Clostridium difficile: Can you smell the new updates?
Sunish Shah, Pharm.D.
PGY-2 Infectious Disease Pharmacy Resident Yale-New Haven Hospital
Learning objectives
• Recognize the epidemiology and virulence of Clostridium difficile infection
• Apply an appropriate treatment plan for a patient with Clostridium difficile infection based on presentation and severity of the infection
• Compare different treatment strategies for recurrent Clostridium difficile infection
History of CDI
1935
NAP1/BI/027 induced outbreak
Clostridium difficile was first isolated from the
stool of a healthy infant
1977
CDI associated with human disease + found to be the organism to cause the majority of antibiotic-
associated diarrhea
1978
Metronidazole and vancomycin found to have
activity against CDI
2017
2002
Fidaxomicin approved for the treatment of CDI
Heinlen et al. Am J Med Sci. 2010 Sep:247-52.
McDonald et al. N Engl J Med. 2005 Dec: 2433-41.
Burden of CDI
CDI is associated with a 6% to 30%
mortality rate
Rate of CDI hospitalizations has
tripled from 5.6/ 1000 discharges in 2001 to 12.7/ 1000 discharges in 2011
$ Approximately $3.2
billion annually
Up to $29,000 in attributable costs
for nosocomial CDI
Hota et al. Emerg Infect Dis. 2012 Feb:305-7.
Lessa et al. Clin Infect Dis. 2012 Feb:S65-70.
Microbiology
• Gram-positive anaerobic bacillus
• Spore forming
• Toxin producing
• NAP1/B1/027 – Increased toxin production
– Associated with severe disease
– Difficult to treat
– Associated with relapses
Eze et al. J Glob Health. 2017 Jun:22-3.
NAP1 Worldwide distribution
United States ‘05 69%
Europe ‘08 6.2%
Asia ‘06 < 1%
Canada ‘04 80%
McDonald et al. N Engl J Med. 2005 Dec:2431-41.
CDI Pathogenesis
CDI spores and vegetative cells are ingested
Spores
Vegetative cells
Peniche et al. Curr Opin Infect Dis. 2013 Oct:447-53.
CDI Pathogenesis
Stomach Only vegetative cells are
killed in the acidic environment
Spores
Vegetative cells
Peniche et al. Curr Opin Infect Dis. 2013 Oct:447-53.
CDI Pathogenesis
Small bowel Only vegetative cells are
killed in the acidic environment
Spores
Vegetative cells
Peniche et al. Curr Opin Infect Dis. 2013 Oct:447-53.
CDI Pathogenesis
Colon Clostridium difficile
multiplies and produces Toxins A, B and hydrolytic
enzymes
Spores
Vegetative cells
A
A
A
A
B
B
B
B
B
A
B
Toxin A
Toxin B
Peniche et al. Curr Opin Infect Dis. 2013 Oct:447-53.
CDI Pathogenesis
Toxins A + B Production of interleukins,
increased vascular permeability, neutrophil
and monocyte recruitment
Spores
Vegetative cells
A
A
A
A
B
B
B
B
B
A
B
Toxin A
White blood cell WBC
Toxin B
Peniche et al. Curr Opin Infect Dis. 2013 Oct:447-53.
CDI Pathogenesis
Hydrolytic enzyme connective tissue
degradation, leading to colitis, pseudomembrane
formation and watery diarrhea
Spores
Vegetative cells
A
A
B
B
B
B
A
B
Toxin A
White blood cell WBC
Toxin B
H Hydrolytic enzymes
H
H
H
H
H
H
H
H
Peniche et al. Curr Opin Infect Dis. 2013 Oct:447-53.
Risk factors for CDI
• Advanced age
• Increased duration of hospitalization
• Antibiotics – Clindamycin > 3-4th generation cephalosporins >
Fluoroquinolones
• Chemotherapy
• Manipulation of gastrointestinal tract
• Inflammatory bowel disease
• Solid organ transplantation
• Proton pump inhibitors
Eze et al. J Glob Health. 2017 Jun:22-3.
Audience response
Which of the following is true?
