C. difficile prevention & treatment

Monika Fischer, MD, MSCR

Assistant Professor of Clinical Medicine

DisclosureDisclosure

Rebiotix, Consultant Openbiome, Volunteer scientific advisor

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

Epidemic of CDIEpidemic of CDI

• 2011: 500,000 cases and 29,000 associated deaths in the US• 66% health-care related • 86% of community onset patients had a doctor’s or dentist visit

within 12 weeks of CDI diagnosis

Lessa NEJM 2015

C. difficile – the leading cause of nosocomial infections

1% of all hospital stays

An urgent public health threatAn urgent public health threat

No longer limited to nosocomial infections or to the elderly

Significant morbidity and mortality in healthy ambulatory patients with no antibiotic exposure

500.000 cases per year 15.000 annual death $ 3 billion excess cost

HCUP Statistical Brief #124 2009

31% of health-care and 19% of community associated casesIncreased need for ICU stay and prolonged antibiotic courses to clear infectionHigh colectomy rates (10%)High case mortality: 10-fold increase since 1999Refractory disease in low risk populations

Beginning of 2000 Epidemic strain of C. difficile: BI/NAP1/027

.

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 risk factorsHost risk factors Age ≥ 65 year Previous CDI 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

Obesity (↑ 20%/BMI unit) H/o intraabdominal surgery > 3 fold

Bishara. Clin.Inf.Dis 2013

Immunocompromised hostImmunocompromised host

CDI incidence among SOT patients:

16% kidney tpx, 13% liver tpx, 23% in lung tpx

• Highest risk within 6 months of tpx

• Lung tpx: 7% during initial hospitalization

• Lung tpx: 54% within 6 months of tpx

• 40% of SOT patients- no recent Abx exposure

Lee. J. Heart and Lung Transpl. 2013

DIAGNOSISDIAGNOSIS

Diagnostic testsDiagnostic tests

Only stools from patients with diarrhea should be tested

Nucleic acid amplification tests (PCR) are superior to toxins A+B EIA testing

GDH screening with subsequent toxin A+B EIA can be used but sensitivity is lower than PCR

Repeat testing is discouraged (<5% chance for positive after 1 negative test)

Testing for cure is not recommended

ACG guidelines 2013

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

THERAPYTHERAPY

Supportive careSupportive 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

2013 ACG guidelines for CDI Rx2013 ACG guidelines for CDI Rx

Severe and Complicated CDISevere and Complicated CDI

Surgery should be considered– Hypotension requiring vasopressor tx– Sepsis– Organ dysfunction– Mental status changes– WBC≥50.000– lactate≥5– Failure to respond to medical tx after 5 days

ACG guidelines 2013

Surgical tx for complicated C. diffSurgical tx for complicated C. diff

Mortality rates of 35-80% associated with subtotal colectomy

Early surgery is associated with increased survival

Loop ileostomy with intraoperative PEG lavage and postoperative antegrade colonic vancomycin flushes → 90% preserved colon and ↓mortality 19% (vs 50%)

Neal. Annals of Surg. 2011

Recurrent Recurrent C. difficileC. difficile

McFarland et al, Am J Gastroenterol, 2002;97:1769; Pepin et al Clin Infect Dis2005:40:159

20 - 30%

40 - 50%

60 - 70%

3rd

2nd

1st

Infection

Percent

First episode of recurrent CDI First episode of recurrent CDI is not trivialis not trivial

C. difficile infection

Incidence Mortality

Healthcare acquired

20.9% 9.3%

Community acquired

13.5% 1.3%

Lessa et al, NEJM 2015: 372: 825; data from 2011

After emergence of BI/NAP1/027 high failure rates After emergence of BI/NAP1/027 high failure rates with MZ and high recurrence rates with both MZ and with MZ and high recurrence rates with both MZ and vancovanco

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

Fidaxomicin vs. Vanco Fidaxomicin vs. Vanco

Louie TJ. NEJM. 2011; Mullane. Clin. Inf. Dis. 2011

Nonhypervirulent subgroupFidaxo recurrence rate 8% vs 25% with vanco

Fidaxo is superior to vanco (90% vs 80%) in patients with concurrent systemic antibiotic use with CDI treatment

