1. No category

Objectives
Fecal Microbiota Transplant (FMT)
The Power of Poop
• Review the burden and patient outcomes related to C.
difficile infection and disease.
• Understand the rationale for FMT as an option in
treating recurrent C. difficile disease.
Fecal Microbiota Transplants in
the 21st Century
• Describe the options for preparing and administering
FMT.
Kathy Aureden MS, MT(ASCP)SI, CIC
March 23th, 2015
• Review the challenges related to donor testing and FD’s
enforcement policy on FMT as an investigational new
drug.
Epidemiology and Infection Prevention
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Definitions and acronyms
C. difficile disease (CDI)
CDC information
Clostridium difficile = C. difficile = C dif
Anaerobic spore-forming bacteria ubiqitous in nature, often found in soil.
Some strains make toxins that cause inflammation and diarrhea.
Clostridium difficile infection = C. difficile disease = CDI
CDI is of concern as a hospital associated infection. It is one of the most
common causes of antibiotic associated diarrhea (10 – 25%)
Pseudomembranous colitis – infectious, inflammatory condition of the gut
resulting from CDI.
Microbiota or microbiome = bacteria, viruses, and eukaryotic microbes in
and on our bodies, which impact physiology in health and in disease.
Note: In stool culture results, “normal flora” refers to healthy gut
microbiota
Fecal microbiota transplant = FMT = “stool transplant”
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http://www.cdc.gov/hai/pdfs/cdiff/CDiff-OnePager.pdf
Estimated U.S. Burden of Clostridium difficile Infection (CDI), According to
the Location of Stool Collection and Inpatient Health Care Exposure, 2011.
CO-HCA : community-onset
healthcare associated
NHO: Nursing Home onset
HO: Hospital onset
Burden of Clostridium difficile in U.S.
Lessa et. al.
Study estimate of 500,000 cases (2011 data)
> one recurrence of C. difficile infection
• 21% after Healthcare Associated (HCA) CDI
event
• 14% after Community associated (CA) CDI event
83,000 CDI cases – at least one recurrence
29,000 died within 30 days
Lessa FC, et al . Burden of Clostridium difficile infection in the United States. N Engl J Med. Feb 2015
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Lessa FC et al. N Engl J Med 2015;372:825-834
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Risk to patients: poor antimicrobial prescribing practices
50% hospitalized patients get an antibiotic in hospital
30-50% of those antibiotics are unnecessary or incorrect
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HOW C. DIFFICILE SPREADS
CDI can be prevented by using infection control
recommendations and more careful antibiotic use.
SOURCE: CDC 2012
• George, a 68-year-old man,
goes to the doctor's office
and is diagnosed with
pneumonia.
• Antibiotics are prescribed to
treat the pneumonia.
• These drugs put him at risk
for C. difficile infection for
several months.
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ONE MONTH LATER
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TWO DAYS LATER
• George breaks his leg
•George transfers to a rehab
facility and gets begins to
experience diarrhea.
• He is admitted to a hospital.
• A health care worker forgets to
wear gloves when caring for a
C.difficile infected patient prior
to providing care to George.
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•He is not tested for
C.difficile.
•The health care worker
doesn't wear gloves and
infects other patients.
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Background: Pathogenesis of CDI
THREE DAYS LATER
• George goes back to the
hospital for treatment of
diarrhea
• He tests positive for C.difficile.
• Health care workers wear gloves
and do not spread C. difficile.
3. Altered lower intestine flora
(due to antimicrobial use) allows
proliferation of C. difficile in colon
1. Ingestion
of C. difficile
spores
4. Toxin A & B production
leads to colon damage
+/- pseudomembrane
2. Germination into
growing (vegetative)
form
George recovers upon completing
treatment : Metronidazole, oral
Vancomycin, or Fidaxomicin for
10 – 14 days
Sunenshine et al. Cleve Clin J Med. 2006;73:187-97.
