Clostridium difficile : Epidemiology, Management and Focus on Fecal Bacteriotherapy/Fecal Microbiota Transplantation

1. Jayesh Patel, MD, DTM&H Infectious Disease Consultant Chair Infection Prevention and Pharmacy/Therapeutics/Nutrition (Skyline) Clostridium difficile:Epidemiology, Management and Focus on Fecal Bacteriotherapy/Fecal Microbiota Transplantation

2. C. difficile management :Financial disclosure • No financial conflict of interest • ( Past speaker for Dificid)

3. Objectives: C. difficile • Learn current epidemiology of C. difficile infection • Understand clinical presentation of C. difficile disease • Understand testing methodology for C. difficile infection • Learn about prevention and treatment of C. difficile infection • Learn about rationale and methods of treatment by fecal microbiota transplantation

4. Clostridium difficile • Gram positive anaerobic bacillus • Produces spores • Commensal intestinal flora in 2-5 % of healthy adults, over 50% of infants • Fecal-oral transmission • Colonizes 20-40 % hospitalized patients • Produces toxins A, B, and Binary toxin

5. C. difficile: Epidemic Strain • NAP1/BI/027strain of C. difficile •  "North American Pulse-field type 1" pattern (on gel electrophoresis) and a "BI" pattern (on restriction endonuclease analysis), and type "027" (on ribotyping) • Resistance to quinolone antibiotics • Hypersporulation • Binary toxin production • High levels of toxin A,B (20 x greater) • High morbidity and mortality

6. Epidemiology • USA 15,000 – 20,000 deaths annually, rising • 20 % of all episodes of antibiotic associated diarrhea are due to C. difficile • 4-10 cases per 10,000 patient days • Relapse occurs in over 20 % of cases • Increase in average hospital cost : $ 27,000 • Over 1 billion dollars in costs annually

7. Risk Factors • Current and prior antibiotics • Elderly • Immunocompromized • Hospital stay, nursing home residence • NG tube, tube feeding • Recent Endoscopy, Gastrointestinal surgery • Proton pump inhibitors, H2 blockers, Chemotherapy

8. Prevention of Transmission • Private rooms • Contact isolation: gloves, gowns • Hand washing ( instead of alcohol based ) • Special entry signs • EPA approved sporicidal agents, diluted bleach for cleansing all environmental surfaces and reusable devices • Isolation till diarrhea resolved or discharged

9. Clinical Manifestations • Diarrhea, abdominal pain, N/V, fever, loss of appetite • Pseudomembranous colitis • Toxic megacolon • Perforation of colon • Severe sepsis • Death

10. Testing in C. difficile • ? Smell • WBC , creatinine, albumin • Stool testing • Culture for C. difficile • slow • labor intensive, technical expertise • expensive • requires second test for toxin detection

11. Stool Testing • Cell Cyto-toxicity Neutralization Assay • Toxin B detection only • Slow, Labor Intensive/technical expertise • Moderate sensitive, High specificity

12. Stool Testing • Antigen detection ( Glutamate DeHydrogenase EIA) • Highly Sensitive • Rapid • Cheaper • Not specific

13. Stool Testing • Toxin Enzyme Immuno Assay • Detects toxin A and B • Quick, inexpensive • Less sensitive • Toxin is heat labile so testing must be done within 2 hours or keep stool sample refrigerated

14. Stool Testing • PCR • Toxin B gene • Very sensitive and specific • Rapid if done in house • Expensive

15. Multistep Testing • Antigen negative: no further testing, not C. difficile • Antigen positive, Toxin positive: has C. difficile • Antigen positive, Toxin negative: send for PCR • PCR negative: not C. difficile • PCR positive: has C. difficile

16. C. Difficile treatment:Metronidazole • Indication: mild to moderate CDI • Administration: 500 mg PO or IV tid for 10-14 days • First line therapy for mild to moderate CDI, but increasing rates of refractory infection are being observed

17. Vancomycin • Indication: Moderate to severe CDI • Administration: ~125-500 mg PO qid for 10-14 d • Oral, nasogastric, or rectal therapy may be combined with IV metronidazole in critically ill patients. • Tapered/Pulse therapy for recurrent CDI

18. Nitazonxanide • Indication: index infection or recurrent CDI • Administration: 500 mg PO bid for 10 days • More studies are needed to clarify its role in CDI.

19. Rifaximin • Indication: recurrent CDI • Administration: 200 mg PO bid to 400 mg PO tid for 28 d. May be given as a “chaser” after completion of vancomycin therapy for recurrent CDI. • More controlled studies needed to decide best use of this drug.

20. Fidaxomicin • Indication: index infection of recurrent CDI • Administration: 200 mg PO bid for 10 d • Non-inferior to vancomycin and is associated with a significantly lower rate of recurrent infection • Expensive

21. Toxin Binders • Indication: symptomatic adjunct to antibiotic treatment • Administration: Cholestyramine4 g PO tid or qid. ?? Duration • Toxin binders such as cholestyramine should be used to control symptomatic diarrhea but not as the only treatment.

