C.Difficile an epidemic that is waiting for answers - PowerPoint Presentation

Slide1

C.Difficilean epidemic that is waiting for answers

Michael Gavin MD

Division of Gastroenterology

University of New Mexico

Slide2

Burden of Clostridium difficile Infectionin the United

States

n engl j med 372;9 nejm.org february 26, 2015

C. difficile

-

almost half a million

infections/

yr

Approximately

29,000 deaths in

2011

(within 30 days of infection)

Persons 65 years of age or older

,

whites &

females had higher incidences than their comparators.

Slide3

C. Difficile Infection in the Elderly Keller JM Clinics in Geriatric Medicine 2014, 30:79-83.

92% deaths (C.

Dif) occurred in age 65 & older

Age itself is a risk factor

-after age 65, risk increases 2% a year

50% of residents of long-term facilities are

*asymptomatic carriers

*(20% of hospitalized pts.)

Slide4

C. Difficile Infection in the Elderly Keller JM Clinics in Geriatric Medicine 2014, 30:79-83.

Increase rates-

Severe Disease

Medical complications

Mortality

Slide5

Burden of Clostridium difficile Infectionin the United

States

n engl j med 372;9 nejm.org february 26, 2015

24%

of cases occurred

inhospital

settings,

(107,600

hospital-onset infections

nationally)

Of

community-associated

CDI,

82%

estimated to be associated with

outpatient health

care exposure

.

The rate of

asymptomatic colonization

in

nonhospitalized

adults

is to

be

2%,

with a higher rate, up

to 26

%, in those with health care exposures.

Slide6

Burden of Clostridium difficile Infectionin the United

States

n engl j med 372;9 nejm.org february 26, 2015

At

least one recurrence of

C.

difficile

infection

occurred in approximately

21%

of cases

of health care–associated

infection

14

%

of cases of community-associated infection

E

st.

burden of 83,000

first recurrent infections

* repeated stool testing between 14 & 56 days after the initial

C. difficile

episode

Slide7

Burden of Clostridium difficile Infectionin the United

States

n engl j med 372;9 nejm.org february 26, 2015

Counties under

Surveillance:

(10 Nationally)

New

Mexico

Bernalillo

: 661,779 (

population

):

Community-Associated CDI Cases:

354

Incidence per 100,000 Persons:

53.4 (

All

sites

:

48.2)

Health

Care–Associated

CDI Cases:

727

Incidence per 100,000 Persons:

109.9 (

All

sites

:

92.8)

Slide8

Burden of Clostridium difficile Infectionin the United

States

n engl j med 372;9 nejm.org february 26, 2015

NAP1 (PCR

ribotypes

027): Binary toxin

NAP4 (PCR

ribotypes

020):

NAP11(PCR

ribotype

106):

*

The

NAP1 strain

was more common among health

care–associated

cases than among

community-associated cases (30.7% vs. 18.8%, P<0.001)

Slide9

Pathogenesis

Fecal-oral route

(20% of hospitalized pts. colonized/hands of healthcare workers)

Ingested: vegetative form or spores

(resistant to gastric acid)

Spores germinate in small intestine

Colonization (colon

)-

microbiome

disrupted by antibiotic

therapy

Slide10

Virulence factors

Toxin A (

TcdA) & Toxin (TcdB): exotoxins- bind human intestinal

epithelial cells

Tcd

A-

enterotoxin

(+)

IL-6, IL-8 (epithelial cells), plus IL-1, TNF-A (monocytes)

Tcd

B-

cytotoxin

cell

retraction and apoptosis (grossly visible as cell rounding in tissue culture assays and as shallow ulceration on the intestine mucosal surface)

Majority disease attributable to both toxins

7-10% B toxin only

Binary toxin: different toxin and

hypervirulent

strains

Slide11

Pseudomembranous Colitis

Histopathology

Type 1 PMC:

mildest form (inflammatory changes confined to the

superficial

epithelium) Typical

pseudomembranes

are

present

Type 2 PMC:

severe disruption of glands, marked

mucin

secretion,

more

intense inflammation of basal

lamina

Type 3 PMC:

severe, intense necrosis of the full thickness of the mucosa with a confluent

pseudomembrane

Slide12

Pseudomembranes

Slide13

B1/NAP1/027*

Name

B1

:

by

its pulsed-field gel electrophoresis (PFGE)

patttern

NAP1:

