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CCO Managing Recurrent and Hypervirulent CDI

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Confronting Challenges in the Management of
C difficile: Recurrent Infection and
Hypervirulent Strains
Faculty and Disclosures
Ciarán P. Kelly, MD
Professor of Medicine
Department of Medicine
Harvard Medical School
Attending Physician
Division of Gastroenterology
Department of Medicine
Beth Israel Deaconess Medical Center
Boston, Massachusetts
Ciarán P. Kelly, MD, has disclosed that he has received consulting fees from
Artugen, Merck, and Vedanta; fees for non-CME/CE services from Biocodex;
and funds for research support from Institut Merieux.
Program Overview
 Burden of Disease
 Diagnosis in 2018
 Initial Management
 Management of Recurrent Disease
 Prevention of Recurrence
Burden of Disease
CDI: An Opportunistic Infection
Antibiotic therapy
Disturbed colonic microbiota
C difficile exposure and colonization
Toxin A and toxin B
Symptomless carriage
Kelly. NEJM. 2008;359:1932.
Diarrhea and colitis
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CDI: Incidence and Mortality
 > 450,000 CDI cases annually[1]
 29,000 CDI-related deaths
annually[1]
 CDI designated by the CDC as
urgent threat to public health[2]
Rate per 1000 Discharges
‒ 60% are hospital-associated
infections
CDI-Related US Hospitalizations, 2001-2013[3]
20
15
10
5
0
Yr
Observed
1. Lessa. NEJM. 2015;372:825. 2. CDC. Antibiotic resistance threats in the US. 2013.
3. Healthcare Cost and Utilization Project. Report 2012-01.
Projected
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Contributing Factors to Increased CDI Incidence
Host factors
Age
Immune response
Underlying disease
C difficile
bacterial factors
Environmental
factors
Virulence
Sporulation
Antibiotic resistance
Antibiotic use
PPI use
Burden of C difficile
spores
Kelly. NEJM. 2008;359:1932. Bauer. Clin Microbiol Infect. 2009;15:1067.
Cohen. Infect Control Hosp Epidemiol. 2010;31:431.
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“Hypervirulent” Strains of C difficile
 Emerged in the US, Canada, and
Europe in the early 2000s[1-4]
‒ Ribotypes 027 (& 078)
 Associated with[1-3]:
‒ High-level fluoroquinolone
resistance
‒ Increased spore formation
 Approaches to diagnosis and
management are the same as for
other C difficile strains[6]
‒ Multiple disease outbreaks
‒ High toxin production
‒ Increased disease severity and
mortality rates
1. Loo. NEJM. 2005;353:2442. 2. McDonald. NEJM. 2005;353:2433. 3. Yakob. Sci Rep. 2015;5:12666.
4. Pepin. Clin Infect Dis. 2005;41:1254. 5. CDC. Tracking Clostridium difficile infection. 2015.
6. McDonald. Clin Infect Dis. 2018;66:987.
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Diagnosis in 2018
Principles of CDI Diagnosis and Management
Suspect CDI based on clinical signs
Discontinue nonessential antibiotics
Confirm presence of toxin-producing C difficile by
stool testing (usually NAAT or EIA)
Treat CDI if laboratory-confirmed diagnosis*
*Empiric treatment best avoided unless high clinical index of suspicion and either expectation
of substantial delay (> 24 hrs) in laboratory confirmation or fulminant disease.
McDonald. Clin Infect Dis. 2018;66:987.
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IDSA-SHEA Guideline Recommendations for
Diagnostic Testing
 Clinical signs of CDI:
‒ Diarrhea, defined as ≥ 3
unformed stools in 24 hrs
‒ New onset
 Difficulties :
‒ Not induced by laxatives
 4% of healthy adults are colonized
by Cl. difficile
 20-25% of the C.difficile strains
may be non-toxigenic
McDonald. Clin Infect Dis. 2018;66:987.
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Commonly Used Stool Tests for CDI
Test
Nucleic acid amplification
test
Accuracy
Cost
Highly sensitive
High but
falling
Specific but not
highly sensitive
Low
 Rapid
 Potential concerns: sensitivity moderate
(~ 85%); frequent false-negative results
Sensitive but not
specific
Low
 Rapid
 Used as a “triage” step
 Potential concerns: frequent false-positive
results; confirmation with another assay
required
 eg, PCR-based assays
Stool toxin EIA test
 Enzyme immunoassay
Glutamate dehydrogenase
test
 “C difficile antigen”
Comments
 Rapid
 Increasingly used (in place of toxin test)
 Potential concerns: may detect bacteria or
spores in the absence of toxin or disease
 Other stool tests for CDI include anaerobic bacterial culture and tissue culture cytotoxicity
Cohen. Infect Control Hosp Epidemiol. 2010;31:431. Surawicz. Am J Gastroenterol. 2013;108:478.
