Clostridium difficile

1
Clostridium difficile

• David B. Blossom, MD MS
• Division of Healthcare Quality Promotion
• Coordinating Center for Infectious Diseases
• Centers for Disease Control and Prevention

2
Objectives

• Review of Clostridium difficile
• Discuss the transmission and virulence of C.
  difficile
• Describe briefly the clinical manifestations,
  evaluation and treatment of C. difficile-associate
  d disease (CDAD)
• Identify the changing epidemiology of CDAD
• Define surveillance strategies
• Clarify preventive measures

3
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
133-7 2. Hall I O'Toole E. Am J Dis Child 1935
49 390 3. Larson HE et al. Lancet 1978 8073
10631066.
4
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
5
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 200453887-94
6
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
• (gt10,000/cubic mm )

Healthy colon
Pseudo-membranous colitis
1. Bartlett JG, et al. Gastroenterology 1978
75778-82

7
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/i
magepages/17189.htm
8
Summary Pathogenesis of C. difficile

• Exposed to C. difficile
• Antibiotic therapy
• Disturbed colonic microflora
• Toxin A Toxin B
• Diarrhea colitis

9
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
199011 283-90 2. Johnson S, et al Lancet
199033697-100 3. M. Delmee Clin Microbiol
Infect 2001 7 411-416
10
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 gt65 y.o increased from 120 to 800 per
  100,000
• Rates in under 65 y.o stayed stable (lt100 per
  100,000

1.Karlstrom et al. Clin Infect Dis 199826141-5
2.Pepin et al. CMAJ 2004171466-72
11
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
20014743-50 2. Pepin J. Clin Infect Dis. 2005
Nov 141(9)1254-60
12
Flouroquinolones

• Quebec1
• 12 hospitals in 2004, OR for quinolones was 3.9
  (95CI 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 3532442-9 2 Muto CA
et al. Infect Control Hosp Epidemiol 1005
26273-80
13
Length of Hospitalization

• Related to rates of colonization1,2
• Rates increase from lt5 at admission to 26 after
  hospitalization

1.McFarland et al. N Engl J Med
1989320204-10 2. Clabots et al. JID
1992166561-67
14
Other Risk FactorsCDAD Pressure

• Number of concurrent inpatients with CDAD on the
  same ward increases a patients risk of
  developing CDAD
• daily exposure to CDAD patients

Length of stay at risk
15
CDAD Pressure
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
Dubberke et al. Arch Int Med 2007 167 1092-7
16
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
17
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

18
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
19
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. 200234346-353
20
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
21
National Estimates of US Short-Stay Hospital
Discharges with C. difficile as First-Listed or
Any Diagnosis
McDonald LC, et al. Emerg Infect Dis.
200612(3)409-15
22
Rates of US Short-Stay Hospital Discharges with
C. difficile Listed as Any Diagnosis by Age
McDonald LC, et al. Emerg Infect Dis.
200612(3)409-15
23
Increasing Severity of CDAD

• 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

1. MacGowan AP, et al. J Antimicrob Chemother
199739537-41 2. Dallal RM, et al. Ann Surg.
2002235363-372. Loo VG, et al. NEJM
20053532442-2449 3. Pepin J et al. CMAJ.
2005173(23)1037-42.
24
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

25
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

26
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

27
No relationship between alcohol-based hand rubs
and increasing rates of CDAD
Boyce et al. Infect Control Hosp Epidemiol 2006
27479-483
28
Hypothesis Change in antimicrobial prescribing

• Quinolones
• Popular for the management of CAP 1
• Most common treatment for uncomplicated UTI in
  women4
• Increased use by gt50 from 2000 2002 (plt0.001) 2
• Multiple antimicrobials and longer course of
  therapy
• - Increases risk for C. difficile3

