c. difficile prevention & treatment monika fischer, md, mscr assistant professor of clinical...
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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