North American PFGE type 1 pattern

027:

PCR

ribotype

designation

(

Europe)

Binary

toxin

*

- similar to iota toxin of

C.perfringens

Produces higher levels of

TcdA & TcdB

-due to truncated

tcdC

gene (negative regulator)

Resistant to

fluoroquinolones* first reported in Canada (2004)* an enzymatic & a binding component

Ananthakrishnan

NR: Gastroenterology & Hepatology 8:17-25

Slide14

Antibiotics

Prior Exposure Antibiotics

: 85% pts with CDI within 28 days

Antibiotic Utilization:

Increased duration & multiple antibiotics

Clindamycin

(1970-1980

)

Parenteral

Cephalosporins

(

1980-1990’s)

Fluoroquinolones

(2000’s):

inpts

&

outpts

Slide15

PPI- risk factor for CDI

70% increased risk for CDI

Independent risk factor for CDI in ICU pts.FDA (2/2012): “may predispose to CDI” Dickinson B

Surawicz

Curr

Gastroenterol

Rep (2014) 16:399

Slide16

Commercially available tests

EIA against toxins (

A&B)Detect both toxinsGreater sensitivity

False negatives high

Hence the classic thought of multiple tests

GDH (

glutamase

dehydrogenase)

Common antigen

High sensitivity

Low specificity

Can rule-out

C. difficile

PCR

: new test with sensitivity and specificity

Slide17

Toxin testing (Tricore)

EIA-GDH

(glutamate dehydrogenase)

-C. Difficile “common antigen”

plus

EIA-toxin A/B

If both tests (-), C. Difficile negative.

If both tests (+), C. Difficile positive.

*Discordant

results are reflexed to PCR assay.

Turn around time: 4-5 hrs.

Slide18

Testing (Tricore)

Discordant results are reflexed to PCR assay:

PCR toxin B gene

:

If PCR positive,

C.Difficile

is present.

If PCR negative,

C.Difficile

is negative.

*Testing only on diarrheal stools (exception: Ileus- rectal swap)

*Resubmissions after 7-day period

Slide19

Diagnosis

Stool tests:

Identification of C. diff toxins A and/or B (Sensitivity 94-100%; Specificity 99%)EIA (Sensitivity 60-95%; Specificity 99%)

PCR

(Sensitivity 94%; Specificity 97%)

Slide20

Diagnosis: Treat the Pt. Not the Test

Polage CRJAMA Intern Med. doi:10.1001/jamainternmed.2015.4114

(50%) (+) PCR

results

for

C

difficile

do not experience adverse

events without treatment (asymptomatic colonization)

2-step testing with a screening test, such as

glutamate dehydrogenase

antigen detection, followed by a

toxin test

to confirm active infection is a reasonable

diagnostic strategy.

Slide21

Clinical Features

Diarrhea (mild disease)

watery diarrhea with “manure” odorDiarrhea with colitis —  watery diarrhea up to 10 or 15 times daily with lower abdominal pain and cramping, low grade fever, and leukocytosis, lactic acid elevation

*Inpatients with unexplained leukocytosis or fever consider CDI

(

20% of patients with severe CDI have ileus)

Slide22

Stages of Disease

C. difficile Diarrhea

: mild-mod. diarrhea , (-) blood, (+)C.Dif toxin

C. Difficile Colitis

: high-volume watery diarrhea , fever,

malaise, Leukocytosis

, Flex

Sigm

: erythematous , patchy mucosa

Pseudomembranous Colitis (PMC):

systemic illness (yellow raised

plagues ranging

from 2-10 mm in diameter)

Fulminant Colitis

(paralytic ileus- toxic

megacolon

- colonic perforation)

-dilated colon with severe toxicity

Slide23

SHEA-IDSA Guideline

Clinical Case Defination

Initial Episode

:

Mild or Moderate

Initial Episode

:

