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The Human Microbiome
Brian Koll, MD, FACP, FIDSA
Professor of Medicine
ICAHN School of Medicine at Mount Sinai
Mount Sinai Health System Executive Director For
Infection Prevention
April 8, 2014
Outline of Talk
1. The Human Microbiome Project
2. C. difficile and Fecal Microbiome
3. Fecal Transplant and the Microbiome
4. Cost Effectiveness of Fecal Transplant with Restoration
of the Microbiome
Human Microbiome Project
• United States National Institutes of Heath
• Five year project 2007 - 2012
• Identify and characterize the microorganisms which
are found in association with both healthy individuals
and those with diseases (the human microbiome)
• Second phase 2013 - 2015
• Explore the relationship between disease and changes
in the human microbiome
Human Microbiome Project
•
Metagenomics
• Genetic makeup of microbial communities from various
body sites
•
Whole genome sequencing
• Individual bacterial species
•
16S rRNA sequences amplified by PCR
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Five body sites
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Oral
Skin
Vagina
Gut
Nasal/Lung
Human Microbiome Project
Human Microbiome Project
Human Microbiome Project
Human Microbiome Project
Human Microbiome Project
Human Microbiome Project
Human Microbiome Project
•
Different body sites have their
own distinctive communities
•
Microbes colonize each site
to use available sugars
•
Variations in the enzymes for
carbohydrate
metabolism
from site to site
•
Carbohydrate
metabolites
may be the most important
factor
shaping
the
composition of microbial subcommunities of the human
microbiome
Human Microbiome Project
•
Mouth and the gut have
greater diversity of organisms
than the skin and vagina
•
Bacterial makeup for a given
body site varies from person
to person by type and
abundance
•
Bacteria of the same species
composed
of
multiple
subtypes
Human Microbiome Project
•
The vast majority of bacteria
live in the large intestine
• Archaea
• Bacteria
• Fungi
•
Mutualistic, symbiotic
relationship
•
•
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•
Fermentation for energy
Digestion
Train our immune system
Produce vitamins such as
Vitamin K
• Produce hormones to help
store fat
Decreased Diversity of the Fecal Microbiome in
Recurrent Clostridial difficile (CDI) Associated
Diarrhea
•
Diarrhea is a common side effect of the administration
of antibiotics
•
CDI is associated with most of the severe cases of
antibiotic-associated diarrhea (AAD)
• Ingestion of environmental spores
• Overgrowth of indigenous CDI
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•
Standard treatment for CDI includes metronidazole or
vancomycin
Treatment of recurrent CDI can be difficult and has led
to dramatic interventions, such as the administration of
donor stool from healthy volunteers
Decreased Diversity of the Fecal Microbiome in
Recurrent CDI Associated Diarrhea
•
The mechanisms by which antibiotics lead to CDI are
not entirely clear
•
16S rRNA sequences amplified by PCR to profile the
community structure of the gut microbiota of patients
with initial CDI and recurrent CDI
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Sequences grouped into operational taxonomic units
(OTUs)
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Ecological diversity measures calculated using the
Shannon Index
Chang JY, Antonopoulos DA, Kalra A, et al. JID 2008:197 435 -438
Decreased Diversity of the Fecal Microbiome in
Recurrent CDI Associated Diarrhea
•
3 control subjects and 7 patients with CDI
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Microbial communities in each subject were compared
and characterized at the phylum level
•
3 control subjects and the 4 patients with initial CDI
• Bacteroides and Firmicutes
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3 patients with recurrent CDI
• More variable microbiota and lack of predominance of
Bacteroides and Firmicutes
Chang JY, Antonopoulos DA, Kalra A, et al. JID 2008:197 435 -438
Decreased Diversity of the Fecal Microbiome in
Recurrent CDI Associated Diarrhea
Chang JY, Antonopoulos DA, Kalra A, et al. JID 2008:197 435 -438
