Clostridium difficile Infection (CDI): Increasingly Severe and Rapidly Fatal Disease Requires High Certainty of Treatment Efficacy

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Clostridium difficile Infection (CDI)
Increasingly Severe and Rapidly Fatal Disease
Requires High Certainty of Treatment Efficacy

• Dale N. Gerding, MD
• Associate Chief of Staff for Research
• Edward Hines Jr. Veterans Affairs Hospital
• Professor of Medicine (Infectious Diseases)
• Loyola University Chicago Stritch School of
  Medicine

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• Disclosures DNG is a consultant for Genzyme,
  GOJO, Optimer, Salix, Merck, Cepheid, BD Genome,
  Schering-Plough and ViroPharma. His institution
  has research grants in his name from Genzyme,
  GOJO, Massachusetts Biological Laboratories,
  Optimer, and ViroPharma. He holds patents for the
  treatment and prevention of CDI with
  non-toxigenic Clostridium difficile (NTCD)
  licensed to ViroPharma.
• Views expressed are those of the presenter and do
  not necessarily reflect the views of the U.S.
  Department of Veterans Affairs, the major funding
  source for his research.

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Clostridium difficile Infection (CDI)

• CDI rates of diarrhea and colitis have continued
  to increase in the United States since 2000.
• A common epidemic hypervirulent C. difficile
  strain continues to be reported from hospitals in
  an expanding list of states.
• More severe CDI with higher mortality and higher
  rates of colectomy, especially in the elderly,
  continues to be reported.
• Currently, non-absorbed oral agents that are
  locally active such as vancomycin and new
  investigational drugs are the most effective
  treatments available for severe CDI.

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Rates of CDI Nearly Tripled in U.S. Hospitals
between 2000 and 2005
Any listed Primary
From McDonald LC, et al. Emerg Infect Dis.
200612(3)409-15 And unpublished CDC data
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States with the Epidemic Strain of C. difficile
Confirmed by CDC (N37) Updated November 9, 2007
DC
37 States and DC confirmed by CDC
HI
PR
AK
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CDI Rates and Mortality Increase with Increased
Patient Age
Age (Years) CDI Rate per 1000 Admissions Attributable 30-Day Mortality Rate ()
lt40 3.5 2.6
41-50 11.2 1.2
51-60 20.0 3.2
61-70 24.4 5.1
71-80 38.3 6.2
81-90 54.5 10.2
gt90 74.4 14.0
Loo et al NEJM 20053532442-9
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Dilated Loops of Colon in a Patient with CDI
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Fulminant CDI Severe and Rapidly Fatal Disease

• 51 yo male underwent coronary artery bypass
  grafting and received cefazolin pre-surgery.
  Previous antibiotic Rx with gatifloxacin,
  piperacillin/tazobactam, ceftriaxone, and
  azithromycin.
• Rapidly progressive 4-day course from diarrhea to
  shock and death. WBC elevated throughout course
  and rose precipitously near the time of death.

Diarrhea Onset
Hospital Admission for Community Pneumonia
65,000
CABG Surgery
27,000
17,700
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Abdominal CT Findings in Fulminant CDI
Ascites
Thickened Colonic Wall
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Normal Colon and Pseudomembranous Colitis (PMC)
as seen at Colonoscopy
Colon with PMC due to Clostridium difficile
Infection
Normal Colon
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Histological Appearance of Pseudomembranous
Colitis (PMC)
Pseudomembrane
Mucosal Destruction and Inflammatory Response
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Colon Autopsy Specimen of a Patient who Died of
Severe CDI Confluent PMC is Evident
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Inflammatory Response to C. difficile Toxins
alters GI Tract Physiology

• Toxin A is a potent enterotoxin (causes fluid
  loss) and a very active white blood cell
  attractant.
• Toxin B is a potent cell cytotoxin (kills cells)
• CDI patients commonly demonstrate an elevated
  White Blood Cell count Clin Infect Dis
  2002341585-92
• Fecal Lactoferrin, Interleukin-1beta, and
  Inter-leukin-8 are elevated in patients with
  severe CDI. Clin
  Diagnostic Lab Immuno 19974719-722
• Cyclooxygenase (Cox)-2 expression and
  prostaglandins are elevated in the presence of
  Toxin A. JID 2001184648-52

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Summary

• CDI is a severe inflammatory colonic disease with
  high mortality and morbidity, especially in the
  elderly.
• C. difficile Toxins A and B and the associated
  inflammation produced cause structural,
  functional, and biochemical changes in the GI
  tract of CDI patients that are poorly understood.
• Currently, no in vitro model has been developed
  for the C. difficile-infected GI tract and the
  best in vitro model to demonstrate bioequivalence
  in CDI is uncertain.

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Summary (cont.)

• Given that vancomycin is currently the preferred
  treatment for severe CDI, we must have some
  clinical evidence of efficacy for generic agents
  prior to exposure of patients with
  life-threatening CDI to formulations that have
  never been given to humans.
• I suggest FDA openly discuss both the
  uncertainties inherent in any bioequivalence
  method proposed for CDI as well as the risks and
  benefits to patients associated with approving a
  bio-inequivalent formulation.