Severe

Initial Episode

:

Severe, complicated

Laboratory Data and Clinical Findings

WBC

<

15 K

Serum Creatinine< 1.5X

pt’s premorbid baseline

WBC >15K

Serum creatinine>1.5x

pt’s premorbid baseline

Hypotension, shock, ileus,

megacolon

Slide24

SHEA-IDSA

GuidelineInitial Episode

Mild or Moderate:

Severe:

Severe, complicated

Treatment

Metronidazole 500mg

po

tid

(10-14 days)

Vancomycin

125 mg

po

qid

(10-14 days)

Vancomycin

500mg

po

qid

*Metronidazole 500mg IV q 8

hrs

,

For Ileus, rectal

vancomycin

500mg

qid

(mixed in 100 cc NS)

Consider surgical consultation

Slide25

Clinical Case Definition

First recurrence:

Same as initial episode,

based on severity

Second Recurrence:

Infectious Disease Consult

recommended

Do not use metronidazole beyond first recurrence due

to risk of neurotoxicity.

Vancomycin

taper:

125 mg

po

qid

10-14 days

then

125 mg

po

bid 7days

then

125 mg

po

qd

7 days

then

125 mg

po

qod

2-8 weeks

Recommended

Treatment

Slide26

Breaking the cycle: treatment strategies for 163 cases of recurrent Clostridium difficile

 McFarland L Elmer G 

Surawicz C ACG (2002)

97

, 1769–1775

choice of antibiotic treatments was limited to either low dose or high dose

vancomycin

(500 or 2 g/day for 10 days) or metronidazole (1 g/day for 10 days). If the patient failed the initial study's antibiotic treatment, the patient was considered a treatment failure and the choice of the subsequent therapy was decided by the patient's physician.

Subsequent antibiotic treatments chosen by physicians included repeated 10- to 16-day courses of an antibiotic; a "tapered regimen" (dose of

vancomycin

or metronidazole started at one dose [500 mg to 3 g/day] and then decreased stepwise over a period of time to doses ranging from 125 to 750 mg/day); a "pulsed regimen," which may or may not have followed a 10- to 14-day course of

vancomycin

, followed by a pulse of a dose of

vancomycin

(125–500 mg) every 2–3 days over a period of time (usually 3

wk

); and a combination of the above.

Vancomycin

was significantly more effective in clearing C. difficile culture and/or toxin by the end of therapy than metronidazole (89% vs 59%, respectively; p < 0.001).

Slide27

Recurrent or relapsing CDI

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. 

At least three episodes of mild-to-moderate CDI and failure of a 6- to 8-week taper with

vancomycin

with or without an alternative antibiotic (e.g.,

fidaxomicin

,

rifaximin

) or at least two episodes of severe CDI resulting in hospitalization and associated with significant morbidity.

Slide28

Refractory CDI 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. 

Moderate CDI not responding to standard therapy (

vancomycin

) for at least a week.

Slide29

Severe CDI

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. 

White

blood cells ≥15,000 cells/mm

3

, albumin <3g/dl, and abdominal tenderness.

Slide30

Complicated CDI

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. 

defined

by at least one of the following

:

Admission to the intensive care

unit

hypotension

with or without the use of

vasopressors

fever ≥38.5 °C

ileus or significant abdominal distention, mental status

changes

white blood cells ≥35,000 cells/mm

3

, or serum lactate >2.2 mmol/l, or any evidence of end-organ failure.

Slide31

Metronidazole

First line Therapy

(+)Inexpensive

(+)Less risk of selecting

vancomycin

-resistant

enterococci

(-) absorbed rapidly (6-15% drug excreted in stool) and

decreases after treatment of CDI is initiated.

(-) peripheral neuropathy, nausea, headache,

dysgeusia

Disease severity

:

Vancomycin

superior to

Metronidazole

in severe disease

.

Zar

, FA et al

Clin

. Infect.

