1. C. difficile prevention & treatment
Monika Fischer, MD, MSCR
Assistant Professor of Clinical Medicine

2. Disclosure Rebiotix, Consultant
Openbiome, Volunteer scientific advisor

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
The traditional medical school fact that C. difficile is pseudo mebranous colitis needs revision

4. Epidemic of CDI
Lessa NEJM 2015
2011: 500,000 cases and 29,000 associated deaths in the US
66% health-care related
86% of community onset patients had a doctor’s or dentist visit within 12 weeks of CDI diagnosis

5. C. difficile – the leading cause of nosocomial infections
1% of all hospital stays

6. An urgent public health threat
No longer limited to nosocomial infections or to the elderly
Significant morbidity and mortality in healthy ambulatory patients with no antibiotic exposure
cases per year
annual death
$ 3 billion excess cost
HCUP Statistical Brief #

7. Epidemic strain of C. difficile: BI/NAP1/027
Beginning of 2000
Epidemic strain of C. difficile: BI/NAP1/027
31% of health-care and 19% of community associated cases
Increased need for ICU stay and prolonged antibiotic courses to clear infection
High colectomy rates (10%)
High case mortality: 10-fold increase since 1999
Refractory disease in low risk populations .
Beginning of 2000, hyper virulent strains emerged appeared to be linked to increased use of fluoroquinolones and cephalopsporins.
The epidemic strains have caused more severe and refractory colitis, increased the need for ICU stay and required longer Abx therapy. We have witnessed an unprecedented colectomy rate and case mortality. Populations previously considered to be low risk are increasingly becoming afflicted with refractory c. diff. The increase in incidence and severity of CDI is largely attributed to the emergence of a new strain, designated restriction endonuclease analysis type BI, North American pulsed-field electrophoresis type 1 (NAP1), PRC ribotype 027 - 7

8. 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
The mechanism of action of these hypervirulent strains characterized and BI/NAP1/027 has been shown to the be result Several characteristics found in BI/NAP1/027 contribute to its hypervirulence:
Polymorphysm in an important toxin production downregulatory gene, tcdC resulting in 18 fold increased toxin production c/w non-epidemic strains
Presence of the gene producing binary toxin: toxin with dual function, enzymatic component and membrane altering component/transport component which facilitates translocation of the bacterria into the cells
high-level fluroquinolone resistance: explain why this strain is selected over other non-epidemic strains of c. diff in the setting of fluoroquinolone use
But, there are other reasons for the c. diff epidemic

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

10. Host risk factors Age ≥ 65 year Previous CDI 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
Obesity (↑ 20%/BMI unit)
H/o intraabdominal surgery > 3 fold
More than half of C. diff burden originates from healthcare facilities. With each additional day of hospitalization the risk of CDI increases. It is estimated that 13% of patients get colonized with c. diff during a 1-2 week hospital stay while more than 50% get colonized if treated in the hospital for more than 4 weeks
Bishara. Clin.Inf.Dis 2013

11. Immunocompromised host
CDI incidence among SOT patients:
16% kidney tpx, 13% liver tpx, 23% in lung tpx
Highest risk within 6 months of tpx
Lung tpx: 7% during initial hospitalization
Lung tpx: 54% within 6 months of tpx
40% of SOT patients- no recent Abx exposure
Lee. J. Heart and Lung Transpl. 2013

12. Diagnosis

13. Diagnostic tests
Only stools from patients with diarrhea should be tested
Nucleic acid amplification tests (PCR) are superior to toxins A+B EIA testing
GDH screening with subsequent toxin A+B EIA can be used but sensitivity is lower than PCR
Repeat testing is discouraged (<5% chance for positive after 1 negative test)
Testing for cure is not recommended
ACG guidelines 2013

