1. Clostridioides difficile colitis Update on current treatment
Eben True, MD
Surgeon
Lafayette Surgical Clinic
October 5th, 2019

2. Disclosures
None

3. Goals
Describe the current medical and surgical therapies employed in treating Clostridioides difficile colitis.
Discuss emerging treatments and the evidence for their use.
Discuss patient factors that impact success and failure of treatment.

4. Goals

5. Goals

6. A rose, by another name…

7. Clostridioides difficile
Gram positive rod
Forms spores
Resistant to alcohol based hand cleansers
Can survive gastric acid and reach small bowel and colon
Can be cultured in 2-5% normal population

8. A community of bacteria
One of many, many GI bacteria
species are long-term GI inhabitants and make up the intestinal microbiota
A functional group that assists digestion, immune response, and resistance to outsiders
A dense, normal flora (especially in the colon)
1012 bacteria / gram of stool

9. “There goes the neighborhood”
Factors altering the micro-biome
Proton pump inhibitors
Colonization risk 1.7 – 2.4x normal (QD vs BID)
Antibiotics of any type or duration
Increasing duration is most important factor
Immune suppression
Malnutrition (short chain fatty acids for colon)
Hospitalization !!

10. Transmission Fecal – oral route
Spore formation is induced by a variety of stress stimuli
Can remain viable on contaminated surfaces for more than one month
Colonization proportional to length of stay
13% at 2 weeks, 50% at 4 weeks

11. Prevention Hand washing with soap and water Barrier precautions
Surface sterilization
Bleach
Hydrogen peroxide vapor
Toilet seats
Judicious use of antibiotics
Best EL, et al. Potential for aerosolization of Clostridium difficile after flushing toilets: the role of toilet lids in reducing environmental contamination risk, J Hosp Infection. 2012, 80(1), 1-5

12. Prevention
Anderson DJ, et al., Lancet Infect Dis Aug;18(8): doi: /S (18) Epub 2018 Jun 4.

13. Prevention
Avoid antibiotic overuse / inappropriate use.

14. Impact C. diff rates are increasing Mortality
National Hospital Discharge Survey
2003: 61/100K (nearly double from 1996)
Incidence in 2010: ~500,000 cases
Mortality
15 to 20K / year
Cost of treatment (additional)
Estimated $1 billion / year
$2000 – 5000 per hospitalization, $11K overall
Bakken JS, Borody T, et al. Treating Clostridium difficile Infection with Fecal Microbiota Transplantation, Clin Gastroenterol and Hepatol. 2011

15. Diagnosis Symptoms, clinical suspicion, testing
Diarrhea can present 1 day to 6 weeks after antibiotic administration
3 diarrhea stools daily
Culture methods (colonic tissue or stool)
Slow (24 to 96 hours), labor intensive
Very sensitive and specific
Immunoassay for toxins A or B, A
65-85% sensitive with rapid reporting
False positives and negatives…

16. Diagnosis PCR amplification for toxin B
93% sensitive, 97% specific
Had been the most common method.
Due to high negative predictive value, repeat testing is not recommended for at least 3 days
Can be + without colitis.
Paired toxin and expression studies
Recently adopted at Franciscan
Reduces false positives

17. Diagnosis
Endoscopy
Yellow-tan, raised lesions ranging from a few millimeters to confluent plaques
More severe disease poses a greater risk for perforation during endoscopy

19. Radiographic findings
Increased colonic diameter, luminal narrowing demonstrated with oral contrast, “thumb printing”

20. Pathophysiology

22. Disease severity Non-severe Severe Fulminant
Symptoms of diarrhea, at least 3 BMs / day, and usually less than 6 BMs / day
Abdominal pain but without peritonitis
WBC <15,000
Creatinine < 1.5 x baseline
Severe
6+ BM / day, WBC > 15K, fever, Cr > 1.5 x
Fulminant
Hypotension, MOSF, peritonitis on exam
Kelly CP, LaMont JT. Clostridium difficile: more difficult than ever. NEJM. 2008;359:

23. Conventional Treatment
All Cases: Stop other antibiotics if possible
Non-severe, Initial episode
Vancomycin 125 mg PO QID
Fidaxomicin 200 mg PO BID
Metronidazole 500 mg PO BID
Mean time to symptomatic improvement 3-4 days, majority resolve within 7 days

24. Recurrence Risk increases with each course of therapy
~20% after 1
~40% after 2
~60% after 3
With recurrent disease. Duration of vancomycin is at least 14 days, but extended duration therapy (4 to 6 weeks) should be considered.
Failure of therapy indicated by persistent symptoms

