C. difficile prevention

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C. difficile prevention treatment
Probiotics, antibiotics fecal microbiota
transplantation The scoop on therapeutic poop
Monika Fischer, MD, MSCR Assistant Professor of
Clinical Medicine
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Disclosure

• No conflict of interest

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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

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Beginning of 2000 Epidemic strain of C. difficile

• US rates hospital discharges with CDI doubled
  between 2000 and 2008
• Increased need for ICU stay and prolonged
  antibiotic courses to clear infection
• High colectomy rates (10)
• High case mortality 7500/year (10-fold increase
  since 1999)
• Refractory disease in low risk populations

.
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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

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C. difficile infectious inoculum is 10 spores

Poutanen SM et al. CMAJ.
July 6,2004171(1).
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Host factors

• Age 65 year
• 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 gt 50
  colonization rate
• Previous CDI

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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
• lt 5 chance for positive test
• Routine screening in hospitalized patients
  without diarrhea is not recommended

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Hospital-based infection control program

• Antibiotic stewardship
• Contact precautions should be maintained at a
  minimum until the resolution of the diarrhea
• Private rooms
• Hand hygiene soap (preferably 4 chlorhexidine)
  water. Alcohol based antiseptic does not kill
  C.diff spores!
• Barrier precautions (gloves gowns)

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Prevention infection control

• Single use disposable equipment
• Environmental disinfection with10 bleach (5,000
  p.p.m. chlorine) for at least 10 minutes
• Infection control bundle decreased CDI hospital
  rates by 33 (7.2/1000 to 4.8/1000)

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Prevention Probiotics

• Annals 2012 SER and Meta-analysis of 20 trials
  Probiotics given for the duration of the
  antibiotic therapy or up to 2 weeks after reduced
  the incidence of CDI by 66
• No difference in outcome
• Between species Bifidobacterium, Lactobacillus,
  Saccharomyces, or Streptococcus
• Single species vs. mixture
• Adults vs. children
• Lower or higher doses (lt10 billion CFU/d vs.10
  billion CFU/d)

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Treatment 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

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Treatment antibiotics

• Patients with mild-to-moderate CDI should be
  treated with metronidazole 500 mg po tid for 10
  days
• Patients with severe CDI should be treated with
  vancomycin 125 mg po qid for 10 days
• Failure to respond to metronidazole therapy
  within 5-7 days should prompt change to
  vancomycin

ACG guidelines 2013
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Patients with ileostomy, Hartmans pouch, or
colon diversion

• Vancomycin via enema should be included in the
  treatment
• Oral vancomycin cant reach the disconnected
  segments
• Metronidazole as adjunctive therapy colonic
  excretion is high across the inflamed mucosa but
  drops dramatically once mucosa starts to heal

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CDI severity

• Mild-to-moderate diarrhea any other
  sign/symptom - not meeting criteria for severe
• Severe serum albuminlt 3g/dl plus one of the
  following
• WBC 15,000
• Abdominal tenderness

ACG guidelines 2013
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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 gt 2.2 mmol/L
• End organ failure

ACG guidelines 2013
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Severe and Complicated CDI

• Vancomycin 500 mg po qid plus metronidazole 500
  mg iv q 8 hrs, and vancomycin per rectum (500 mg
  in 500ml saline as enema) qid (patients with
  ileus)
• Consult surgery colectomy vs. loop ileostomy
  with lavage and vancomycin flushes
• Fidaxomicin po and tigecycline iv.
• ((Fecal transplant?))

ACG guidelines 2013
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Special situations

• Pregnancy and breastfeeding Oral Vancomycin
• IBD
• All patients with IBD flare need testing for
  c.diff empirical therapy
• Highest risk with corticosteroid use gt 3-fold
• Reduced dosing of corticosteroids
• Immunosuppression can be maintained but
  escalation should be avoided
• Initiation of anti-TNF 72-hrs after starting
  therapy for CDI
• C. diff can cause enteritis and pouchitis!