14. 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

15. 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

16. Therapy

17. 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
Maintenance of oral or enteral feeding is important in the absence of ileus or significant abdominal distention as fermentable carbohydrates are crucial for colonic microbiota and contribute to restoration of microbial communities. In addition to fluid resuscitation and electrolyte replacement ,we should not forget about DVT prophylaxis: paitent with C. diff ( especially with severe cdi) at at high risk for thromboembolic events similarly to IBD patients. The use of antimotility agents was discouraged in the past due to concerns of toxic megacolon. A recent summary to studies concluded that anti-diarrheals do not cause harm as long as they are used on conjunction with c. diff therapy

18. 2013 ACG guidelines for CDI Rx

19. Severe and Complicated CDI
Surgery should be considered
Hypotension requiring vasopressor tx
Sepsis
Organ dysfunction
Mental status changes
WBC≥50.000
lactate≥5
Failure to respond to medical tx after 5 days
ACG guidelines 2013

20. Surgical tx for complicated C. diff
Mortality rates of 35-80% associated with subtotal colectomy
Early surgery is associated with increased survival
Loop ileostomy with intraoperative PEG lavage and postoperative antegrade colonic vancomycin flushes → 90% preserved colon and ↓mortality 19% (vs 50%)
Neal. Annals of Surg. 2011

21. Recurrent C. difficile 1st 2nd 3rd Infection 20 - 30% 40 - 50%%
3rd
Percent
McFarland et al, Am J Gastroenterol, 2002;97:1769; Pepin et al Clin Infect Dis2005:40:159

22. First episode of recurrent CDI is not trivial
C. difficile infection
Incidence
Mortality
Healthcare acquired
20.9%
9.3%
Community acquired
13.5%
1.3%
Even the first recurrence should not be taken lighlty: nearly 10% of those who have health care acquired CDI DIE during the first recurrence.
Lessa et al, NEJM 2015: 372: 825; data from 2011

23. After emergence of BI/NAP1/027 high failure rates with MZ and high recurrence rates with both MZ and vanco
The published treatment rates with meteronidazole and vacomycin were similar before After 2000, the treatment failure rate rose to 18% with metronidazole while remained 3% with vanco.
This rise in treatment failure coincided with the dramatic increase in CDI incidence and the emergence of the epidemic strain NAP1. These issues resulted in an ongoing debate about whether vanco is superior to metronidazole and should therefore be used as first-line despite the concerns about the higher cost and the possibly increased nosocomial vancomycin resistance, particulary VCE.
Relapses occur at 25% of patients that are adeQUATELY treated with these agents. Relapses usually occur within the first several days after the completion of antimicrobial therapy
Aslam S. et al. Lancet Infec.Dis : (pooled results from 25 studies)

24. Louie TJ. NEJM. 2011; Mullane. Clin. Inf. Dis. 2011
Fidaxomicin vs. Vanco
Nonhypervirulent subgroup
Fidaxo recurrence rate 8% vs 25% with vanco
Fidaxo is superior to vanco (90% vs 80%) in patients with concurrent systemic antibiotic use with CDI treatment
Louie TJ. NEJM. 2011; Mullane. Clin. Inf. Dis. 2011

25. Fidaxomicin is superior to vanco for the 1st recurrence
20%
Fidaxo $ 2800/10 days
36%
Vanco capsules $ 680
Recurrence of Clostridium difficile infection (CDI) occurs in approximately 25% of successfully treated patients. Two phase 3 randomized, double-blind trials were conducted at 154 sites in the United States, Canada, and Europe to compare fidaxomicin vs vancomycin in treating CDI. Patients with CDI received fidaxomicin 200 mg twice daily or vancomycin 125 mg 4 times daily for 10 days. The primary end point was clinical cure of CDI at end of treatment, and a secondary end point was recurrence during the 28 days following clinical cure. In all, 1164 subjects were enrolled, of which a subgroup of 128 in the per-protocol population had another recent episode of CDI prior to the CDI diagnosis at study enrollment. In the analysis of this subgroup, initial response to therapy was similar for both drugs (>90% cure). However, recurrence within 28 days occurred in 35.5% of patients treated with vancomycin and 19.7% of patients treated with fidaxomicin
Vanco compounded $
MZ $22
Cornelly OA. Clin Infect Dis :