25. Recurrence Fidaxomicin
inhibits bacterial RNA polymerase, bactericidal rather than Vanco / Metro
Lower recurrence rate than Vancomycin (15% vs 25%)
Effective when other antibiotics cannot be held
~90% vs 73%, however this was a subgroup analysis
Louie TJ, et al. Fidaxomicin versus Vancomycin for Clostridium difficile Infection. NEJM, 2011; 364:
Cornely OA, et al. Fidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double-blind, non-inferiority, randomised controlled trial The Lancet Infectious Diseases, 2012(12)4, ,

26. Conventional Treatment
First recurrence
Vanco 125 mg QID x 14 days, then BID x 1 w, then daily 1 w, then every h x 2-8 w.
Fidaxomicin 200 mg PO BID
Standard Vanco QID if Metro of Fidaxo prior
Second Recurrence
As above
Vanco 125 mg PO QID x 10 d, then Rifamixin 400mg PO TID x 20 d

27. Conventional Treatment
Severe infection
M 500mg IV TID
V 125mg PO QID or 500 mg PR Q6 hours
Fidaxomicin as prior
Obtain early surgical consultation

28. Conventional Treatment
Fulminant colitis
Colectomy
Mortality rate is variable
WBC > 50K or Lactic acid > 5 mmol/L = 75%
Surgical management reduces mortality by half
Age < 70, WBC < 30K, no respiratory failure = 0%
Sailhammer EA, et al. Fulminant Clostridium difficile colitis: patterns of care and predictors of mortality Arch Surg May;144(5):433-9;

29. Colectomy considerations
The colonic wall is weakned and may rupture if not handled carefully
Sparing segments not advised as mucosal involvement may still be present
Consider a decompression tube pre-op

30. Minimally invasive option?
Consecutive case series
42 patients
Laparoscopic diverting ileostomy performed in 83% of patients.
Intra-operative lavage and post-operative colonic vancomycin administered (Q6 hours)
Mortality 19%, compared to same center mortality for colectomy (50%)
Neal MD, et al. Diverting loop ileostomy and colonic lavage: an alternative to total abdominal colectomy for the treatment of severe, complicated Clostridium difficile associated disease. Ann Surg Sep;254(3):423-7

31. Balancing fecal flora
Many oral microbial therapies have been attempted
“Probiotics” have shown improvements in frequency of recurrence.
Long-term abx may still be needed for other illness. These are destructive to the probiotic.
May have no impact on initial cure rates
No firm data on their preventative utility

32. Balancing fecal flora

33. State of the art therapy…

34. Fecal “bacteriotherapy”
Also called fecal microbiota therapy (FMT)
Dr Ben Eiseman, 1958
VA hospital in Denver
4 patients with fulminant pseudomembranous colitis treated with fecal retention enema
“Immediate and dramatic” response
Eiseman B, Silen W, et al. Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis. Surgery. 1958;44:

35. FMT re-emerges
1988: First confirmed case of C diff infection treated with FMT
Systematic review performed in 2011
317 patients in 27 series (1-65 patients)
Resolution rate : % (average 92%)
Methods varied (NJ, NG, enema, colonoscopy)
Gough E, Shaikh H, Manges AR. Systematic review of intestinal microbiota transplantation (fecal bacteriotherapy) for recurrent Clostridium difficile infection, Clin Infec Dis. 2011:53;

36. Randomized-controlled trial
Dutch study, N=51
3 treatment groups randomized, open label
81% success with one infusion, 93% overall
Vancomycin 31% success, Lavage 23% (p <0.001)
Van Nood E, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. NEJM 368;5:407145

37. Further details of Dutch study
Further enrollment was halted because FMT was clearly more effective
16 patients received stool infusion via a naso-duodenal tube
Pooled donor feces were banked after initial screening for communicable disease
31% were inpatients at enrollment
All ICU patients or those who had received a vasopressor were exluded

38. Further details of Dutch study
Diversity of fecal flora was measured before and after treatment in 9 patients
Simpson reciprocal index
Donor stool had broadest diversity
Patient pretreatment index was significantly lower
Post-treatment index was comparable to normal donors 2 weeks post treatment

39. FMT in Peoria, IL
Departments of Medicine (GI, ID) and Surgery cooperated for 5-10 years prior to a IRB approved research protocol
Referral of patients with recurrent infection unresponsive to multiple courses of therapy
Administration of donor fecal microbiota via colonoscopy +/- retention enema

40. Methods Retrospective review Data obtained 1/2007 to 12/2012
Single institution, 2 surgeons
Review of data IRB approved
Data obtained
Age at Dx
Duration of symptoms
Outpatient, Inpatient, or ICU setting
Comorbidities and Physiologic data at Dx

41. Methods Standard osmotic bowel prep
Colonoscopy, typically to the cecum unless not tolerated
Distribution of strained solution of donor feces on scope withdrawal
Donors were screened with health questionnaire, policy approved by hospital safety committee and infection control