Chang JY, Antonopoulos DA, Kalra A, et al. JID 2008:197 435 -438
Conclusions
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Changes in the gut microbiome have been associated
with obesity, inflammatory bowel disease and AAD
• Changes in metabolic activity of the altered microbial
community
• Changes in the interaction between the microbiome and
the host immune system
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“Colonization Resistance” of indigenous gut microbiota
Breakdown in colonization resistance
• Suppression of indigenous microbiota
• Expansion of pre-existing CDI or germination and
expansion of CDI spores acquired from the environment
Chang JY, Antonopoulos DA, Kalra A, et al. JID 2008:197 435 -438
Conclusions
•
Standard treatment with metronidazole or vancomycin
• Suppress CDI and allow recovery of indigenous
microbiota with restoration of colonization resistance
• Assumption: remaining microbiome is sufficiently diverse
to recover to a “normal” state
•
Recurrent CDI
• Recrudescence of the original strain or acquisition of a
new strain
• Assumption: remaining microbiome is deficient in the
ability to restore colonization resistance
Chang JY, Antonopoulos DA, Kalra A, et al. JID 2008:197 435 -438
Treatment Options
European Society of Clinical Microbiology and
Infections
1. For nonepidemic, nonsevere CDI clearly induced by
antibiotic use, with no signs of severe colitis, it may be
acceptable to stop the inducing antibiotic and observe
the clinical response for 48 hours.
Patients must be monitored very closely and treated
immediately for any signs of clinical deterioration.
Treatment Options
European Society of Clinical Microbiology and
Infections
2. Antibiotic treatment is recommended for all cases of
CDI except for very mild CDI, which is actually triggered
by antibiotic use.
Suitable antibiotics include metronidazole, vancomycin, and
fidaxomicin
1. For mild/moderate disease, metronidazole is recommended as
oral antibiotic treatment of initial CDI (500 mg 3 times daily for
10 days)
2. Fidaxomicin may be used in all CDI patients for whom oral
antibiotic treatment is appropriate. Specific indications for
fidaxomicin may include first-line treatment in patients with first
CDI recurrence or at risk for recurrent disease, in patients with
multiple recurrences of CDI, and in patients with severe
disease and nonsevere CDI.
Treatment Options
European Society of Clinical Microbiology and
Infections
• Recommendations based on two large phase 3 clinical
studies
• 400 mg/day oral fidaxomicin vs 500 mg/day oral
vancomycin
• the rate of CDI recurrence was lower with fidaxomicin, but
the cure rate was similar for both treatments
February 3, 2011Louie T.J., Miller M.A., Mullane K.M., et al.
N Engl J Med 2011; 364:422-431
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Treatment Options
European Society of Clinical Microbiology and
Infections
3. For severe CDI
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vancomycin 125 mg 4 times daily (may be increased to
500 mg 4 times daily) for 10 days
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fidaxomicin 200 mg twice daily for 10 days.
• In life-threatening CDI, there is no evidence supporting the
use of fidaxomicin
• In severe CDI or life-threatening disease, the use of oral
metronidazole is strongly discouraged
Treatment Options
European Society of Clinical Microbiology and
Infections
4.
For multiple recurrent CDI, fecal transplantation is
strongly recommended
5.
Total abdominal colectomy or diverting loop ileostomy
combined with colonic lavage is recommended for
CDI with colonic perforation and/or systemic
inflammation and deteriorating clinical condition
despite antibiotic treatment
Annals of Surgery Volume 254, Number 3, September 2011
6.
Additional measures for CDI management include
discontinuing unnecessary antimicrobial therapy,
adequate fluid and electrolyte replacement, avoiding
antimotility medications, and reviewing proton pump
inhibitor use
Fecal Transplantation
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Amsterdam
Adults with CDI relapse
Not immunosuppressed
Not on pressors
Not in ICU
Not pregnant
January 31, 2013
van Nood E., Vrieze A., Nieuwdorp M., et al.