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Antibiotic disrupts normal intestinal
flora “colonization resistance”
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Pseudomembranous colitis
Medscape Dec 2014
<3 months for microbiota to normalize
Exposure to C difficile
Endoscopic image of pseudomembranous
colitis
Pathogenesis
Spore form – resistant to gastric acid
Yellow pseudomembranes
On wall of the sigmoid colon
Spore passes easily through stomach into intestinal mucosa
Toxins open tight junctions between intestinal mucosal cells
Suggestive for CDI
Resultant increased vascular permeability and hemorrhage
Gross pathology specimen
revealing characteristic
yellowish plaques
http://emedicine.medscape.com/a
rticle/193031-overview
Induction of TNF-alpha and pro-inflammatory interleukins
inflammation and formation of pseudomembranes
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http://emedicine.medscape.com/article/186458overview#a0101
Gregory Ginsberg, MD, U of Penn
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GEORGE HAS RECURRENT C DIFFICILE DISEASE
ONE MONTH LATER
• George has symptoms of UTI and is treated
with antibiotics at local ED
• A few days after starting antibiotics, he is
still weak, lethargic, slightly feverish (UTI?)
Recurrent CDI: episode < 8 weeks after a previous resolved
event
Historically, recurrent CDI occurs in 20%–25% of patients after
the initial event
• Symptoms worsen and he starts having
diarrhea
Recurrent CDI patients experience additional events more than
45% after the first recurrence
He is admitted for dehydration and sepsis.
He tests positive for C. difficile.
Severe pseudomembranous colitis is
found.
Mortality rate if C. difficile infection becomes fulminant may be
up to 50%
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RECURRENT C DIFFICILE DISEASE
RISK FACTORS FOR RECURRENCE OF C. DIFFICILE INFECTION
CDI due to epidemic strain BI/NAP1/027
Failure to mount systemic anti-toxin antibody response. This
may be due to age, or genetic factors
Use of antibiotics for non-C.difficile infections
Use of proton-pump inhibitors (gastric acid suppressive agents)
Severe underlying illness
• Study during a 30 day follow-up period after original episode
• Molecular testing of original and recurrent strain per enrolled patient
Clin Infect Dis. 2012 Aug 1; 55(Suppl 2): S104–S109.
Figueroa, Iris et al. “Relapse Versus Reinfection: Recurrent Clostridium Difficile Infection Following Treatment
With Fidaxomicin or Vancomycin.”
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Treatment Of Recurrent CDI
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An old therapy comes of age
American College of Gastroenterology
Fecal transplantation consists of putting healthy donor stool into
the stomach, small intestine, or colon to restore normal flora.
ACG guidelines for the management of recurrent CDI
1. repeat metronidazole or a pulsed vancomycin regimen
This is more effective than vancomycin for the treatment of
patients with recurrent CDI, but natural antipathy toward fecal
therapy hinders its wide implementation.
2. consider fecal microbiota transplantation after 3
recurrences
Kelly CP. Fecal microbiota transplantation—an old therapy comes of age. N Engl J Med. 2013;
368:474–475.
*Surawicz CM, Brandt LJ, Binion DG, et al. Guidelines for diagnosis, treatment, and prevention of
Clostridium difficile infections. Am J Gastroenterol. 2013;108:478–498.
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Treatment Options : FMT
“Re-establish
the balance of nature”
1958: Denver doctors used enema of a stool infusion to treat patients with
life-threatening pseudomembranous enterocolitis with “immediate and
dramatic” responses.
“This simple yet rational therapeutic method should
be given more extensive clinical evaluation.”
Eiseman B, Silen W, Bascom GS, Kauvar AJ. Fecal enema as an adjunct in the treatment of pseudomembranous
enterocolitis. Surgery 1958;44:854-9.
What has happened since1958?
Why is this therapy not adopted?
A: Antibiotic use destroys sensitive bacteria. It reduces microbiota diversity and resistance to colonization by
opportunistic pathogens
B: In the absence of opportunistic infection, microbiota usually recover its homeostasis
C: Infection with C. difficile can lead to persistent dysbiosis
D: Fecal microbiota transplantation restores microbiota diversity and colonization resistance and allows the
elimination of C. difficile.
•Aesthetically unappealing
•Logistically challenging
•Lack of efficacy data from randomized, controlled trials
Kelly CP. Fecal microbiota transplantation—an old therapy comes of age. N Engl J Med. 2013;
368:474–475.
