Clostridium difficile: An Emerging Threat

1
Clostridium difficile An Emerging Threat

• L. Clifford McDonald, MD, FACP, FSHEA
• Division of Healthcare Quality Promotion

2
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
3
The Historic Impact of CDAD

• Rates
• Acute care 3-25/10,000 patient days
• Long term care carriage in 5-7 of patients
• Boston, 19981
• Very low attributable mortality
• Average of 3,600 excess costs per case
• Average of 3.6 extra hospital days

• Kyne L, et al. Clin Infect Dis. 200234346-353.

4
Annual CDAD Rates, Hospitals with gt500 Beds,
Intensive Care Unit Surveillance Component, NNIS
From Archibald LK, et al. J Infect Dis.
20041891585158.
5
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
6
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
7
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
8
Proportion of US Short-Stay Hospital Discharges
with C. difficile Listed as Any Diagnosis by
Hospital Bed Size
From McDonald LC, et al. Emerg Infect Dis.
200612(3)409-15
9
Increasing Severity of CDAD

• Pittsburgh, 20002
• Life-threatening disease from 1.6 to 3.2
• 2000-2001 26 colectomies and 18 deaths
• Quebec, 2004
• 30-day attributable mortality 6.9
• 12-month attributable mortality 16.7

• Dallal RM, et al. Ann Surg. 2002235363-372.
• Muto C, et al. Infect Control HospEpid. 2005
• Pepin J, et al. CMAJ. 2005

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CDAD in long term care

• Number of patients with CDAD diagnosis
  transferred to long term care
• Doubled between 2000 and 2003
• 2 of all transferred patients
• Ohio, 2006

11
Emerging Infections Network (EIN) Surveys, 2004
2 surveys conducted 6 months apart, 531 unique
Infectious Disease Clinician respondents with
observations over prior 6 months
Layton BA, et al. 15th Annual Scientific Meeting
of The Society for Healthcare Epidemiology of
America (SHEA), April 9-12, 2005 Los Angeles,
CA.
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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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Acute Care Hospitals with CDAD Outbreaks
Between 2001-2004
Detected by increases in the number of positive
routine clinical laboratory tests for C.
difficile.
Data from McDonald LC, et al. N Engl J Med.
20053532433-2441.
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Epidemic (BI/NAP1) Strain
From McDonald LC, et al. N Engl J Med.
20053532433-2441.
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Nonepidemic (Non-BI/NAP1) Strains
From McDonald LC, et al. N Engl J Med.
20053532433-2441.
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Resistance of Current (after 2000) BI/NAP1
Isolates to Clindamycin and Fluoroquinolones
Compared with Current Non-BI/NAP1 Isolates and
Historic (before 2001) BI/NAP1 Isolates
From McDonald LC, et al. N Engl J Med.
20053532433-2441.
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Distribution of Levofloxacin Minimum Inhibitory
Concentrations in Current (ie, after 2000)
BI/NAP1 and Non-BI/NAP1 Isolates
From McDonald LC, et al. N Engl J Med.
20053532433-2441.
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Increased Toxin A Production in vitro
In vitro production of toxins A and B by C.
difficile isolates. Median concentration and IQRs
are shown. C. difficile strains included 25
toxinotype 0 and 15 NAP1/027 strains (toxinotype
III) from various locations.
From Warny M, et al. Lancet. 20053661079-1084.
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Increased Toxin B Production in vitro
In vitro production of toxins A and B by C.
difficile isolates. Median concentration and IQRs
are shown. C. difficile strains included 25
toxinotype 0 and 15 NAP1/027 strains (toxinotype
III) from various locations.
From Warny M, et al. Lancet. 20053661079-1084.
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States with the Epidemic Strain of C. difficile
Confirmed by CDC and Hines VA labs
(N23),Updated 2/9/2007
DC
HI
PR
AK
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Lethal hospital bug cases rocket, United Kingdom

• Potentially lethal cases of C. difficile
  rocketed from 1990s to 2004
• Cases had increased from 1,000 in 1990 to over
  35,000 in 2003
• 44,488 cases of C. difficile in gt 65 year olds in
  2004.

