clostridium difficile david b. blossom, md ms division of healthcare quality promotion coordinating...
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Clostridium difficile
David B. Blossom, MD MSDivision of Healthcare Quality Promotion
Coordinating Center for Infectious DiseasesCenters for Disease Control and Prevention
Objectives
• Review of Clostridium difficile• Discuss the transmission and virulence of C.
difficile • Describe briefly the clinical manifestations,
evaluation and treatment of C. difficile-associated disease (CDAD)
• Identify the changing epidemiology of CDAD • Define surveillance strategies• Clarify preventive measures
Clostridium difficile
• Anaerobic spore-forming bacillus• Ubiquitous in nature
– Prevalent in soil– Isolated also from river, lake, sea, and swimming pool water
as well as from farm animals, dogs, and cats1
• 1935 - First described by Hall and O'Toole2 – Known colonizer of neonates (50% to 60%)
• 1978 - recognized as cause of antimicrobial-
associated pseudomembranous colitis3 • Now regarded as most common cause of
antimicrobial-associated diarrhea (20-30% of cases)
1. Brazier JS, al Saif. J Med Microbiol 1996; 45: 133-72. Hall I; O'Toole E. Am J Dis Child 1935; 49: 3903. Larson HE et al. Lancet 1978; 8073: 1063–1066.
Clostridium difficile : Pathogenesis
• Fecal oral transmission
• Survive gastric acidity
• Small intestine – spores germinate into vegetative forms
• Large intestine – normal flora disrupted by antibiotics
Diagram: Sunenshine et al Clev Clin J Med 2006 73(2) 187-197
C. difficile : Pathogenesis (cont)
• C. difficile can produce 3 toxins– Toxin A – enterotoxin– Toxin B – cytotoxin– (Binary toxin)
• Toxins cause the disease– Some strains only
produce one toxin• (A-, B+) 1% in a recent
study from Chicago1
Diagram: Sunenshine, et al. Clev Clin J Med 2006 73: 187-197
1.Geric B, et al. J Med Micro 2004;53:887-94
C. difficile-Associated Disease (CDAD)
• Incubation period – not known
• Diarrhea• Pseudomembranous colitis
- Has become the hallmark of
CDAD1
- Bloody diarrhea
- Raised whitish-yellow plaques
- Unexplained leukocytosis
(>10,000/cubic mm )
Pseudo-membranous
colitis
Healthy colon
1. Bartlett JG, et al. Gastroenterology 1978; 75:778-82
Toxic megacolon• Life-threatening acute dilation
• Characterized by - a dilated colon (megacolon) - Diameter : ≥ 5.5 cm - Fever, abdominal pain, abdominal distension - Radiograph: apparent edema of bowel wall • Complications - Perforation of colon - Sepsis, Shock - Death
Diagram: http://www.nlm.nih.gov/medlineplus/ency/imagepages/17189.htm
Summary: Pathogenesis of C. difficile
Exposed to C. difficile
Antibiotic therapy
Disturbed colonic microflora
Toxin A & Toxin B
Diarrhea & colitis
C. difficile : Risk Factors
• Increasing age1
• Exposure to antimicrobials• Length of stay in hospital2
• Infected patients/CDAD pressure• Immune response – IgG or local IgA against
toxin A3
• Severe underlying gastrointestinal diseases– GI procedures or GI surgery
• PPI/H2 blockers?
