Epidemiology and Diagnosis of Clostridium Difficile Infection

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Epidemiology and Diagnosis of Clostridium
Difficile Infection

• LCDR Raquel Peat, MS, MPH
• Microbiologist
• FDA/CDRH/OIVD/DMD

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• The findings and conclusions in this presentation
  are those of the author and do not necessarily
  represent the views of the Food and Drug
  Administration

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Overview

• Review current epidemiologic trends in
  Clostridium difficile
• Review current knowledge regarding pathogenesis
  of Clostridium difficile disease
• Identify novel devices that aid in the diagnosis
  of Clostridium difficile.
• Eradication

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Clostridium difficile

• Anaerobic spore-forming bacillus
• Clostridium difficile-associated disease (CDAD)
• Pseudomembranous colitis, toxic megacolon,
  sepsis, and death
• Fecal-oral transmission through contaminated
  environment and hands of healthcare personnel
• Antimicrobial exposure is major risk factor for
  disease
• Acquisition and growth of C. difficile
• Suppression of normal flora of the colon
• Clindamycin, penicillins, and cephalosporins

Healthy colon
Pseudo-membranous colitis
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Background

• Clostridium difficile is responsible for 20 of
  all cases of antibiotic associated diarrhea and
  has been increasingly recognized as a major
  nosocomial pathogen
• Barbut, F. Journal of Clinical Microbiology. June
  2000. p2386-2388

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Annual CDAD Rates, Hospitals with gt500 Beds,
Intensive Care Unit Surveillance Component, NNIS
From Archibald LK, et al. J Infect Dis.
20041891585158.
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Clostridium difficile infection

• Range in severity from asymptomatic to severe and
  life- threatening
• Many deaths have been reported
• Infected in hospitals, nursing homes, or
  institutions
• Outpatient setting is increasing

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National Estimates of US Short-Stay Hospital
Discharges with C. difficile as First-Listed or
Any Diagnosis
From McDonald LC, et al. Emerg Infect Dis.
200612(3)409-15
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Rates of US Short-Stay Hospital Discharges with
C. difficile Listed as Any Diagnosis by Age
From McDonald LC, et al. Emerg Infect Dis.
200612(3)409-15
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Rates of US Short-Stay Hospital Discharges with
C. difficile Listed as Any Diagnosis by Region
From McDonald LC, et al. Emerg Infect Dis.
200612(3)409-15
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Potential Reasons for Increased CDAD Incidence
and Severity

• Changes in underlying host susceptibility
• Changes in antimicrobial prescribing
• New strain with increased virulence
• Changes in infection control practices

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BI/NAP1 C. difficile Strain

• Virulent
• Produce greater quantities of toxins A and B
• Resistant to the antibiotic group

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Epidemic (BI/NAP1) Strain
From McDonald LC, et al. N Engl J Med.
20053532433-2441.
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Retail Meats

• C. difficile organisms, including recently
  identified human epidemic strains, have been
  identified in retail meats, including beef, pork,
  turkey and ready-to-eat meats
• It is not known how these bacteria got into the
  meat

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Pathogenesis of C difficile-associated disease
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Anaerobic Stool Culture

• Not specific for toxin-producing bacteria
• asymptomatic patients may have positive stool
  cultures because of colonization of nontoxigenic
  strains
• Results are available within 2 to 5 days

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Toxigenic bacterial culture

• Organisms are cultured on selective medium and
  tested for toxin production
• Enrichment debate vs direct plating
• Methods not standardized
• Results are available within 2 to 5 days
• Clinical and Laboratory Standards Institute.
  2004. Protocol for Determination of Limits of
  Detection and Limits of Quantitation Approved
  Guideline (EP17-A)

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Cell Culture Cytotoxin assay

• Toxigenic anerobic cell culture toxin testing
• gold standard laboratory test
• Detecting toxin A and B strains
• Sensitivity 94-100
• Specificity 99
• 24 to 48 hours for results
• Fekety R, Shah AB. Diagnosis and treatment of
  Clostridium difficile colitis. JAMA 199326971-5
  

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Enzyme immunoassays (ELISA)

• Detect toxin A or B
• 2 to 6 hours for results
• Sensitivity 70-90
• Specificity 99
• Limitations
• False positive- grossly bloody stool
• False negative- if the toxin was not being shed
  by the isolate at the time the sample was
  obtained
• Lack of correlation with severity of the disease
• Inability to perform repetitive analyses because
  toxins degrade over time
• Fekety R, Shah AB. Diagnosis and treatment of
  Clostridium difficile colitis. JAMA 199326971-5
  

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Latex agglutination

• Detect glutamate dehydrogenase
• Convenient and inexpensive
• gt30 minutes
• Not reliable
• Fekety R, Shah AB. Diagnosis and treatment of
  Clostridium difficile colitis. JAMA 199326971-5

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Change we can believe in
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Molecular Testing

• Recently cleared by FDA
• Sensitivity 90-100
• PPV76
• NPV 99
• Rarely used in laboratories
• Peterson, LR et a. Clin Infec Dis. 2007, 45
  1152-1160

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Endoscopy

• Major non-laboratory procedure for detecting C.
  difficile
• Should only be pursued in special cases
• Immediate results
• Limitations
• Expensive to perform
• Require trained personnel
• Contraindicated in patients with toxic megacolon
  due to the risk of bowel perforation
• Fekety R, Shah AB. Diagnosis and treatment of
  Clostridium difficile colitis. JAMA 199326971-5
  

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Advantages and disadvantages of diagnostic
testing methods for C difficile
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Relative Sensitivity of C. difficile Tests

• Culture toxin confirmationgt
• GDH EIAgt
• PT-PCR?gt
• Cell Cytotoxingt
• Toxin A and B EIAgt
• Toxin A EIAgt
• GDH Latex testgt
• Endoscopy

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CDI Outbreaks and Epidemics

• Definition for what constitutes an outbreak,
  epidemic and hyper-endemic rate do not exist
• An outbreak or epidemic can be defined as an
  increase in CDI greater than that expected
• When CDI rates are high, try to identify high
  risk healthcare facility location to focus
  intervention
• General guidance CDI rates below 5/1,000
  discharges are good

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What is Need to Achieve Eradication

• Antibiotic precribing methods
• Improved Diagnostics
• Perform hand hygiene
• Infection Control
• Disinfectants

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Conclusion

• Greater emphasis on infection control
• The will- need for increased awareness among
  health providers
• Promote the use of Culture toxin confirmation
  testing in laboratories

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• Thank you!
• LCDR Raquel Peat
• Raquel.Peat_at_fda.hhs.gov
• 240-276-1497