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. 2002;34:

4. Annual CDAD Rates, Hospitals with >500 Beds, Intensive Care Unit Surveillance Component, NNIS
From Archibald LK, et al. J Infect Dis. 2004;189:1585–158.

5. National Estimates of US Short-Stay Hospital Discharges with C
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. 2006;12(3):409-15

6. Rates of US Short-Stay Hospital Discharges with C
Rates of US Short-Stay Hospital Discharges with C. difficile Listed as Any Diagnosis by Age
From McDonald LC, et al. Emerg Infect Dis. 2006;12(3):409-15

7. Rates of US Short-Stay Hospital Discharges with C
Rates of US Short-Stay Hospital Discharges with C. difficile Listed as Any Diagnosis by Region
From McDonald LC, et al. Emerg Infect Dis. 2006;12(3):409-15

8. Proportion of US Short-Stay Hospital Discharges with C
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. 2006;12(3):409-15

9. Increasing Severity of CDAD
Pittsburgh, 20002
Life-threatening disease from 1.6% to 3.2%
: 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. 2002;235:
Muto C, et al. Infect Control HospEpid. 2005
Pepin J, et al. CMAJ. 2005

10. 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.

12. 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

13. 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. 2005;353:

14. Epidemic (BI/NAP1) Strain
From McDonald LC, et al. N Engl J Med. 2005;353:

15. Nonepidemic (Non-BI/NAP1) Strains
From McDonald LC, et al. N Engl J Med. 2005;353:

16. 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
No. (%)
Intermediate or
Resistant to:
Current
BI/NAP1
Isolates
n=24 (%)
non-
P-Value for
vs. Non-
Historic
n=14 (%)
Current vs.
Clindamycin
19 (79)
1.0
10 (71)
0.7
Levofloxacin
24 (100)
23 (96)
14 (100)
Gatifloxacin
10 (42)
<0.001
Moxifloxacin
From McDonald LC, et al. N Engl J Med. 2005;353:

17. 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. 2005;353:

18. Increased Toxin A Production in vitro
Approximately 16 fold increased toxin A production by the epidemic strain
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. 2005;366:

19. 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.
Approximately 23 fold increase in toxin B production
From Warny M, et al. Lancet. 2005;366:

20. States with the Epidemic Strain of C
States with the Epidemic Strain of C. difficile Confirmed by CDC and Hines VA labs (N=23), Updated 2/9/2007 DC HI PR AK

21. 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 > 65 year olds in 2004.
BBC News.

22. BI/NAP1 in the Netherlands, 2006
Kuiper EJ et al. Emerg Infect Dis 2006;12(5):

23. Challenges Emergence of a new epidemic strain
Toxinotype III or “BI” by REA
Distinct from “J” strain of
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. 1999;341:
Warny M, et al. Lancet. 2005;366:

24. 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; 28:
2See CDC C. difficile Fact Sheets:

25. Severe CDAD in Populations Previously at Low Risk—Four 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. 2005;54:

26. Severe CDAD in Populations Previously at Low Risk—Four States, 2005 (2)
Characteristic,
No. (%)
Community
(N=23)
Peripartum
(N=10)
Total
(N=33)
Aged < 18 years
11 (48)
0 (0)
11 (33)
Female
15 (65)
10 (100)
25 (76)
Antimicrobial exposure
9 (90)
24 (73)
Bloody diarrhea
6 (26)
2 (20)
8 (24)
Hospitalization necessary
4 (40)
10 (24)
ER visit necessary
3 (13)
5 (15)
Relapse
8 (35)
5 (50)
13 (39)
CDC. MMWR. 2005;54:

27. Severe CDAD in Populations Previously at Low Risk—Four 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 < 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. 2005;54:

28. Comparison of Molecular Characteristics of 2 C
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
Characteristic
Standard Strain
Epidemic Strain
Ohio Strain
Pennsylvania Strain
Toxinotype
PFGE* pattern
Binary toxin
18 bp deletion in tcdC
< 80% related to NAP1† _
III
NAP1 + IX
85% related to NAP1
XIV/XV
64% related to NAP1
*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. 2005;353:
CDC. MMWR. 2005;54:

29. Stomach Acid-Suppressing Medications and Community-Acquired CDAD, England
From Dial S, et al. JAMA. 2005;294:

30. 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