Download Clostridium difficile

Clostridium difficile:
An Emerging Threat
L. Clifford McDonald, MD, FACP, FSHEA
Division of Healthcare Quality Promotion
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
Healthy
colon
- Acquisition and growth of C. difficile
- Suppression of normal flora of the colon
• Clindamycin, penicillins, and
cephalosporins
Pseudomembranous
colitis
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
1.
Kyne L, et al. Clin Infect Dis. 2002;34:346-353.
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.
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
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
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
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
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%
1.
2.
3.
Dallal RM, et al. Ann Surg. 2002;235:363-372.
Muto C, et al. Infect Control HospEpid. 2005
Pepin J, et al. CMAJ. 2005
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
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.
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
Acute Care Hospitals with
CDAD Outbreaks* Between 2001-2004
2
1
2 1
1
1
*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;353:2433-2441.
Epidemic (BI/NAP1) Strain
From McDonald LC, et al. N Engl J Med. 2005;353:2433-2441.
Nonepidemic (Non-BI/NAP1) Strains
From McDonald LC, et al. N Engl J Med. 2005;353:2433-2441.
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 (%)
Current
nonBI/NAP1
Isolates
n=24 (%)
P-Value for
BI/NAP1
vs. NonBI/NAP1
Isolates
Historic
BI/NAP1
Isolates
n=14 (%)
P-Value for
Current vs.
Historic
BI/NAP1
Isolates
Clindamycin
19 (79)
19 (79)
1.0
10 (71)
0.7
Levofloxacin
24 (100)
23 (96)
1.0
14 (100)
1.0
Gatifloxacin
24 (100)
10 (42)
<0.001
0
<0.001
Moxifloxacin
24 (100)
10 (42)
<0.001
0
<0.001
From McDonald LC, et al. N Engl J Med. 2005;353:2433-2441.
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;353:2433-2441.
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. 2005;366:1079-1084.
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. 2005;366:1079-1084.
States with the Epidemic Strain of C. difficile
Confirmed by CDC and Hines VA labs (N=23),
Updated 2/9/2007
DC
HI
AK
PR
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. http://news.bbc.co.uk/2/hi/health/4186834.stm
BI/NAP1 in the Netherlands, 2006
Kuiper EJ et al. Emerg Infect Dis 2006;12(5):827-830.
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
1.
2.
Johnson S, et al. N Engl J Med. 1999;341:1645-1651.
Warny M, et al. Lancet. 2005;366:1079-1084.
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; 28:140-145
2See CDC C. difficile Fact Sheets: http://www.cdc.gov/ncidod/dhqp/.
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;54:1201-1205.
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
15 (65)
9 (90)
24 (73)
Bloody diarrhea
6 (26)
2 (20)
8 (24)
Hospitalization
necessary
6 (26)
4 (40)
10 (24)
ER visit necessary
3 (13)
2 (20)
5 (15)
Relapse
8 (35)
5 (50)
13 (39)
CDC. MMWR. 2005;54:1201-1205.
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 communityassociated disease
– 7.6 cases per 100,000 population
– 1 case per 5,000 outpatient antimicrobial prescriptions
CDC. MMWR. 2005;54:1201-1205.
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
Standard
Strain
Epidemic
Strain
Ohio
Strain
Pennsylvania
Strain
0
III
IX
XIV/XV
< 80% related
to NAP1†
NAP1
85% related
to NAP1
64% related to
NAP1
Binary toxin
_
+
+
+
18 bp deletion in
tcdC
_
+
_
+
Characteristic
Toxinotype
PFGE* pattern
*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;353:2433-2441.
CDC. MMWR. 2005;54:1201-1205.
Stomach Acid-Suppressing Medications
and Community-Acquired CDAD, England
From Dial S, et al. JAMA. 2005;294:2989-2995.
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