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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 – PowerPoint PPT presentation

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Title: C. difficile prevention


1
C. difficile prevention treatment
Probiotics, antibiotics fecal microbiota
transplantation The scoop on therapeutic poop
Monika Fischer, MD, MSCR Assistant Professor of
Clinical Medicine
2
Disclosure
  • No conflict of interest

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

4
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

.
5
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

6
C. difficile infectious inoculum is 10 spores


Poutanen SM et al. CMAJ.
July 6,2004171(1).
7
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

8
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

9
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)

10
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)

11
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)

12
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

13
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
14
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

15
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
16
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
17
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
18
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!

19
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

20
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
21
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)
22
Fidaxomicin
  • New bacteriocidal antibiotic
  • Poorly absorbed narrow-spectrum macrolide
  • FDA approval for CDI in 2011

23
Fidaxomicin vs.Vancomycin
Louie TJ. NEJM. 2011364422-31
24
Vancomycin vs. fidaxomicin for the first
recurrence of CDI
20 recurrence
36 recurrence
Cornelly OA. Clin Infect
Dis. 2012. 55 154-61
25
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

26
A 1,700-year-old method
  • 4th century China human fecal suspension by
    mouth yellow soup for food poisoning, severe
    diarrhea

27
Fecal transplantation in veterinary medicine
since the 17th century
  • Transfaunation
  • Horses with diarrhea per rectum
  • Cattle per os as rumen

28
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

29
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
30
  • 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

31
15
13
Nood et al NEJM. Jan. 2013
32
Microbiota diversity increases after stool
transplant
Nood NEJM 2013
33
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
34
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
35
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

36
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

37
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

38
Donors badge
39
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

40
FMT via colonoscopy at IU
41
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.
42
Why and how does FMT work?
43
Borody, T. J. Khoruts, A. (2011) Nat. Rev.
Gastroenterol. Hepatol.
44
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

45
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
46
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

47
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48
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
49
  • 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
50
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
51
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.
52
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

53
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

54
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

55
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
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