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CDI Diagnosis: IDSA-SHEA–Recommended Approach
Option A
GDH antigen plus stool toxin tests
Option B
NAAT
 Both tests positive: consistent with CDI
 Positive: consistent with CDI*
 GDH negative/stool toxin test positive:
consistent with CDI
 Negative: not consistent with CDI
 GDH positive/stool toxin test negative:
inconclusive; consider NAAT (see right
column)
 Both tests negative: not consistent with
CDI
*Consider stool toxin EIA if clinical characteristics of CDI are not clearly present.
Note that > 10% of patients in hospital receiving antibiotics without diarrhea will test positive by NAAT (ie, asymptomatic carriers).
McDonald. Clin Infect Dis. 2018;66:987. Surawicz. Am J Gastroenterol. 2013;108:478.
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Initial Management
Vancomycin vs Metronidazole for Treating CDI
‒ Patients stratified by disease
severity*
CDI Cure Rate†
100
98
Vancomycin
Metronidazole
97
90
90
Cure (%)
 Prospective, double-blind study
in which patients with CDI were
randomized to receive
vancomycin 125 mg QID or
metronidazole 250 mg QID for
10 days (N = 172)
80
76
70
60
n/N =
37/41
39/40
29/38
30/31
50
Mild/
Moderate CDI
P = .36
Severe CDI
P = .02
*≥ 2 points = severe disease. 1 point for age > 60 yrs, temperature > 101°F, albumin < 2.5 mg/dL, WBC > 15,000 cells/mm3; 2 points for PMC at
colonoscopy, ICU patient. †Cure: diarrhea resolution by Day 6 and negative C difficile toxin A assay at Days 6 and 10.
Zar FA, et al. Clin Infect Dis. 2007;45:302-307.
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Fidaxomicin vs Vancomycin for Treating CDI
 Double-blind phase III trial in which patients with CDI were randomized to receive
fidaxomicin or vancomycin (N = 629)
100
88.2 85.8
92.1 89.8
P = .006
77.7
74.6
67.1
64.1
P = .006
Patient (%)
80
Vancomycin
Fidaxomicin
60
40
P = .005 P = .004
25.3
24.0
15.4
13.3
20
0
mITT
PP
Initial Response*
mITT
PP
Recurrence
mITT
PP
Sustained Response†
*Clinical cure: resolution of diarrhea with maintenance of resolution for duration of therapy plus no additional need for CDI treatment as of the
second day after the end of therapy. †Global cure: resolution of diarrhea without recurrence.
Louie. NEJM. 2011;364:422.
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2017 IDSA-SHEA Guidelines for Treatment of an
Initial Episode
CDI Severity
Nonsevere*
Severe
Fulminant (severe,
complicated)†
Treatment
Vancomycin
125 mg 4 times daily PO for 10 days
Fidaxomicin
200 mg BID PO for 10 days
Vancomycin
500 mg 4 times daily PO or by nasogastric tube or enema
plus metronidazole 500 mg Q8H IV
*If vancomycin or fidaxomicin are unavailable for a patient with nonsevere CDI only, metronidazole (500 mg 3 times daily PO for 10 days) may be
considered. †May be characterized by hypotension or shock, ileus, or toxic megacolon.
McDonald. Clin Infect Dis. 2018;66:e1.
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Management of Recurrent Disease
Recurrent CDI: A Self-Perpetuating Cycle
Antibiotic therapy
Disturbed colonic microflora
“Dysbiosis”
(loss of colonization resistance)
C difficile exposure and colonization
Antitoxin
immunity
Toxin A and toxin B
Symptomless carriage
Diarrhea and colitis
Kelly. NEJM. 2008;359:1932. Kyne. Lancet. 2001;357:189. Almeida. J Gastroenterol. 2016;51:1.