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World J Gastroenterol. 2014 Jun 21; 20(23): 7416–7423. Recurrent Clostridium difficile infections: the importance of the
intestinal microbiota.
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Disruption of fecal microbiome CDI and non-CDI
Treatment Options : FMT
However, today there is sufficient evidence in
randomized, controlled trials to prove efficacy and
sustainable outcomes.
Supplementary Figure 7. Interindividual variation in the proportion
of major phyla. Each bar is a subject. The y-axis shows the relative
proportion of reads that mapped to each phylum. Subjects are
ordered from left to right according to increasing proportions of
Firmicutes reads.
(A) HC: healthy cohort (n=40)
(B) CDI: C. difficile infection (n=39)
(C) CDN: subjects with nosocomial diarrhea
but C. difficile negative (n=36).
Fecal microbiota transplant can successfully reestablish appropriate microbe diversity and
normalcy.
Evidence……..
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Compositional comparison of donor, pre-, and post-FMT samples.
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Duodenal Infusion of Donor Feces for Recurrent Clostridium
difficile
This trial was closed to
new enrollment after only
43 of a planned 120
patients had undergone
randomization.
Almost all patients in the
two control groups had a
recurrence.
Of patients having 1 or 2
infusions, nearly 95%
had not recurred.
Anna M. Seekatz et al. mBio 2014; doi:10.1128/mBio.00893-14
van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N28Engl
J Med 2013;368:407-15.
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Long-term follow-up of colonoscopic fecal microbiota transplant for
recurrent Clostridium difficile infection
Am J Gastroenterol. 2012 Jul;107(7):1079-87. doi: 10.1038/ajg.2012.60. Epub 2012 Mar 27.
Study:
Multicenter long-term follow-up study of 77 of 94 eligible patients
Follow-up timeframe > 90 days post FMT
Average suffering prior to FMT was 11 months
Patients had failed an average of 5 conventional antimicrobial
regimens
Results:
Diarrhea resolved in 82% and improved in 17% of
patients within an average of 5 days after FMT.
•Primary cure rate was 91%.
–7 patients failures had subsequent FMT success
•Secondary cure rate was 98%
.
“Physician attitudes toward the use of fecal microbiota transplantation for the treatment
of recurrent Clostridium difficile infection”
Can J Gastroenterol Hepatol. 2014 Jun; 28(6): 319–324.
Physicians greatly overestimated intensity of patients’ aversion and how much the
gross factor would act to deter patients’ willingness to consider FMT
All late recurrences of CDI
occurred after antimicrobial
therapy for infections unrelated to
C. difficile.
In all, 53% of patients stated they
would have FMT as their preferred
first treatment option if CDI were
to recur.
No definite adverse effects of FMT
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were noted (more studies needed)
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“Patient Attitudes Toward the Use of Fecal Microbiota Transplantation in the
Treatment of Recurrent Clostridium difficile Infection “
Treatment by FMT
So what do patients think?
But there are other significant considerations and/or
impediments to FMT
Antibiotics Antibiotics
+ FR
Alone
Conditions
After reading scenario 1 - did not explicitly disclose fecal nature of FR
162 (85%)
29 (15%)
After reading scenario 2 - disclosed fecal nature of FR
154 (81%)
37 (19%)
If FR provided as colorless, odorless liquid given by NGT, enema, or
colonoscopy
158 (83%)
33 (17%)
If FR provided as colorless, odorless pill
171 (90%)
20 (10%)
If FR (in any form) recommended by doctor
179 (94%)
12 (6%)
•FDA guidance
•Fees and insurance
•Harvesting and processing donor stool
•Testing protocols
•In-patient vs Out-patient procedure
Abbreviations: FR, floral restoration; NGT, nasogastric tube.
Table 2. Patient Preferences for Antibiotics Alone vs Antibiotics Plus “Floral Restoration”
in the Treatment of Recurrent Clostridium difficile Infection
Clin Infect Dis. (2012) 55 (12): 1652-1658.
