clostridium difficile: can you smell the new updates? · leukocytosis with a white blood cell count...

Clostridium difficile: Can you smell the new updates?

Sunish Shah, Pharm.D.

PGY-2 Infectious Disease Pharmacy Resident Yale-New Haven Hospital

[email protected]

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


CDI Pathogenesis

Small bowel Only vegetative cells are

killed in the acidic environment

Spores

Vegetative cells


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


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


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


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


Treatment options

• Vancomycin

• Fidaxomicin

• Metronidazole

• Nitazoxanide

• Rifaximin

• Tigecycline

• Bacitracin

• Fusidic acid


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


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


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


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


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)


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. 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


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


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)


• 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


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


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


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


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)


• Oral vancomycin X 14 days and BL (n=13)


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

clostridium difficile: can you smell the new updates? · leukocytosis with a white blood cell count...

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