26. ACG guidelines for recurrent CDI 2013

27. Antibody and Vaccine
Fully human monoclonal antibodies against C. diff toxin A and B (Merck)
- single infusion (10mg/kg)
200 pts, on vanco for active CDI
Recurrence w/in 84 days
Placebo: 25%
Antibody: 7%
Pts with prior recurrence: 38% vs 7%
Vaccines (C. diff toxoid)
Sanofi started late-stage trials ( pts) in August Lowy NEJM 2010

28. Non-toxigenic C. difficile (NTCD) Strain VP20261
Phase II trial (Viropharma)
CDI patients on vanco
Placebo (n=43)
NTCD (n=125) for 7-14 days
69% colonized
2% CDI recurrence in colonized pts

29. Johnson, Annals of Internal Med 2012; Allen. Lancet. 2013
Probiotics
Not useful for tx of CDI
Weak evidence supports Saccharomyces boulardii to decrease risk of recurrence
Role in CDI prevention
Meta-analysis of 20 trials and 3818 pts CDI
↓ 66% reduction ↕
---Large RTC > 1400 patients in each arm comparing Lactobacilli, Bifidobacteria to placebo—no effect on risk of CDI
Johnson, Annals of Internal Med 2012; Allen. Lancet. 2013

30. Fecal microbiota transplant

31. Fecal microbiota transplantation
Placement of suspension of fresh (or frozen) stool harvested from healthy individual into the gastrointestinal tract of the recipient
As is turns out , FMT is a great and highly efficacious alternative therapy BUT not certainly not new

32. Rational for using FMT in recurrent CDI
Avoid prolonged courses of antibiotics
Re-establish diversity of gut microbiota
restore “colonization resistance”
reverse metabolic changes promoting C. diff

33. Mouse model for C. difficile associated dysbiosis and successful bacteriotherapy
NAP1/BI/027
↓butyrate
↓acetate
Mixture of 6 strains
Lawley 2012 PLOS

34. Harnessing Microbiota to Kill a Pathogen: Fixing the microbiota to treat Clostridium difficile infections
Nature 2014

35. Fecal transplant: A 1,700-year-old method
4th century China: Ge Hong, famous
traditional Chinese medicine doctor
prescribed human fecal suspension
by mouth for food poisoning,
severe diarrhea
16th century Ming dinasty: Li Shizhen described using fermented, fresh, or dried poop for treatment of severe diarrhea, pain, fever, vomiting and constipation in the most known book of traditional Chinese medicine “Ben Cao Gang Mu” (Compendium Materia Medica)
The herb doctors called it “yellow soup“
4th century in China, Ge Hong, a well-known traditional Chinese medicine doctor, described the use of human fecal suspension by mouth for patients who had food poisoning or severe diarrhea
in the Ming dynasty of the 16th century, Li Shizhen described a series of prescriptions using fermented fecal solution, fresh fecal suspension, dry feces, or infant feces for effective treatment of abdominal diseases with severe diarrhea, fever, pain, vomiting, and constipation in the most-known book of traditional Chinese medicine, “Ben Cao Gang Mu” (Compendium of Materia Medica). For aesthetic considerations, the herb doctors did not label the fecal suspension by its original name, but called it yellow soup or used other exhilarating names

36. Fecal transplantation in veterinary medicine since the 17th century
Transfaunation
Horses with diarrhea per rectum
Cattle per os as rumen
The definition for transfaunation is a symbiotic fauna (usually mutualistic protozoa) transfer from one host to another.
The first fecal transplantation in humans was performed in 1958 for diarrhea. However, and it has been performed in animals for more than 100 years. For example, veterinarians perform fecal transplantation to treat horses with diarrhea by infusing stool from healthy horses into the rectum of the sick animals, and they administer rumen fluid to cows and alpacas to treat a variety of conditions. The latter application is referred to as transfaunation.
Although, it was found to be very efficacious in last 10 years in multiple case reports, it has been slow to gain acceptance. Besides the undeniable “ ick factor” The reason for this the need to screen donors, lack of reimbursement among providers and patients.

