c. difficile prevention & treatment probiotics, antibiotics & fecal microbiota...

C. difficile prevention & treatment

Probiotics, antibiotics & fecal microbiota transplantationThe scoop on therapeutic poop

Monika Fischer, MD, MSCRAssistant Professor of Clinical Medicine

DisclosureDisclosure

No conflict of interest

Clostridium difficile infection Clostridium difficile infection (CDI)(CDI)

Traditional medical school fact: Clostridium difficile pseudomembranous colitis is a Clindamycin aftermath and highly treatable with metronidazole

C. difficile infection (CDI) associated with numerous other antibiotics and often resistant

to metronidazole

US rates hospital discharges with CDI doubled between 2000 and 2008

Increased need for ICU stay and prolonged antibiotic courses to clear infection

High colectomy rates (10%) High case mortality: 7500/year (10-fold increase

since 1999) Refractory disease in low risk populations

Beginning of 2000Epidemic strain of C. difficile

.

BI/NAP1/027BI/NAP1/027

Linked to widespread fluoroquinolone and cephalosporin use

High-level fluoroquinolone resistance “Hypervirulent” 18-fold more toxin A & B Binary toxin: Improved toxin-binding and

translocation into the cells

Poutanen SM et al. CMAJ. July 6,2004;171(1).

C. difficile infectious inoculum is 10 spores

Host factorsHost factors Age ≥ 65 year Immunosuppression

– recipients of organ transplants (3-11%), chemotherapy, corticosteroids, HIV, IBD, ESRD, ESLD

PPI use ≥ 3-fold Hospitalization, long-term care facilities

– After 1 week 13%, after 4 weeks > 50% colonization rate

Previous CDI

Prevention: infection controlPrevention: infection control

Early detection– High index of suspicion in patients with risk factors– Empiric therapy should be started regardless of

laboratory testing– Use of best diagnostic test for toxigenic C. diff.

with a rapid turn-around time (PCR)– Repeat stool testing is discouraged

• < 5% chance for positive test

Routine screening in hospitalized patients without diarrhea is not recommended

Hospital-based infection Hospital-based infection control programcontrol program

Antibiotic stewardship Contact precautions should be maintained

at a minimum until the resolution of the diarrhea

– Private rooms– Hand hygiene: soap (preferably 4%

chlorhexidine) & water. Alcohol based antiseptic does not kill C.diff spores!

– Barrier precautions (gloves & gowns)

Prevention: infection controlPrevention: infection control

Single use disposable equipment Environmental disinfection with10% bleach

(5,000 p.p.m. chlorine) for at least 10 minutes

Infection control “bundle” decreased CDI hospital rates by 33% (7.2/1000 to 4.8/1000)

Prevention: ProbioticsPrevention: Probiotics

Annals 2012 SER and Meta-analysis of 20 trials: Probiotics given for the duration of the antibiotic therapy or up to 2 weeks after reduced the incidence of CDI by 66%

No difference in outcome – Between species: Bifidobacterium, Lactobacillus,

Saccharomyces, or Streptococcus– Single species vs. mixture– Adults vs. children– Lower or higher doses (<10 billion CFU/d vs.≥10 billion

CFU/d)

Treatment: supportive careTreatment: supportive care

Any inciting antimicrobial agent should be discontinued

Maintain enteral nutrition Fluid resuscitation, electrolyte replacement DVT prophylaxis Anti-motility agents are allowed but only in

combination with medical therapy

Treatment: antibioticsTreatment: antibiotics

Patients with mild-to-moderate CDI should be treated with metronidazole 500 mg po tid for 10 days

Patients with severe CDI should be treated with vancomycin 125 mg po qid for 10 days

Failure to respond to metronidazole therapy within 5-7 days should prompt change to vancomycin

ACG guidelines 2013

Patients with ileostomy, Hartman’s Patients with ileostomy, Hartman’s pouch, or colon diversionpouch, or colon diversion

Vancomycin via enema should be included in the treatment

Oral vancomycin can’t reach the disconnected segments

Metronidazole as adjunctive therapy: colonic excretion is high across the inflamed mucosa but drops dramatically once mucosa starts to heal

CDI severityCDI severity

Mild-to-moderate: diarrhea ± any other sign/symptom - not meeting criteria for severe

Severe: serum albumin< 3g/dl plus one of the following

– WBC≥ 15,000– Abdominal tenderness

ACG guidelines 2013

Severe and complicated CDISevere and complicated CDI

Any of the following attributable to CDI:– Admission to ICU– Hypotension– T≥ 38.5 °C– Ileus or significant abdominal tenderness– Mental status changes– WBC ≥ 35,000 or ≤ 2,000– Serum lactate level > 2.2 mmol/L– End organ failure

ACG guidelines 2013

Severe and Complicated CDISevere and Complicated CDI

Vancomycin 500 mg po qid plus metronidazole 500 mg iv q 8 hrs, and vancomycin per rectum (500 mg in 500ml saline as enema) qid (patients with ileus)

Consult surgery: colectomy vs. loop ileostomy with lavage and vancomycin flushes

Fidaxomicin po and tigecycline iv. ((Fecal transplant?))