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FDA guidance on FMT
FDA guidance on FMT
March 2014 update “Guidance for Industry” for FMT in treatment of
recurrent CDI
May 2013 FDA statement
Fecal microbiota defines FMT as a biologic product
Point #1:
Interim FDA decision: will exercise discretion on IND use provided
that the treating physician obtains adequate informed consent from
the patient or his or her legally authorized representative. This
enforcement discretion does NOT extend to other FMT uses.
Therefore it requires an investigational new drug (IND) before use in
humans.
big outcry! Stakeholder meeting convened
“ Informed consent should include, at a minimum, a statement
that the use of FMT products to treat C. difficile is investigational
and a discussion of its potential risks. “
July 2013 UPDATED guidance
http://www.gpo.gov/fdsys/pkg/FR-2013-07-18/html/2013-17223.htm
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformati
on/Guidances/Vaccines/ucm387023.htm
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http://fmt.gastro.org/
FDA guidance on FMT
March 2014 update “Guidance for Industry”
Point #2:
the FMT product is obtained from a donor known to either the
patient or to the licensed health care provider treating the
patient
Point #3
the stool donor and stool are qualified by screening and testing
performed under the direction of the licensed health care
provider for the purpose of providing the FMT product to treat
his or her patient.
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformati
on/Guidances/Vaccines/ucm387023.htm
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Recipient
Consensus guidelines – donor screening and
stool testing
Who is a Candidate for FMT?
FMT may be an option for people who have had one of the following:
• At least three episodes of mild to moderate C. difficile infection
that have not responded to six to eight weeks of treatment with
antibiotics.
• Have had at least two episodes of severe C. difficile infection that
required them to be admitted to the hospital.
• Moderate C. difficile infection that did not respond to antibiotics
(namely vancomycin) for at least a week.
• Severe C. difficile infection or severe colitis caused by C. difficile
that did not respond to antibiotics within two days.
http://www.gastro.org/research/Joint_Society_FMT_Guidance.pdf
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Donors
Recipient
Who is NOT a Candidate for FMT?
Not everyone is a good candidate for FMT. The procedure may
be risky for people who:
•are taking immunosuppressive drugs
•have had a recent bone marrow transplant
•have cirrhosis of the liver
Preferred donor is
– an intimate, long-time partner of adult patient
– in the case of a pediatric patient, an adult first-degree
relative
– close family friend
– well-screened universal donor
– over the age of 18
Children could potentially serve as donors as long as both parental consent
and child assent are obtained.
•have advanced HIV or AIDS
Donor questionnaire – similar to current screening blood donors
http://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/ApprovedPro
ducts/LicensedProductsBLAs/BloodDonorScreening/ucm164185.htm
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Donor exclusions
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Donor Testing - Guidelines
Donor exclusion criteria:
•Antibiotic treatment during the preceding 3 months
•History of intrinsic GI illnesses, including inflammatory bowel disease,
irritable bowel syndrome, GI malignancies or major GI surgical
procedures
•History of autoimmune or atopic illnesses, or ongoing Immune
modulating therapy
•A history of chronic pain syndromes (fibromyalgia, chronic fatigue) or
neurologic, neurodevelopmental disorders
•Metabolic syndrome, obesity (BMI of >30), moderate-to-severe
undernutrition (malnutrition)
Serum Testing (to be performed within 4 weeks of donation):
•HAV-IgM
- hepatitis A virus Antibody (IgM)
•HBsAg
- hepatitis B surfage antigen
•HCV-Ab
- hepatitis C virus antibody
•HIV-EIA
- HIV screening test
•RPR
- syphilis screening test
Stool Testing (to be performed within 4 weeks of donation):
•C. difficile toxin B (preferably by PCR)
•Culture for enteric pathogens
•O+P, if travel history suggests
•A history of malignant illnesses or ongoing oncologic therapy
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The Procedures
Insurance, coding, Medicare beneficiaries
All appropriate donor testing has been completed and
patient has been approved per protocol.
http://www.gastro.org/practice/coding/aga-provides-fmt-codingguidance
CPT code 44705, "Preparation of fecal microbiota for instillation,
including assessment of donor specimen”
Patient and donor have met pre-FMT questionnaire
requirements.