37. 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”
In the modern history“re-establish the balance of nature” within the intestinal flora to correct the disruption caused by antibiotic treatment. They reported “immediate and dramatic” responses and concluded that “this simple yet rational therapeutic method should be given more extensive clinical evaluation.” During the ensuing 50 years, the association between Clostridium difficile infection and pseudomembranous enterocolitis was established, and effective antimicrobial treatments were identified. Despite these advances, C. difficile became the most commonly identified cause of nosocomial infectious diarrhea in the United States. During the past decade, there has been an alarming increase in the incidence and severity of this disorder, with associated increases in mortality and economic cost

38. "Should further clinical experience substantiate the beneficial effect of fecal enemas...the oral administration of pure cultures of these organisms in enteric-coated capsules might be both more aesthetic and more effective"
Ben Eiseman, 1958

39. Use of FMT in recurrent CDI
Multiple systematic and meta analyses show 90% efficacy
Guol APT Sofi Scand J Gastro 2013;
Kassam Am J Gastroenterol Drekonja JAMA 2015
Colonoscopy delivery may be slightly better than NG/NJ delivery
Now, 3 randomized controlled trials
VanNood
Youngster
Cammarota

40. Vancomycin therapy for 14 days
The last impediment is addressed by Nood and colleagues from the Netherlands.
Randomized, controlled but unblinded study where the investigators compared duodenal infusion of donor feces after vancomycin therapy with vancomycin therapy alone vs vancomycin therapy with bowel l
Duodenal infusion of donor feces after vancomycin for 4 days and bowel lavage
Vancomycin therapy for 14 days
Vancomycin therapy for 14 days plus bowel lavage on day 4-5

41. Duodenal Infusion of Donor Feces for recurrent CDI
Study stopped early due to strong results
Van Nood et al, N Engl J Med 2013; 368:407
Pretreatment with vanco 500 mg qid for 4 days then lavage and fmt versus vanco for 14 days and vanco plus bowel lavage
Van Nood et al NEJM 2013; 368:4-7

42. Recurrent CDI: RCT OF FROZEN STOOL
Colonoscopy
NG tube
10 pts
Cure after 1st FMT
8 (80%)
6 (60%)
Cure after 2nd FMT
+ 2, ( 100% )
+ 2, ( 80% )
5 patients were retreated
Overall cure rate 90%
Youngster et al, Clin Infect Dis 2014; 58; 1515

43. Recurrent CDI: RCT OF FMT
Response to:
Colonoscopy after 3 days vancomycin
Vancomycin 10 days and 3 week pulse
FIRST FMT
13/20 (65%)
5/19 (26%)
Multiple FMTs
18/20 (90%)
7 / 20 patients with pseudomembranous colitis
All of failures / deaths (2/20) from CDI had pseudomembranes
Cammarota et al, Alim Pharm Ther 2015:41:835

44. Steps of FMT : How its done
1. Patient selection
2. Stool/donor selection
Patient directed vs. universal
Fresh or frozen
On site preparation vs. stool bank
3. Mode of delivery
Colonoscopy / sigmoidoscopy
Enema
NG/NJ tube
Pill
4. Follow-up

45. Regulation: US
May use to treat C. difficile not responding to standard therapy
Informed consent
State it is investigational
Discuss real and theoretical risks
Theoretical Risks
Autoimmune disease
Metabolic syndrome
IBD flare
Real Risks
Infections
Colonoscopy
Sedation
Aspiration

