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
Diagnostic methods and clinical interpretation of laboratory results
Treatment options and updates

3. 1. Importance of C. difficile Infection
Leading cause of HCA diarrhea >72 hrs IP
HA rates: /100,000 patient days
/100,000
/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 % 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/ /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. Entamoeba Histolytica Yersina Enterocolitica
GPMP results so far
Analysis of 500 patient results
#1 pathogen C. difficile 12% (insert table here)
Negative
394
Indeterminate 1
C.difficile
63​
Campylobacter 16
Salmonella  7
​​Norovirus GI ​6
Norovirus GII 3
Entamoeba Histolytica
Yersina Enterocolitica
ECOLI  0157
Adenovirus 2
Rotavirus 2​
STEC stx1/stx2
ETEC LT/ST
Shigella 
​Salmonella ​1
Giardia

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. Severity Criteria Treatment Comment Mild-to-moderate disease
Diarrhea plus any additional signs or symptoms not meeting severe or complicated criteria
Metronidazole 500mg orally three times a day for 10 days. If unable to take metronidazole, vancomycin 125 mg orally four times a day for 10 days
If no improvement in 5–7 days, consider change to vancomycin at standard dose (vancomycin 125mg four times a day for 10 days)
Severe disease
Serum albumin <3g/dl plus ONE of the following: WBC ≥15,000 cells/mm3, Abdominal tenderness
Vancomycin 125 mg orally four times a day for 10 days
Severe and complicated disease
Any of the following attributable to CDI: Admission to intensive care unit for CDI Hypotension with or without required use of vasopressors Fever ≥38.5 °C  Ileus or significant abdominal distention  Mental status changes  WBC ≥35,000 cells/mm3 or <2,000 cells/mm3 Serum lactate levels >2.2 mmol/l  End organ failure (mechanical ventilation, renal failure, etc.)
Vancomycin 500 mg orally four times a day and metronidazole 500 mg IV every 8 h, and vancomycin per rectum (vancomycin 500 mg in 500 ml saline as enema) four times a day
Surgical consultation suggested
Recurrent CDI
Recurrent CDI within 8 weeks of completion of therapy
Repeat metronidazole or vancomycin pulse regimen
Consider FMT after 3 recurrences
CDI, Clostridium difficile infection; FMT, fecal microbiota transplant; IV, intravenous; WBC, white blood cell.

13. 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?

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. ?? 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

16. 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??

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

18. 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?

19. 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??

20. 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

21. 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?

22. 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
Wenisch and colleagues from Austria conducted a hospital-based, prospective, cohort study involving 250 patients with mild CDI.
All pts were able to take oral medication. Choice of regimen was at the discretion of treating physician.
The study is limited by its nonrandomized design. However, the findings support current guidelines that advocate oral treatment for CDI.
Worse outcomes with IV metronidazole may be explained by insufficient gut drug levels following infusion.
Confirmatory trials are definitely needed.

23. 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 200 mg 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

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

25. Recurrent CDI Mechanism Risk Factors Rates of recurrence
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

26. 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

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

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

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

30. IPS Liverpool 29th September 2015
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

31. IPS Liverpool 29th September 2015
Referral to MM
Sent: Friday, December 23, 2016, 10:41 AM To: Dr Christine Lee Subject: 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

32. How Does FMT Work? Mechanism not yet understood Recurrent CDI FMT:
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);

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

34. IPS Liverpool 29th September 2015

35. FMT Donor Screening No standardized 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

36. IPS Liverpool 29th September 2015

37. 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

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

39. IPS Liverpool 29th September 2015
Microbiota Diversity
IPS Liverpool 29th September 2015

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

41. Efficacy and safety of FMT: 6 Randomized Controlled Trials
Van Nood20
Cammarota21
Youngster22
Lee23
Kelly24
Hota25
No patients1 16 20
178 22
Route of administration
ND2 tube
colonoscopy
10(NG3)
10 (colonoscopy4)
enema
No. of FMTs/response rate (%)
1(81)
2(93.7)
1 (65)
2 (90)
1 - NG (60)
1 - colonosc (80)
2 via NG/NG
(80)
2 via colonos & NG
(100)5
1(55)
2 (84)
1 (91)
1 (41.7)6
FMT type
fresh
frozen
fresh & frozen
Follow-up (weeks) 10 24 8 13
1no of patients treated with FMT 2ND = nasoduodenal 3NG = nasogastric 4colonos = colonoscopy
52nd FMT via NG only FMT for acute episode of rCDI

42. 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.

43. 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

44. IPS Liverpool 29th September 2015
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

45. 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

46. IPS Liverpool 29th September 2015
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 hrs before. Refractory cases 6 hr.
Referral to OPAT or Dr Christine Lee MM IH
IPS Liverpool 29th September 2015

47. IPS Liverpool 29th September 2015
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

48. IPS Liverpool 29th September 2015
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

49. 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

50. Thank you!