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Treatment of Recurrent CDI
ACG guidelines 2013

• Repeat metronidazole if the first epidose was
  treated with metronidazole
• Treat with vancomycin pulse regimen for severe or
  if the first episode was treated with vanco
• Vancomycin 125 mg po qid for 10 days followed by
  125 mg every 3 days for 10 doses
• Consider FMT for the third recurrence

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Recurrent C. difficile infection

• 25 of patients have a recurrence after the
  initial treatment
• Patient with first recurrence have a 35-45
  chance for second recurrence
• With subsequent recurrence risk gt 50
• Antibiotics are not very helpful

Kelly and Lamont. NEJM 2008
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After emergence of BI/NAP1/027 high failure rates
with metronidazole and high recurrence rates with
both metronidazole and vancomycin
Aslam S. et al. Lancet Infec.Dis. 2005. 5549-557
(pooled results from 25 studies)
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Fidaxomicin

• New bacteriocidal antibiotic
• Poorly absorbed narrow-spectrum macrolide
• FDA approval for CDI in 2011

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Fidaxomicin vs.Vancomycin
Louie TJ. NEJM. 2011364422-31
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Vancomycin vs. fidaxomicin for the first
recurrence of CDI
20 recurrence
36 recurrence
Cornelly OA. Clin Infect
Dis. 2012. 55 154-61
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The New Kid on the block Stool

• FMT is placement of suspension of fresh stool
  harvested from healthy individual into the
  gastrointestinal tract of an individual with CDI
• Through standard colonoscopy
• Rectal enema
• NJ and NG tube
• Alternative therapy, but by no means new

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A 1,700-year-old method

• 4th century China human fecal suspension by
  mouth yellow soup for food poisoning, severe
  diarrhea

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Fecal transplantation in veterinary medicine
since the 17th century

• Transfaunation
• Horses with diarrhea per rectum
• Cattle per os as rumen

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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

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Explosion of FMT case studies since 2010

• gt 500 cases reported with 92 success rate with
  the first treatment and up to 98 if a second
  infusion was necessary
• Longest follow up 17 months of 77 pts zero
  recurrence without antibiotics (all recurrences
  related to antibiotic use 8/30)
• 97 of patients would undergo another FMT if
  needed
• 57 voted for FMT as their preferred first
  treatment option

Brandt, L. ACG. 2012
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• Duodenal infusion of donor feces after vancomycin
  for 4 days and bowel lavage

• Vancomycin therapy for 14 days plus bowel lavage
  on day 4-5

• Vancomycin therapy for 14 days

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Nood et al NEJM. Jan. 2013
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Microbiota diversity increases after stool
transplant
Nood NEJM 2013
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Who should be treated with FMT?

• After 3 episodes or after failure of vancomycin
  pulse regimen (ACG guidelines)
• L. Brandt recommendations
• First line therapy in severely ill patients
• FMT may be preferred for the first episode of CDI
  because antibiotic perturbs the microbiota and
  may lead to antibiotic resistance

Brandt, L. JCGE. 2011
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Risks of FMT

• Colonoscopic perforation
• Transmission of infections and other diseases
• Long-term risk?
• Increased incidence of autoimmune conditions 4
  out of 77 patients developed peripheral
  neuropathy, Sj?gren syndrome, RA, ITP within
  median 17 months f/u

Brandt LJ. ACG. 20121071079-1087
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Donor selection

• Intimate contacts, family members to mitigate
  risk of transmissible diseases
• But, results with standardized or universal
  donors are similarly excellent with fresh or
  frozen/thawed preparations

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Donor screening

• Stool
• Bacterial culture
• Ova parasites including Giardia,
  Cryptosporidium, Cyclospora, Isospora
• C.difficile
• H. pylori
• Blood
• Hepatitis A, B, C
• HIV 1/2
• Syphilis

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Donor selection

• Exclusion criteria
• IBD, IBS, functional diarrhea or constipation,
  h/o GI malignancy
• Antibiotic use within 3 months
• Systemic chemotherapy or immunosuppression within
  1 year
• Known HIV, hepatitis B and C, illicit drug use,
  incarceration, tattoo/piercing within 6 months

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Donors badge
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Which route of administration is the best?
Nasogastric Nasoenteric tube EGD Quick Convenient Inexpensive Avoid colonoscopy Fecal enemas Easy to administer Cheap Can be performed at home Via colonoscopy Highest patient acceptance Ability to assess disease severity and colonic mucosa

• SER 1 colonoscopy and enema (required repeated
  infusions) with superior cure rate gt 85 vs.
  76 upper GI route
• SER 2 colonoscopy superior 93 vs. 85
  nasogastric tube