46. Step 1: Patient Selection
Eligible cases: ACG guidelines 2013
3 or more recurrences with adequate treatment
2 severe episodes requiring hospitalization
Failed Vanco taper / pulse regimen
Make sure it is recurrent CDI and not post infectious IBS
Surawicz et al, Am J Gastro 2013:108;
Debast et al Clin Infect Dis 2014: 20(suppl 2); 1-26

47. Step 2. Patient directed vs. universal donor
Source: family or friend
Source: unrelated donor
Pros:
Patient comfort
Cons:
Multiple tests
Expensive
Delays care
Physician’s time
Unreliable donors
Pros:
Routinely tested, healthy individual- proven donor track
Minimize cost
On site: fresh stool vs frozen stool bank

48. Frozen stool from a bank: OpenBiome ModelH
1 Clinician orders fecal preparations from a stool bank
3 The clinician thaws material and performs FMT
2 Stool bank provides rigorously screened, processed, frozen material
<6% pass rate
Donor Assessment
Stool & Serological Testing
Processing, Monitoring & Re-testing
109-point clinical assessment for transmissible infectious diseases and potentially microbiome-mediated conditions
E.g. IBD, IBS, depression, anxiety, age, obesity, metabolic syndrome, autoimmune diseases and others
Stool testing
C. diff toxin PCR, Ova & Parasites, Isospora, Cyclospora, Giardia EIA; Cryptosporidium EIA; H. pylori Ag, Common enteric pathogens (e.g. Salmonella, Shigella, E. coli, Campylobacter, Vibrio, Norovirus PCR, Adenovirus EIA, Rotovirus EIA, VRE culture, Microsporidium
Serological testing
HIV 1 & 2, HAV, HBV, HCV, HTLV 1 & 2, Treponema pallidum. CBC, LFTs
60-day quarantine procedure
Continuous requalification
Processing controls
Filtering & homogenization
Safety aliquots
Storage & shipping controls
Traceability
16s rRNA (microbiome) sequencing & characterization

49. Proposal was NEVER ENACTED!
FDA correspondence to national stool bank on regulatory status of universally banked stool
Do donors need to be “known” to the physician or patient? No.
March 2014: FDA issued draft guidance proposing that unless stool donors were “known” to the clinician or patient, an IND would be needed
Proposal was NEVER ENACTED!
“to treat patients with C. difficile infection that failed standard therapy an IND is not needed…. Practitioners may obtain their product from any reasonable source”

50. Step 4: Preparation and Follow up
Before FMT, screen for Hep A,B,C, HIV and syphilis
Standard colon prep
Phone calls at 24 hrs, 2 weeks and clinic visit at 3 months
Intermittent diarrhea common, usually resolves
If diarrhea persists, test for C diff
- If positive, repeat FMT or Vanco pulse regimen

51. What if They Need Antibiotics Again?
Reassure: recurrence unlikely post FMT
Suggest the most narrow spectrum antibiotics
Prophylactic Flagyl or Vancomycin unnecessary
- No proven benefit, possible harm
Consider probiotics … but which one?

52. FMT in Severe and Severe /complicated CDI
First use of FMT in patients with PMC in 1958
Multiple case reports- dramatic results
Recent retrospective case series
Some severe data from a recent RCT
Eiseman. Surgery 1958, You Ann Intern Med 2008, Weingarden 2013 CGH, Zainah 2015 Dig Dis Sci, Aroniadis JCG 2015, Jones DDW 2015 Mo 1216
Neemann K, Eichele DD, Smith PW, Bociek R, Akhtari M, Freifeld A. Fecal microbiota transplantation for fulminant Clostridium difficile infection in an allogeneic stem cell transplant patient. Transplant infectious disease : an official journal of the Transplantation Society 2012;14:E161-5.
7. AR, Hamilton MJ, Sadowsky MJ, Khoruts A. Resolution of severe Clostridium difficile infection following sequential fecal microbiota transplantation. J Clin Gastroenterol 2013;47:735-7.
8. Brandt LJ, Borody TJ, Campbell J. Endoscopic fecal microbiota transplantation: "first-line" treatment for severe clostridium difficile infection? J Clin Gastroenterol 2011;45:655-7.
9. Zainah H, Hassan M, Shiekh-Sroujieh L, Hassan S, Alangaden G, Ramesh M. Intestinal microbiota transplantation, a simple and effective treatment for severe and refractory Clostridium difficile infection. Dig Dis Sci 2015;60:181-5.
Eiseman. Surgery 1958, You Ann Intern Med 2008, Weingarden 2013 CGH, Zainah 2015 Dig Dis Sci, Aroniadis JCG 2015, Jones DDW 2015 Mo 1216

