The Human Microbiome Brian Koll, MD, FACP, FIDSA Professor of Medicine

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 The Human Microbiome Project
C. difficile and Fecal Microbiome Fecal Transplant and the Microbiome Cost Effectiveness of Fecal Transplant with Restoration of the Microbiome

Human Microbiome Project
United States National Institutes of Heath Five year project Identify and characterize the microorganisms which are found in association with both healthy individuals and those with diseases (the human microbiome) Second phase Explore the relationship between disease and changes in the human microbiome

Metagenomics Genetic makeup of microbial communities from various body sites Whole genome sequencing Individual bacterial species 16S rRNA sequences amplified by PCR Five body sites Oral Skin Vagina Gut Nasal/Lung

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 sub-communities of the human microbiome

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

The vast majority of bacteria live in the large intestine Archaea Bacteria Fungi Mutualistic, symbiotic relationship 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 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 Sequences grouped into operational taxonomic units (OTUs) Ecological diversity measures calculated using the Shannon Index Chang JY, Antonopoulos DA, Kalra A, et al. JID 2008:

3 control subjects and 7 patients with CDI 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 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:

Chang JY, Antonopoulos DA, Kalra A, et al. JID 2008:

Chang JY, Antonopoulos DA, Kalra A, et al. JID 2008:197 435 -438

Conclusions 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 “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:

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:

Treatment Options European Society of Clinical Microbiology and Infections
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.

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 For mild/moderate disease, metronidazole is recommended as oral antibiotic treatment of initial CDI (500 mg 3 times daily for 10 days) 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.

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:

For severe CDI vancomycin 125 mg 4 times daily (may be increased to 500 mg 4 times daily) for 10 days 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

Annals of Surgery Volume 254, Number 3, September 2011
Treatment Options European Society of Clinical Microbiology and Infections For multiple recurrent CDI, fecal transplantation is strongly recommended 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 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
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:

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 50 ml over 3 minutes January 31, 2013 van Nood E., Vrieze A., Nieuwdorp M., et al. N Engl J Med 2013; 368:

January 31, 2013 van Nood E., Vrieze A., Nieuwdorp M., et al. N Engl J Med 2013; 368:

Bacteriotherapy 16sRNA sequencing before and after fecal transplant Prior to therapy Deficient in Bacteroides and Firmicutes 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);

ID Week 2013 Fecal Transplantation
University of Calgary Pills Centrifuge Encapsulate in three layers of gelatin Release in colon 24 – 34 capsules 27 patients 100% with resolution 40 patients 98% with resolution ID Week Abstract 89. Presented October 3, 2013

ID Week 2013 Fecal Transplantation
University of Calgary Patient Satisfaction 9.6 overall 9.9 for ease 9.9 would recommend ID Week Abstract 89. Presented October 3, 2013

“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 Abstract 89. Presented October 3, 2013

Cost-effectiveness for Management of Recurrent CDI
Decision analytic model 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

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 Healthy Mild-moderate CDI Severe CDI Persistent recurrent disease Postcolectomy Death Konijeti GG, Sauk J, Shrime MG, et al. March 31, 2014: 1 - 6

Treatment algorithms consistent with previously presented guidelines Median hospital duration of two weeks FMT colonoscopy was the most cost-effective strategy for recurrent CDI 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:

Thank You

The Human Microbiome Brian Koll, MD, FACP, FIDSA Professor of Medicine

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