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Management of C. difficile Disease: From Flagyl to Fecal Transplants

Learn about the epidemiology, diagnostic methods, and treatment options for C. difficile colitis. Explore the importance of C. difficile infection, the diagnostic techniques, and the various treatment options available.

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Management of C. difficile Disease: From Flagyl to Fecal Transplants

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  1. Clostridium difficile disease Management: Flagyl to Fecal Transplants – A Step Wise Approach to C. difficile colitis September 22, 2017 CSGNA Pamela Kibsey MD, FRCPC Medical Director, Medical Microbiology and Infection Prevention and Control, IH

  2. Objectives 1. Refresh disease epidemiology and definitions 2. Diagnostic methods and clinical interpretation of laboratory results 3. Treatment options and updates

  3. 1. Importance of C. difficile Infection • Leading cause of HCA diarrhea >72 hrs IP • HA rates: 2005 - 84/100,000 patient days 2011 - 70/100,000 2015 - 48/100,000 • Reduced efficacy of abx therapy • Metronidazole failure rates for uncomplicated CDI: 18% vs 2.5% • Following 2 recurrences: > 60% risk of recurrence with abx • Increased length of stay and hospital costs • 4d increase in LOS; additional $12,000 in costs/CDI episode • Increasing number of cases in the community. 39-47% of all new cases • New risk groups: pregnant women, pediatrics, oncology patients

  4. Provincial rate and number of new cases of CDI associated with the reporting facility, by fiscal year and quarter, 2012/13- 2016/17, British Columbia

  5. Definition of a Case • Sustained watery diarrhea 3/24 hrs or 6+/36 hrs • +/- elevated WBC, fever, dehydration • Abdominal pain, distention, ileus • Sometimes bloody • Not induced by laxatives, enema, bowel prep in the previous 48 hrs or when co-existing viruses present (norovirus or rotavirus) • Risk factors: previous antibiotics 8 wks, chemotherapy, abdominal surgery, malnutrition, deconditioning, age>65, co-morbidities, 027 ribotype

  6. Definition of Colonization • Sample induced by laxative, enema or bowel prep in the previous 48 hrs • Non-sustained diarrhea • Mixed infection eg enteric pathogen or virus/C. difficile • Bristol stool chart NOT # 6 or 7

  7. Environmental control • Vegetative forms susceptible to most detergents • Spores R to dessication and disinfectants • High concentration H₂O₂ or 10 % bleach • Many spores removed with neutral detergent and microfibre cloth • New agents: Xenon or blue light, H₂O₂ vapor, UV light • HH: ABHR or soap/water/friction when soiled

  8. 2. Diagnostic Methods • Culture of the organism is the gold standard • Surrogate for culture is C. difficile antigen = GDH, plus toxin detection. Results can be +/+ or +/- • Supplementary test is detection of toxin gene by PCR. Higher sensitivity but lower specificity. Not all results = case. • Many labs perform toxin PCR only. Needs careful clinical correlation to avoid unnecessary treatment.

  9. New test GPMP in VIHA • Multiplex PCR that detects 15 pathogens: Campylobacter, Salmonella, Shigella, STEC, ETEC, Vibrio cholera, Yersinia enterocolitica, C. difficile, norovirus 1/2, rotavirus, adenovirus 40/41, Giardia, E. histolytica, Cryptosporidium • 5 hr test • Performed on all OP, ER, LTC and IP <72 hrs • C. difficile Ag/toxin +/- toxin PCR IP >72 hrs • Replaces routine stool C&S, O&P x 2, C. difficile Ag/toxin, virus. • O&P high risk still orderable

  10. GPMP results so far • Analysis of 500 patient results • #1 pathogen C. difficile 12% (insert table here)

  11. 3. Treatment options and updates • Efficacy of current treatments for CDI • Primary and 1st recurrent episode • Recurrent CDI treatment/prevention • Current evidence for use of FMT • Review of cases

  12. Case 1 CA Mild CDI • 48yF. Recently completed Rx clindamycin for abscessed tooth • 2 wk later presents with abdominal cramping, watery diarrhea 4-6/day for 3 days • Lab positive C. difficile toxin PCR • What treatment would you pick first line?

  13. ?? Rx • Metronidazole 500 mg po bid for 7 days • Metronidazole 500 mg po tid for 10 days • Metronidazole 500 mg po tid for 14 days • Vancomycin 125 mg po qid for 10 days

  14. ?? Rx • Metronidazole 500 mg po bid for 7 days • Metronidazole 500 mg po tid for 10 days • Metronidazole 500 mg po tid for 14 days • Vancomycin 125 mg po qid for 10 days

  15. Case 2 Mild CDI, compromised pt 67yF – fever, nausea, copious diarrhea and abdominal pain following ingesting of raspberries Stool O & P: Cyclospora Started on TMP/SMX 160/800mg2 – improved on day 4 of treatment Recurrent diarrhea 7d following Rx. Next steps??