53. RCT OF FMT – severe CDI in the colonoscopy group
In Cammarota study, the first 2 pts in the colonoscopy group had pseudomembranes
Initial improvement after FMT but both later died due to CDI-related sepsis
Then, modified protocol to give FMT every 3 days until colitis responded
All subsequent 5 pts were cured (2 pts- 2 FMTs, 2-pts 3 FMTs, 1 pt-4 FMTs)
Cammarota , Alim Pharm Ther 2015:41:835

54. Khoruts described a single patient with fulminant CDI with a dramatic, but unsustained improvement in CDI after a single FMT
Reinitiation of antibiotics against CDI and repeat FMT might be needed for cure in some cases of severe FMT
Weingarden CGH 2013

55. 29 cases, prospective study, inpatients
FMT plus selected use of antibiotics for severe and severe-complicated CDI : Indiana University experience
29 cases, prospective study, inpatients
19 severe/complicated, 10 severe CDI
12 in ICU
7 ARF and hypovolemic/septic
5 toxic megacolon
4 vasopressors
21/29 (73%) pseudomembranous colitis
Cristin mccoy
Fischer ACG 2014 abstract

56. Severe and Severe/Complicated CDI
Vancomycin po/rectal ± metronidazole ≥ 5 days
Colonoscopy / Sigmoidoscopy
Fecal Microbiota Transplantation
Pseudomembranes present
Pseudomembranes absent
Vancomycin 125 mg orally four times a day for 5 days
Clinical observation with no further intervention
Symptomatic resolution
Vancomycin for 5 additional days (10 days total)
Optional FMT as outpatient
Still symptomatic
Fischer ACG 2014

57. Results : FMT and selected use of Vancomycin Indiana University experience
27/29 (93%) complete symptom resolution and discharge from the hospital at 1 month
76% cumulative survival at 3 months
Of the 27pts, 15 (56%) -1FMT, 11 (40%)- 2 FMTs, 1-3 FMTs
Two failures / death
Sepsis, arterial pH 7.1 at FMT
S/P OLT failed 3 FMT, died s/p colectomy
Fischer ACG 2014 abstract

58. Refractory CDI (severe and/or complicated) - efficacy and follow-up
Retrospective series of 17 pts; 8 sites
76% women; 66 yrs. mean age
Results:
Diarrhea resolved or improved in 15/17 (88%) after a single FMT
Overall cure rate 16/17 (94%)
Follow up 11 months
No adverse events related to FMT
Aroniadis et al J Clin Gastro in press 2015

59. Summary FMT very effective for recurrent CDI
Excellent safety profile to date
Patient selection, donor screening, methods and follow up are very important
FMT treatment protocols in severe and severe / complicated CDI is evolving
Repeat FMTs or FMT plus anti-CDI antibiotics may be necessary
What is the role of pseudomembranes
What is the role of endoscopy
RCTs are needed

60. Poop-frozen,pill,synthetic
Frozen fecal material from a universal donor via colonoscopy single center 43 pts 95% success
OpenBiome: screened frozen product– available for internet order
Frozen poop: RCT of 20 pts (via NJ vs colonoscopy) 70% cured with 1 FMT, 90% with 2 FMTs
Poop pills 27 pts 100% cured
Synthetic stool (33 bacterial strains) from a single donor (Repoopulate) 2 patients cured
Hamilton CGH 2012, Youngster Clin Infect Dis 2014 , Louie 2013, Petrof 2013

