ADVANCES IN FECAL MICROBIOTA TRANSFORMATION · Smits LP, et al. Gastroenterology 2013 FMT PROCESS...
Transcript of ADVANCES IN FECAL MICROBIOTA TRANSFORMATION · Smits LP, et al. Gastroenterology 2013 FMT PROCESS...
American Pediatric Surgical Nurses Association
One Parkview Plaza, Suite 800 | Oakbrook Terrace, IL 60181 | www.apsna.org
25th Annual Scientific Conference | May 12-15, 2016 | San Diego, CA
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ADVANCES IN FECAL MICROBIOTA TRANSFORMATION
Amanda Bradshaw, MPAS, PA-C Seattle Children’s Hospital
Seattle, WA
DISCLOSURE STATEMENT
• Neither I nor any member of my immediate family has a financial relationship or interest with any proprietary entity producing heath care goods or services related to the content of this CME activity.
• My content will not include discussion/reference of any commercial products or services.
• I do not intend to discuss an unapproved/investigative use of commercial products/devices
OBJECTIVES
• Applications for Fecal Microbial Transplant
• Methods involved in Fecal Microbial Transplant
• Outcomes of Fecal Microbial Transplantation
American Pediatric Surgical Nurses Association
One Parkview Plaza, Suite 800 | Oakbrook Terrace, IL 60181 | www.apsna.org
25th Annual Scientific Conference | May 12-15, 2016 | San Diego, CA
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HUMAN MICROBIOME
Microbiome – Referring to the distinctive populations of microrganisms inhabiting a location
Wu and Lewis. CGH 2013
HUMAN MICROBIOME
Weight Cells Genes Microbiome Human
99% 10% 1%
• 100 trillion microorganisms
• Human gut - 2lbs of bacteria
• Outnumber human cells by a factor of ten • Genomes encode around 3 million different genes
FECAL MICROBIOME
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Who’s there?
What are they doing?
Who’s they are varies: your microbiota is plastic and
personalized.
What they’re doing is adapting to
their environment:
you, your body, and your environment.
Savage, DC. Annu Rev Microbiol 1977; 31:107-133
Backhed, F ,et al Science. 2005; 307: 1915-1920.
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25th Annual Scientific Conference | May 12-15, 2016 | San Diego, CA
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FECAL MICROBIOME
Diversity within the human fecal microbiome may supply broader insight into the overall health of the individual.
Hollister, et al Gastroenterology 2014
MICROBIOME AND HUMAN DISEASE
Dysbiosis – Alterations in the microbiota composition associated with disease
Impacted by:
Diet
Antibiotics
Other
Wu and Lewis. CGH 2013
EFFECTS OF MODIFYING THE DIET ON MICROBIOME
Wu, G, Science 334, 105 (2011); 105-108
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MICROBIOME AND HUMAN DISEASE
Described possible associations in the gut for numerous disease processes:
Infection (Clostridium Difficile)
Inflammatory Bowel Disease (IBD)
Cancer
Metabolic Disorders
C. DIFFICILE PARADIGM
C. difficile Dysbiotic Microbiome
Environment
Antibiotics
Diet
CDI: PATHOGENESIS Step 1- Ingestion
of spores
transmitted
from other
patients Step 2- Germination into
growing (vegetative) form
Step 3 - Altered lower intestine
flora (due to antimicrobial use)
allows proliferation of C. difficile
in colon
Step 4 . Toxin B & A production leads to
colon damage +/- pseudomembrane
American Pediatric Surgical Nurses Association
One Parkview Plaza, Suite 800 | Oakbrook Terrace, IL 60181 | www.apsna.org
25th Annual Scientific Conference | May 12-15, 2016 | San Diego, CA
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CLOSTRIDIUM DIFFICILE
Increasing rates of relapsing C. dificile
Cure is common; resurgence is common too!
Nosocomial infection resistance to metronidazole
Flagyl, vancomycin, rifixamin, nitazoxanide, and probiotics
INCIDENCE RATE OF CDI
Pepin et al. CMAJ. 2004;171:466-472.
CURRENT APPROVED FMT APPLICATIONS
Recurrent C. Difficile Infections
Research Applications:
IBD
Obesity
Antibiotic resistant bacterias
Graft versus host
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25th Annual Scientific Conference | May 12-15, 2016 | San Diego, CA
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FECAL BACTERIOTHERAPY FOR RELAPSING C. DIFFICILE IN A CHILD
2 year old girl – 8 months ordeal
Watery diarrhea 1
Treatment
10 days of metronidozole
30 day of vancomycin and lactobacillus gg
Vanco plus rifixamin plus Saccharomyces boulardii plus lactobaccillus gg
Re-occurred after 14 days
George Russell, et al Pediatrics 126, number 1, July 2010
FECAL BACTERIOTHERAPY FOR RELAPSING C. DIFFICILE IN A CHILD
Vanco another 2 weeks
Then
Vanco – 2 weeks
Nitazoxanide 3 days then
Vanco 2 weeks then
Rifixamin 7 days then
Pulsed dose of vanco over 6 weeks
DID NOT WORK! What next! George Russell, et al Pediatrics 126, number 1, July 2010
FMT AND… IT WORKED!
