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![Page 1: Fecal Microbiota Transplant for Recurrent C.difficile ... · PDF fileFecal Microbiota Transplant for Recurrent C.difficile Infection: Here and Now Darren A. Kastin, MD Medical Director](https://reader034.vdocuments.us/reader034/viewer/2022042619/5a78ac067f8b9ab8768e891f/html5/thumbnails/1.jpg)
Fecal Microbiota
Transplant for Recurrent
C.difficile Infection:
Here and NowDarren A. Kastin, MD
Medical DirectorDivision of Gastroenterology
Edward Hospital, Naperville, ILSuburban Gastroenterology, LTD
March 11, 2017
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Introduction: CDI
• Major cause of morbidity and morality worldwide
• Over 400,000 infections and ~29,000 deaths in
the US alone
• Most common cause of hospital acquired
diarrhea in the developed world
• Has been complicated by the emergence of
hypervirulent strains (NAP1/BI/027, and 078)
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C. difficile
• What is Clostridium difficile (aka C.difficile, C.diff)
• Gram (+), anaerobic spore forming bacterium
• Present in soil, air, water, human and animal feces
• A small percentage of healthy people naturally carry
• Produces 2 toxins (A and B)
• Controversy over whether both are important for
c.diff infection
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C.Difficile
• Transmitted by fecal – oral contamination
• Seen in Hospitals, nursing homes, health care facilities, and increasingly in the community
• Can persist for weeks or months
• Survives on surfaces such as bathroom vanities, toilets, sinks, kitchen counter tops
• Infection often occurs in the setting of recent prior antibiotics
• Fluoroquinolones, Cephalosporins, Clindamycin, Penicillins
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C.difficile
• Once established, the organism produces toxins which induce
injury to the colonic cell
• Plaques of inflammatory cells and cellular debris
• watery diarrhea
• abdominal pain
• fever
• rectal bleeding
• toxemia
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CDI Diagnosis
• Testing for C. difficile or its toxins should be performed only on diarrheal (unformed) stool
• Testing asymptomatic patients or as a test for cure is not useful and is not recommended
• Stool culture is not practical due to slow turnaround time, but is the gold standard
• Toxin assay is clinically helpful, but has low sensitivity
• PCR testing is rapid, sensitive, and specific
• Repeat testing during the same episode of diarrhea is of limited value.
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CDI Treatment
• Conventional treatments utilize antibiotics with
activity against C.difficile, but which also have
activity against other gut bacteria – prevents
microbiota recovery
• Low serum Ab response to C.difficile toxins
• Use of medications such as PPI
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CDI
• 10-20% chance of recurrent CDI within 8 weeks
after treatment of an initial episode
• After a single recurrence, the rate of subsequent
recurrences increases to 45 - 65%
• Recurrence may be the same strain or a different
strain
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CDI
• Recurrence may be due to impaired immune
response and/or alteration of the colonic
microbiota
• Compared to normal controls, patients with
recurrent CDI demonstrate a marked decrease in
the diversity of flora.
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Infect Dis Clin North Am. 2015 Mar;29(1):109-122
Progressive reduction in microbiota diversity in patients with recurrent CDI(green) vs patients successfully treated for CDI (red) vs healthy controls(blue)
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What is the microbiome?
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Introduction
Human Microbiome• What is the human microbiome?
• The aggregate of microorganisms present on or within the human body (skin, saliva, oral mucosa, conjunctiva, gastrointestinal tract)
• 10-100 trillion symbiotic microbial cells
• Bacteria, fungi, viruses, protozoa, archaea
• The gut microbiota are predominantly bacterial and are symbiotic with the host
• An evolving appreciation has lead to the discovery of the microbiome impact on human metabolism, immunity, and genetics
• Unique variation in each individual
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Microbiome continued
• Provides essential signals for the development
and appropriate function of the immune system
• Plays a critical role in health and disease
• Alterations in the gut microbiota have been
show to influence susceptibiity to a variety of
diseases
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Microbiome continued
• The GI tract becomes colonized by microbes
early in life and reaches an adult state by the
age of 3
• The predominant organisms are of the phyla
Bacteroidetes and Firmicutes, which make up
more than 90% of the microbial population in
humans.