Fidaxomicin is superior to vanco Fidaxomicin is superior to vanco for the 1for the 1stst recurrence recurrence

20%

36%

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

Fidaxo $ 2800/10 days

Vanco capsules $ 680

Vanco compounded $100-400 MZ $22

ACG guidelines for recurrent CDI 2013ACG guidelines for recurrent CDI 2013

Antibody and VaccineAntibody and Vaccine Fully human monoclonal antibodies against C.

diff toxin A and B (Merck)- single infusion (10mg/kg)-200 pts, on vanco for active CDI-Recurrence w/in 84 days

- Placebo: 25%- Antibody: 7%- Pts with prior recurrence: 38% vs 7%

Vaccines (C. diff toxoid)–Sanofi started late-stage trials (15.000 pts) in August 2013 Lowy NEJM 2010

Non-toxigenic C. difficile Non-toxigenic C. difficile (NTCD) Strain VP20261(NTCD) Strain VP20261

Phase II trial (Viropharma) CDI patients on vanco

– Placebo (n=43)– NTCD (n=125) for 7-14 days

69% colonized 2% CDI recurrence in colonized pts

ProbioticsProbiotics

Not useful for tx of CDI Weak evidence supports Saccharomyces

boulardii to decrease risk of recurrence Role in CDI prevention

– Meta-analysis of 20 trials and 3818 pts CDI

↓ 66% reduction ↕

---Large RTC > 1400 patients in each arm comparing Lactobacilli, Bifidobacteria to placebo—no effect on risk of CDI

Johnson, Annals of Internal Med 2012; Allen. Lancet. 2013

FECAL MICROBIOTA FECAL MICROBIOTA TRANSPLANTTRANSPLANT

Fecal microbiota transplantationFecal microbiota transplantation

Placement of suspension of fresh (or frozen) stool harvested from healthy individual into the gastrointestinal tract of the recipient

Rational for using FMT in Rational for using FMT in recurrent CDIrecurrent CDI

Avoid prolonged courses of antibiotics Re-establish diversity of gut microbiota

– restore “colonization resistance”– reverse metabolic changes promoting C. diff

Mouse model for C. difficile associated dysbiosisMouse model for C. difficile associated dysbiosisand successful bacteriotherapyand successful bacteriotherapy

Lawley 2012 PLOS

NAP1/BI/027

↓butyrate↓acetate

Mixture of 6 strains

Harnessing Microbiota to Kill a Harnessing Microbiota to Kill a Pathogen: Fixing the microbiota to treat Pathogen: Fixing the microbiota to treat

Clostridium difficileClostridium difficile infections infections

Nature 2014

Fecal transplant: A 1,700-year-old method

• 4th century China: Ge Hong, famous traditional Chinese medicine doctor prescribed human fecal suspension by mouth for food poisoning, severe diarrhea

• 16th century Ming dinasty: Li Shizhen described using fermented, fresh, or dried poop for treatment of severe diarrhea, pain, fever, vomiting and constipation in the most known book of traditional Chinese medicine “Ben Cao Gang Mu” (Compendium Materia Medica)

• The herb doctors called it “yellow soup“

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”

"Should further clinical experience substantiate the beneficial effect of fecal enemas...the oral administration of pure cultures of these organisms in enteric-coated capsules might be both more aesthetic and more effective"

Ben Eiseman, 1958

Use of FMT in recurrent CDIUse of FMT in recurrent CDI

Multiple systematic and meta analyses show 90% efficacy

– Guol APT 2012 - Sofi Scand J Gastro 2013;

– Kassam Am J Gastroenterol 2013 - Drekonja JAMA 2015

• Colonoscopy delivery may be slightly better than NG/NJ delivery

Now, 3 randomized controlled trials VanNood Youngster Cammarota

• 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

Duodenal Infusion of Donor Duodenal Infusion of Donor Feces for recurrent CDIFeces for recurrent CDI

