CDI 2019

© 2012 Virginia Mason Medical Center© 2012 Virginia Mason Medical Center
Clostridium difficile Infection
2019: Management Options
Including Fecal Transplantation
Michael Gluck, MD
Section of Gastroenterology
January 2019

© 2017 Virginia Mason Medical Center
Three Patients
1. 37 y/o M, recent antibiotics, post operative
gastric bypass, tube feeds, diarrhea, VS stable.
2. 41 y/o F, antibiotics for sinus infection, severe
diarrhea, c. diff positive, recurrent c. diff after
discontinuing metronidazole.
3. 83 y/o F, recent UTI, NH resident, confused,
febrile, WBC=20K, Albumin=2.7, Cr=2.0, C. diff
negative.

CDI: The Result of Overuse of Antibiotics
• 453,000 new cases and 29,000 deaths (2011)
• Virulent strain and high recurrence rates
• #1 healthcare acquired infection
 40% Hospital acquired
 40% SNF acquired
 20% community onset/healthcare associated
• $4.8 billion dollars in healthcare expenses
• Multiple new therapies
• Guidance in healthcare institutions environmental
management

Microbiome
• Over 10,000 species of
microorganisms in the average
human
• Microorganisms outnumber
human cells 10 to 1
• 2-6 pounds of the average
human is bacteria or fungi
• Majority of bacteria are
Bacteroides and Firmicutes in
the colon
Harvard School of public health; NIH Human Microbiome NYTimes June 18, 2012
Brandt Am J of Gastroenterology 15 Jan 2013

CDI history
1893
• Finney describes pseudomembranous colitis
1935
• Hall and O’Toole identify Clostridium difficile from the stool of a healthy infant.
1943
• Hambre et al describes toxicity of PCN in guinea pigs
1974
• Tedesco et al finds 10% of Pseudomembranous colitis among recipients of Clindamycin,
Green et al identifies C. difficile cytotoxin, Hafiz published PhD thesis on C difficile.
1978
• George et al associated C. difficile with antibiotic-associated diarrhea.
2001
• McDonald et al identified BI/NAP1/027 epidemic strain
Bartlett JG. CID 1994. Heinlen and Ballard. Am J Med Sci 2010.

A Toxic Mix
Clostridium difficile infection
Patient risk
factors
•Age
•Acid suppression
•Comorbidities
Exposure to
spores
•50% infants carry
•3-5% healthy adult
carriage
•20-40% in hospital
Dysbiosis
Antibiotics
• Quinolone
• Clindamycin

Definitions
Case definition for C. difficile colitis
Symptoms
diarrhea (3+ BM’s that conform to a container)
Fever
Abdominal Pain
Ileus
Confirmation
Positive stool test for C. difficile toxin and/or
Colonoscopic/histopathologic findings of
pseudomembranous colitis

Pathogenesis
C. difficile releases two potent exotoxins, A and B.
 Toxin A elicits a profound inflammatory
response in the lamina propria with marked
epithelial cell necrosis and leukocyte
chemotaxis=enterotoxin.
 Toxin B is a more potent cytotoxin but does
not produce fluid secretion.
 Control of toxin secretion is dependant on
genetic characteristics of a specific strain.

Diagnosis
Gold standard
 Toxigenic cultures and cytotoxin assays
• But slow 48-72 hours
Currently used techniques
 PCR (Cepheid Xpert CD assay)
• High sensitivity, high specificity
• “one and done”
• Fast but expensive
 Enzyme immunoassays and toxin A/B
• Good sensitivity, good specificity
• Fast and inexpensive
 Virginia Mason 2013
• Two stage procedure with Enzyme immunoassays and if Ag positive
and toxin negative, reflex to PCR

Severity Classifications
Severity classifications IDSA ACG 2013
Mild to Moderate
WBC<15,000
Serum Creatinine<1.5
times baseline
Diarrhea Mild
No other criteria meeting
severity
Severe
WBC>15,000
Serum Creatinine>1.5
times pre-morbid
Serum Albumin<3
Plus 1 or more of WBC>15K
and abdominal tenderness
Severe and complicated
Hypotension
Ileus
Megacolon
>1 or more
ICU, hypotension,
fever>38.5, Ieus, Mental
Status changes, WBC>35K,
serum Lactate.2.2, end
organ failure

C difficile 027/BI/NAP1
• Epidemic hyper-
virulent strain
• Characterized by
 Quinolone resistance
 Increased virulence
 Increased mortality
and recurrence.
• Worldwide
McDonald et al, N Engl J Med 2005.
He et al, Nature Genetics 2013.