22. Immunoglobulins • Indication: refractory CDI • Administration: IV infusion at a dose of 400 mg/kg (IVIG) of body weight given with antibiotic therapy. • Enhances overall efficacy of treatment and reduces further recurrences. • Expensive

23. ProbioticsSaccharomyces boulardi • Indication: prevention of recurrent CDI • Administration: 500 mg PO bid for 28 d. Usually started after 7 days of antibiotic treatment. • Avoid using in severely immunosuppressed patients; should not be given chronically. • (Lactobacillus not proven to help)

24. Other treatments • Bacitracin suspension • Rifampin • Teichoplanin • Tigecycline • Surgery: Colectomy • Fecal bacteriotherapy/FMT

25. Fecal Microbiota Transplantation • Indication: recurrent/refractory CDI; unclear role in severely ill CDI patients as first-line therapy. • Administration: stool suspension from a healthy donor administered by nasogastric/NJ tube, via colonoscopy or enema. • Excellent preliminary results in patients with severe and refractory disease. Best methodology is yet to be clarified.

26. Case Report • 62 yr old white male • Had URI ( ? Viral), got abx. and 3 days later, develops diarrhea, becomes severe, Metronidazol started. Gets worse, abd cramping, weakness, mucousy stools, stools every ½ hour. • PMH: splenectomy, multiple sinus surgeries, fracture/laceration finger one month earlier, had pinning and got prophylactic antibiotic.

27. Case Report • Admitted to Hospital • WBC 12.9k, Cr 1.2, C. diff Ag/Toxin positive • Oral vancomycin started • Slow/poor response, Nitozoxanide added • Slow improvement, discharged on oral Nitozoxanide. • Nitozoxanide not covered by insurance so changed to Metronidazol. Had 1-2 soft/loose stools daily.

28. Case Report • 2 days after completing Metronidazol, develops explosive diarrhea • 20 BM/day, nausea, chills, abdominal pain, weak • Readmitted • Ill looking, T 100.1, HR 110, BP 100/52 • Abdomen tender

29. Case report: CT Abdomen

30. Case Report • Treatment: IV fluids, Vanco PO, Metronidazol, Nitozoxanide • Poor response: ? Fidoxamicin ? FMT ?Colectomy • Patient elects to have FBT/FMT

31. Case Report • Approx. 70 grams donor stool instilled via Naso-duodenal tube, partial response, 2nd instillation of fresh 100 gram stool next day. Diarrhea resolves 3rd day. • Patient observed 2 more days than discharged home free of symptoms • Patient free of symptoms after 6 months

32. Procedure for FBT/FMT • Diagnosis will be confirmed by Gastroenterologist or Infectious Disease Specialist. • Gastroenterologist or Infectious Disease Specialist wishing to use(FBT) will notify designated departments to schedule the testing/procedure, and discuss the process with donor and recipient for Informed Consent.

33. Consents and Education • FBT/FMT Policy and Procedure • Patient Consent • Patient Education Brochure • Donor Consent • Donor Instruction • Bowel Motion Record

34. Recipient testing • All recipients will have the following laboratory tests: • HIV antibody • Hepatitis A antibody • Hepatitis B surface antigen • Hepatitis C antibody

35. DONOR: • Ideally the stool transplant donors should be related to the recipient but not the spouse, significant other or a family household member. They should be healthy and have not received antimicrobial therapy in the last 2 months. • The donor should have normal bowel habits and be free of blood-borne or stool-borne pathogens. • Screening tests prior to the transplant • Acute Hepatitis Panel, HIV antibody, and CBC • Donor stool testing for Clostridium difficile toxin, Stool culture , Cryptosporidium stain, Stool O & P

36. Patient Prep • Obtain signed consent for Fecal Bacteriotherapy/FMT • Start Liquid diet the day prior to the scheduled FBT/FMT • Cleanse patients’ bowel using 3-4 liters of Golytely, the day before FBT/FMT • Give PPI agent day of procedure for upper GI administration • Stop antibiotics 24-48hr before FMT

37. Stool Specimen Preparation for Lower GI Administration • Obtain 250-300 gms (approx one cup) of fresh stool from donor as soon as possible prior to the transplantation procedure, never more than 4 hours prior. • Using a blender, add stool to 250ml of Normal Saline or Sterile Water. Mix until stool particles are dispersed throughout the liquid • Remove large particles by straining the stool/liquid mixture twice, utilizing strainer.

38. Stool Specimen Preparation for Lower GI Administration • Mixture should be administered within 2 hours of preparation. No more than 6 hours should elapse between stool specimen collection and fecal administration. • Administer as Enema or by Colonoscopy into terminal ileum and colon. • Enema can be given by standard enema set or by Fecal Management System (ActiFlo). Retain enema for 1-2 hours. • Repeat enema with fresh stool next day if ordered.

39. Stool Preparation for Upper GI Administration • On the day of the procedure, obtain 100 g (approx 1/3 to 1/2 cup) of donor stool. • Using a blender, add stool to 100 ml (or necessary amount to facilitate installation) of Normal Saline or Sterile water. Mix until stool particles are dispersed throughout the solution. • Remove large particles by straining the stool/saline mixture twice, utilizing a strainer. • Transfer solution into catheter tip syringes for transport to patient.

40. FMT via Upper GI Tract • Place NG tube or Naso-duodenal tube morning of procedure in radiology department. • If NJ tube is used, it is inserted into Jejunum through endoscope. • Don gown, gloves, mask, and eye protection.

41. FMT Via Upper GI Tract • Using a syringe administer the freshly mixed stool via NJ/ Dobhoff tube. • After stool installation, flush with 50ml of normal saline. (DO NOT REMOVE NJ/DOBHOFF TUBE). • Repeat stool infusion procedure next day. • Do not remove NJ/Dobhoff tube until ordered by physician.

42. Naso-duodenal Tube Placement

43. FMT: Upper GI Tract Route

44. FMT: Upper GI Tract Route

45. Goodbye ! • Listen to your mother: Don’t forget to wash your hands after using the restroom and before eating!