Study stopped early due to strong results

Van Nood et al, N Engl J Med 2013; 368:407

Van Nood et al NEJM 2013; 368:4-7

Recurrent CDI: RCT OF FROZEN Recurrent CDI: RCT OF FROZEN STOOLSTOOL

Colonoscopy NG tube

10 pts 10 pts

Cure after 1st FMT

8 (80%) 6 (60%)

Cure after 2nd FMT

+ 2, ( 100% ) + 2, ( 80% )

Youngster et al, Clin Infect Dis 2014; 58; 1515

Overall cure rate 90%

Recurrent CDI: RCT OF FMTRecurrent CDI: RCT OF FMT

Response to: Colonoscopy after 3

days vancomycinVancomycin 10 days

and 3 week pulse

FIRST FMT 13/20 (65%) 5/19 (26%)

Multiple FMTs 18/20 (90%)

Cammarota et al, Alim Pharm Ther 2015:41:835

• 7 / 20 patients with pseudomembranous colitis• All of failures / deaths (2/20) from CDI had

pseudomembranes

Steps of FMT : How its doneSteps of FMT : How its done

1. Patient selection

2. Stool/donor selection• Patient directed vs. universal• Fresh or frozen • On site preparation vs. stool bank

3. Mode of delivery • Colonoscopy / sigmoidoscopy• Enema• NG/NJ tube• Pill

4. Follow-up

Regulation: USRegulation: US

May use to treat C. difficile not responding to standard therapy

Informed consent– State it is investigational– Discuss real and theoretical risks

Real RisksInfections

ColonoscopySedationAspiration

Theoretical Risks•Autoimmune disease•Metabolic syndrome

•IBD flare

Step 1: Patient SelectionStep 1: Patient Selection

• Eligible cases: ACG guidelines 2013– 3 or more recurrences with adequate

treatment– 2 severe episodes requiring hospitalization– Failed Vanco taper / pulse regimen

• Make sure it is recurrent CDI and not post

infectious IBS

Surawicz et al, Am J Gastro 2013:108;478-498Debast et al Clin Infect Dis 2014: 20(suppl 2); 1-

26

Step 2. Step 2. Patient directed vs. universal Patient directed vs. universal

donordonorSource: family or friend Pros:

• Patient comfort

• Cons:• Multiple tests• Expensive• Delays care • Physician’s time• Unreliable donors

Source: unrelated donor Pros:

• Routinely tested, healthy individual- proven donor track

• Minimize cost

On site: fresh stool vs frozen stool bank

Frozen stool from a bank: OpenBiome ModelFrozen stool from a bank: OpenBiome Model

Donor Assessment

Stool & Serological

Testing

<6% pass rate

• 109-point clinical assessment for transmissible infectious diseases and potentially microbiome-mediated conditions

• E.g. IBD, IBS, depression, anxiety, age, obesity, metabolic syndrome, autoimmune diseases and others

• Stool testing- C. diff toxin PCR, Ova & Parasites,

Isospora, Cyclospora, Giardia EIA; Cryptosporidium EIA; H. pylori Ag, Common enteric pathogens (e.g. Salmonella, Shigella, E. coli, Campylobacter, Vibrio, Norovirus PCR, Adenovirus EIA, Rotovirus EIA, VRE culture, Microsporidium

• Serological testing- HIV 1 & 2, HAV, HBV, HCV, HTLV 1 &

2, Treponema pallidum. CBC, LFTs

• 60-day quarantine procedure

• Continuous requalification

• Processing controls

• Filtering & homogenization

• Safety aliquots

• Storage & shipping controls

• Traceability

• 16s rRNA (microbiome) sequencing & characterization

1 Clinician orders fecal preparations from a

stool bank

2 Stool bank provides rigorously screened, processed, frozen

material

3 The clinician thaws material and performs FMT

Processing, Monitoring & Re-

testing

FDA correspondence to national FDA correspondence to national stool bank on regulatory status stool bank on regulatory status

of universally banked stoolof universally banked stool Do donors need to be “known” to the

physician or patient? No.- March 2014: FDA issued draft guidance

proposing that unless stool donors were “known” to the clinician or patient, an IND would be needed

