Clostridium Difficile Associated Diseases

1
Clostridium Difficile Associated Diseases

• ???, M.D. PhD
• Division of Infectious Diseases
• Infection Prevention and Control Team
• The First Hospital of China Medical University
• May 2010

2
AAD antibiotic-associated diarrhea
CDAD
hospital-acquired diarrhea
2
3
Antibiotic Associated Diarrhea?

• Most causes unknown.
• Several candidates studied
• Clostridium difficile is the major recognized
  cause
• Candida species
• Clostridium perfringens
• Staphylococcus aureus
• Serendipitous infection by viruses, Salmonella,
  etc.
• Non-infectious changes in colonic fatty acid and
  carbohydrate metabolism induced by antibiotics

infectious
4
AAD antibiotic-associated diarrhea

• C difficile-causative agent in
• 10-25 of patients with AAD
• 50-75 of patients with antibiotic-associated
  colitis (AAC)
• 90-100 of patients with PMC
• Aslam
  et al, Lancet Inf. Dis, 2005

CDAD
hospital-acquired diarrhea
4
5
Confusing terminology

• Antibiotic-associated diarrhea(AAD)
• C. difficile is only one cause
• Clostridium difficile-associated diarrhea(CDAD)
• diarrhea positive stool test
• Clostridium difficile colitis(CDC)
• underlying pathologic process
• Pseudomembranous colitis(PMC)
• endoscopic demonstration of exudative lesions
• Toxic megacolon
• radiologic and surgical diagnosis

Clostridium Difficile-Associated Disease
6
Clostridium Difficile Associated Diseases

• History and Epidemiology
• Pathogenesis
• Clinical pictures
• Diagnosis
• Management
• Prevention and control
• Future
• Summary

7
History

• 1893-first case of PMC
• -reported as diphtheritic colitis.
• 1935-Bacillus difficile first isolated
• -Hall OToole
• 1970s-antibiotic-asociated colitis identified.
• 1977 - Birmingham General Hospital-C. difficile
  identified as cause
• 1978-C. difficile toxins identified in humans.
• 1979-therapy with metronidazole or
• vancomycin
• 2000-increased incidence and virulence

microbiology

• The difficult clostridium
• Obligate anaerobe/Motile
• G sporeformomg bacillus
• spores resistant to Heat/Desiccation/Disinfection/
  Alcohol
• Source
• Environment
• Stool flora

8
Why are we concerned?

• Increasing numbers of infections.
• Potential for severe disease
• Emergence of hypervirulent strains that may be
  more transmissible and/or cause more severe
  disease e.g. ribotype O27.
• Concerns over possible antibiotic resistance.
• Increasingly recognized as a major nosocomial
  pathogen capable of causing outbreaks

8
9
Increase in cases

• More than 50,000 cases reported in England in
  2007
• Fifty-fold increase since 1990 20 of cases lt65

9
10
National Estimates of US Short-Stay Hospital
Discharges with C. difficile as First-Listed or
Any Diagnosis
10
From McDonald LC, et al. Emerg Infect Dis.
200612(3)409-15
11
C.difficile deaths

• CDAD cited on 1 in every 250 death certificates
  in 2005
• Further 72 increase in 2006

11
12
CDAD Rates and Mortality Increasein Parallel
with Patient Age
Loo et al NEJM 20053532442-9
13
Acute care hospitals with CDADoutbreaks between
2001 and 2004
14
Public concern
14
15
Official reports
15
16
Clostridium Difficile Associated Diseases

• History and Epidemiology
• Pathogenesis
• Clinical pictures
• Diagnosis
• Management
• Prevention and control
• Future
• Summary

17
CDAD

• Transmission
• Carried in GIT of 3 of general population
• Up to 30 of hospitalized patients become
  colonized
• Fecal-Oral Route
• -sensitive individuals can become
  infected if they touch items or surfaces that are
  contaminated with feces and then touch their
  mouth or mucous membranes.
• Hands of hospital personnel are important
  intermediary
• -can spread the bacteria to other
  patients or contaminate surfaces with contact.