Antibiotic
treatment
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Recurrent CDI
 Common: ~ 25% of patients treated with metronidazole or vancomycin
suffer a recurrence[1,2]
 Mechanisms of recurrence[3,4]:
‒ NOT primarily due to antimicrobial resistance
‒ Instead, antimicrobial therapy perpetuates dysbiosis
 Recurrent infection can be same strain as initial episode (relapse) or a
new strain (reinfection)[3]
1. Cornely. Clin Infect Dis. 2012;55(suppl 2):S154. 2. Pepin. Clin Infect Dis. 2005;40:1591.
3. Kyne. Lancet. 2001;357:189-193. 4. Almeida. J Gastroenterol. 2016;51:1.
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Prior CDI Recurrence and Recurrence Risk
80
Recurrence Rate (%)
> 50%
60
~ 40%
40
~ 25%*
20
0
Initial
Episode
First
Recurrence
Second
Recurrence
*Whether treated with metronidazole or vancomycin.
McFarland. JAMA. 1994;271:1913. Pepin. Clin Infect Dis. 2005;40:1591. McFarland. Am J Gastroenterol. 2002;97:1769.
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Risk Factors for Recurrent CDI
 Previous episode of recurrent
CDI
 Aged 65 yrs or older
 Additional antibiotic use
(perpetuates dysbiosis)
 Impaired immune response to
C difficile toxins
 Severe underlying disease
‒ ICU admission
‒ Immunocompromise
‒ Renal impairment
 Acid antisecretory medication?
 Prolonged hospitalization
Bauer. Clin Microbiol Infect. 2009;15:1067. McFarland. Am J Gastroenterol. 2002;97:1769.
Hu. Gastroenterology. 2009;136:1206. Do. Clin Infect Dis. 1998;26:954.
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2017 IDSA-SHEA Guidelines for Treatment of
Recurrent CDI
Recurrent Episode
If initial therapy was
with metronidazole
If initial therapy was
with vancomycin
Treatment
Vancomycin 125 mg 4 times daily PO for 10 days
Fidaxomicin 200 mg BID PO for 10 days
or
Prolonged taper and pulsed vancomycin if standard
regimen used for initial therapy: 125 mg 4 times daily for
10-14 days, 2 times daily for 1 wk, QD for 1 wk,
then every 2-3 days for 2-8 weeks
 Metronidazole not recommended
McDonald. Clin Infect Dis. 2018;66:e1.
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Fidaxomicin vs Vancomycin for a First CDI Recurrence
 Subgroup analysis of randomized phase III trials assessing treatment with
fidaxomicin or vancomycin for patients with a first CDI recurrence (N = 128)
Patients With No Recurrence (%)
Time to Recurrence by Treatment Group
1.0
Fidaxomicin
20% (13/66) recurred
0.9
0.8
0.7
Vancomycin
36% (22/62) recurred
0.6
0.5
0
Cornely. Clin Infect Dis. 2012;55(suppl 2):154.
5
10
15
20
Days of Follow-up
25
30
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2017 IDSA-SHEA Guidelines for Treatment of
Multiple Recurrent CDIs
Treatment for Second or Subsequent Recurrent Episode
Vancomycin in a tapered or pulsed regimen
Vancomycin 125 mg 4 times daily PO x 10 days followed by
rifaximin 400 mg 3 times daily for 20 days
Fidaxomicin 200 mg BID PO for 10 days
Fecal microbial transplantation
McDonald. Clin Infect Dis. 2018;66:e1.
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Turning to Nature’s Cures for CDI:
Nonantibiotic Approaches
Antibiotic therapy
Disturbed colonic microflora
Restore
colonization
resistance
C difficile exposure and colonization
Toxin A and toxin B
Symptomless carriage
Kelly. NEJM. 2008;359:1932.
Diarrhea and colitis
Immunity:
active vaccine or
passive
immunotherapy
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Duodenal Infusion of Donor Feces for Recurrent CDI
 Randomized, open-label clinical trial comparing abbreviated vancomycin + bowel lavage + donor
feces infusion vs standard vancomycin vs standard vancomycin + bowel lavage in adults with
relapsed CDI (N = 43)
Patients Without Relapse
Microbiota Diversity
Patients With No Relapse (%)
P < .001
P = .008
P = .003
93.8
100
80
81.3
60
40
30.8
20
0
23.1
First Infusion Infusion of Vancomycin Vancomycin
of Donor Donor Feces (n = 13) With Bowel
Feces
Overall
Lavage
(n = 16)
(n = 16)
(n = 13)
van Nood. NEJM. 2013;368:407. Kelly. NEJM. 2013;368:474.
Simpson’s Reciprocal Index
P < .001
250
200
150
100
50
0
Donors
Patients
Before
Infusion
Patients
After
Infusion
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FMT and Beyond
 Nonoral delivery:
‒ Naso-enteric infusion
‒ Luminal instillation at
colonoscopy
‒ Enema
 Oral delivery:
‒ Encapsulated fecal preparations
(frozen or lyophilized)
‒ Defined bacterial cultures
‒ Fecal spores preparations
‒ Nontoxigenic C difficile spores
Youngster. JAMA. 2014;312:1772. Baktash. Front Microbiol. 2018;9:1242.
