and recurrence prophylaxis of CDI • Limited evidence for adjunct probiotics to reduce risk of recurrence • S. boulardii showed efficacy in few trials reducing recurrence rate to 35% vs. 65% but only in patients on high dose vancomycin • Why probiotics don’t work? • Insufficient CFU count • Not the right species or mixture • Wrong media (milk) to culture probiotics

48. Animal experiment – murine model of C. difficile colitis • Mice treated with Clindamycin for 7 days • Infected with C. difficile BI/NAP1/027 from hospitalized patients • Mice developed severe colitis • Dysbiosis • Reduced diversity • Reduced Bacteriodetes and Firmicutes • Increased opportunistic pathogens (Klebsiella, E. coli, Proteus mirabilis, Enterococcus faecalis) • Up-regulated pro-inflammatory genes Lawley et al. PLOS 2012

49. 5. Mice treated with vancomycin • Suppression of C. difficile shedding • 6. Relapse upon cessation of therapy • 7. FMT using healthy mice stool per os • Durable suppression of C. difficile shedding for several months resolve disease and contagiousness Lawley PLOS 2012

50. Targeted bacteriotherapy Instead of stool from healthy mice A mixture of six phylogenetically diverse bacterial species including obligate and facultative anaerobes Bacteriodetes and Firmicutes cured CDI in mice with severe colitis infected with BI/NAP1/027 Lawley, T. 2012