18
Pathogenicity of C. difficile

• Exotoxin A (enterotoxin)
• MOA unknown/causes outpouring of fluid and a
  watery diarrhea
• Exotoxin B (cytotoxin)
• damages colonic mucosa leading to pseudomembrane
  formation
• mechanism is via ADP-ribosylation of Rho (a
  GTP-BP)
• this causes depolymerization of actin in the
  cytoskeleton

• Pathogenicity in a pathogenicity locus (PaLoc) of
  five genes
• Binary toxin -its clinical significance is
  unravelling

Spigaglia and Mastrantonio. J Clin Microbiol.
2002 Sep40(9)3470-3475.
19
Host Protection AgainstCDAD Occurs at Two Levels

• Normal bacterial flora
• -prevent establishment of C. difficile
• colonization of the GI tract
• Antibodies (serum and mucosal?)
• -prevent CDAD disease if colonization
• occurs
• -Antibodies are probably first acquired in
• infancy

20
Risk Factors

• Age gt65 years
• Severe underlying disease
• Antimicrobial therapy
• Clindamycin, 3rd G cephalosporins, penicillin,
  FQs
• Nasogastric intubation
• Anti-ulcer medications
• Proton pump inhibitors
• Chemotherapy
• Long hospital stay or long-term care residency

20
21
Role of Antibiotics in CDAD

• Any antibiotic may be associated with CDAD.
• Disruption of normal intestinal flora
• -the determining antibiotic event
• susceptibility window following an antibiotic
  there is a variable-length window during which a
  patient is susceptible.
• C. difficile resistance to the precipitating
• antibiotic is thought to be important, but is
  not
• always present (e.g. ampicillin).

22
Time-Course of Antimicrobial Effect onthe Normal
Gut Flora and CDAD Risk
No Antibiotics Normal Flora
Antibiotic Use Flora Disrupted
No Antibiotics Flora Disrupted
No Antibiotics Normal Flora
2. Variable Time
1.
No risk of CDAD
Higher risk of CDAD, if C. difficile is resistant
to the Abx used
High risk of CDAD, C. difficile resistance is not
an issue
No risk of CDAD

• 1. C. difficile resistance to the antibiotic used
  enables the organism to infect while the
  antibiotic is being given.
• 2. Resistant and Susceptible C. difficile can
  infect after the antibiotic has been stopped and
  the flora remains disrupted.

23
Original (Incorrect) Hypothesis for C. difficile
Hospital Infection
24
Rate of CDAD in Patients Colonized and
Non-colonized with CD

• Data from four prospective studies in which
  rectal swab cultures were obtained weekly from
  hospitalized patients

Non-colonized (n 618) Colonized (n 192)
CDAD Cases 22 (3.6) 2 (1.0)
CDAD/ 100 wks of observation 2.1 0.7
Risk difference 2.34 95 CI -4.34, -0.34
P 0.021

• The risk was also significantly decreased when
  only patients who received antibiotics were
  analyzed. (P0.024)
  

Shim JK, et al. Lancet 1998351633-636
25
Revised Hypothesis for CDAD
Acquisition of a toxigenic strain of C.
difficile and failure to mount an anamnestic
Toxin A antibody response results in CDAD.
26
Pathogenesis of CDAD
Owens, CID, 2008, 46, S19-31
26
27
Pathogenesis of CDAD
27
Poutanen, S. M. et al. CMAJ 200417151-58
28
TcdC Variants
Challenges -Emergence of a new outbreak epidemic
strain in U.S. Quebec and Europe

• 18 bp deletion in tcdC gene of PaLoc
• Could lead to increased toxin production (18-fold
  for toxin A, 23-fold for toxin B) observed by
  Warny et al.2
• Highly resistant to FQs and clindamycin
• Metronidazole, vancomycin susceptible

29
Epidemic C. difficile Strains ProduceIncreased
Toxins A and B in vitro

• Epidemic strains from Quebec/UK/US-carry binary
  toxin/have tcdC deletion/toxinotype III tested in
  vitro for toxin A and B,(compared with
  non-epidemic toxinotype 0 strains).