A. Clindamycin is less likely to induce CDI compared to flouroquinolones B. CDI is associated with up to a 30% mortality rate C. The NAP1/B1/027 strain is associated with increased virulence and is common in the United States D. B + C only E. All of the above
Diagnostic testing
Test Method Molecular Target Characteristics
EIA GDH Requires confirmation with toxin testing High sensitivity; Low specificity
EIA Toxin A or Toxin B Used to confirm positive GDH test High sensitivity; Moderate specificity
NAAT or PCR tcdB or tcdC gene Used when GDH and Toxin tests are discordant High sensitivity; Low specificity
EIA: Enzyme immunoassay; GDH: Glutamate dehydrogenase; NAAT: Nucleic acid amplification test; PCR: Polymerase chain reaction
Stool testing should only be performed on patients with unexplained new-onset diarrhea
Gupta et al. JAMA. 2016 Dec:2422-3.
JZ is a 48 year old male with a past medical history of Chron’s disease and living donor renal transplantation (2015) secondary to uncontrolled hypertension. He presents to the emergency department with right upper quadrant abdominal pain, fever and jaundice. He denies vomiting and has not had any bowel movements today.
Patient Case
BP HR RR SpO2 Temp
101/80 98 22 96 101 F CrCl= 130 ml/min
17
0.9 95
15.1
43
138
3.8 25
103
240 8.9
Which of the following is true regarding JZ’s case?
A. The patient should be tested for CDI with GDH alone B. Given the patient’s risk factor for Chron’s disease and renal transplantation, CDI testing should not be performed and oral vancomycin should be started C. The patient should be tested for CDI with GDH. A positive GDH test should be confirmed with toxin testing D. The patient should not be tested for CDI at this time
Audience response
JZ was also found to have hyperbilirubinemia, elevation of biliary enzymes and elevation of liver enzymes. Endoscopic retrograde cholangiopancreatography is performed for the treatment of acute ascending cholangitis. He is discharged to finish a 7 day course of amoxicillin/ clavulanate. Ten days following discharge JZ returns to the emergency department complaining of diarrhea, fever and dizziness. The diagnosis of CDI is made through a positive GDH and detection of CDI toxins.
Patient Case
BP HR RR SpO2 Temp
90/72 98 22 96 104 F CrCl= 24 ml/min
17
3.2 95
15.1
43
138
2.9 25
103
240 29
Management of CDI
CDI Management
Clinical diagnosis Recommended treatment
Non-severe CDI
Leukocytosis with a white blood cell count of ≤15 000 cells/mL and a serum creatinine level <1.5 mg/dL
Severe CDI
Leukocytosis with a white blood cell count of ≥15 000 cells/mL or a serum creatinine level >1.5 mg/dL
Fulminant CDI
Hypotension or shock, ileus, megacolon
McDonald et al. Clin Infect Dis. 2018 Mar:e41-8.
CDI Management
Clinical diagnosis Recommended treatment Quality of evidence
Non-severe CDI
• VAN 125mg orally QID X 10 days • FDX 200mg BID X 10 days • Alternative: MDZ 500mg orally TID X 10 days
High High High
Severe CDI
• VAN 125mg orally QID X 10 days • FDX 200mg BID X 10 days
High High
Fulminant CDI
• VAN 500mg orally or via NG tube QID • Ileus: Consider adding VAN rectal instillation • Ileus: Consider adding intravenous MDZ
Moderate Low
Moderate
VAN: Vancomycin; FDX: Fidaxomicin; MDZ: Metronidazole; BID: Twice daily; QID: Four times daily; NG: Nasogastric
McDonald et al. Clin Infect Dis. 2018 Mar:e41-8.
Treatment options
• Vancomycin
• Fidaxomicin
• Metronidazole
• Nitazoxanide
• Rifaximin
• Tigecycline
• Bacitracin
• Fusidic acid
McDonald et al. Clin Infect Dis. 2018 Mar:e41-8.
NAG NAM
NAM NAG NAM
NAG NAM
NAG
NAG
NAM
NAM
NAG
NAM
NAG
Vancomycin mechanism of action
D-Alanine
L-Lysine
D-Glutamate
Pentaglycine chain Hammes et al. Antimicrob Agents Chemother. 1974 Dec:722-8.