61. Stool derived & Full spectrum microbiota Synthetic & Probiotics
FMT products
Stool derived & Full spectrum microbiota
Synthetic & Probiotics
Recreates normal GI microbiome - can restore any missing components
Can restore unknown missing components - can be used for multiple indications
There is evidence of durable implantation
No evidence of infection transmission BUT CMV and listeria cases in IC patients
Small number of bacterial components – may fail to supply crucial components
Cannot restore unknown missing components- can be used for specific indication
Some components can implant for variable times
Probiotics can be contaminated in manufacture!
Fatal cases of Mucormycosis, neurotoxigenic C.butyricum, invasive Saccharomyces

62. Stool derived & Full spectrum microbiota
Synthetic & Probiotics
Complex composition - difficult to standardize and define composition
Ongoing need to source from donors
No need for culturing – thereby avoiding "passaging"
Perception of being stool-derived may influence consumers
“ick factor”
Composition is readily defined, reproducible, and standardized
No need for ongoing use of human donors
Repeated culturing changes nature of probiotic mix via “passaging”
The original stool-derived source can be more readily masked.
No “ick factor”

63. Possible Future Indications of FMT
Colonization with MDR organism: VRE, MRSA
IBD and IBS
Diverticulitis, Parkinson’s disease, chronic fatigue syndrome, multiple sclerosis, myoclonus dystonia, obesity, insulin resistance,metabolic syndrome, depression, and autism

64. Safety and ethical considerations
Acute infections
Bacterial, viral, parasitic
Acute allergic reactions
Long-term concerns
How long will the donor microbiota populate the recipient’s colon?
Predisposing the recipient to some diseases that the donor will develop in his/her lifetime?
Are were creating a “microbiomic clone” of the donor?

65. Prevention

66. Hospital-based infection control program
Antibiotic=strongest risk factor for C. diff
Clindamycin, cephalosporins and fluorokinolons pose highest risk
Antibiotic stewardship: can decrease CDI incidence by 60%
Infection control “bundle” (education, early case finding, reinforcement of contact precautions) decreased CDI hospital rates by 33% (7.2/1000 to 4.8/1000) in 1 year
Hospital based infection control program can help to decrease the incidence of c. diff. Antibotic use is the strongest risk factor for c.diff. Any antibiotic can cause CDI but clindamycin, cephalosporins and fluorokinolones pose the highest risk. In one study, antimicrobial stewardship decreased CDI incidence by 60 %.
C. Difficile can be cultured from the surfaces of rooms of asymptomatic patients but to much lesser degree than from the rooms of symptomatic pts. Patients skin surfaces may contain c. diff spores up to 2 weeks after the resolution of the diarrhea---- some institutions use contacts precautions for the entire duration of the hospitalization.
Hand hygiene and is the cornerstone of prevention of nosocomial infections including c.diff.

67. 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

68. Prevention: infection control
Cornerstone of CDI prevention: hand hygiene
Soap (preferably 4% chlorhexidine) & water
Alcohol based antiseptic does not kill C. diff spores!
Barrier precautions (gloves & gowns)
Private rooms
Single use disposable equipment
Environmental disinfection with10% bleach (5,000 p.p.m. chlorine) for at least 10 minutes
In one large prospective study, infection control bundle consisting of education, early case finding, reinforcement of contact precautions decreased hospital c. diff rates by 33%

69. Prevention: infection control
Contact precautions should be maintained at a minimum until the resolution of the diarrhea
C. Difficile can be cultured from the surfaces of rooms of asymptomatic patients but to much lesser degree than from the rooms of symptomatic patients.
Patients skin surfaces may contain c. diff spores up to 2 weeks after the resolution of CDI!
Spores resist desiccation and can survive up to 5 months on hard surfaces.
C. diff
FACTS

70. Thank you