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Gut microbiota
• The gut microbiota is dominated by 2 bacterial
phyla
• Bacterioidetes - gram (-) organisms
• Firmicutes - gram (+) organisms
• The loss and / or disturbance in the homeostasis
of these organisms has substantial impact on
the evolution of recurrent c.diff infection
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Microbiome continued
• The gut microbiota contributes to homeostasis of
metabolic pathways, nutrient metabolism, and
vitamin production
• Important in maturation of mucosal and systemic
immune responses, and maintenance of the
intestinal epithelial barrier function.
• Disturbances in the microbiota can lead to
disease states
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Microbiome and CDI
• Antibiotics disturb the human microbiome
• Normal human response:
• Spontaneously restore normal colonization
• Re-establish unique microbial diversity
• Re-establish microbial homeostasis
• This prevents toxigenic C.difficile infection
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Infect Dis Clin North Am. 2015 Mar;29(1):109-122
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Microbiome and CDI
• Failure of spontaneous re-colonization of normal
colonic flora can lead to a c.diff infection (CDI)
• Primary treatment is conventional antibiotics
• Metronidazole (Flagyl) x 10-14 days
• Vancomycin x 10-14 days (Prolonged taper)
• Fidaxomicin (Dificid) x 10 days
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CDI
• A subset of patients will develop recurrent c.diff
infection
• Most can be treated safely with a 2nd course of
antibiotics
• A subset of this group will develop further
recurrent infections
• Reports of up to 60% chance of further recurrence
after 2 episodes of recurrent c.diff infection
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Definitions
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Definitions• Severe
• Episode of CDI with one or more specific clinical (fever, hemodynamic instability, respiratory failure, s/s peritonitis, colonic ileus), laboratory (peripheral leukocytosis, rise in serum creatinine, lactate, decreased serum albumin), radiological (colon distention, colonic wall thickening), or endoscopic (pseudomembranous colitis), symptoms and signs of severe colitis or complicated course of disease
• Recurrent
• CDI recurs within 8 weeks after onset of a previous CDI episode, provided complete symptom resolution after initial treatment. Recurrence due to un-cleared CDI vs reinfection can not be distinguished
• Refractory
• CDI unresponsive to antimicrobial treatment, based on persistence of diarrhea with CD toxin (+) or persistence of diarrhea with CD toxin (-), and no other identifiable etiology of diarrhea (eg IBS, IBD, non-CDI antibiotic-associated diarrhea)
Gut 2017;0:1-12
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Table 3. CDI severity scoring system and summary of recommended treatments
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 125mg 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 ≥15,000cells/mm3,
Abdominal tenderness
Vancomycin 125mg 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 ≥35,000cells/mm3 or
<2,000 cells/mm3 Serum lactate
levels >2.2mmol/l
End organ failure (mechanical
ventilation, renal failure, etc.)
Vancomycin 500mg orally four
times a day and metronidazole
500mg IV every 8h, and
vancomycin per rectum
(vancomycin 500mg in 500ml
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.
Am J Gastroenterol 2013; 108:478-498
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Recurrent c.diff infection
• HUGE ECONOMIC IMPACT
• BILLIONS OF DOLLARS
• Hospitalizations
• Antibiotic prescriptions
• Lost days of work
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Table 4. Cost of antibiotic therapy for C. difficile infection
Cost per dose Regimen Cost per 10-day regimen
Metronidazole 500 mg $0.73 500mg three times a day $22.00
Vancomycin 125mg pills $17.00 125mg four times a day $680.00
Vancomycin 125 mg
IV compounded for oral $2.50– $10.00 125mg four times a day $100.00–$400.00
Fidaxomicin 200 mg $140.00 200mg twice a day $2,800.00
IV, intravenous.
