Clostridium difficile Associated Diarrhea (CDAD)

1
Clostridium difficile Associated Diarrhea (CDAD)

• Whats going on?

2
New Issues

• PPIs appear to be a risk factor for CDAD
• CDAD rates are increasing
• An epidemic C. difficile strain has been found in
  the US, Canada, and Europe
• CDAD-associated mortality/morbidity is increasing
• Alcohol hand cleaning inadequate for C. difficile

3
Background
4
Clostridia

• Gram , spore forming, obligate anaerobes
• Worldwide distribution
• Infections range from localized wound infection
  to overwhelming systemic disease

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C. difficile Pathogenesis

• 2 major toxins
• A mediates alteration in fluid secretion,
  enhances inflammation, induces postcapillary
  venules to leak albumin
• B more active in causing damage to and
  exfoliation of superficial epthelial cells
• Both cause electrophysiologic alterations of
  colonic tissue

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C. difficile Pathogenesis
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Gastric Acid Suppression and CDAD

• Case-control study
• 1672 cases with CDAD
• 16720 controls
• Adjusted risk ratio (95 CI)
• PPI 2.9 (2.4-3.4)
• H2 antagonist 2.0 (1.6-2.7)
• NSAIDs 1.3 (1.2-1.5)

Dial S et al. JAMA 2005 2942989
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Clinical Manifestations

• 20-30 of antibiotic-associated diarrhea
• Toxins detectable in stool
• Onset during or within 10 weeks antibiotic use
• Associated with all antibiotics
• 4 categories based on colon appearance
• Normal colonic mucosa
• Mild erythema with some edema
• Granular, friable, or hemorrhagic mucosa
• Pseudomembrane formation - mucosa shows raised
  plaques with skip areas

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Diagnosis

• Diverse clinical spectrum
• Diarrhea may be profuse/watery
• Blood or mucus may be present
• Abdominal cramps
• Fever leukocytosis
• Large numbers of RBCs and WBCs in stool
• 95 have positive stool toxin assays
• C. difficile toxin is very unstable
• Toxin degrades at room temperature and may be
  undetectable within 2 hours after collection of a
  stool specimen
• False-negative results occur when specimens are
  not promptly tested or kept refrigerated until
  testing can be done

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Epidemiology
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Annual CDAD rates, hospitals gt500 beds, ICU
surveillance component, NNIS
Archibald LK, et. al. J Infect Dis 2004
18915859
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Discharges
McDonald et al. 14th Annual Scientific Meeting of
the Society for Healthcare Epidemiology of
America, Philadelphia, PA. 2004
13
Overall rates of any listed CDAD discharge
diagnosis by various demographic factors,
1996-2003
Demographics Category Estimated rate 95 CI P value
Geographic region Northeast 68 56-79
Midwest 49 36-61 0.03
Southern 36 27-45 lt0.001
Western 31 26-37 lt0.001
Hospital size by number of beds lt100 0.30 0.23-0.36
100-200 0.42 0.37-0.47 0.004
gt300 0.38 0.35-0.40 0.03
Per 100,000 population
McDonald et al. 14th Annual Scientific Meeting of
the Society for Healthcare Epidemiology of
America, Philadelphia, PA. 2004
14
PFGE Epidemic Strain
80
Maine, Hospital A Pennsylvania Pennsylvania Maine,
Hospital B
Maine, Hospital B Illinois Illinois Georgia
Maine, Hospital A New Jersey New Jersey
Oregon Historic, 1988-1991 Historic, 1993
BI strain by REA
Historic, 1993-2000 Oregon
Historic, 1990-1991 Historic, 1984-1991
BI strain by REA
McDonald et al. 42nd Annual Meeting of the
Infectious Diseases Society of America, Boston,
Massachusetts. 2004
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US Map
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Distribution of isolates by healthcare facility
outbreak and proportion attributed to the BI/NAP1
strain
Location Date of outbreak onset No. of isolates tested No. () epidemic strain
Georgia October, 2001 46 29 (63)
Illinois July, 2003 14 6 (43)
Maine, Facility A March, 2002 13 9 (69)
Maine, Facility B July, 2003 48 30 (63)
New Jersey June, 2003 12 9 (75)
Oregon April, 2002 30 3 (10)
Pennsylvania, Facility A 2000-2001 18 7 (40)
Pennsylvania, Facility B October, 2003 6 3 (50)
Total 187 96 (51)
McDonald et al. 42nd Annual Meeting of the
Infectious Diseases Society of America, Boston,
Massachusetts. 2004
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Fluoroquinolones as a risk factor in outbreaks
involving the epidemic strain, 2001-2004