Dis.2007

45:302-307

Slide32

Vancomycin

(+)FDA –approved for CDI

(+)High fecal concentrations throughout treatment

(+)Lack of systemic toxicity

(-)Expensive (* compounded form: IV to elixir form)

(-) Bacterostatic

(-)20-30% recurrence of illness within 60 days

(occurs with metronidazole or vancomycin)

Slide33

Fidaxomicin (

DIFICID

)

FDA–approved for CDI

Macrolide antibacterial drug:

200mg bid X 10 days.

Spectrum of activity:

primarily against clostridia species

92% recovered in stool

Bactericidal

Adverse reactions:

Nausea (11%), Vomiting (7%), Abdominal pain (6%)

(similar to vancomycin adverse reaction profile)

*Neutropenia (2%)

Slide34

Fidaxomicin versus

Vancomycin

for Clostridium DifficileN

Engl

J Med 2011;364:422-31

(629) Adults(CDI):

FID

200mg

bid

vs

VAN

125mg

qid

10 days

Primary End point

:

Clinical cure- FID: 88%

vs

VAN: 86%

Secondary End point

:

Recurrence (4 weeks): FID: 15%

vs

VAN: 25% (p=0.005)

Clinical cure: resolution of diarrhea (

ie

3 or fewer unformed stools for 2 days)

as of the second day after the end of treatment

Slide35

Fidaxomicin versus

Vancomycin

for Clostridium DifficileN

Engl

J Med 2011;364:422-31

Bi/

NAP1

/027 strain

: 35.9% of patients

Rates of Recurrence : FID: 24.4% vs. VAN: 23.6%

Subgroup analysis

: No significant difference

Severity of Disease

Patient’s age

Recurrent CDI

Slide36

Fecal Microbiota

Transplant

Recurrent/Refractory CDI (RCDI)

Antibiotic-associated diarrhea (CDI?) 1958

-4 pts treated with human fecal enemas (cure: 4/4)

Eiseman Surgery 1958;444:854-859

Recurrent CDI (1980’s):

(6 pts)

-

Human fecal enemas or bacterial mixture enema

-Bacteroides spp. absent during course of illness, restored!

Tvede et al Lancet 1,1156-1160 (1989)

Slide37

Fecal Microbiota Transplant

Nasogastrically

Administered

:

11 of 15

pts

cured

(30 ml of “

faecal

fluid” via NGT- 30grms stool/150 ml

nl

saline)

Macconnachie

AA et al QJ Med 2009; 102:781-784

Nasogastrically

Administered

:

15

of 16 pts

cured after 5 days of

vancomycin

then bowel lavage and administration of fecal fluid through a

nasoduodenal

tube compared to 4/13 with standard treatment with vancomycin and 3/13 with vancomycin treatment and bowel lavage van

Nood

E

N

Engl

J Med. 2013 Jan 31;368(5):

407-15

Retention Enema

:

7 of 7

pts

cured

(50 ml of stool in 200 ml

nl

saline- given via enema bag.)

Silverman MS et al

Clin

Gastroenterol

.

Hepatol

. 8,471-473 (2010)

Slide38

Fecal Microbiota

Transplant

Colonoscopy

12 of 12 pts. with RCDI cured:

-400 cc injected from distal TI to rectum

Yoon SS & Brandt, LJ J.

Clin

Gastroenterol

. 44,562-566(2010)

18 of 19

pts

with RCDI cured:

Rohlke

F,

Surawicz

J

Clin

Gastroenterol

. 44, 567-570 (2010)

25 of 26 pts. with RCDI cured:

Kelly, C

J

Clin

Gastroenterol

.

Feb;46(2

):

145-9 (2012)

Slide39

Screening and Selection

Patient Selection

A. Adult patients following a third or further recurrence of C.

difficile

colitis who have failed standard therapy with oral metronidazole and/or oral

vancomycin

.

B.

Patient may not be severely immunocompromised: (advanced HIV/AIDs, receiving chemotherapy or anti-TNF agents

)

Patient Screening:

(document status prior to stool transfer)

1. HIV 1 & 2

2. Hepatitis A total, Hepatitis B surface antigen, surface antibody

and core antibody and Hepatitis C antibody

3. RPR (syphilis)

Slide40

FMT for

Treatment of 

Clostridium difficile Infection in Immunocompromised Patients

Kelly CR. 