ACG guidelines 2013

Special situationsSpecial situations Pregnancy and breastfeeding: Oral Vancomycin IBD

– All patients with IBD flare need testing for c.diff – empirical therapy

– Highest risk with corticosteroid use > 3-fold– Reduced dosing of corticosteroids – Immunosuppression can be maintained but

escalation should be avoided– Initiation of anti-TNF 72-hrs after starting therapy

for CDI

C. diff can cause enteritis and pouchitis!

Treatment of Recurrent CDITreatment of Recurrent CDI

Repeat metronidazole if the first epidose was treated with metronidazole

Treat with vancomycin pulse regimen for severe or if the first episode was treated with vanco

– Vancomycin 125 mg po qid for 10 days followed by 125 mg every 3 days for 10 doses

Consider FMT for the third recurrence

ACG guidelines 2013

Recurrent Recurrent C. difficile C. difficile infectioninfection

• 25% of patients have a recurrence after the initial treatment

• Patient with first recurrence have a 35-45% chance for second recurrence

• With subsequent recurrence: risk > 50%

• Antibiotics are not very helpful

Kelly and Lamont. NEJM 2008

After emergence of BI/NAP1/027 high failure After emergence of BI/NAP1/027 high failure rates with metronidazole and high recurrence rates with metronidazole and high recurrence rates with both metronidazole and rates with both metronidazole and vancomycinvancomycin

Aslam S. et al. Lancet Infec.Dis. 2005. 5:549-557 (pooled results from 25 studies)

FidaxomicinFidaxomicin

New bacteriocidal antibiotic Poorly absorbed narrow-spectrum

macrolide FDA approval for CDI in 2011

Fidaxomicin vs.Vancomycin Fidaxomicin vs.Vancomycin

Louie TJ. NEJM. 2011;364:422-31

Vancomycin Vancomycin vs.vs. fidaxomicin for fidaxomicin for the first recurrence of CDIthe first recurrence of CDI

20% recurrence

36% recurrence

Cornelly OA. Clin Infect Dis. 2012. 55: 154-61

The New Kid on the block: The New Kid on the block: StoolStool

FMT is placement of suspension of fresh stool harvested from healthy individual into the gastrointestinal tract of an individual with CDI

– Through standard colonoscopy– Rectal enema– NJ and NG tube

Alternative therapy, but by no means new…

A 1,700-year-old method

• 4th century China: human fecal suspension by mouth “yellow soup“ for food poisoning, severe diarrhea

Fecal transplantation in veterinary Fecal transplantation in veterinary medicine since the 17medicine since the 17thth century century

• Transfaunation

• Horses with diarrhea per rectum

• Cattle per os as rumen

Modern history of human fecal Modern history of human fecal transplantationtransplantation

1958 Ben Eiseman reported “miraculous cure” with FMT in 4 patients with fulminant pseudomembranous colitis

“re-establish the balance of nature” “immediate and dramatic” responses “this simple yet rational therapeutic method should

be given more extensive clinical evaluation”

Explosion of FMT case studies Explosion of FMT case studies since 2010since 2010

• > 500 cases reported with 92% success rate with the first treatment and up to 98% if a second infusion was necessary

• Longest follow up 17 months of 77 pts – zero recurrence without antibiotics (all recurrences related to antibiotic use 8/30)

• 97% of patients would undergo another FMT if needed• 57% voted for FMT as their preferred first treatment option

Brandt, L. ACG. 2012

• Duodenal infusion of donor feces after vancomycin for 4 days and bowel lavage

• Vancomycin therapy for 14 days

• Vancomycin therapy for 14 days plus bowel lavage on day 4-5

Nood et alNEJM.

Jan. 2013

13

15

NoodNEJM2013

Microbiota diversity increases after stool

transplant

Who should be treated with Who should be treated with FMT?FMT?

After 3 episodes or after failure of vancomycin pulse regimen (ACG guidelines)

L. Brandt recommendations:• First line therapy in severely ill patients• FMT may be preferred for the first episode of

CDI because antibiotic perturbs the microbiota and may lead to antibiotic resistance

Brandt, L. JCGE. 2011

Risks of FMTRisks of FMT

• Colonoscopic perforation• Transmission of infections and other

diseases

• Long-term risk? Increased incidence of autoimmune conditions: 4 out of 77 patients developed peripheral neuropathy, Sjӧgren syndrome, RA, ITP within median 17 months f/u

Brandt LJ. ACG. 2012;107:1079-1087

Donor selectionDonor selection

Intimate contacts, family members to mitigate risk of transmissible diseases

But, results with “standardized” or “universal” donors are similarly excellent with fresh or frozen/thawed preparations

Donor screeningDonor screening

Stool– Bacterial culture– Ova & parasites including Giardia,

Cryptosporidium, Cyclospora, Isospora– C.difficile– H. pylori

Blood– Hepatitis A, B, C– HIV 1/2– Syphilis

Donor selectionDonor selection

Exclusion criteria– IBD, IBS, functional diarrhea or constipation,

h/o GI malignancy – Antibiotic use within 3 months– Systemic chemotherapy or

immunosuppression within 1 year– Known HIV, hepatitis B and C, illicit drug use,

incarceration, tattoo/piercing within 6 months

Donor’s badgeDonor’s badge

Which route of administration Which route of administration is the best? is the best?