1.Brown E et al. Infect Control Hosp Epi 1990;11: 283-90 2. Johnson S, et al Lancet 1990;336:97-100 3. M. Delmee Clin Microbiol Infect 2001; 7: 411-416
Biggest Risks
Increasing Age
• Population based study in Sweden– Rate in those over 65 y.o = 20 times higher than
those under 20 y.o
• Quebec 2002 to 2003– Rates in >65 y.o increased from 120 to 800 per
100,000– Rates in under 65 y.o stayed stable (<100 per
100,0001.Karlstrom et al. Clin Infect Dis 1998;26:141-5 2.Pepin et al. CMAJ 2004;171:466-72
Antimicrobial Exposure
• Major risk factor for disease - Acquisition and growth of C. difficile- Suppression of normal flora of the colon- The risk doubles with longer than three days of antibiotic
therapy (risk ratio: 2.28) 1
• Clindamycin, penicillins, cephalosporins
• Fluroquinolones2
1.Wistrom J et al. J Antimicrob Chemother 2001;47:43-50 2. Pepin J. Clin Infect Dis. 2005 Nov 1;41(9):1254-60
Flouroquinolones• Quebec1
– 12 hospitals in 2004, OR for quinolones was 3.9 (95%CI 2.3-6.6)
– Ciprofloxacin, gatifloxacin and moxifloxacin associated, levofloxacin was not
• Pittsburgh2
– Formulary change: ciprofloxacin to levofloxacin
– C. diff rate = 2.7/1000 d/c increased to 6.8/1000 d/c
• OR 2.0 (95% CI 1.2-3.3)
1 Loo VG, et al. NEJM 2005; 353:2442-92 Muto CA et al. Infect Control Hosp Epidemiol 1005; 26:273-80
Length of Hospitalization
• Related to rates of colonization1,2
• Rates increase from <5% at admission to 26% after hospitalization
1.McFarland et al. N Engl J Med 1989;320:204-102. Clabots et al. JID 1992;166:561-67
Other Risk Factors:CDAD Pressure
• Number of concurrent inpatients with CDAD on the same ward increases a patient’s risk of developing CDAD
= daily exposure to CDAD patients
Length of stay at risk
CDAD Pressure
Dubberke et al. Arch Int Med 2007; 167: 1092-7
Variable Rel. Risk 95% CI
Sum CDAD pressure
1 or less Ref. Ref.
2-8 3.9 2.8-5.5
More than 8 9.7 7.1-13.1
Mean CDAD pressure
Less than 0.3 Ref. Ref.
0.3-1.4 6.4 4.6-8.9
More than 1.4 8.7 6.3-12.0
C. difficile : Laboratory Tests
• Stool culture: Most sensitive - Requiring 2-3 days for growth - Unable to distinguish between the
presence of toxin positive strains or toxin negative strains
• Cell cytotoxin test – most specific - Cytotoxin B• Direct Enzyme immunoassay (EIA) – most
common - May detect Toxin A only or Toxin A and B
C difficile colonies on agar plate: http://en.wikipedia.org/wiki/Clostridium_difficile
C. difficile: Resolution and Recurrence
• Resolution: 15 to 23% of patients - Within 2 to 3 days after discontinuation
- But most patients require specific
treatment
• C. difficile diarrhea recurs after treatment in ~20% of cases
• Historically mortality rate was 1 to 2.5 percent
Treatment• Initial Course of Antibiotics
– At least 10 days– Metronidazole (mild/moderate disease)– Oral vancomycin (severe disease)1
• Treatment of Recurrence– Longer course of metronidazole– Vancomycin with a taper– Rifaximin – Nitazoxanide – Vancomycin and rifaximin2
1. Zar FA, et al. CID 2007; 45: 302-7 2. Johnson S, et al. CID 2007; 44: 846-8
Costs
• Responsible for more than $1 billion annually in excess healthcare costs*
- Average of $3,600 excess costs per case
- Average of 3.6 extra hospital days
* Kyne L, et al. Clin Infect Dis. 2002;34:346-353
Increasing Rates of C. difficile-associated Disease
(CDAD) in US Hospitals
McDonald et al. 14th Annual Scientific Meeting of the Society for Healthcare Epidemiology of America, Philadelphia, PA. 2004
McDonald LC, et al. Emerg Infect Dis. 2006;12(3):409-15
National Estimates of US Short-Stay Hospital Discharges with C. difficile as First-Listed
or Any Diagnosis
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
United Kingdom, 1994-5 1
- Comparing well-matched C difficile patients and controls – no difference in mortality at d/c, 3 mos. and 6 mos.