NAP1 / ribotype 027
log phase
stationary phase

• Toxin A/B 16-23 fold higher in toxinotype III
  isolates (Plt.0001).
• Toxinotype III isolates produce toxins during the
  log phase whereas toxinotype 0 strains did not
  produce toxin until the stationary phase

Warny, et al. Lancet 20053661079-84
30
Epidemic C. difficile Strains ProduceIncreased
Toxins A and B in vitro
NAP1 / ribotype 027
log phase
stationary phase
Warny, et al. Lancet 20053661079-84
31
States with the epidemic strain of C. difficile
confirmed by CDC 11/15/2005 (N16)
32
States with the Epidemic Strain of C. difficile
Confirmed by CDC and Hines VA labs (N23),Updated
2/9/2007
DC
HI
PR
AK
33
Outbreak Strains are NOT New Comparisonof
Historic and Epidemic REA BI types

• Historic BI (Bee-Eye) isolates were found from
  1983 to 1992, were of BI types BI1 to BI5,
  contained binary toxin genes, and the 18 bp
  deletion in the tcdC gene.
• Historic isolates were NOT resistant to newer
  fluoroquinolone antibiotics.
• New epidemic BI isolates (types BI6-BI19) are
  uniformly resistant to the newer FQs
  (gatifloxacin, moxifloxacin).

34
Is Increased Toxin A and B in vitro the Answer to
Increased Pathogenicity?
Previous measures of toxin A and B production in
vitro have not correlated with disease severity
in hamsters.
Preliminary data from hamster studies with REA
type BI isolates show mortality rates similar to
high virulence controls.
Borriello et al J Med Micro 19872453-64
35
What is the Role ofFluoroquinolone Resistance?

• Resistance to newer fluoroquinolones
• (gatifloxacin and moxifloxacin) is the only
• detectable difference between historic
  nonepidemic BI group isolates and epidemic
  current BI group isolates.
• Fluoroquinolone use has been a risk factor for
  CDAD in hospitals with outbreaks caused by the
  epidemic strain of C. difficile.

Gaynes et al CID 200438640-645 Pepin et al CID
200541(1) Loo et al NEJM 20053532442-2449
36
Clostridium Difficile Associated Diseases

• History and Epidemiology
• Pathogenesis
• Clinical pictures
• Diagnosis
• Management
• Prevention and control
• Future
• Summary

37
Clinical Presentation

• Asymptomatic colonization
• Mild disease
• Non-bloody diarrhea
• Mild abdominal tenderness
• Severe disease
• Pseudomembranous colitis
• Paralytic ileus
• Ileitis
• Toxic megacolon
• Ulcerative colitis
• Perforation(peritonitis)
• Ascites

37
38
Clinical presentation Epidemic

• Similar to old cases but more severe
• More toxic megacolon (less diarrhea)
• Profound leukemoid reactions
• Severe hypoalbuminemia (PLE)
• Septic shock
• Need for colectomy
• Increased mortality

Ann Intern Med 2006245
39
(No Transcript)
40
(No Transcript)
41
Leukocytosis and CDAD Do Not Missthis Clue to
Possible Fulminant Disease

• Toxin A is a potent neutrophil chemoattractant
• CDAD found
• in 16 of patients with WBCgt15,000/mm3
• 25 of patients with WBCgt30,000/mm3.
• Clin Infect Dis
  2002341585-92
• 58 of 60 patients with unexplained WBC
  gt15,000/mm3 had CD toxin in stool.
• AJM 2003115543-6

42
Clostridium Difficile Associated Diseases

• History and Epidemiology
• Pathogenesis
• Clinical pictures
• Diagnosis
• Management
• Prevention and control
• Future
• Summary

43
Diagnosis of CDAD

• S/S
• Endoscopy (pseudomembranous colitis)
• Culture
• Cell culture cytotoxin test
• EIA toxin test
• PCR toxin gene detection

44
(No Transcript)
45
Pseudomembranous Colitis
Yellow lesion against hyperemic bowel
Mushroom-shaped pseudomembrane? Volcano lesion
45
H E, OM 400x
46
Laboratory diagnosis

• Culture
• Easy and sensitive but slow
• High carriage rates in hospitalised patients
• Non-toxigenic isolates detected as well
• Not used for initial diagnosis now
• Toxin detection in faeces
• Cell culture
• Gold standard but relatively slow
• Enzyme immunoassays(EIA)
• Rapid/cheap/specific
• Need test to include Toxin A and B
• Variable sensitivity
• Asymptomatic carriage issue
• Single negative result does not exclude infection
• Regardless of method you must take clinical
  picture into account!