Am J

Gastroenterol

. 2014;doi:10.1038/ajg.2014.133.

 

80  (IC)

pts:(mean

age of 75

adults- 53

yrs

):

recurrent

(55%), severe or complicated (34%) or refractory (11%) 

(CDI

)

 78%

pts.

resolved of CDI, with no recurrence at least 12 weeks

A second FMT was required in 12

pts. (8

were CDI free, resulting in an overall CDI cure rate of

89

%).

In

the IBD subset (n=36), CDI cure rate was

86%

after a single FMT, and

94%

overall

.

-5 (14% of IBD patients) experienced disease flare post FMT.

-3(UC) pts had colectomy related to course of UC >100 days FMT

*SAE:

 

Two deaths occurred within 12 weeks of FMT, one of which was the result of

aspiration

during sedation for FMT administered via

colonoscopy

Slide41

Exclusion Criteria

Risk of infectious agent

Known exposure to HIV or viral hepatitis (within the previous 12 months.)

High-risk sexual behaviors (examples: sexual contact with anyone with HIV/AIDS or hepatitis, men who have sex with men, sex for drugs or money)

Use of illicit drugs

Tattoo or body piercing within 6 months

Incarceration within previous 12 months

Known current communicable disease

Risk factors for variant Creutzfeldt-Jakob disease

Gastrointestinal co-morbidities

History of inflammatory bowel disease

History of irritable bowel syndrome, idiopathic chronic constipation, or chronic diarrhea

History of gastrointestinal malignancy

Other

Antibiotic use within the preceding 90 days

Recent ingestion of a potential allergen (e.g., nuts) where recipient has a known allergy to this agent.

Systemic autoimmunity, e.g., multiple sclerosis, connective tissue disease

Chronic pain syndromes, e.g., chronic fatigue syndrome, fibromyalgia

Donor Screening Questionnaire

C. Kelly MD Brown University Alpert

SOM

Slide42

Stool testing,

Donor

a)

Clostridium

difficile

toxin B by PCR; if unavailable, then evaluation for

toxins A and B by EIA.

b)

Bacterial culture for routine enteric pathogens

c)

Fecal

Giardia

antigen

d)

Fecal

Cryptosporidium

antigen

e) Acid-fast stain for

Cyclospora

,

Isospora

and, if antigen

testing

unavailable

,

Cryptosporidium

f)

Ova and parasites

g)

Helicobacter pylori

fecal antigen (for upper GI routes of FMT administration

)

Slide43

Serologic testing: Donor

(

unless otherwise stated, all tests should be performed using FDA-approved test methods):

a) HIV, type 1 and 2

b) HAV

IgM

c)

HBsAg

, anti-

HBc

(both

IgG

and

IgM

), and anti-HBs.

d) HCV

Ab

e) RPR and FTA-ABS

Slide44

Pre-Procedure Instructions

Donor

Report symptoms of infection which occur between screening and the day of the procedure.

Take single dose of osmotic laxative on the evening prior to the procedure.

Patient

Stop oral

vancomycin

(or

metronidazole

) 3 days prior to procedure

Standard PEG colonoscopy bowel preparation

Fecal Solution Preparation

Universal precautions (gown, gloves, eye protection) during stool processing.

Fresh (< 6 hour) donor stool specimen

6-8 Tablespoons of fresh donor stool specimen added to ~1 Liter bottle of sterile water or saline and shaken vigorously to emulsify.

Filtered through gauze if necessary

Fecal suspension drawn up into 60 cc Slip Tip syringes

Procedure

Informed consent for colonoscopy obtained including the additional theoretical risk of infection related to fecal transfusion.

Document that examination of the colon is not adequate for cancer screening purposes (stool infusion interferes with visualization).

Colonoscopy performed; biopsies taken if necessary

Upon withdrawal, dilute fecal suspension delivered through the

colonoscope

(majority into the right colon)

Post-Procedure and Follow-Up

Patient encouraged to retain stool (if possible) for 30-45 minutes

Patient does not resume

vancomycin

Patient asked to report symptoms of recurrent infection and stool is tested for

C.

difficile

only if these occur.