NAG NAM
NAM NAG NAM
NAG NAM
NAG
NAG
NAM
NAM
NAG
NAM
NAG
Vancomycin mechanism of action
Van
co
Van
co
Van
co
Van
co
Van
co
Van
co
Van
co
Van
co
Van
co
Hammes et al. Antimicrob Agents Chemother. 1974 Dec:722-8.
NAG
NAG
NAM
NAG
NAM
NAG
Vancomycin mechanism of action
Van
co
Van
co
Van
co
Van
co
Van
co
Van
co
Van
co
Van
co
Van
co
Hammes et al. Antimicrob Agents Chemother. 1974 Dec:722-8.
Metronidazole mechanism of action
Muller et al. Surgery. 1983 Jan:165-171.
Outcome Year Cure (%) RR (95% CI); P-value Reference
Resolution of diarrhea at end
of (10 days) treatment
RCT Prior to 2000 95 (MTR) 98 (VAN)
0.97 (0.91-1.03); P= 0.40 Teasley et al Wenisch et al
RCT since 2000 75 (MTR) 85 (VAN)
0.89 (0.82-0.96); P=0.002 Zar et al Johnson et al
All RCTs 78 (MTR) 87 (VAN)
0.89 (0.85-0.96); P=0.0008
Why is metronidazole not first line?
Outcome Year Cure (%) RR (95% CI); P-value Reference
Resolution of diarrhea at end
of treatment without CDI recurrence
RCT Prior to 2000 85 (MTR) 84 (VAN)
1.0 (0.90-1.2); P= 1.0 Teasley et al Wenisch et al
RCT since 2000 59 (MTR) 70 (VAN)
0.84 (0.74-0.94); P=0.002 Zar et al Johnson et al
All RCTs 63 (MTR) 73 (VAN)
0.87 (0.79-0.96); P=0.003
McDonald et al. Clin Infect Dis. 2018 Mar:e41-8.
Zar et al
Design Outcomes
• Controlled trial of adult patients with > 3 unformed stools and CDI toxin demonstrated in the stool or pseudomembranous colitis
• Patients randomly assigned to receive oral metronidazole (250 mg 4 times per day) or oral vancomycin (125 mg 4 times per day) for 10 days
• Cure rates for mild CDI
– Metronidazole (90%) vs Vancomycin (98%); (P=0.36)
• Cure rates for severe CDI
– Metronidazole (76%) vs Vancomycin (97%); (P=0.02)
Zar et al. Clin Infect Dis. 2007 Aug:302-7.
Johnson et al
Design Outcomes
• Patients with CDI were randomly assigned in a 2:1:1 ratio to oral tolevamer, vancomycin 125 mg every 6 hours for 10 days, or metronidazole 375 mg every 6 hours for 10 days
• Overall clinical cure rates
– Tolevamer (44.2%) vs Metronidazole (72.7%) vs Vancomycin (81.1%); (P< 0.001)
• Cure rates for severe CDI
– Metronidazole (66.3%) vs vancomycin (78.5%); (P= .059).
Johnson et al. Clin Infect Dis. 2014 Aug:345-54.
Other agents for primary CDI
Agents with probable efficacy
Agent Adult dose Side effects Supporting data
Nitazoxanide 500 mg PO bid × 10 days
GI symptoms Small RCT comparison to vancomycin Modest RCT comparison to metronidazole
Fusidic acid 250 mg PO tid × 10 days
GI symptoms
Modest RCT comparison to metronidazole Small RCT comparison to vancomycin
Nitazoxanide vs Vancomycin cure rates 74% (20/27) vancomycin vs. 77% (17/22) nitazoxanide
Nitazoxanide vs Metronidazole cure rates 58% (19/33) metronidazole vs. 66% (25/38) nitazoxanide
Fusidic Acid
Not available in the United States
McDonald et al. Clin Infect Dis. 2018 Mar:e41-8.
Musher et al. Clin Infect Dis. 2009 Feb:e41-6.
Musher et al. Clin Infect Dis. 2006 Aug:421-7.