Proposal was NEVER ENACTED!“to treat patients with C. difficile infection that

failed standard therapy an IND is not needed…. Practitioners may obtain their product from any reasonable source”

Step 4: Preparation and Follow upStep 4: Preparation and Follow up

Before FMT, screen for Hep A,B,C, HIV and syphilis

Standard colon prep

• Phone calls at 24 hrs, 2 weeks and clinic visit at 3 months

• Intermittent diarrhea common, usually resolves

• If diarrhea persists, test for C diff- If positive, repeat FMT or Vanco pulse regimen

What if They Need Antibiotics What if They Need Antibiotics Again?Again?

Reassure: recurrence unlikely post FMT Suggest the most narrow spectrum

antibiotics Prophylactic Flagyl or Vancomycin

unnecessary- No proven benefit, possible harm

Consider probiotics … but which one?

FMT in Severe and FMT in Severe and Severe /complicated CDI Severe /complicated CDI

First use of FMT in patients with PMC in 1958

Multiple case reports- dramatic results Recent retrospective case series Some severe data from a recent RCT

Eiseman. Surgery 1958, You Ann Intern Med 2008, Weingarden 2013 CGH, Zainah 2015 Dig Dis Sci, Aroniadis JCG 2015, Jones DDW 2015 Mo 1216

RCT OF FMT – severe CDI in the RCT OF FMT – severe CDI in the colonoscopy groupcolonoscopy group

In Cammarota study, the first 2 pts in the colonoscopy group had pseudomembranes

Initial improvement after FMT but both later died due to CDI-related sepsis

Then, modified protocol to give FMT every 3 days until colitis responded

All subsequent 5 pts were cured (2 pts- 2 FMTs, 2-pts 3 FMTs, 1 pt-4 FMTs)

Cammarota , Alim Pharm Ther 2015:41:835

Khoruts described a single patient with fulminant CDI with a dramatic, but unsustained improvement in CDI after a single FMT

Reinitiation of antibiotics against CDI and repeat FMT might be needed for cure in some cases of severe FMT

Weingarden CGH 2013

FMT plus selected use of antibiotics for FMT plus selected use of antibiotics for severe and severe-complicated CDI :severe and severe-complicated CDI :

Indiana University experienceIndiana University experience

29 cases, prospective study, inpatients 19 severe/complicated, 10 severe CDI

– 12 in ICU – 7 ARF and hypovolemic/septic– 5 toxic megacolon– 4 vasopressors

21/29 (73%) pseudomembranous colitis

Fischer ACG 2014 abstract

Severe and Severe/Complicated CDI

Vancomycin po/rectal ± metronidazole ≥ 5 days

Colonoscopy / Sigmoidoscopy

Pseudomembranes present

Pseudomembranes absent

Vancomycin 125 mg orally four times a day

for 5 days

Clinical observation with no further

intervention

Fecal Microbiota Transplantation

Symptomatic resolutionVancomycin for 5 additional days (10 days

total) Optional FMT as outpatient

Still symptomaticFischer ACG

2014

Results : Results : FMT and selected use of FMT and selected use of VancomycinVancomycin

Indiana University experienceIndiana University experience

27/29 (93%) complete symptom resolution and discharge from the hospital at 1 month

76% cumulative survival at 3 months Of the 27pts, 15 (56%) -1FMT, 11 (40%)-

2 FMTs, 1-3 FMTs Two failures / death

Sepsis, arterial pH 7.1 at FMT S/P OLT failed 3 FMT, died s/p colectomy

Fischer ACG 2014 abstract

Refractory CDI (severe and/or Refractory CDI (severe and/or complicated) - efficacy and complicated) - efficacy and

follow-upfollow-up

Retrospective series of 17 pts; 8 sites 76% women; 66 yrs. mean age Results:

– Diarrhea resolved or improved in 15/17 (88%) after a single FMT

– Overall cure rate 16/17 (94%)– Follow up 11 months– No adverse events related to FMT