Fecal

Microbiota

Transplantation Protocol

C. Kelly MD Brown University Alpert SOM

Slide45

Open Biome

Methodology implemented for first public stool bank for FMT

www.openbiome.orgWho are your donors?

Currently all of our donors are young researchers and scientists within the MIT, Harvard, and Tufts communities, and young professionals from the Tufts University area

.

(Reported Donor Alias: Vladimir Poo-tin NYT,2014)

Does FMT have regulatory approval in the U.S.?  

The FDA classifies fecal microbiota for FMT as an investigational drug, which typically requires an Investigational New Drug application (IND).  However, in July 2013, the FDA issued guidance stating that it would exercise 

enforcement discretion

 for physicians administering FMT to treat patients with refractory 

C. difficile

 infections. In these cases, physicians may proceed without filing an IND, provided that they have received the appropriate informed consent from the patient, at minimum indicating that

FMT is an investigational therapy, and discussing its potential risks.

 

Physicians who wish to use FMT in the treatment of all other indications are required to do so as part of an Investigative New Drug application to the FDA.  

Slide46

UNM FMT via Colonoscopy Experience

(22) patients : (15 females/ 7 males)

(1) Fecal enema

Successful treatment: 21/22

Failure

: (1)

Pt. hospitalized within 1 week with

worsening bladder outlet obstruction

requiring IV antibiotics for 1 week

Recurrence

: (2)*

(1) Crohn’s Colitis- 12 months following FMT

after antibiotic treatment for

peri

-rectal abscess

(1) Chronic

Pouchitis

- placed on chronic suppressive

antibiotics with recurrence 6 months later

*both cases treated with second FMT with success.

Slide47

UNM FMT via Colonoscopy Experience

Complications:

Short Bowel Syndrome with recurrent CDI developed intraperitoneal abscess 2 weeks later s/p IR drainage; no recurrent CDI

*

Tarik

Alhmoud

, MD

, Michael Gavin, MD. An unusual complication after a fecal microbiota transplant via colonoscopy.

AJG

, S424,

vol

109, Supplement 2, Oct 2014

.

Slide48

UNM FMT via Colonoscopy Experience

Complications:

Post-infectious IBS- likely due to relapsing/recurrent C. Difficile

(c/w post-infectious IBS)

(2) cases document with (+) LHBT c/w SIBO.

Slide49

Weight Gain After FMT

Alang

N Kelly C Open Forum Infectious Diseases

Volume

2, Issue

1

10.1093/

ofid

/ofv004

FMT for Relapsing C.

Dif

(36

yo

female Baseline BMI-26)

As

per the patient’s request, her

16-year-old

daughter

was chosen as the stool donor.

D

aughter’s

weight was ∼140 pounds (BMI of 26.4), but it

increased

later to 170 pounds

.

The patient presented again 16 months after FMT, and reported an unintentional weight gain of 34 pounds. She weighed 170 pounds

and had become obese (BMI of 33

).

Conclusion: The possible transmission

of an obese phenotype

Slide50

Gut microbiota from

twins discordant for obesity

modulate metabolism in mice. Ridaura

VK

Science 2013; 341:1241214.

germ-free mice receiving

a stool

lavage

from

an obese twin

Developed significantly

greater adiposity than

mice

infused with the lean twin’s

microbiota

Slide51

Transfer of intestinal microbiota from lean donors

Vrieze A Gastroenterology 2012;

143:913–916.

transfer of a lean

microbiota

to individuals

with metabolic

syndrome

improved

insulin sensitivity when

compared with

controls

butyrate-producing bacterial strains

(activate intestinal gluconeogenesis

)

increased

in both

lean stool

samples

&

lean

individual’s intestinal

biopsies

Slide52

Recovery of the Gut Microbiome following Fecal Microbiota Transplantation

Seekatz

AM. mBio. 2014;doi:10.1128/mBio.00893-14.

16S

rRNA

sequencing on pre- and post-FMT samples of 14 patients who had at least two recurrent

CDI

compared with

samples from 10 donors

Proteobacteria

 made up 48.2% of pre-FMT OTUs compared with 11.2% of post-FMT (

P

<.001) and 0.73% of donor OTUs (

P

<.0001). 