Other agents for primary CDI
Agents with limited efficacy
Agent Adult dose Side effects Supporting data
Tigecycline 50 mg IV bid × 10 days
GI symptoms Small case series
Bacitracin 25,000 units PO qid × 10 days
Minimally absorbed
Two small RCT comparisons to vancomycin
Rifaximin 400 mg PO tid × 10 days
Minimally absorbed
RCT for recurrent CDI
Rifaximin vs Placebo CDI recurrence 31% (11/35) placebo vs. 77% (5/33) rifaximin (P=0.11)
McDonald et al. Clin Infect Dis. 2018 Mar:e41-8.
Garey et al. J Antimicrob Chemother. 2011 Dec:2850-5.
JZ was also found to have hyperbilirubinemia, elevation of biliary enzymes and elevation of liver enzymes. Endoscopic retrograde cholangiopancreatography is performed for the treatment of acute ascending cholangitis. He is discharged to finish a 7 day course of amoxicillin/ clavulanate. Ten days following discharge JZ returns to the emergency department complaining of diarrhea, fever and dizziness. The diagnosis of CDI is made through a positive GDH and detection of CDI toxins.
Patient Case
BP HR RR SpO2 Temp
90/72 98 22 96 104 F CrCl= 24 ml/min
17
3.2 95
15.1
43
138
2.9 25
103
240 29
JZ is started on oral vancomycin 125mg every 6 hours before being admitted to the intensive care unit for norepinephrine administration. The following day, he still remains critically ill but he is having less frequent bowel movements. An abdominal X-ray is suggestive of paralytic ileus. Ultrasonography and computed tomography of the abdomen and pelvis identify colonic dilatation. How should JZ be managed?
A. The oral vancomycin dose should be increased to 500mg every 6 hours B. Consideration should be given to additional rectal vancomycin C. Consideration should be given to additional oral metronidazole 500mg every 8 hours D. A+B E. All of the above
Audience response
Patient Case JZ responds clinically to medical therapy and does not require surgery. He is discharged to home after finishing a 10 day course of therapy. Unfortunately, one month following discharge, JZ presents to the emergency department again with diarrhea and fever. The diagnosis of CDI is made through a positive GDH and detection of CDI toxins. He is also found to have NAP1/B1/027 colonization.
BP HR RR SpO2 Temp
124/82 98 18 96 102.1 F CrCl= 43 ml/min
17
1.5 95
15.1
43
138
3.4 25
103
240 17
Management of CDI recurrence
CDI recurrence
• After a first diagnosis of CDI, 10%–30% of patients develop at least 1 recurrent CDI episode
• The risk of recurrence increases with each successive recurrence
• NAP1/B1/027
• McDonald et al – Continuous use of PPIs was independently associated with a 50%
increased risk for recurrence
– Re-exposure to antibiotics was associated with only a 30% increased risk
McDonald et al. Clin Infect Dis. 2018 Mar:e41-8.
McDonald et al. JAMA. 2015 Mar:784-91.
Management of CDI recurrence
Clinical diagnosis Recommended treatment Evidence level
First recurrence • Initial MDZ use: VAN 125mg orally QID X 10 days • Initial VAN use: FDX 200mg BID X 10 days • Prolonged and tapered pulsed VAN regimen
Low Moderate Low
2nd or subsequent recurrence
• VAN in a tapered and pulsed regimen • VAN 125mg orally QID X 10 days followed by rifaximin 400mg 3 times daily for 20 days • FDX 200mg given twice daily for 10 days • Fecal microbiota transplantation
Low Low Low Moderate
VAN: Vancomycin; FDX: Fidaxomicin; MDZ: Metronidazole; BID: Twice daily; QID: Four times daily
McDonald et al. Clin Infect Dis. 2018 Mar:e41-8.
Fidaxomicin
• Macrocylic antibiotic with activity against C. difficile
• Produced by Dactylosporangium aurantiacum
• Mechanism of action
– Inhibits bacterial RNA polymerase at transcription initiation
– Demonstrated to inhibit toxin A and B production
• Resistance has been reported
– rpoB and rpoC
• Reduced incidence of VRE and Candida
Zhanel et al. Can J Infect Dis Med Microbiol. 2015 Dec:305-12.