46
47
Performance characteristics of diagnostic tests
48
CDAD Case Definition

• Stool characteristic
• Diarrhea (most common)
• No diarrhea
• Associated with toxic megacolon or ileitis
• Documented by radiology
• 1 of the following
• Stool positive for
• C. difficile toxin
• C. difficile determined to be a toxin producer
• Pseudomembranous colitis by
• Endoscopy
• Histological exam

48
49
CDAD vs Antibiotic-Associated Diarrhea
49
50
Clostridium Difficile Associated Diseases

• History and Epidemiology
• Pathogenesis
• Clinical pictures
• Diagnosis
• Management
• Prevention and control
• Future
• Summary

51
Treatment of CDAD - General
principles

• Whenever possible withdraw the offending
  antibiotic
• Use oral antimicrobials whenever possible
• Be patient
• -some improvement seen in first 2 days but
  mean time until resolution of diarrhea is 2-4
  days. Dont call them nonresponders until 6 days
  of therapy
• Treat for 10-14 days
• Avoid antiperistaltic agents

52
Rate of antibiotic resistance in 91 C. difficile
isolates from a Pittsburg hospital that
experienced a large CDAD outbreak beginning
January 2000
53
Treatment of 1st 2nd episodes of CDAD
53
54
Vancomycin Enemas

• Non-randomized open trial
• -6/8 patients with ileus responded in 4-17
  days
• -2 patients died, one following colectomy
• Inf Cont Hosp Epidemiol 199415371-381
• Adjunct treatment for severe C. difficile Entry
  criteria not clearly defined
• -8/9 cases resolved
• Apisarnthanarak et al Clin Inf Dis
  200235690-96

55
Patient Management
Surgical consultperforation, toxic megacolon,
colonic-wall thickening, ascites.
55
56
Relapsed Disease

• Due to spores that germinate in gut after
  withdrawal of the antibiotic
• Happens in 20 of patients who initially
  respond. Increased risk in
• Age gt 65
• Increased severity of underlying disease
• Exposure to additional antibiotics after
  treatment
• Low serum IgG response to toxin A
• Half of relapses are actually re-infections
• Antibiotic resistance unlikely
• Most patients will respond to a second course of
  the same antimicrobial

57
Treatment of Multiple Relapses

• No controlled studies, lots of anecdotes and
  personal favorite regimens
• -tapering courses of vancomycin or
  metronidazole
• -vancomycin plus rifampin
• -yogurt or other Lactobacillus preparations
• -Saccharomyces boulardii plus antibiotics
• -Intravenous immune globulin
• -Cholestyramine with or without antimicrobials

58
Stool infusion therapy or fecal transplant
has been shown to be highly effective.
58
59
Fecal bacteriotherapy
goods

• effective 94-100 success in limited published
  investigations
• reduces the risk of resistant bacteria or drug
  allergy
• safe No published adverse effects
• Low-tech therapy that can be administered easily
• inexpensive

bads

• Appropriate donor of fecal sample may not be
  available
• New pathogens may be introduced with the donor
  stool sample
• Potential physical complications from the
  procedure
• Medico-legal limitations may be imposed at the
  treatment facility
• Lack of coverage of Medicare for experimental
  therapy
• Fecal bacteriotherapy may be esthetically
  unappealing

Aas et al. Clin Infect Dis 200336580-585
60
Treatment Controversies

• Is metronidazole still effective therapy for
  CDAD?
• Have clinically important metronidazole-resistant
  C. difficile strains been detected?
• The good news is that new treatment drugs are in
  clinical trials for the first time in 25 years.