• Fluoroquinolone N Ratio 95 CI
• Any 1570 3.4 2.7-4.4
• Moxifloxacin 27 2.0 0.5-8.3
• Levofloxacin 368 2.5 1.7-3.8
• Ciprofloxacin 1153 3.7 2.8-5.0
• Gatifloxacin 22 6.1 2.2-16.7

Pepin et al. CID Nov 1, 200541
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CDAD Rate in Relation to Fluoroquinolone Use in a
LTCF
p lt 0.002
Gaynes et al. CID 200438640
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Increasing severity of CDAD

• Pittsburgh, PA 20001
• Life threatening disease from 1.6 to 3.2
• 44 colectomies and 20 deaths
• Recent reports from Quebec, Canada
• Severe outcomes
• Deaths

1Dallal RM et al. Ann Surg 2002 235 363-70
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Emerging Infections Network Survey

• 525 ID Physicians responded
• 38 reported increasing caseload
• 40 reported increased severity of cases
• 435 cases of toxic megacolon
• 181 requiring colectomy
• 94 colonic perforations
• 198 patient deaths

Layton BA et al. 15th Annual Scientific Meeting
of the Society for Healthcare Epidemiology of
America, Los Angeles, CA. 2005
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Changes in Epidemiology

• Emergence of a new epidemic strain
• Toxinotype III or BI by REA
• Distinct from J strain of 1989-1992
• 18 bp deletion in tcdC
• Could lead to increased toxin production
• Increased resistance to fluoroquinolones
• Appears responsible for increase in cases
• 16- and 23- fold increase in toxins A B
  production, respectively, may be responsible for
  increased disease severity

Johnson S, et al. N Engl J Med 19993411645-51
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Treatment
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CDAD Treatment Principles

• Stop offending antibiotic if possible 25
  respond without further therapy
• Oral therapy preferred
• Mean time for diarrhea to stop 2 - 4 days
• Treat for 10 days
• Treat for 7 days before declaring failure if the
  patient is not worsening
• Avoid antiperistaltic agents
• Do not perform test of cure toxin assays

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Primary CDAD (First Episode)

• Metronidazole (first-line treatment)
• Dose 250 mg qid or 500 mg tid x 10 days
• Not FDA approved for CDAD
• Inexpensive
• Systemic absorption
• No drug in stool in absence of diarrhea

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Primary CDAD Vancomycin

• Oral dose 125 mg QID x 10 days
• More expensive than metronidazole -
  approximately 400-600
• No systemic absorption
• Stool levels in the range of 1000-3000 µg/gm
  stool
• Use discouraged in hospitals because of risk of
  resistance in enterococci and staphylococci
  (HICPAC recommendations, 1995)

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Response Time for Treatment of CDAD with
Metronidazole or Vancomycin
Wilcox MH, Howe R. J Antimicrob Chemother 1995
36 673-9
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CDAD Recurrences

• Recurrence rate following treatment of the
  initial episode 15-25
• Genetic typing studies show a new strain for a
  recurrence 50 of the time
• Failure to develop serum antibodies against toxin
  A has been correlated with recurrence
• Treatment for first recurrence is repeat
  treatment with metronidazole for 10 days
• No consensus for treatment beyond first
  recurrence

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Response to treatment ofClostridium difficile
associated diarrhea
Vancomycin
Year of publication
treated subjects
19 Recurrence 4 Failure
Aslam et al. Lancet, 2005
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Multiple Recurrences of CDAD