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Additional Investigational Strategies in
Phase III Development
Agent
Ridinilazole
SER-109
MoA
Trial
Nonabsorbable
narrow-spectrum
antibiotic with
MoA still under
investigation[1]
Ri-CoDIFy 1
(NCT03595553)
Ri-CoDIFy 2
(NCT03595566)
Oral formulation
of ~ 50 species of
Firmicutes spores
derived from
healthy donor
stool[2]
ECOSPOR III
(NCT03183128)
Comparator
Population
Status
Vancomycin
Adults with CDI
signs/symptoms warranting
antimicrobial tx, stool
presence of toxin A and/or B
(target total N = 1360)
Not yet
recruiting
Placebo
Adults with qualifying
episode of CDI
(target N = 320)
Recruiting
--
Adults previously enrolled in
SERES 012 study with CDI
recurrence within 8 wks of
receiving study drug
(target N = 100)
Recruiting
ECOSPOR IV
(NCT03183141;
open-label
extension of
SERES 012 study)
1. Peng. Emerg Microfes Infect. 2018;7:15. 2. Khanna. J Infect Dis. 2016;214:173.
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Prevention of Recurrence
Bezlotoxumab for Prevention of CDI Recurrence
 Human monoclonal antibody that binds C difficile toxin B, preventing
effects on host cells[1,2]
‒ IV systemic half-life ~ 19 days[1]
 FDA approved to reduce CDI recurrence in adults receiving
antibacterial treatment for CDI and who are at high risk for
recurrence[2]
‒ Not an antibacterial drug and not indicated for the treatment of CDI;
must be used in conjunction with antibacterial drug treatment of CDI
1. Wilcox. NEJM. 2017;376:305. 2. Bezlotoxumab PI.
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MODIFY I and II: CDI With Bezlotoxumab vs Actoxumab +
Bezlotoxumab vs Placebo
 International, randomized, double-blind phase III trials
Stratified by oral antibiotic, hospitalization
status (inpatient vs outpatient)
Bezlotoxumab 10 mg/kg*
(n = 781)
Adults with primary or
recurrent CDI receiving
SoC oral antibiotics for
10-14 days
(N = 2559)
Bezlotoxumab 10 mg/kg +
Actoxumab 10 mg/kg*
(n = 773)
Placebo*
(n = 773)
Monitoring through Wk 12 with
patients recording unformed
bowel movements to Day 80-90
MODIFY I only:
Actoxumab 10 mg/kg*
(n = 232)
 Primary endpoint: proportion of patients in mITT with recurrent CDI during 12-wk follow-up
*Single dose; infusions administered while receiving SoC antibiotics.
Wilcox. NEJM. 2017;376:305.
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CDI Recurrence Through Wk 12 (%)[1]
MODIFY I and II: Bezlotoxumab Efficacy in Reducing CDI
Recurrence in Subgroups With Baseline Risk Factors
45
40
35
30
29
28
27
15
25
22
17*
15*
15
15
153 178
405 390

10
5
0
Bezlotoxumab
Bezlotoxumab +
actoxumab
Placebo
32
31
25
20
42
41
773 781 773
115 102
219 216
126 100
In post hoc analysis,
for patients with no
CDI risk factors, no
difference between
bezlotoxumab and
placebo groups in
CDI recurrence[2]
*P < .001 vs placebo. Nonoverlapping 95% confidence intervals for all comparisons except the following: no risk factors and hypervirulent strain.
All patients also received SoC antibiotics.
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1. Wilcox. NEJM. 2017;376:305. 2. Gerding. Clin Infect Dis. 2018;67:649.
Key Take-home Points
 CDI is an increasingly prevalent nosocomial infection with a high burden of
morbidity, mortality, economic cost
 Diagnosis should utilize clinical criteria and laboratory testing
 2017 IDSA-SHEA treatment guideline recommendations
‒ Initial CDI: vancomycin or fidaxomicin for nonsevere or severe disease;
combination of oral vancomycin and IV metronidazole for fulminant disease
‒ Recurrent CDI: standard vancomycin (if initial metronidazole); prolonged taper
and pulsed-dose vancomycin or fidaxomicin (if initial vancomycin)
‒ Multiple recurrent CDI: taper and pulsed-dose vancomycin, standard
vancomycin plus rifaximin, fidaxomicin, FMT
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