61
Retrospective Reports of Poor CDADResponses to
Metronidazole

• Reduced response rates and higher recurrence
  rates with metronidazole in 207 CDAD patients
  compared to prospective published studies.
• Musher DM et al, CID
  2005401586-90
• Reduced response rates and higher recurrence
  rates with metronidazole in 438 Quebec patients
  treated in 2003-2004 than in 688 patients treated
  from 1991-2002 Epidemic strain identified in
  Quebec since 2003.
• Pepin J et al,
  CID 2005401591-7

62
Metronidazole Treatment Failure wasNot Caused by
Metronidazole(MTR)Resistance in One Study

• 10-year prospective surveillance 14/632 (2)
• episodes of CDAD did not respond to treatment
  with MTR
• Susceptibility of 10 isolates from MTR treatment
  failures compared to 20 isolates from MTR
  treatment successes

Sanchez J, et al. Anaerobe 1999
63
Treatment of First Recurrence of CDAD with MTD

• 33 of patients with 1st recurrence had a 2nd
• Recurrence rate correlates with age and LOS
• 64 second recurrences occurred within 30 days
  and the remainder between 31-60 days.
• Metronidazole was not inferior to vancomycin for
  treatment of first recurrence of CDAD
• Treatment of first recurrence with the same or a
  different agent made no difference in outcome
• Complications (shock, colectomy, perforation,
  megacolon, death) developed in 11 with first
  recurrence, a higher rate than previously
  observed

Pepin et al CID 200642758-64, Louie CID
200642765-7
64
Investigational Rx for CDAD
Hamster data showing reduced relapse
65
Clostridium Difficile Associated Diseases

• History and Epidemiology
• Pathogenesis
• Clinical pictures
• Diagnosis
• Management
• Prevention and control
• Future
• Summary

66
CDAD prevention and control

• Antimicrobial stewardship
• -protocols/consumptionsurveillance
  /Audit and feedback
• Surveillance
• -active surveillance
• Education
• -staff and visitors
• Early diagnosis
• -timely stool specimens/toxin
  testing/

66
67
CDAD prevention and control

• Isolation precautions
• -single rooms or cohorts / designated
  staff
• -hand washing facilities/en-suite
  toilet
• -dedicated care equipment/door kept
  closed
• Hand hygiene-handwashing or alcohol?
• Personal protective equipment (PPE)
• Environmental cleaning
• Use of care equipment

67
68
CDAD prevention and control

• Hand hygiene
• Personal protective equipment (PPE)
• Environmental cleaning
• Use of care equipment

• Hand washing with soap and water or chlorhexidine
  recommended
• Alcohol-based hand rubs are not effective in
  removing C. difficile spores from hands,not be
  the only hand hygiene measure when caring CDAD
  patients
• Patients and visitors strongly encouraged to wash
  their hands with soap and water, especially
  before eating and after using the toilet

68
69
CDAD prevention and control

• Hand hygiene
• Personal protective equipment (PPE)
• Environmental cleaning
• Use of care equipment

• All staff should wear disposable gloves for
  contact with a CDAD patient this includes
  contact with body substances contaminated
  environment, including the immediate vicinity of
  the patient
• Disposable plastic aprons should always be used
  for managing patients who have diarrhoea

69
70
CDAD prevention and control

• Hand hygiene
• Personal protective equipment (PPE)
• Environmental cleaning
• Use of care equipment

• Regular environmental disinfection of rooms/areas
  of CDAD patients be done using sporocidal agents
  with (at least) 1000 ppm hypochlorite
• Hospital wards be cleaned regularly (at least
  once a day) concentrating on frequently touched
  surfaces
• Cleaning (and decontamination) of environmental
  faecal contamination to be done as soon as
  possible
• Toilets and commodes and items which are likely
  to be contaminated with faeces should be cleaned
  meticulously
• After discharge of a CDAD patient, the patient
  area/room should be cleaned and disinfected
  thoroughly
• Products containing a combination of a detergent
  and hypochlorite are considered the most
  effective

70
71
CDAD prevention and control

• Hand hygiene
• Personal protective equipment (PPE)
• Environmental cleaning
• Use of care equipment

• Care equipment (e.g. commodes, blood pressure
  cuffs and stethoscopes) should be dedicated to a
  single patient
• All care equipment should be carefully cleaned
  and disinfected using a sporocidal agent (with at
  least 1000 ppm hypochlorite) immediately after
  use on a CDAD patient
• Thermometers should not be shared and use of
  electronic thermometers with disposable sheaths
  should be avoided
• The use of single use items (incl. thermometers
  and other care equipment) should be considered
  when possible