1. Jones RN, Mandell LA. Diagn Microbiol Infect
Dis. 2002446976 2. MacDougall C et al Emerg
Infect Dis . 2005 11(3)380-4 3. Bignardi GE. J
Hosp Infect 1998 40115. 4. Kallen et al. Arch
Int Med. 2005
29
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 AB 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
19993411645-51 2 Warny M, et al. Lancet 2005
366 1079-84
30
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.
20053532433-2441.
31
Common (Epidemic) Strain by PFGE
32
Toxinotype and Potential Virulence Factors of
Isolates
Characteristic 1 Epidemic strain n62 () Non-epidemic strain n36 ()
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 isolates 2 32 (89)
were toxinotype 0 or wild type
33
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.
Warny M, et al. Lancet. 20053661079-1084.
34
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.
Warny M, et al. Lancet. 20053661079-1084.
35
Increased Resistance in Epidemic Strain Isolates
(After 2000)
No. () Intermediate or Resistant Epidemic strain (n18) Non-epidemic strains (n18) P
Clindamycin 16 (89) 10 (56) 0.06
Fluoroquinolones 18 (100) 8 (44) lt0.001
36
States with the Epidemic Strain of C. difficile
Confirmed by CDC and Hines VA labs
(N27),Updated 4/3/2007
DC
HI
PR
AK
37
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
38
NAP1/BI/027 in the Netherlands, 2006
1.Kuiper EJ et al. Emerg Infect Dis
200612(5)827-830. 2. Goorhuis A et al. CID
2007 45 695-703
39
Other Places

• Canada
• France
• Poland
• Austria
• Japan

Eurosurveillance Weekly Release.
http//www.eurosurveillance.org/index.asp
40
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

41
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.
42
Severe CDAD in Populations Previously at Low
RiskFour States, 2005 (2)
Characteristic, No. () Community (N23) Peripartum (N10) Total (N33)
Aged lt 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. 2005541201-1205.
43
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)

CDC. MMWR. 2005541201-1205.
44
Community-associated CDAD may be Increasing,
Atlanta VA Hospital
67 total cases
99 total cases
93 total cases
73 total cases

• Through July 31, 2006
• Chi-square for trend Plt0.05

Gaynes, R et al. ICAAC 2006, San Francisco
45
Gaynes, R et al. ICAAC 2006, San Francisco
46
Many Patients Develop CDAD without Recent
Hospital or Antimicrobial Exposure, Atlanta VA
Hospital, 2003-2006
Gaynes, R et al. ICAAC 2006, San Francisco
47
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 1-4
2Rodriguez-Palacios A, et al. EID 2007 13 485-7
3Arroyo LG, et al. J Med Microbiol 2005 54 163-6
48
Defining CDAD Below the Waterline
Dramatic, Severe Disease In Healthy, Young
Persons
Antibiotic-associated Inpatient Disease
?
Diarrhea in older ambulatory patients /-
chronic conditions
Antibiotics? NSAIDS? PPIs? H2 blockers?
Source Human-to-Human and ?
49
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

50
CDAD Definitions

• CDAD
• Diarrhea in a patient with a
• Positive C. difficile laboratory assay
• or
• 2. Pseudomembranous colitis on endoscopy or
  surgery
• or
• 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

51
Community vs. Hospital

• Hospitalization

Admission
Discharge
3 months after Discharge
48 h
4 weeks
8 weeks
CA
HO
CO-HCFA
CA
Indeterminate
McDonald LC, et al. ICHE 2007 28 140-45
52
Expression of Rates

• Inpatient rates
• Case patients per 10,000 patient-days
• Community-associated rates
• Case patients per 100,000 person-years

McDonald LC, et al. ICHE 2007 28 140-45
53
Recommendations for Hospitals

• 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

See C. difficile fact sheets http//www.cdc.gov/
ncidod/dhqp/
54
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 20032891274
55
Impact of Hydrogen Peroxide Vapor Room
Bio-Decontamination on Environmental
Contamination and Nosocomial Transmission by
Clostridium 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

56
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

57
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

58
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

Use Antimicrobials Wisely
59
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

60
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
dblossom_at_cdc.gov
http//www.cdc.gov/ncidod/dhqp/index.html