Ref: Pepin J et al. CMAJ 2004; 171: 466-72.
Musher DM et al. Clin Infect Dis 2005; 40(11): 1586-90.
Evidence of Increasing Virulence
• Epidemic in Quebec 2003-4
• Incidence of CDAD increased from 35/100,000 to 156/100,00 between
1991 and 2003
• In older patients, incidence as high as 866/100,000
• Attributable 30-day mortality increased from 4% to 13%
• 2/3 of isolates were NAP1/027 strain; 16-23 x more toxin. High
percentage of Quinolone exposure
• Severe relapsing disease more common with metronidazole
• Musher et al prospectively observed C. difficile in 207 patients
• 22% had persistent colitis for >10 days, 28% relapsed
• Overall mortality 27%, higher in those who did not respond to initial
therapy

Genes tcdA and tcdB encode toxins A and B, respectively, whereas tcdD encodes
a positive regulator of the production of toxins A and B. Gene tcdE encodes a
protein that may be important for the release of toxin from the cell. Gene tcdC is a
putative negative regulator of the production of toxins A and B. Genes cdtA and
cdtB are located at an unknown distance from the PaLoc and encode the
enzymatic and binding components, respectively, of binary toxin. B1 and A3
designate the location and relative size of the gene fragments that underwent
polymerase-chain-reaction (PCR) amplification for toxinotyping.
Ref: McDonald LC et al NEJM 2005; 353 (23): 2433-2441

Characteristics of D. diff Infections in Minnesota:
1991-2005
Community acquired
n=157
Hospital acquired
n=72
Age, median 50 72
% Antibiotic exposure 78 60
% Acid suppression 22 47
Charleson comorbidity
index
1.3 3.3
% Severe CDI 20 31
% Recurrent CDI 28 30
% Female 76 60

Treatment Approaches
Antibiotics
C. Difficile
colonization
Toxin production
Diarrhea
Recurrent
Diarrhea
Probiotics
Antibiotics
Toxin binder
Active immunization:
Toxoid vaccine
Passive immunization:
Monoclonal antibodies
Immune globulin (IVIG)
Anti-Toxin
Response
Protection
Immune system

Treatment (First Episode)
Mild-moderate disease
 Vancomycin 125mg PO every 6 hours x 14 d
• Preferred: unable to tolerate/allergy to metro, preg/lactate,
<10yrs age, failed metro tx ≥5 days, on warfarin tx, expensive
Severe disease
 Vancomycin 125mg PO every 6 hours x14 d
• Metronidazole inferior to vancomycin
Infect Control Hosp Epidemiol 2010; 31(5):431-455

Treatment of Fulminant Disease
• PO high dose vancomycin +/- IV metronidazole
• Intracolonic vancomycin
 500 mg in 500mL (100ml) retention enema q6 hrs
• IV Tigecycline (case reports)
• Intravenous gamma globulin (IVIG)
 Dose: 150-400mg/kg IV daily x1-3 days
 Limited data, expensive, side effects, dose?
 Bezlotuxamab: Toxin B antibody: FMT: both experimental
• Surgery (Total versus loop ileostomy)
 Indications
• toxic megacolon, perforation, peritonitis, systemic toxicity
• comorbidities

Treatment (Recurrences)
First Recurrence: vancomycin x 14 days (metronidazole
if vancomycin is contraindicated)
2nd Recurrence and beyond
 Taper/pulse dosing of vancomycin
• May use if first recurrence is severe
• No metronidazole due to risk for peripheral neuropathy
 Fecal bacteriotherapy (fecal transplant)
 Fidaxomicin
 Rifaximin chaser after vancomycin (resistance)
 Probiotics + vancomycin (limited data)
 Older treatments (ineffective):
• colestipol, cholestyramine, bacitracin, fusidic acid, rifampin