Vancomycin IV form can be compounded for oral use as well as used for enema therapy.
Am J Gastroenterol 2013; 108:478-498
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CDI
• Recurrent c.diff infections severely impact health and
quality of life
• Recurrent or continued diarrhea
• Abdominal pain
• Sense of personal withdrawal
• Post-infectious Irritable bowel syndrome (IBS)
• Post-infectious Inflammatory bowel disease (IBD)
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Treatment
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CDI Prevention• Healthcare workers and visitors must use gloves and
gowns on entry to a room of a patient with CDI
• Compliance with hand hygiene (soap and water)
• Isolate patients with CDI to a private room and singular bathroom
• Identification and removal of environmental sources of C.difficile, including replacement of electronic rectal thermometers with disposables
• Use chlorine-containing cleaning agents or other sporicidal agents
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Prevention
• Minimize the frequence and duration of antimicrobial therapy and the number of antimicrobial agents prescribed, to reduce CDI risk
• Implement an antimicrobial stewardship program; especially with the restriction of cephalosporinsand clindamycin, may be particularly useful
• Administration of probiotics is not recommended
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CDI Treatment
Shea – IDSA Guidelines• Discontinue therapy with inciting antimicrobial as
soon as possible
• When severe or complicated CDI is suspected, initiate empirical treatment as soon as the diagnosis is suspected
• If the stool toxin assay is (-), the decision to treat or stop treatment must be individualized
• Avoid antiperistaltic agents, as they may obscure symptoms and precipitate toxic megacolon
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CDI Treatment
• Metronidazole 500 mg po TID x 10-14 days for mild-to-moderate CDI
• Vancomycin 125 mg po QID x 10-14 days for initial episode of severe CDI
• Vancomycin 500 mg QID and 500 mg in 100 ml NS per rectum QID with or without IV Metronidazole for severe complicated CDI
• Consider subtotal colectomy for severely ill patients in whom toxic megacolon is strongly suggested (wbc >50, rising lactate level, low albumin, progressive abdominal distention)
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CDI Treatment
• 1st recurrence – use same regimen as for initial episode
• 2nd or later recurrences – Pulsed or Tapered dosing of Vancomycin
• Fidaxomicin 200 mg po twice daily x 10 days
• Probiotics are not recommended as primary prevention for CDI, due to limited data and risk for bloodstream infection.
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Probiotics
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Probiotics
• Probiotics are live microorganisms, which
when administered in adequate amounts,
confer a health benefit on the host
• Can interfere with the growth or survival of
pathogens in the gut lumen, improve barrier
function and immunity, or affect the systemic
immune system
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Probiotics continued• Saccharomyces boulardii (Florastor)
• Strain of S. cerevisiae
• Effective in treating antibiotic-associated diarrhea illnesses
• Modulates gastrointestinal immune system
• Interferes with pathogen cell adherence
• Increases pathogen clearance and blunts inflammatory response
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S.boulardii
• Mixed data has suggested benefits in reducing
CDI. However, the efficacy benefit is weak
• Risk of systemic fungal infection in
immunocompromised, ICU patients, and/or
patients with central venous catheters (central
lines)
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Probiotics
• Trials with Lactobacillus plantarum suggested a statistically non-significant benefit when combined with metronidazole
• 2 small trials using Lactobacillus rhamnosus GG failed to show efficacy
• 1 uncontrolled study using Kefir as an adjunct to antibiotics did result in decreased recurrence of C.difficile
• Reports of Lactobacillus bacteremia in immunocompetent patient
Am J Gastroenterol 2013; 108:478-498
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There is limited role for the
use of probiotics in the
treatment of initial or recurrent
CDI
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Fecal Microbiota Transplant
(FMT)
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Emergence of Fecal Microbiota
Transplantation
• Also referred to as FMT
• Restoration of colonization resistance, re-establish diversity, and facilitate microbial homeostasis in order to protect against toxigenic CDI
• Analyses of observational data has described a clinical cure in ~90% of patients with a single treatment
• More recent data has suggested a range of 78-92% success based on route of administration, and patient characteristics