 

Bacteroidetes

constituted

1.3% of pre-FMT OTUs compared with 32.3% of post-FMT (

P

<.0001) and 32.8% (

P

<.0001) of

donor OTUs.

Firmicutes

 and Bacteroidetes correlated with healthy post-FMT and donor status while Proteobacteria

 correlated with pre-FMT

.

*operational

taxonomic units (OTUs)

Slide53

C.Difficile infection (CDI)

in IBD

Prevalance: 8X greater than non-IBD pts.

(hospitalized)

Outcomes: Increased risk for colectomy in UC

*

Check stool for CDI with any flair in IBD!

Berg A

Inflamm

Bowel Dis Jan 2013;19:1

Slide54

Oral, Capsulized, Frozen Fecal Microbiota Transplantation for Relapsing Clostridium difficile

Infection

Youngster I. JAMA. 2014;doi:10.1001/jama.2014.13875.

 

20 pts

(median age, 64.5 years; range, 11-89 years

)

-

at least 3 episodes of mild to moderate 

C difficile

 

infection

-

failure of a 6- to 8-week taper with

vancomycin

or at least 2 episodes

of severe

 

C difficile

 infection requiring hospitalization were enrolled

.

 Healthy volunteers

screened for donors/

FMT capsules were generated

Patients received 15 capsules on 2 consecutive days and were followed up for symptom resolution and adverse events for up to 6 months

.

 Resolution of diarrhea was achieved in 14 patients (70%) after a single capsule-based FMT.

6

nonresponders

:

re-treated; 4 had resolution of

diarrhea

(90% overall)

Slide55

Stool substitute transplant therapy for the eradication of Clostridium

difficile

 infection: ‘RePOOPulating’ the gutPetrof E

Microbiome

 2013, 

1

:3  

doi:10.1186/2049-2618-1-3

 

(33)

isolates were recovered from a healthy

donor

stool

sample

.

 Purified isolates were identified by 16S

rRNA

gene sequencing and were subjected to antibiotic susceptibility profiling. 

one-half (50 ml) of the solution was deposited in the region of the cecum/proximal ascending colon and the other half was drizzled throughout the transverse colon as the

colonoscope

was withdrawn.

Slide56

Stool substitute transplant therapy for the eradication of Clostridium

difficile

 infection: ‘RePOOPulating’ the gutPetrof E

Microbiome

 2013, 

1

:3  

doi:10.1186/2049-2618-1-3

(2) patients were infected with the hyper virulent 

C. difficile

 strain,

ribotype

078.

Following stool substitute treatment,

-reverted to their normal bowel pattern within 2 to 3 days

-remained symptom-free at 6 months.

The analysis demonstrated that

rRNA

sequences,

-found in the stool substitute were rare in the

pre-treatment stool samples

-constituted over 25% of the sequences up to 6 months

after treatment.

Slide57

Administration of Spores of Nontoxigenic Clostridium difficile

Strain M3 for Prevention of Recurrent

C difficile Infection Gerding

DN ,

JAMA

. 2015;313(17):1719-1727. doi:10.1001/jama.2015.3725

Clostridium difficile

infection recurrence

:

-

30% (

placebo)

- 11% (NTCD-M3)

(

odds ratio [OR], 0.28; 95% CI, 0.11-0.69;

P

= .006)

Slide58

Fulminant CDI

CT findings-colonic wall thickening, colonic dilation, ascites

Slide59

Fulminant CDI

Surgical treatment

: organ failure, shock, vasopressors requirement, worsening CT findings, peritonitis, or lack of response to max medical therapy within 24-72 hrs.Surgical Procedure

:

Subtotal abdominal colectomy with

end ileostomy(rectal stump)

*

Loop

ileostomy and colonic lavage

(PEG)- reduced

morbidity and preservation of the colon.

30 day Mortality

(CDI requiring ICU admission):

Surgical treatment: 34% Medical treatment:58%

Ann

Surg

2007;245:267-72.