Pittsburgh, 2000 2
– “Life-threatening disease” from 1.6% to 3.2% from 1989 to 2000– Colectomies increased from 0.48% to 2.6%– In hospital deaths (attr. to C. difficile) increased from 0.21-1.4%
Quebec, Canada, 2004 3
– Attributable mortality of 16.7% in 2005 epidemic in Quebec (in one hospital)
– Attributable 30 day mortality 6.9% in 12 Quebec hospital prospective study
Increasing Severity of CDAD
1. MacGowan AP, et al. J Antimicrob Chemother 1997;39:537-412. Dallal RM, et al. Ann Surg. 2002;235:363-372. Loo VG, et al. NEJM 2005;353:2442-24493. Pepin J et al. CMAJ. 2005;173(23):1037-42.
Potential reasons for increased CDAD incidence and severity
• Changes in underlying host susceptibility
• Changes in antimicrobial prescribing
• Changes in infection control practice
• New strain with increased virulence
Hypothesis: Change in underlying host susceptibility
• Increase in the average age of the population
- Increase in exposure to healthcare facilities
- Increase exposure to antimicrobials
• Possible, but probably not the whole story
Hypothesis: Use of alcohol-based hand rubs
• Hand hygiene
- Important prevention strategy
- HCWs can transmit C. difficile
• Traditional: Soap and water hand washing
• Increased use of alcohol-based hand rub over the last several years
Boyce et al. Infect Control Hosp Epidemiol 2006; 27:479-483
No relationship between alcohol-based hand rubs and increasing rates of CDAD
Hypothesis: Change in antimicrobial prescribing
• Quinolones– Popular for the management of CAP 1
– Most common treatment for uncomplicated UTI in women4
– Increased use by >50% from 2000– 2002 (p<0.001) 2
• Multiple antimicrobials and longer course of therapy
- Increases risk for C. difficile3
1. Jones RN, Mandell LA. Diagn Microbiol Infect Dis. 2002;44:69–76 2. MacDougall C et al Emerg Infect Dis . 2005 ; 11(3):380-4
3. Bignardi GE. J Hosp Infect 1998; 40:1–15.4. Kallen et al. Arch Int Med. 2005
Fact: Epidemic C. difficile Strain • Characteristics
– North American Pulsed Field Type 1 (NAP1) by PFGE– PCR ribotype 027– Toxinotype III or “BI” by REA
• Distinct from “J” strain of 1989-19921
– Binary toxin as a possible virulence factor• In addition to Toxin A&B containing
– 18 bp deletion in tcdC gene• May allow increased toxin production2
– Increased resistance to fluoroquinolones– No resistance to metronidazole
1 Johnson S, et al. N Engl J Med 1999;341:1645-512 Warny M, et al. Lancet 2005; 366: 1079-84
Acute Care Hospitals with CDAD Outbreaks* Between 2001-2004
*Detected by increases in the number of positive routine clinical laboratory tests for C. difficile.
McDonald LC, et al. N Engl J Med. 2005;353:2433-2441.
2
12
1
1
1
Common (Epidemic) Strain by PFGEDice (Opt:0.50%) (Tol 1.3%-1.3%) (H>0.0% S>0.0%) [0.0%-100.0%]
100
959085
Maine, Hospital APennsylvaniaPennsylvaniaMaine, Hospital B
Maine, Hospital BIllinoisIllinoisGeorgia
Maine, Hospital ANew JerseyNew JerseyOregonHistoric, 1988-1991Historic, 1993
Historic, 1990-1991Historic, 1984-1991
Historic, 1993-2000Oregon
Toxinotype and Potential Virulence Factors of Isolates
Characteristic:
1 Epidemic strain
n=62 (%)
Non-epidemic strain n=36 (%)
Toxinotype III 62 (100) 02
Binary toxin positive 62 (100) 2 (6)
18 bp tcdC deletion 62 (100) 1 (3)
1 Includes 5 historic “BI” isolates2 32 (89%) were toxinotype 0 or wild type
Increased Toxin A Production in vitro
Warny M, et al. Lancet. 2005;366:1079-1084.