Aroniadis et al J Clin Gastro in press 2015

SummarySummary FMT very effective for recurrent CDI

– Excellent safety profile to date Patient selection, donor screening,

methods and follow up are very important FMT treatment protocols in severe and

severe / complicated CDI is evolving – Repeat FMTs or FMT plus anti-CDI

antibiotics may be necessary– What is the role of pseudomembranes– What is the role of endoscopy– RCTs are needed

Poop-frozen,pill,syntheticPoop-frozen,pill,synthetic

Frozen fecal material from a universal donor via colonoscopy single center 43 pts 95% success

OpenBiome: screened frozen product– available for internet order

Frozen poop: RCT of 20 pts (via NJ vs colonoscopy) 70% cured with 1 FMT, 90% with 2 FMTs

Poop pills 27 pts 100% cured Synthetic stool (33 bacterial strains) from a single

donor (Repoopulate) 2 patients cured

Hamilton CGH 2012, Youngster Clin Infect Dis 2014 , Louie 2013, Petrof 2013

FMT productsFMT productsStool derived & Full spectrum

microbiota

Recreates normal GI microbiome - can restore any missing components

Can restore unknown missing components - can be used for multiple indications

There is evidence of durable implantation

No evidence of infection transmission BUT CMV and listeria cases in IC patients

Synthetic & Probiotics

Small number of bacterial components – may fail to supply crucial components

Cannot restore unknown missing components- can be used for specific indication

Some components can implant for variable times

Probiotics can be contaminated in manufacture!

• Fatal cases of Mucormycosis, neurotoxigenic C.butyricum, invasive Saccharomyces

Stool derived & Full spectrum microbiota

Complex composition - difficult to standardize and define composition

Ongoing need to source from donors

No need for culturing – thereby avoiding "passaging"

Perception of being stool-derived may influence consumers

“ick factor”

Synthetic & Probiotics

Composition is readily defined, reproducible, and standardized

No need for ongoing use of human donors

Repeated culturing changes nature of probiotic mix via “passaging”

The original stool-derived source can be more readily masked.

No “ick factor”

Possible Future Indications of Possible Future Indications of FMTFMT

Colonization with MDR organism: VRE, MRSA

IBD and IBS Diverticulitis, Parkinson’s disease, chronic

fatigue syndrome, multiple sclerosis, myoclonus dystonia, obesity, insulin resistance,metabolic syndrome, depression, and autism

Safety and ethical considerationsSafety and ethical considerations

Acute infections– Bacterial, viral, parasitic

Acute allergic reactions Long-term concerns

– How long will the donor microbiota populate the recipient’s colon?

– Predisposing the recipient to some diseases that the donor will develop in his/her lifetime?

– Are were creating a “microbiomic clone” of the donor?

PREVENTIONPREVENTION

Hospital-based infection Hospital-based infection control programcontrol program

Antibiotic=strongest risk factor for C. diff Clindamycin, cephalosporins and fluorokinolons

pose highest risk Antibiotic stewardship: can decrease CDI

incidence by 60% Infection control “bundle” (education, early case

finding, reinforcement of contact precautions) decreased CDI hospital rates by 33% (7.2/1000 to 4.8/1000) in 1 year

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

Prevention: infection controlPrevention: infection control

Cornerstone of CDI prevention: hand hygiene Soap (preferably 4% chlorhexidine) & water Alcohol based antiseptic does not kill C. diff spores! Barrier precautions (gloves & gowns) Private rooms Single use disposable equipment Environmental disinfection with10% bleach (5,000

p.p.m. chlorine) for at least 10 minutes

Prevention: infection controlPrevention: infection control Contact precautions should be maintained at a

minimum until the resolution of the diarrhea

– C. Difficile can be cultured from the surfaces of rooms of asymptomatic patients but to much lesser degree than from the rooms of symptomatic patients.

– Patients skin surfaces may contain c. diff spores up to 2 weeks after the resolution of CDI!

– Spores resist desiccation and can survive up to 5 months on hard surfaces.

C. diffFACTS

Thank youThank you