• Prospective, multicenter, double-blind trial
• Patients randomized to 200 mg of fidaxomicin q12h with intervening matching doses of placebo or 125 mg of vancomycin q6h X 10 days
Inclusion Exclusion
16 years of age or older Fulminant CDI
Diarrhea with CDI toxin Prior fidaxomicin exposure
Ulcerative colitis or Crohn’s disease
CDI within prior 3 months
Louie et al. N Engl J Med. 2011 Feb:422-31.
Louie et al
Characteristic Fidaxomicin (N=265) Vancomycin (N=283)
Age (yr) 59.9 + 17.1 62.7 + 17.0
Female sex (%) 57.4 54.8
Unformed stools/day (no.) 8.2 + 4.3 8.4 + 5.5
Inpatient (%) 55.1 57.2
Prior CDI episode, n (%) 16.2 17.0
BI/NAP1/027 strain* (%) 35.3 36.4
*Based on the 415 patients who had a strain type that could be evaluated
Baseline demographics
Louie et al. N Engl J Med. 2011 Feb:422-31.
Global Cure Recurrence Clinical Cure
Pat
ien
ts (
%)
100
80
60
40
20
0
92 90
13
24
78 67
P=0.004 P=0.006
Fidaxomicin Vancomycin
Results
Clinical cure Defined as the resolution of diarrhea Global cure Defined as the resolution of diarrhea without recurrence
Recurrence NAP1: 24.4% fidaxomicin vs. 23.6% vancomycin (p=0.93) Non-NAP1: 7.8% fidaxomicin vs. 25.5% vancomycin (p<0.001)
Louie et al. N Engl J Med. 2011 Feb:422-31.
• 45 sites in Europe; 41 sites in Canada and the United States
• Patients randomized to 200 mg of fidaxomicin q12h with intervening matching doses of placebo or 125 mg of vancomycin q6h X 10 days
Inclusion Exclusion
16 years of age or older Fulminant CDI
Diarrhea with CDI toxin Prior fidaxomicin exposure
Ulcerative colitis or Crohn’s disease
CDI within prior 3 months
Cornely et al. Lancet Infect Dis. 2012 Feb:281-9.
Cornely et al
Characteristic Fidaxomicin Vancomycin P-value
Clinical Cure
All 221/252 (87.7%) 223/257 (86.8%) 0.754
Europe 89/100 (89.0%) 82/98 (83.7%) 0.275
USA and Canada 132/152 (86.8%) 141/159 (88.7%) 0.621
Recurrence
All 28/221 (12.7%) 60/223 (26.9%) 0.0002
Europe 8/89 (9.0%) 19/82 (23.2%) 0.011
USA and Canada 20/132 (15.2%) 41/141 (29.1%) 0.006
Sustained Response
All 193/252 (76.6%) 163/257 (63.4%) 0.001
Europe 81/100 (81.0%) 63/98 (64.3%) 0.008
USA and Canada 112/152 (73.7%) 100/159 (62.9%) 0.041
Results
Cornely et al. Lancet Infect Dis. 2012 Feb:281-9.
Results Clinical cure Fidaxomicin (n=252) Vancomycin (n=257) p-value
Non-BI/NAP1/027, n (%) 120/131 (91.6%) 106/121 (87.6%) 0.297
Concomitant antibiotics, n (%) 46/51 (90.2%) 33/45 (73.3%) 0.031
Recurrence Fidaxomicin (n=221) Vancomycin (n=223) p-value
Non-BI/NAP1/027, n (%) 11/120 (9.2%) 29/106 (27.4%) 0.0003
First episode, n (%) 21/184 (11.4%) 49/191 (25.7%) 0.0004
Sustained Response Fidaxomicin (n=252) Vancomycin (n=257) p-value
Non-BI/NAP1/027, n (%) 109/131 (83.2%) 77/121 (63.6%) 0.0004
Severe, n (%) 44/63 (69.8%) 29/61 (47.5%) 0.012
Cornely et al. Lancet Infect Dis. 2012 Feb:281-9.
Bezlotoxumab
• Monoclonal antibody with high binding affinity for Toxin B
– Binding prevents attachment to colonic mucosal cells
– No binding affinity to Toxin A
• Actoxumab with activity against Toxin A
• Approved as adjunct therapy for recurrent CDI
• No evidence of resistance
Navalkele et al. Biologics: Targets & Therapy. 2018 Jan:11-21.