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.
Increased Toxin B Production in vitro
Warny M, et al. Lancet. 2005;366:1079-1084.
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.
Increased Resistance in Epidemic Strain Isolates (After 2000)
No. (%) Intermediate or Resistant:
Epidemic strain (n=18)
Non-epidemic strains
(n=18) P
Clindamycin 16 (89) 10 (56) 0.06
Fluoroquinolones 18 (100) 8 (44) <0.001
States with the Epidemic Strain of C. difficile Confirmed by CDC and Hines VA labs (N=27),
Updated 4/3/2007
DC
PRAK
HI
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
NAP1/BI/027 in the Netherlands, 2006
1.Kuiper EJ et al. Emerg Infect Dis 2006;12(5):827-830.2. Goorhuis A et al. CID 2007; 45: 695-703
Other Places…
• Canada
• France
• Poland
• Austria
• Japan
Eurosurveillance Weekly Release. http://www.eurosurveillance.org/index.asp
Community-associated CDAD: Sentinel Cases of Severe Disease
•23 cases of severe community-associated CDAD (CA-CDAD)•Generally young and healthy•Approximately 1/3 without precedent antimicrobial use
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)
CDC. MMWR. 2005;54:1201-1205.
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)
• 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)
Severe CDAD in Populations Previously at Low Risk—Four States, 2005 (3)
CDC. MMWR. 2005;54:1201-1205.
Community-associated CDAD may be Increasing, Atlanta VA Hospital
0%
5%
10%
15%
20%
25%
30%
35%
2003 2004 2005 2006
Year
Pro
po
rtio
n o
f a
ll c
as
es
73 totalcases
93 total cases
99 total cases
67 total cases*
•Through July 31, 2006•Chi-square for trend: P<0.05
Gaynes, R et al. ICAAC 2006, San Francisco
Gaynes, R et al. ICAAC 2006, San Francisco
Many Patients Develop CDAD without Recent Hospital or Antimicrobial Exposure, Atlanta
VA Hospital, 2003-2006
Gaynes, R et al. ICAAC 2006, San Francisco
What is the Source?• Is it in the food supply?
– Pathogen of food animals1
– C. difficile has been found in retail meat (beef and veal)2
• 20% of Canadian convenience sample• Only 3 of the 12 isolates found had corresponding isolated that had caused
disease in humans• C difficile reported to live after being exposed to 71 degrees Celsius for 120
min.
– Potential for interspecies transmission3
• Turkey fed to dogs
1Songer JG, et al. Anaerobe 2006; 12: 1-42Rodriguez-Palacios A, et al. EID 2007; 13: 485-73Arroyo LG, et al. J Med Microbiol 2005; 54: 163-6
Defining CDAD Below the Waterline
Diarrhea in older ambulatory patients +/-
chronic conditions
Antibiotics? NSAIDS? PPIs?H2 blockers?
Dramatic, Severe Disease In Healthy,
Young Persons
Source: Human-to-Human and ?
Antibiotic-associated Inpatient Disease
?