N Engl J Med 2013; 368:407-415
27
Fecal Transplantation
• Donors
• < 60 years of age
• Screened for a variety of transimissable
diseases
• Sample collected on the day of infusion
• 500 ml of saline
• Infused via NGT
o 50 ml over 3 minutes
January 31, 2013
van Nood E., Vrieze A., Nieuwdorp M., et al.
N Engl J Med 2013; 368:407-415
28
Fecal Transplantation
January 31, 2013
van Nood E., Vrieze A., Nieuwdorp M., et al.
29
N Engl
J Med 2013; 368:407-415
Fecal Transplantation
January 31, 2013
van Nood E., Vrieze A., Nieuwdorp M., et al.
30
N Engl
J Med 2013; 368:407-415
Fecal Transplantation
January 31, 2013
van Nood E., Vrieze A., Nieuwdorp M., et al.
31
N Engl
J Med 2013; 368:407-415
Fecal Transplantation
January 31, 2013
van Nood E., Vrieze A., Nieuwdorp M., et al.
32
N Engl
J Med 2013; 368:407-415
Fecal Transplantation
January 31, 2013
van Nood E., Vrieze A., Nieuwdorp M., et al.
33
N Engl
J Med 2013; 368:407-415
Fecal Transplantation
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Bacteriotherapy
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16sRNA sequencing before and after fecal transplant
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Prior to therapy
• Deficient in Bacteroides and Firmicutes
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14 days post transplant
• Fecal composition of the recipient highly similar to the
donor
• Dominated by Bacteroides
• Resolution of symptoms
Khoruts A, Dicksyed J, Jansson JK, Sadowsky MJ. J Clin Gastroenterol
2010 May – Jun; 44(5); 354-60
34
ID Week 2013 Fecal Transplantation
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University of Calgary
Pills
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Centrifuge
Encapsulate in three layers of gelatin
Release in colon
24 – 34 capsules
27 patients
• 100% with resolution
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40 patients
• 98% with resolution
ID Week 2013. Abstract 89. Presented October 3, 2013
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ID Week 2013 Fecal Transplantation
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University of Calgary
Patient Satisfaction
• 9.6 overall
• 9.9 for ease
• 9.9 would recommend
ID Week 2013. Abstract 89. Presented October 3, 2013
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Fecal Transplantation
“It's the yuck factor that has to be overcome,
and it's the physicians, not the patients.”
Dr. Tom Moore
University of Kansas School of Medicine
ID Week 2013. Abstract 89. Presented October 3, 2013
37
Cost-effectiveness for Management of
Recurrent CDI
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Decision analytic model
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Metronidazole
Vancomycin
Fidaxomycin
Fecal microbiota transplant (FMT)
FMT
• Colonoscopy
• Duodenal infusion
• Enema
Konijeti GG, Sauk J, Shrime MG, et al. March 31, 2014: 1 - 6
Cost-effectiveness for Management of
Recurrent CDI
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Cohorts of patients with a median age of 65 years
1 year follow-up
PCR testing for CDI
Heterogeneous patient population of 027 and non-027
strains
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Healthy
Mild-moderate CDI
Severe CDI
Persistent recurrent disease
Postcolectomy
Death
Konijeti GG, Sauk J, Shrime MG, et al. March 31, 2014: 1 - 6
Cost-effectiveness for Management of
Recurrent CDI
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Treatment algorithms
presented guidelines
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Median hospital duration of two weeks
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FMT colonoscopy was the most cost-effective strategy
for recurrent CDI
consistent
with
previously
• Cure rates > 88%
• Recurrence rates < 15%
• $2,724
•
Vancomycin preferred in settings where FMT not
available
Konijeti GG, Sauk J, Shrime MG, et al. March 31, 2014: 1 - 6
It may end with the microbiome
but it begins with antibiotics and stewardship
Chang JY, Antonopoulos DA, Kalra A, et al. JID 2008:197 435 -438
Thank You