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FMT via colonoscopy at IU
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FMT at IU Hospital

• Patient preps for colonoscopy
• Stops vancomycin 36-48 hrs before FMT
• Fresh stool (not older than 6 hrs) emulsified in
  the endo suite and infused into the terminal
  ileum or right colon
• Patient receives Imodium and observed for 2-3
  hrs.
• Environmental cleaning at home
• CPT code 44705

Bakken J, Borody T, Brandt L et al. Treating
Clostridium difficile Infection With Fecal
Microbiota Transplantation. Clinical
Gastroenterology and Hepatology, December 2011,
9(12)1044-1049.
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Why and how does FMT work?
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Borody, T. J. Khoruts, A. (2011) Nat. Rev.
Gastroenterol. Hepatol.
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Mechanism of action

• FMT is introduction of a complete, stable
  community of gut-organisms to repair or replace
  the disrupted native microbiota
• Reestablishment of the host defense against C.
  difficile
• Engraftment of the donor microbiota is durable

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Bacterial fingerprints of the donor and recipient
stool before and after FMT
Khoruts A. J Clin Gastroenterol. 201044354-360
Donor Day 0 Patient Day 14 Patient Day 33
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Probiotics in the treatment and recurrence
prophylaxis of CDI

• Limited evidence for adjunct probiotics to reduce
  risk of recurrence
• S. boulardii showed efficacy in few trials
  reducing recurrence rate to 35 vs. 65 but only
  in patients on high dose vancomycin
• Why probiotics dont work?
• Insufficient CFU count
• Not the right species or mixture
• Wrong media (milk) to culture probiotics

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Animal experiment murine model of C.
difficile colitis

• Mice treated with Clindamycin for 7 days
• Infected with C. difficile BI/NAP1/027 from
  hospitalized patients
• Mice developed severe colitis
• Dysbiosis
• Reduced diversity
• Reduced Bacteriodetes and Firmicutes
• Increased opportunistic pathogens (Klebsiella, E.
  coli, Proteus mirabilis, Enterococcus faecalis)
• Up-regulated pro-inflammatory genes

Lawley et al. PLOS 2012
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• 5. Mice treated with vancomycin
• Suppression of C. difficile shedding
• 6. Relapse upon cessation of therapy
• 7. FMT using healthy mice stool per os
• Durable suppression of C. difficile shedding for
  several months resolve disease and
  contagiousness

Lawley PLOS 2012
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Targeted bacteriotherapy

• Instead of stool from healthy mice
• A mixture of six phylogenetically diverse
  bacterial species including obligate and
  facultative anaerobes Bacteriodetes and
  Firmicutes cured CDI in mice with severe colitis
  infected with BI/NAP1/027

Lawley, T. 2012
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Stool substitute to rePOOPulate the gut

• Made from purified intestinal bacterial cultures
  derived from a healthy donor after recovering 33
  isolates using Robogut

Petrof, EO. Microbiome 2013.
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Future ?

• Custom designed pill of selected micro-organisms
  to restore the balance of the microbiota or
  correct a deficiency of a specific commensal
  organism curing a disease or reversing
  a metabolic condition

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Summary of FMT

• FMT is a simple, acceptable and currently the
  most efficacious treatment for recurrent CDI---
  may play a role in the treatment of variety of GI
  and non-GI diseases
• FMT via the upper tract seems to be less
  efficacious than via the lower tract
• Long-term safety remains unknown
• The Future Artificial stool or targeted
  bacteriotherapy

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References

• Surawicz, Ch. Guidelines for Diagnosis,
  Treatment, and Prevention of Clostridium difficle
  infections. AJG. 2013
• Johnston, B. Probiotics for the prevention of
  Clostridium Difficile-Associated Diarrhea.
  Annals. 2012
• Van Nood, E. Duodenal Infusion of Donor Feces for
  Recurrent Clostridium difficile. NEJM. 2013

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References

• Brandt, L. Intestinal Microbiota and the Role of
  Fecal Microbiota Transplant in the Treatment of
  C. difficile Infection. AJG. 2013
• Bakken, J. Treating Clostridium difficile
  Infection with Fecal Microbiota Transplantation
  (the Fecal Microbiota Transplantation Workgroup).
  CGH. 2011
• Brandt, L. An overview of fecal microbiota
  transplantation. Gastrointest. Endosc. 2013