  16. Repeat stool investigations • O & P: negative • C & S: negative • Enteric viruses: negative • C. difficile toxin- pending

  17. Patient’s current state and management plan 67F, now has 5 watery bowel movements/day Admitted for monitoring (immunocompromised) • Normal temperature, WBC, lactate • Maintained baseline creatinine • Empiric treatment for suspected C. difficile infection?

  18. Wait for laboratory confirmation for mild CDI • Patient’s stool: C. difficile Ag/toxin positive • Which antibiotic? • Metronidazole 500mg po tid • Vancomycin 125 mg po qid • Fidaxomicin 200mg po bid • Combination therapy??

  19. Vancomycin 125mg po qid for 10 days • Multinational, RCT. S Johnson. CID Aug 2014 • Clinical success: MTZ (72.7%)was inferior to VM (81.8%) (p = 0.02) • Clinical success: 4% (mild); 8.3% (mod); 12.2% (severe cases) more in VM than MTZ

  20. Back to Mild Case of CDI • Patient unable to take any oral medications due to intractable nausea and vomiting • Is IV metronidazole the only option? • Is it equivalent to oral treatment?

  21. CDI: treat orally Prospective, cohort study of 250 patients with mild CDI • Mean patient age: 77; > 50% moderate/severe comorbidity (Charlson index > 2 points) • 121: oral metronidazole • 42: IV metronidazole • 42: oral vancomycin • All cause 30-day mortality rate: 13% • 38% in IV metronidazole • 7% for oral metronidazole; 10% oral vancomycin group • Adjusted for sex, age > 65; severity of comorbidity – risk for death within 30 days > 4-fold higher with IV metronidazole Wenisch, JM. AAC Apr 2012

  22. Case 3 Ongoing diarrhea 76yM. L BKA – SSI, complicated CDI • CDI Rx: MTZ 500mg IV q8h, VAN 500 mg po q6h, VAN 500 mg enema and FDX 200mg po q12h • Referred for FMT for ongoing diarrhea (q20-30min; 2.5 – 5L/d) • Normal WBC, creatinine, hemodynamically stable • Repeat stool for C. difficile toxin: negative

  23. Ongoing diarrhea • When should you consider switching therapy or making an alternate diagnosis?

  24. Recurrent CDI Mechanism • Resistance to metronidazole 0%; vancomycin-rare • Reinfection (environment) • Proper immune response is important Risk factors Risk Factors • Additional antibiotic therapy • Age > 65 years • Severe underlying illness • ICU stay • Prolonged hospital stay • Immunodeficiency Rates of recurrence

  25. Management of recurrence • First recurrence use the same Rx as initial episode if patient responded • Tapered or pulsed dose vancomycin • Persistent spores • Recurrence rates 31% compared with 45% • Fidaxomicin narrow spectrum antibiotic – less damaging to background microbiota. • Similar efficacy to vancomycin but less recurrence IPS Liverpool 29th September 2015

  26. Why does C. diff recur? IPS Liverpool 29th September 2015

  27. From me ... to poo IPS Liverpool 29th September 2015

  28. Overview of FMT Case history Recurrent CDI Why FMT? History of FMT Our journey The future? IPS Liverpool 29th September 2015

  29. Case history FMT • Mr MW 76 year old man • Admitted to RJH October 2016 • Severe CAP- managed in RICU • Cardiac arrest • Coronary angioplasty • Developed ARF • Haemodialysis • Developed C difficile diarrhea • Metronidazole 14 days • Vancomycin 14 days • Vancomycin + metronidazole 28 days • Fidaxomicin 10 days IPS Liverpool 29th September 2015

  30. Referral to MM Sent: Friday, December 23, 2016, 10:41 AMTo: Dr Christine LeeSubject: Stool transplant Hi, I am trying to get hold of the gastroenterologist who does stool transplants. Is that you? We have a patient I would like to discuss. Thanks IPS Liverpool 29th September 2015

  31. How Does FMT Work? Fecal Microbiota Results of Patients pre and post FMT: Relative Abundance • Mechanism not yet understood • Recurrent CDI • Decreased microbiome diversity, promotion of C. difficile growth • FMT: • restoration of healthy microbiome  Resistance to C. difficile (Colonic Resistance) Acitinobacteria (blue); Bacteroidetes (yellow); Firmicutes (white); Fusobacteria (red);