SER 1: colonoscopy and enema (required repeated infusions) with superior cure rate > 85% vs. 76% upper GI route

SER 2: colonoscopy superior 93% vs. 85% nasogastric tube

NasogastricNasoenteric tubeEGD

Quick ConvenientInexpensiveAvoid colonoscopy

Fecal enemas

Easy to administerCheapCan be performed at home

Via colonoscopy

Highest patient acceptance

Ability to assess disease severity and colonic mucosa

FMT via colonoscopy at IU

FMT at IU Hospital

Patient preps for colonoscopy Stops vancomycin 36-48 hrs before

FMT Fresh stool (not older than 6 hrs)

emulsified in the endo suite and infused into the terminal ileum or right colon

Patient receives Imodium and observed for 2-3 hrs.

Environmental cleaning at home CPT code 44705

Bakken J, Borody T, Brandt L et al.

Treating Clostridium difficile Infection With Fecal Microbiota Transplantation.

Clinical Gastroenterology and

Hepatology, December 2011, 9(12):1044-

1049.

Why and how does FMT work?Why and how does FMT work?

Borody, T. J. &

Khoruts, A. (2011)Nat. Rev. Gastroen

terol. Hepatol.

Mechanism of actionMechanism of action

FMT is introduction of a complete, stable community of gut-organisms to repair or replace the disrupted native microbiota

Reestablishment of the host defense against C. difficile

Engraftment of the donor microbiota is durable

Bacterial fingerprints of the donor and Bacterial fingerprints of the donor and recipient stool before and after FMTrecipient stool before and after FMT

Khoruts A. J Clin Gastroenterol. 2010;44:354-360

Donor Day 0; Patient Day 14; Patient Day 33

Probiotics in the treatment and Probiotics in the treatment and recurrence prophylaxis of CDIrecurrence prophylaxis of CDI

Limited evidence for adjunct probiotics to reduce risk of recurrence

S. boulardii showed efficacy in few trials reducing recurrence rate to 35% vs. 65% but only in patients on high dose vancomycin

Why probiotics don’t work? – Insufficient CFU count– Not the right species or mixture – Wrong media (milk) to culture probiotics

Lawley et al. PLOS 2012

1. Mice treated with Clindamycin for 7 days2. Infected with C. difficile BI/NAP1/027 from

hospitalized patients3. Mice developed severe colitis4. Dysbiosis

• Reduced diversity • Reduced Bacteriodetes and Firmicutes• Increased opportunistic pathogens (Klebsiella,

E. coli, Proteus mirabilis, Enterococcus faecalis) • Up-regulated pro-inflammatory genes

Animal experiment – murine model of C. difficile colitis

5. Mice treated with vancomycin

• Suppression of C. difficile shedding

6. Relapse upon cessation of therapy

7. FMT using healthy mice stool per os

Durable suppression of C. difficile shedding for several months resolve disease and contagiousness

Lawley PLOS 2012

Targeted bacteriotherapyTargeted bacteriotherapy

Instead of stool from healthy mice

A mixture of six phylogenetically diverse bacterial species including obligate and facultative anaerobes Bacteriodetes and Firmicutes cured CDI in mice with severe colitis infected with BI/NAP1/027

Lawley, T. 2012

Stool substitute to Stool substitute to ‘rePOOPulate’ the gut‘rePOOPulate’ the gut

• Made from purified intestinal bacterial cultures derived from a healthy donor after recovering 33 isolates using “Robogut”

Petrof, EO. Microbiome

2013.

Future ?Future ?

Custom designed pill of selected micro-organisms to restore the balance of the microbiota or correct a deficiency of a specific commensal organism curing a disease or reversing a metabolic condition

Summary of FMT Summary of FMT

• FMT is a simple, acceptable and currently the most efficacious treatment for recurrent CDI--- may play a role in the treatment of variety of GI and non-GI diseases

• FMT via the upper tract seems to be less efficacious than via the lower tract

• Long-term safety remains unknown

• The Future… “Artificial stool” or targeted bacteriotherapy

ReferencesReferences

Surawicz, Ch. Guidelines for Diagnosis, Treatment, and Prevention of Clostridium difficle infections. AJG. 2013

Johnston, B. Probiotics for the prevention of Clostridium Difficile-Associated Diarrhea. Annals. 2012

Van Nood, E. Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile. NEJM. 2013

ReferencesReferences Brandt, L. Intestinal Microbiota and the Role

of Fecal Microbiota Transplant in the Treatment of C. difficile Infection. AJG. 2013

Bakken, J. Treating Clostridium difficile Infection with Fecal Microbiota Transplantation (the Fecal Microbiota Transplantation Workgroup). CGH. 2011

Brandt, L. An overview of fecal microbiota transplantation. Gastrointest. Endosc. 2013