Within 36 hours, abdominal symptoms and diarrhea resolved and did not re-occur during 6 months of monitoring.
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25th Annual Scientific Conference | May 12-15, 2016 | San Diego, CA
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FMT FOR RECURRENT CLOSTRIDIUM DIFFICILE
0
10
20
30
40
50
60
70
80
90
100
First Infusion ofDonor Feces (n=16)
Infusion of DonorFeces
Overall(n=16)
Vancomycin (n=13) Vancomycin withbowel lavage
(n=13)
81.3
93.8
30.823.1
Percentage Cured without Relapse
FMT AND C. DIFFICILE
Fecal Microbial Tansplant (Transfer) - Alteration of the gut microbiota by direct transfer of entire communities in the same relative abundance as exists in the healthy donor
Approximately 90% success rate
Wu and Lewis. CGH 2013
Smits LP, et al. Gastroenterology 2013
FMT PROCESS
Typically administered:
• Enema
• Colonoscopy
• Nasogastric – Infused, then followed with a normal saline flush
• Nasoduodenal
• Nasojejunal
• Capsules
It appears as if all routes are equal
Wu and Lewis. CGH 2013
American Pediatric Surgical Nurses Association
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25th Annual Scientific Conference | May 12-15, 2016 | San Diego, CA
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FMT PROCESS
Openbiome – Stool repository
Donor Screening:
HAV antibody (IgM and IgG)
HBV Antibody to hepatitis B surface antigen,
Antibody to hepatitis B core antigen
HCV HCV antibody (RIBA-II)
HIV-1 and HIV-2 EIA
Treponema pallidum Rapid plasma reagin test
Stool Clostridium difficile Toxin A or toxin B (cytotoxin)
Enteric bacterial pathogens
Selective stool culture
Ova and parasites Light microscopy 2013 Joint Societal Guidelines for C. Diff
IBD AND THE MICROBIOME
Intestinal microbiota of IBD patients appears to have reduced diversity compared to healthy subjects.
Unclear whether these differences are a cause or consequence of development of IBD.
Smits LP, et al. Gastroenterology 2013
FMT IN IBD
Will it work
Crohn’s disease
Ulcerative colitis
Route
Dose
Frequency
Who is the best donor
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Study #IBD
pts
IBD
Type
IBD
Severity
FMT
Dosage
FMT
Delivery
Pre-Abs/
Lavage
Frequency Donor Follow-Up
Borody et al.
(1989). 2 UC, CD Active NR NR NR NR NR 1-12 months
Borody et al.
(2001). 3 UC Quiescent Suspended in
200ml saline
Enema NR Daily x 5 days Healthy Adults 8-28 months
Borody et al.
(2003). 6 UC Severe 200-300g
(diluted to 200-
300ml)
Enema Vancomycin,
Metronidazole, and
rifampicin
Daily x 5 days Family or Close
Relation
1-13 years
Borody et al.
(2011). 3 IBD Isevere NR Enema
(Self)
NR Daily/Weekly X34-
70
Clinic donor,
family, partner
1-4 years
Kellermayer et al.
(2013). 4(-1a) UC IM/anti-TMF
Dependent
NR Colonoscopy NR Serial ? >5 months
Suskind et al. (2014) 3 UC Mild-Moderate 60ml NG Rifaximin X 1 Parent 12 weeks
Vermeire et al.
(2012).2 4 CD Medically-
refractory
200g feces NJ infusion NR 3x in 36 hours Healthy Donor 2 months
Kunde et al.
(2013). 10(-1a) UC Mild-moderate 90-113g/250ml Enema up to
(4x60ml)/day
NR x5 days Parents 6 weeks
Kump et al. (2013). 6 UC Therapy-refractory 150g/
200 saline
Colonoscopy Lavage of donor x1 Nonrelatives, 1 year
Angelberger et al.
(2013). 5 UC Severe 6-22g/100ml NJ + Enema Metronidazole x3 days No Family/
Hospital Staff
>1 year
Suskind et al.
(2014). 9 CD Mild-moderate 60ml NG Rifaximin x1 Parents 12 weeks
Landy et al. (2013). 5 UC refractory pouchitis 30g/250ml Saline Nasogastric NR x1 Nominated by
participating pts
4 weeks
Zhang et al.
(2013). 16 CD Refractory (HBI>8) NR Gastroscopic NR x1 NR 1 month
Damman et al.
(2014). 8(-1a) UC Mild-moderate
(UCDAI 3-10)
NR Colonoscopic Standard colon
prep
x1 Chosen by
Recipient
12 weeks
Vaughn et al.