  32. Antibiotics Antibiotics FMT Emma Allen-Vercoe, Univ Guelph , Canada IPS Liverpool 29th September 2015

  33. IPS Liverpool 29th September 2015

  34. FMT Donor Screening • No standardized exclusion criteria • Exclusion criteria: • Positive for any of the following: HIV, HCV, HBsAg, HTLV1/II, syphilis, Salmonella, Shigella, E.coli O157 H7, Yersinia and Campylobacter, VRE, MRSA, ESBL, CRO • Detection of ova, protozoa, C. difficile toxin, norovirus, adenovirus, rotavirus • History of risk factors for acquisition of blood-borne pathogens; prion or any neurological disease as determined by the donor questionnaire, • History of gastrointestinal comorbidites, e.g., inflammatory bowel disease, irritable bowel syndrome, chronic constipation or diarrhea • Antibiotic use or any systemic immunosuppressive agents in the 3 months prior to stool donation • Receipt of any type of live vaccine within 3 months prior to stool donation • Ingestion of nut or shell fish 3 days preceding donation • History of GI cancer • Family history of colon cancer • History of any type of active cancer or autoimmune disease • History of depression, anxiety or panic disorder • Body mass index > 29

  35. IPS Liverpool 29th September 2015

  36. Efficacy and safety of FMT 9 Randomized Controlled Trials. Duodenal Infusion of Donor Feces for Recurrent C. difficile van Nood, et. al . N Eng J Med. 2013 • 3 treatment groups (NJ infusion of FMT: oral vancomycin; bowel lavage and oral vancomycin • Study halted following interim analysis as FMT superior to other treatments ( P <0.001 ) and almost all of the other pts had re-currences. • FMT 13/16 (81% , 1st infusion); 2/3 resolved with 2nd infusion: overall efficacy 94% • Vancomycin 4/13 (31%) • Bowel lavage and oral vancomycin 3/13 (23%) • Similar AE’s between 3 groups; mild diarrhea and abd cramps in FMT group

  37. Cure without relapse at 10 weeks IPS Liverpool 29th September 2015

  38. Microbiota Diversity IPS Liverpool 29th September 2015

  39. Acceptable to patients? Zipursky J. et al. Can J Gastroenterol Hepatol 2014 28(6):319-24 Clinicians often state no patient would ever agree to this procedure No patients who have been considered for procedure has refused it. IPS Liverpool 29th September 2015

  40. Efficacy and safety of FMT: 6 Randomized Controlled Trials 1no of patients treated with FMT 2ND = nasoduodenal 3NG = nasogastric 4colonos = colonoscopy 52nd FMT via NG only 6FMT for acute episode of rCDI

  41. Outcomes of FMT at IH • 30 patients enrolled to date • 20/25 cured with 2 FMT. f/u 60 days • 3/5 cured with 3 FMT. • Remainder are being followed. • Efficacy is 80% with 2 and 92% with 3 FMT.

  42. Outcome of Patients Non-Responsive to FMT • Pts refractory to CDI • Multiple FMTs – no response • Response to oral vancomycin post FMT relapse • 4/94 in SJHH observational study • 6/232 in RCT • 4/6 unresponsive to VAN pre-FMT • 6/6 post FMT, symptom-free on VAN 125mg1 24 – 36m f/up • Ruben, Bakken. Anaerobe 2013 • Brandt. Am J Gastroenterol 2012 • Lee, et. al. Eur J Microbiol Infect Dis 2014

  43. Safety of FMT • Most current data is retrospective • Minor • Abdominal symptoms immediately post FMT are common • Serious • Related to mode of administration • Transmission of infection • Potential • Transmission of infective agent • Induction of chronic disease by altering the microbiome IPS Liverpool 29th September 2015

  44. Multidisciplinary approach Interested in the concept Lack of effective treatment for recurrent disease Discussed with local microbiologists Discussed with gastroenterology and ID/MAP colleagues RCT was trigger to look at developing a service IPS Liverpool 29th September 2015

  45. Who, where and how? Must have had 2 relapses – tapered vancomycin MAP any hospital, ward, at home 50 ml enema given by physician, nurse or patient. 15 minute procedure. No bowel preparation, no loperimide, d/c vancomycin 24-48 hrs before. Refractory cases 6 hr. Referral to OPAT or Dr Christine Lee MM IH IPS Liverpool 29th September 2015

  46. Easier? Material provided as frozen or lyophilized 6 months shelf life in a -20⁰C freezer No more donor finding or screening Allows patients to be treated quickly IPS Liverpool 29th September 2015

  47. Safer? • More extensively screened • Better quality control • Traceability • Tracker codes • Deep frozen reference samples • Established adverse event reporting system • Reduced hazard of processing locally IPS Liverpool 29th September 2015

  48. Take Home Messages for CDI • Metronidazole: no longer routinely recommended for IP • Empiric therapy for ill patients only • Mean time to response: 3 – 5 days • Treat for 10 days for primary or 1st recurrence • Assess for risk of recurrences • Do not perform test of cure assays • Avoid antibiotic treatment in C. difficile colonized pts • Consider FMT after 2nd relapse and in all severe cases

  49. Thank you!

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