Fidaxomicin: Key Features
• First-in-class macrocyclic
antibiotic
• MOA: RNA polymerase
inhibitor
• Narrow spectrum of
activity
 Gm-pos aerobes and
anaerobes, including C.
difficile
 No activity against
Bacteroides spp.
• Bactericidal
• Low bioavailibility
• High feces concentrations
• Low C.difficile MICs
• Long post-antibiotic effect
• Inhibits sporulation/toxins
• FDA approved May 2011,
brand name Dificid™
 Dose 200 mg PO BID x
10d
Clin Microbiol Infect 2012;18 (Suppl. 6): 28-35,
http://www.dificid.com/sites/default/files/prescribing.pdf

Patient Cost (VMMC pharmacy)
• Fidaxomicin
 200mg tabs PO twice daily x 10 d
• $3554.30
• Metronidazole
 500mg tabs PO every 8 hours x 14 d
• $41.10
• Vancomycin
 125mg oral solution PO every 6 hours x 14 d
• $112.02
 125mg oral capsule PO every 6 hours x 14 d
• $1572.70

Infection Control Preventative Measures
IC Measure Intervention efficacy
Barrier precautions
 Gloves
 Handwashing
 Private room/isolation
Proven
Probable
Probable
Environmental cleaning
 Rooms
 Commodes
 Single-use rectal thermometers
 Endoscope disinfection
Possible
Untested
Proven
Probable
Other
 Antibiotic restriction
 Metronidazole tx for asymptomatic carriers
Proven
Ineffective
Gerding DN, et al. Clostridium difficile-associated diarrhea and colitis. ICHE. 1995;16(8):459-77.

Guidelines for controlling C. diff
Infection in healthcare facilities
1. Frequent hand washing with soap
2. Glove when performing patient care
3. Clean environmental surfaces with sporicidals
4. Isolate symptomatic patients and probably C. diff toxin
+ patients.
5. Avoid reusable rectal thermometers
6. Judicious use of antibiotics: anti-microbial stewardship

Rationale for Fecal Transplant
• Normal colonic flora consists of 10,000 or more different bacterial
species.
• Gut flora synthesize vitamins, ferment carbohydrates, and compete
with pathogens, as well as assist in maturation of the immune
system.
• Antibiotics selectively remove bacterial species exposing host to
enteric infections such as C. difficile —successful colonization by
spores or the bacterium.
• Bacteroides and Firmicutes appear most beneficial and protective.
• FMT from healthy individuals restores these strains and provides
competitive pressure against CDI.

Delivery of FMT
Techniques and benefits
• Enemas: cheap, oldest
delivery system:~150
patients/90% + response.
• NG or NJ tube: cheap, small
bowel delivery,~75
patients/80% effective
• Colonoscopy: cecum or ileum,
colonoscopy evaluation, 1000s
patients/91% cure
• Oral: Frozen, encapsulated
fecal material
Limitations
• Only to splenic flexure,
handling issues, lack of
standardization.
• Handling issues, no sedation,
no standardization; family as
technicians.
• Cost, risk for perforation,
insurance coverage, sedation,
recovery room.
• Limited studies, possible
exposure to pathogens, FDA
oversight

Vanco vs. Duodenal Infusion of Donor
Feces for Recurrent CDI
van Nood et al; NEJM 2013; 368:407-15
Pts > 18 yo with > one episode of CDI and life
expectancy of > 3 months
Vanco 500 mg QID x 4-5 daysBLFMT
Vanco 500 mg QID x 14 d
Vanco 500 mg QID x 4-5 days BL
BL = bowel lavage with 4L Klean-Prep
FMT = fecal microbiota transplantation

Vanco vs. Duodenal Infusion of Donor
Feces for Recurrent CDI
van Nood et al; NEJM 2013; 368:407-15
Group N % resolution
VancoBLFMT 17 81
Vanco x 14 days 13 31
VancoBL 13 23

Bezlotoxumab (Toxin B
antibody)
• Two double blind, randomized, placebo
controlled trials involving 2655 adults. Infusion
of Bezlotoxumab. End point was recurrent
infection within 12 weeks.
• Significant reduction in recurrent CDI but only
about 10% less than standard of care.
• Adverse events equivalent in placebo and drug.
• Exact role unknown. Very expensive.
• Wilcox, et al, NEJM January 2017.

CDI 2019

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