(2014). 9 CD Active CD (HBI>6) 50g in 250ml Saline Colonoscopic Standard colon
prep
x1 Healthy Unrelated 12 weeks
FMT IN CROHN’S DISEASE
Mild to moderate active disease
9 Patients
12-19 years of age
Medication therapy continued
Pre-FMT antibiotics
Nasogastric tube
Disease activity and microbiome
Follow up 2, 6, and 12 weeks
Suskind, et al Inflamm Bowel Dis 2015;0:1-8.
* Initiated Standard medical treatment prior to clinic visit
** Initiated Standard medical treatment after 12 week clinic visit
PEDIATRIC CROHN’S DISEASE ACTIVITY INDEX
(PCDAI)
Suskind, et al Inflamm Bowel Dis 2015;0:1-8.
American Pediatric Surgical Nurses Association
One Parkview Plaza, Suite 800 | Oakbrook Terrace, IL 60181 | www.apsna.org
25th Annual Scientific Conference | May 12-15, 2016 | San Diego, CA
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* Initiated Standard medical treatment prior to clinic visit
** Initiated Standard medical treatment after 12 week clinic visit
Normal <0.8 mg/dL
C-REACTIVE PROTEIN (MG/DL)
Suskind, et al Inflamm Bowel Dis 2015;0:1-8.
FMT IN CROHN’S DISEASE
7 of 9 patients were in remission at 2 weeks
5 of 9 patients who did not receive additional medical therapy were in remission at 6 and 12 weeks
No or modest improvement was seen in patients who did not engraft or whose microbiome was most similar to their donor.
Suskind, et al Inflamm Bowel Dis 2015;0:1-8
FMT IN ULCERATIVE COLITIS
Studies suggest remission of disease is possible with multiple FMT’s for a subgroup of patients.
Smits LP, et al. Gastroenterology 2013
American Pediatric Surgical Nurses Association
One Parkview Plaza, Suite 800 | Oakbrook Terrace, IL 60181 | www.apsna.org
25th Annual Scientific Conference | May 12-15, 2016 | San Diego, CA
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POTENTIAL FUTURE APPLICATIONS
Metabolic Disorders
Neuropsychiatric Disorders
Autoimmune Diseases
Allergic Disorders
Tumors
Meng-Que Xu, et al. World J. Gastroentol. 21(1), January 2015
CONCLUSION
• Fecal Microbiome is complex and biologically important in Health and Disease
• Fecal Microbiome modulates us, and we modulate our Fecal Microbiome
• FMT has impressive treatment success in cases of recurrent C. Difficile
• Role of FMT in other disease processes remains to be seen
• Further research is needed to move this discussion forward
REFERENCES
Bäckhed F, Ley RE, Sonnenburg JL, Peterson DA, Gordon JI. Host-bacterial mutualism in the human intestine. Science. 2005 Mar 25;307(5717):1915-20.
Hollister E., Gao C., Versalovic J. Compositional and functional features of the gastrointestinal microbiome and their effects on human health. Gastroenterology. 2014(146): 1449–1458.
Meng-Que X, Hai-Long C, Wei-Qiang W, Shan W, et al. Fecal microbiota transplantation broadening its application beyond intestinal disorders. World J Gastroenterol. 2015 Jan 7; 21(1): 102–111.
Pepin J, Valiquette L, Alary ME, et al. Clostridium difficile-associated diarrhea in a region of Quebec from 1991 to 2003: a changing pattern of disease severity. CMAJ. 2004;171:466-472.
Russell G, Kaplan, J, Ferraro M, Michelow I. Fecal microbiotherapy for relapsing Clostridium Difficile infection in a child: A proposed treatement protocol. Pediatrics. 2010 July; 126 (1).
Savage DC. Microbial ecology of the gastrointestinal tract. Annu Rev Microbiol. 1977;31:107-33.
American Pediatric Surgical Nurses Association
One Parkview Plaza, Suite 800 | Oakbrook Terrace, IL 60181 | www.apsna.org
25th Annual Scientific Conference | May 12-15, 2016 | San Diego, CA
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REFERENCES (CONTINUED)
Suskind, et al. Fecal microbial transplant effect on clinical outcomes and fecal microbiome in active Chron’s Disease. Inflamm Bowel Dis 2015;0:1-8.
Smits LP, Bouter KE, de Vos WM, Borody TJ, Nieuwdorp M.Therapeutic potential of fecal microbiota transplantation. Gastroenterology. 2013 Nov;145(5):946-53.
Van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N. Engl J Med. 2013;368:407–415.
Wu GD, Lewis JD. Analysis of the human gut microbiome and association with disease. Clin Gastroenterol Hepatol. 2013 Jul;11(7):774-7.
Xu MQ, Cao HL, Wang WQ, Wang S, Cao XC, Yan F, Wang BM. Fecal microbiota transplantation broadening its application beyond intestinal disorders. World J Gastroenterol. 2015 Jan 7;21(1):102-11
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