C. difficile Surveillance
• Potential Role– Detect disease trends– Detect outbreaks– Compare CDAD rates between institutions– Guide interventions to control CDAD– Monitor the impact of these interventions
CDAD Definitions
• CDAD – Diarrhea in a patient with a
1. Positive C. difficile laboratory assay or
2. Pseudomembranous colitis on endoscopy or surgeryor
3. Pseudomembranous colitis seen on histopathology
• Recurrent CDAD– An episode of CDAD that occurs 8 weeks or less after the onset
of a previous episode• As long as the earlier episode resolved
Community vs. Hospital
HospitalizationAdmission Discharge
48 h
CA HO CO-HCFA CAIndeterminate
4 weeks 8 weeks
McDonald LC, et al. ICHE 2007; 28: 140-45
3 months after Discharge
• Inpatient rates– Case patients per 10,000 patient-days
• Community-associated rates– Case patients per 100,000 person-years
Expression of Rates
McDonald LC, et al. ICHE 2007; 28: 140-45
• Hospitals should be encouraged to conduct surveillance for CDAD – Track positive lab results (e.g. toxin A or A/B assays)– Consider measures to track outcomes
• Early diagnosis and treatment is important for reducing severe outcomes and should be emphasized
• Strict infection control: CDC fact sheet* – Contact precautions for CDAD patients– An environmental cleaning and disinfection strategy– Hand washing with CDAD patients in outbreak
Recommendations for Hospitals
*See C. difficile fact sheets: http://www.cdc.gov/ncidod/dhqp/
Hand Hygiene Measures • Alcohol-based hand rubs are now widely used
for routinely cleaning hands before/after patient care
• Alcohol-based hand rubs may not be effective against spore-forming organisms1
– Several studies ongoing
• If an institution is experiencing an outbreak of C. difficile disease, it is prudent to wash hands with soap and water after caring for patients with CDAD
1 Weber DJ et al. JAMA 2003;289:1274
Impact of Hydrogen Peroxide Vapor Room Impact of Hydrogen Peroxide Vapor Room Bio-Decontamination on Environmental Bio-Decontamination on Environmental
Contamination and Nosocomial Transmission Contamination and Nosocomial Transmission by by Clostridium difficileClostridium difficile
John M. Boyce1, MD, Nancy L. Havill1, MT,
Jonathan A. Otter2, BSc, L. Clifford McDonald3, MD
Nicholas M.T. Adams2, BSc, Angela Thompson3, MSc,
Lois Wiggs3, Judith Noble-Wang3, PhD
Hospital of Saint Raphael1, New Haven, CT
Bioquell PLC2, Andover, England
Centers for Disease Control & Prevention3, Atlanta, GA
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 are unknown but under study
– May be other toxin variants and/or hospital epidemic strain
• Clinicians should consider the diagnosis - CDAD in patients without traditional risk factors
• Antimicrobial exposure is not benign– Continue to emphasize judicious antimicrobial use
Recommendations for Clinicians
• Vaccinate• Get the catheters out• Target the pathogen• Access the experts• Practice antimicrobial control• Use local data• Treat infection, not contamination• Treat infection, not colonization• Know when to say “no” to vanco• Stop treatment when infection is cured or unlikely• Isolate the pathogen• Break the chain of contagion
Campaign to Prevent Antimicrobial Resistance in Healthcare Settings
Recommendations for Clinicians
• Vaccinate• Get the catheters out• Target the pathogen• Access the experts• Practice antimicrobial control• Use local data• Treat infection, not contamination• Treat infection, not colonization• Know when to say “no” to vanco• Stop treatment when infection is cured or unlikely• Isolate the pathogen• Break the chain of contagion
Campaign to Prevent Antimicrobial Resistance in Healthcare Settings
Use Antimicrobials
Wisely
Some CDC References
• Campaign to Prevent Antimicrobial Resistance: 12 Steps for Healthcare Settings
• Management of Multidrug-Resistant Organisms in Healthcare Settings, 2006
http//:www.cdc.gov/ncidod/dhqp/index.html
[email protected]//:www.cdc.gov/ncidod/dhqp/index.html
Thank You!
The information presented here represents the opinion of the presenter and does not necessarily represent the opinion of the US Public Health Service, the Centers for Disease Control and Prevention or the Department of Health and Human Services