• Two double-blind, randomized, placebo-controlled, phase 3 trials, MODIFY I and MODIFY II
• Participants received an infusion of bezlotoxumab (10mg/kg), actoxumab plus bezlotoxumab (10mg/kg each), or placebo
Inclusion Exclusion
Diarrhea with toxigenic CDI Surgery for CDI within 24 hours
Standard CDI therapy receipt Saccharomyces reciept
Chronic diarrheal illness
Pregnant or beast-feeding
Wilcox et al
Wilcox et al. N Engl J Med. 2017 Jan:305-17.
Characteristic A + B (N=773) B (N=781) Placebo (N=773)
Metronidazole, n (%) 366 (47.3) 365 (46.7) 353 (45.7)
Vancomycin, n (%) 366 (47.3) 370 (47.4) 372 (48.1)
Fidaxomicin, n (%) 25 (3.2) 30 (3.8) 30 (3.9)
> 2 prior CDI episodes 103 (13.3) 100 (12.8) 126 (16.3)
Immunocompromised 163 (21.1) 178 (22.8) 153 (19.8)
BI/NAP1/027 76 (15.9) 89 (18.2) 100 (20.6)
Pooled baseline demographics
Wilcox et al. N Engl J Med. 2017 Jan:305-17.
Results
17 16 17 16 15 15
28 26 27
0
5
10
15
20
25
30
35
40
A +B B Placebo
P< 0.001 P< 0.001 P< 0.001
Pat
ien
ts w
ith
infe
ctio
n r
ecu
rre
nce
th
rou
gh w
eek
12
(%
) P< 0.001 P< 0.001 P< 0.001
Modify I Modify II Pooled data
Wilcox et al. N Engl J Med. 2017 Jan:305-17.
Fecal Microbiota Transplantation
• Restoration of normal gastrointestinal flora with live enteric bacteria from a donor
• How is it done? – Nasogastric tube
– Nasoduodenal (ND) tube
– Esophagogastroduodenoscopy
– Capsulized frozen sample
– Colonoscopy
– Retention Enema
van Nood et al Youngster et al
• Randomized trial of patients with a recurrence of CDI
• Primary end point Resolution of CDI without relapse after 10 weeks
• Oral vancomycin X 14 days followed by bowel lavage (BL) and ND donor feces (n=16)
– 81.3% success rate
• Oral vancomycin X 14 days (n=13)
– 30.8% success rate
• Oral vancomycin X 14 days and BL (n=13)
– 23.1% success rate
Does it work?
• Phase 1 safety and efficacy study
• Patients with recurrent CDI
• Fifteen capsules from unrelated donors administered X 2 days
• Resolution of diarrhea: 14/20 (70%)
Youngster et al. JAMA. 2014 Nov:1772-8.
van Nood et al. N Engl J Med. 2013 Jan:407-15.
Patient Case JZ responds clinically to medical therapy and does not require surgery. He is discharged to home after finishing a 10 day course of therapy. Unfortunately, one month following discharge, JZ presents to the emergency department again with diarrhea and fever. The diagnosis of CDI is made through a positive GDH and detection of CDI toxins. He is also found to have NAP1/B1/027 colonization.
BP HR RR SpO2 Temp
124/82 98 18 96 102.1 F CrCl= 43 ml/min
17
1.5 95
15.1
43
138
3.4 25
103
240 17
Which of the following is true regarding JZ’s case?
A. The patient can be treated with oral vancomycin for 10 days; bezlotoxumab can be used adjunctively B. The patient can be treated with fidaxomicin or an oral vancomycin taper; bezlotoxumab can be used adjunctively C. The patient can be treated with bezlotoxumab alone D. Fidaxomicin would be preferred over bezlotoxumab to prevent subsequent recurrence
Audience response
Conclusion
• CDI is associated with a high mortality rate and an increasing incidence
• Oral vancomycin and fidaxomicin are the drugs of choice
• Strategies to prevent CDI recurrence include prophylactic bezlotoxumab and treatment with fidaxomicin
Questions
A
A
B
B
B
B
H
H
H
H
H
H
H
H
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