42. Results 40 patients, Mean age 71 y/o (27 – 90) 25 women (62.5%)
Mean 111 days from Dx to Tx
28 (70%) had resolution of symptoms after 1 or 2 treatments
8 (20%) were lost to follow up or elected to not have further treatment, evenly divided
4 (10%) required colectomy for worsening disease, 2 subsequent mortalities

43. Results 1 Tx = 40 2nd Tx = 13 (32.5%) Colectomy = 4 (10%)
Lost to f/u = 3
Dropped out = 2
Success = 18 (45%)
Lost to f/u = 1
Dropped out = 1
3rd Tx = 1 (2.5%)
Success = 10 (25%)

44. Results Mean length of follow up = 39 days
Average volume of transplant ~650 ml
Average time to 2nd Tx = 18 days
1st treatment success = 45%
Overall success = 70%

45. A difference in populations
ICU patients 7/40 (17.5%)
Success 29%
Mortality 43%
Inpatients 12/40 (30 %)
Success 75%
Mortality 25%
Outpatients 21/40 (52.5%)
Success 81%
Mortality 0%

46. ICU patients are sick ICU patients N= 7 WBC median = 23K (17 – 49K)
Success after 1 Tx 2/7 (29%)
Care withdrawn after 1 Tx 1/7 (14%)
Colectomy after 1 Tx 4/7 (57%)
2 mortalities after colectomy
WBC median = 23K (17 – 49K)
Albumin median = 1.8 (1.4 – 3)
Temp median = 36 (35-37)
43% mortality rate

47. Significant factors in the ICU
Failure rate significantly higher (p= )
Temperature significantly lower (p= )
WBC significantly higher (p= )
Albumin lower (p= , approaching significance)

48. Differences from the Dutch
Lower than expected success rate
70% overall
This likely reflects 2 factors:
Inclusion of patients that were excluded in the Dutch trial (all ICU patients)
Loss of follow up in outpatients, a population with a greater ratio of success

49. FMT Meta-analysis Risks Most common complaints after treatment:
Death 3.5%
Infection 2.5%
IBD 0.6%
Most common complaints after treatment:
Diarrhea
Bloating
Nausea
Abdominal pain

50. Recipient Criteria Have failed treatment for 2nd recurrence
Cessation of other antibiotics is preferred
No current immune suppressive therapy
No active HIV infection

51. Criteria for donors No acute or chronic diarrheal illness
No h/o IBD, IBS-D, or GI malignancy
No antibiotic / immunosuppressive / chemotherapeutic use in 3 months
Must be otherwise healthy
No recent tattoos or body piercings. No illicit drug use, h/o incarceration… etc etc

52. The government will fix everything… ?
Feces: not clean, not uniformly produced
The FDA considered stool a drug in 2012.
Treatment allowed under 1 of 2 conditions.
Treatment performed as research must undergo IRB approval
An investigational new drug application and protocol has been received and approved

53. What are the implications
FMT is not available outside of strictly regulated research protocols
Extra measures must be taken to assure patient safety and protect MDs / institutions
What is the best way to proceed?
Who will take on the extra cost?

54. Donation procedure Osmotic laxative the night before
Deliver sample in air-tight container within 6-24 hours
All handling of stool should involve mask, protective gown, gloves
Prepare (under a ventilation hood) by blending with saline or milk, then strain

55. Donor testing
May be truncated in the case of intimate partners. The patient’s health and rate of decline should be considered as well
C diff toxin B PCR - Culture and Smear
Giardia Ag - Cryptosporidium Ag
O&P microscopy - H pylori Ag
HIV ½ - Anit HAV IgM
HBSAg - HBCore Ab (IgG/M)
Anti HBS - Anti HCV
RPR

56. Sticky situations Funding for donor testing is inconsistent
Patients may not have a willing or suitable donor
Members of the research team may be screened periodically. Who and how often?
When does the research phase end?
How can stool be standardized for evaluation as a drug?

57. Future directions in research
Designer stool substitutes
RePOOPulate or Sham-poo?
Non-toxigenic C diff strain administration
Reduced recurrent infection rates (30 vs 11%) JAMA May;313(17):
Targeted antibody therapy
C diff toxin B monoclonal Ab (bezlotoxumab)
FDA approved in 2016 to reduce recurrent infection rate in patients undergoing repeat abx.

58. Conclusions
Clostridium difficile infection and subsequent colitis presents in a wide range of disease severity.
Prevention is paramount.
Early surgical consultation, especially severe and fulminant colitis, is important and improves overall mortality

59. Conclusions
Successful treatment of recurrent CDI with FMT depends on severity of disease
Though antecdotal success in severe disease is reported, it is likely a small proportion
Patients who fail FMT and are difficult surgical candidates have a high rate of mortality

60. Thank You