Patient Preparation
Preparation and testing of the donor and specimen may be
covered by the recipient’s insurance – but even with insurance
this may cost the donor several hundred dollars
Thorough laxative prep - no
residual stool on day of
procedure
Stop antibiotics 2-3 days prior
Medicare does not cover the costs of screening of the donor
specimen, thus beneficiaries should be advised of the cost of
screening, which they may be at risk of paying for out-ofpocket.
Donor Preparation
•Purgative (night before)
•Formed soft stool
•Deliver to lab fresh day of
procedure
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The Procedures
Procedure
• Performed by colonoscopy
• A “fistful-sized” amount (50 gms) stool collected in “hat”
• Saline added and stool blended, emulsified
o Onsite: use blender in biolevel 2 safety hood
o At home: some sites require initial emulsifying prior to
bringing in specimen
•
•
•
•
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– Multiple syringes, approx. 100 ml total prepared suspension
• Colonoscope is advanced through the colon, as withdrawn,
the prepared suspension is delivered
• Outpatient Procedure discharge instructions
Strained (coffee filter, layers of gauze, etc)
Refrigerate if not used immediately
Used within 6 hours of collection
Reconstitute in 500-600 ml sterile water or nonbacteriostatic
sterile saline
– Retain contents 35 – 45 minutes (as long as possible)
– Regular activities within a few hours
– Transient diarrhea, abd pain, rectal bleeding, fever
• Alternate procedure : administer via NG tube*
Postigo R1, Kim JH. Colonoscopic versus nasogastric fecal transplantation for the
treatment of Clostridium difficile infection: a review and pooled analysis. Infection. 2012
Dec;40(6):643-8.
Rectal tubes and retention enemas have been used with some success
but this route is not as thoroughly studied and vetted.
Question: What happens to that blender?
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ClinicalTrials.gov Identifier: NCT01914731
Current and future research
updated: October 22, 2014
Massachusetts General Hospital
• Recent literature unequivocally supports the use of FMT in
treating relapsing CDI.
Experimental: Capsule Fecal microbiota transplant ("stool
transplant") from healthy, unrelated donor via frozen capsule
• Trials are underway to determine the therapeutic potential of
FMT in other conditions, particularly inflammatory bowel
disease.
•Healthy volunteers were screened as potential donors
•FMT capsules were generated and stored at −80°C
• Possible potential in autoimmune disease and metabolic diseases
Patients received 15 capsules on 2 consecutive days and were
followed up for symptom resolution and adverse events for up
to 6 months.
• Therapeutic FMT is a dynamic field with new and emerging
indications along with ongoing developments in optimal mode of
administration.
Youngster I, Russell GH, Pindar C, Ziv-Baran T, Sauk J, Hohmann EL. Oral, capsulized, frozen fecal
microbiota transplantation for relapsing Clostridium difficile infection. JAMA. 2014 Nov
5;312(17):1772-8. doi: 10.1001/jama.2014.13875. Erratum in: JAMA. 2015 Feb 17;313(7):729.
• New methodologies for reconstitution of gut microbiota
Therapeutic faecal microbiota transplantation: current status and future developments
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3868025/ Curr Opin Gastroenterol. 2014
Jan; 30(1): 97–105.
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Youngster I., et. All. Fecal Microbiota Transplant for Relapsing Clostridium difficile Infection Using a
Frozen Inoculum From Unrelated Donors: A Randomized, Open-Label, Controlled Pilot Study Clin
Infect Dis. (2014) 58 (11): 1515-1522 (Frozen FMT via NG tube)
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Bacteria – our friends (usually!)
Fig 1 Association of the
microbiota with humans.
Microbiota presents in all parts of
our body which has direct contact
with external environment.
The numbers of bacteria in the
mouth (1010), on the skin (1012), and
in the distal gut (1014) are presented
in a relation to total number of
parenchymal cells (1012).
The composition of the microbiota in
the digestive tract greatly differs in
each of specialized compartments as
illustrated
Physiological functions and chemical
environment of each compartment
are likely key factors influencing the
bacterial habitants.
J Obes. 2012; 2012: 879151.
Published online 2012 Jan 24
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