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FMT
• The administration of human fecal material from a
healthy donor, into the colon or small bowel of a
sick individual
• NG or NJ tube
• Enema
• Colonoscopy
• Oral fecal capsule administration
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FMT continued
• Donor sources
• Intimate partner / spouse
• Close family relative or friend
• Anonymous donor
• Stool donor bank (frozen specimens)
• Rates of success are ~89% for fresh or frozen
Kassam, et al. Am J Gastroenterol 2013; 108:500-508
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FMT
• Experimental procedure with increasing
utilization around the world in the setting of
suboptimal conventional treatment options
• Administration of healthy donor stool introduces
a restoration of the normal diversity of microbiota
• The recipient microbiota then becomes that of
the donor
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Infect Dis Clin North Am. 2015 Mar;29(1):109-122
The darker shades of blue reflect increasing diversity of the microbiota from the donor to the recipient
moving from left to right
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FMT success
• Rates of success are impacted by the severity of disease,
number of recurrences, inpatient / outpatient status of the
patient, and route of administration
• Upper gastrointestinal delivery (nasogastric/nasojejunal,
gastroscopy, gastrostomy tube)
• ~80% success
• Lower gastrointestinal delivery (colonoscopy, enema)
• ~90% success
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Predictors of failure after
FMT
• Severe or severe-complicated CDI
• Inpatient status during FMT
• Previous CDI-related hospitalization, with
increasing odds of failure for each hospitalization
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Adverse reactions
after FMT
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Short-term reactions
• Most patients have little or no symptoms post-procedure
• Abdominal bloating, nausea (with or without vomiting), abdominal pain, diarrhea, constipation, fever are the most common
• Gram (-) bacteremia, anemia, and perforation have been reported
• Mortality has been reported as an outcome of aspiration during sedation
Gut 2017;0:1-12
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Long term consequences
• Long-term follow-up is insufficient
• A single case of weight gain has been reported
• Peripheral neuropathy, Sjogren’s disease, ITP, RA have been reported
• Reports of improvement in IBS, chronic constipation, antibiotic-induced non-infectious colitis, Parkinson’s disease, multiple sclerosis, and ITP
• Some evidence of transmission of malignant, autoimmune, metabolic and neuropsychiatric disease in animal models has been suggested
Gut 2017;0:1-12
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No causality has been
demonstrated
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The Edward Hospital
experience• At Edward - we use anonymous frozen donor specimens from a
donor bank
• Donors are tested as if blood donors
• Screening questionnaire
• Extensive lab testing for HIV, Viral Hepatitis, Syphillis and
other communicable diseases
• Stool is tested for infectious disease
• Specimen is quarantined and then re-tested before release
• Minimal cost burden to the recipient
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Edward experience
• To date, 50 FMT procedures have been performed since October, 2014
• 6 recurrences have been observed ( 88% success rate)
• 2 were re-transplanted with successful eradication
• 2 were treated with a standard course of antibiotics with subsequent resolution of diarrhea and normalization of bowel habits
• 2 have required chronic suppressive ongoing Vancomycin
• 1 pt immunocompromised with recurrent hospitalizations
• 1 pt had failed 2 prior FMT procedures at outside institution prior to presenting to Edward for a 3rd FMT
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Edward clinical trial
• We are accepting enrollment of patients <=75
years old, with recurrent or refractory CDI into an
ongoing multi-center efficacy trial performing
FMT with frozen donor specimens
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Conclusion
• C.diff infection has emerged as a leading cause of
morbidity and mortality in hospital and community
patients with a severe cost and health burden
• Antibiotic failures have lead to the emergence of FMT
as an alternative treatment
• FMT has been observed to have a 90%+ cure rate with
a single treatment
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Conclusion
• A variety of patient factors and clinical settings
impact the overall utility and success of FMT
• FMT is considered to be extremely safe, though
remains an experimental procedure
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Thank you!!