BBC News. http//news.bbc.co.uk/2/hi/health/418683
4.stm
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BI/NAP1 in the Netherlands, 2006
Kuiper EJ et al. Emerg Infect Dis
200612(5)827-830.
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Challenges

• Emergence of a new epidemic strain
• Toxinotype III or BI by REA
• Distinct from J strain of 1989-19921
• Binary toxin as a possible virulence factor
• In addition to toxins A and B containing
• 18 bp deletion in tcdC gene
• Could lead to increased toxin production (18-fold
  for toxin A, 23-fold for toxin B) observed by
  Warny et al.2
• Increased resistance to fluoroquinolones
• Appears responsible for increase in cases
• May be responsible for increase in disease
  severity

• Johnson S, et al. N Engl J Med.
  19993411645-1651.
• Warny M, et al. Lancet. 20053661079-1084.

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Recommendations for Hospitals

• Hospitals should conduct surveillance for CDAD
• Recently proposed surveillance recommendations1
• Early diagnosis and treatment important for
  reducing severe outcomes and should be emphasized
• Subset of epidemic isolates tested metronidazole
  susceptible
• Strict infection control CDC Fact Sheet2
• Contact precautions for CDAD patients
• An environmental cleaning and disinfection
  strategy
• Hand-washing with CDAD patients in outbreak
• Further research needed
• Role for antimicrobial controls in stemming this
  epidemic

1McDonald et al. Infect Control Hosp Epidemiol
2007 28140-145 2See CDC C. difficile Fact
Sheets http//www.cdc.gov/ncidod/dhqp/.
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Severe CDAD in Populations Previously at Low
RiskFour States, 2005 (1)

• Recent reports to the Pennsylvania Department of
  Health and CDC
• Young patients without serious underlying disease
• C. difficile toxin-positive by routine diagnostic
  testing
• Responded to CDAD-specific therapy
• Peripartum
• Within 4 weeks of delivery
• Reports from PA, NJ, OH, and NH
• Community-associated
• No hospital exposure in prior 3 months
• Reports from Philadelphia and 4 surrounding
  counties

CDC. MMWR. 2005541201-1205.
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Severe CDAD in Populations Previously at Low
RiskFour States, 2005 (2)
CDC. MMWR. 2005541201-1205.
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Severe CDAD in Populations Previously at Low
RiskFour States, 2005 (3)

• Recent onset dates
• February 26, 2003 June 28, 2005
• Only 1 case in 2003
• Transmission to close contacts in 4 cases
• 8 cases without antimicrobial exposure
• 5 children 3 required hospitalization
• 3 had close contact with diarrheal illness
• Another 3 cases with lt 3 doses of antimicrobials
• Clindamycin most common exposure (10 cases)
• Estimated minimum annual incidence of
  community-associated disease
• 7.6 cases per 100,000 population
• 1 case per 5,000 outpatient antimicrobial
  prescriptions

CDC. MMWR. 2005541201-1205.
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Comparison of Molecular Characteristics of 2 C.
difficile Isolates with Historical Standard-Type
Strains and a Recently Recognized Epidemic
Strain, by Selected Characteristics, OH and PA,
2005
Pulsed-field gel electrophoresis. North
American pulsed-field type 1. McDonald LC,
Killgore GE, Thompson A, Owens RC Jr, Kazakova
SV, Sambol SP, Johnson S, Gerding DN. An
epidemic, toxin gene-variant strain of
Clostridium difficile. N Engl J Med.
20053532433-2441. CDC. MMWR. 2005541201-1205.
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Stomach Acid-Suppressing Medications and
Community-Acquired CDAD, England
From Dial S, et al. JAMA. 20052942989-2995.
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Recommendations for CDAD in Previously Low-Risk
Populations

• Further investigation and surveillance in these
  populations are warranted
• Strains responsible for severe CDAD in previously
  low-risk populations unknown
• May be other toxin variants and/or hospital
  epidemic strain
• Clinicians should consider the diagnosis
• CDAD in patients without traditional risk factors
• Patients should seek medical attention
• Diarrhea lasting longer than 3 days
• Fever
• Blood
• Antimicrobial exposure is not benign
• Continue to emphasize judicious antimicrobial use