71
72
Clostridium Difficile Associated Diseases

• History and Epidemiology
• Pathogenesis
• Clinical pictures
• Diagnosis
• Management
• Prevention and control
• Future
• Summary

73
Community Associated CDAD(CA-CDAD) and
Peripartum CDAD

• Voluntary reporting of 23 CA-CDAD and 10
  peripartum CDAD cases from 4 states over 28
  months.
• CA-CDAD rate in Philadelphia was calculated to be
  a minimum of 7.6 per 100,000 population (no
  higher than previous community reports).
• 24 of the patients reported no antibiotic use in
  the previous 3 months (highly unusual, but not
  verified).
• 4 patients (12) had exposure to another CDAD
  case.
• Only 2 isolates were recovered each had the
  binary toxin gene and one had the tcdC gene
  deletion, but neither was toxinotype III (the new
  epidemic strain).

MMWR 2005541201-1205 (Dec 2, 2005)
74
CA-CDAD and Gastric Acid Suppression

• Community UK GP data base (1994-2004) searched
  for pts with CA-CDAD and use of gastric acid
  suppressives
• CA-CDAD rate increased from 1/100K to 22/100K.
• PPIs 23 CA-CDAD cases
• 8 controls
  (Adj Rate Ratio 2.9 (95 CI 2.4-3.4).
• H2 antagonists 8 CA-CDAD cases
• 4 controls
  (Adj RR 2.0 (95 CI 1.6-2.7).
• NSAIDS 38 CA-CDAD cases
• 24 controls (Adj
  RR 1.3 (95 CI 1.2-1.5).
• Antibiotics 37 CA-CDAD cases
• 13 controls (Adj
  RR 3.9 (95 CI 2.7-3.6).

JAMA 20052942989-2995
75
Stomach Acid-Suppressing Medications and
Community-Acquired CDAD, England
From Dial S, et al. JAMA. 20052942989-2995.
76
Are PPIs a Risk for CDAD in Canada?

• In 1187, 591 (50) received abx and PPIs
• -CDAD rate of 9.3
  RR2.1(95 CI 1.4-3.4).
• 596 received only abx
• -CDAD rate of 4.4
  CMAJ 200417133-38
• Case control study of 94 CDAD patients, PPI use
• had an Adjusted Odds Ratio2.6 (95 CI
  1.3-5.0)
• 
  CMAJ 200417133-38
• In 7421 admissions, 293 CDAD cases occurred, and
• PPI use had an Adjusted Hazard Ratio1.0 (CI
  0.8-1.3)
• 
  CID 2005411254-1260
• In a case control study of 237 CDAD patients, PPI
  use
• in 47.3 of cases and 46.8 of controls
  (P0.92)
• 
  NEJM 20053532442-9

77
Role of Chemotherapy Administration in CDAD

• True incidence remains unknown
• Of 70 patiens hospitalized with diarrhea after
  chemotherapy ,1/3 responded to empiric
  metrinidazole or vancomycin
• Clostridium difficile can induced in animals with
  metrotrexate or 5- FU administration. Vancomycin
  added to the drinking water of the animals was
  found to be protective.

78
Clostridium Difficile Associated Diseases

• History and Epidemiology
• Pathogenesis
• Clinical pictures
• Diagnosis
• Management
• Prevention and control
• Future
• Summary

79
Summary

• CDAD-important hospital diarrhea and AAD
• Emerging epidemic C. difficile isolates are
  associated with higher CDAD rates and increased
  mortality.
• Candidate pathogenicity factors at present are
  increased toxin A and toxin B production, binary
  toxin, and FQs resistance, which is the only
  factor not found in nonepidemic, but FQs are not
  the only antibiotic risks.
• Emerging CA-CDAD
• The role of PPIs, chemotherapy as risk factors
  for CDAD remains elusive as well.

80
Summary

• Treatment of CDAD
• -metronidazole and vancomycin till the
  maistay
• -metronidazole response may be reduced or
  slowed and
• recurrence rates increased, but retreatment
  is effective
• -vancomycin recommended in severe cases
• Prevention and control
• -alcohol gels remove more C. difficile spores
  than
• expected but are not as effective as hand
  washing.

81

• ????
• THANK YOU