• Risk of subsequent episode in patients who
  already have had a recurrence is 45
• Many empiric treatments advocated
• Vancomycin regimens tapering, pulsed dosing,
  combination treatment with rifampin
• Probiotics using S. boulardii or Lactobacillus
  sp.
• Passive treatment with immunoglobulin
• Toxin binding agents (cholestyramine, cholestipol
  or newer agents)
• Fecal reconstitution using spousal donors

McFarland LV, et al. Am J Gastro 2002971769
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Saccharomyces boulardii

• Saccharomyces boulardii
• Specific strain of Saccharomyces cervesiae
• Survives passage through human GI tract
• Caution fungemia in immunosuppressed patients

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S. boulardii plus High Dose Vancomycin for
Recurrent C. difficile Disease
50
p0.05
16.7
Vancomycin 2 g/d
S. boulardii Vancomycin
Vancomycin (500 mg/d) or metronidazole (1g/d)
plus S. boulardii no more effective than placebo
Surawicz CM et al Clin Infect Dis 2000311012-7.
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Current Treatment Controversies

• Is metronidazole still effective therapy for
  CDAD?
• Is metronidazole-resistance clinically important?
• What, if any, are the alternative therapies

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Recent Reports of Poor CDAD Responses to
Metronidazole

• Musher et al. CID. 2005401586-1590
• 207 CDAD patients at Houston VAMC
• Historical controls
• Reduced response rates and higher recurrence
  rates with metronidazole
• Pepin et al. CID. 2005401591-1597
• 438 Quebec patients treated in 2003-2004
• 688 Quebec patients treated from 1991-2002
• Reduced response rates and higher recurrence
  rates with metronidazole

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Reports of C. difficile with Reduced
Susceptibility to Metronidazole

• 20/105 (19) equine isolates (U.S.) Jang 1997
• 19/20 resistant isolates were identical by AP-PCR
  typing
• 6/198 (3) human isolates (France) Barbut 1999
• 5/6 resistant isolates were non-toxigenic strains
• 1/100 (1) human isolates (China) Wong 1999
• Resistant isolate (MIC 64 ?g/ml) was recovered
  from 65 year old patient with diarrhea
• 26/415 (6) human isolates (Spain) Peláez 2002
• Clinical significance not reported

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Metronidazole Failure Not Associated with
Metronidazole Resistance

• 10-year prospective surveillance 14/632 (2)
  episodes of CDAD did not respond to metronidazole
  (MTR)
• Susceptibility of 10 isolates from MTR failures
  compared to 20 isolates from MTR successes
• MTR Failure MTR success
• MIC (?g/ml) 0.23 0.29

Sanchez J, et al. Anaerobe 1999
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Prospective Randomized Trials for CDAD

• Johnson S, Gerding DN. In Antimicrobial Therapy
  Vaccines, 2nd Ed.

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Management of CDAD in the Presence of Severe
Ileus

• Vancomycin orally or via nasogastric tube 500 mg
  q 6h (DC suction for 45-60 min post dose)
• Metronidazole 500 mg q 6h intravenously
• Vancomycin enemas 500 mg q 6h in 100 cc NS clamp
  catheter for 60 min post dose
• Inf Cont Hosp Epidemiol 199415371-381

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Vancomycin Enemas

• Adjunct treatment for severe C. difficile
• Non-randomized open trials
• Inf Cont Hosp Epidemiol 199415371-381
• 6/8 patients with ileus responded in 4-17 days
• 2 patients died, one following colectomy
• Apisarnthanarak et al Clin Inf Dis 200235690-96
• 8/9 cases resolved

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Investigational Rx for CDAD
Product (type) Pt. Results Stage
Tolevamer (poly) 58/70 Pts Phase III
Ramoplanin (abx) 25/29 Pts Phase III
OPT-80 (abx) None Phase II
Rifalazil (abx) None Phase II
Rifaximin (abx) 9/10 Pts Phase III
Tinidazole (abx) None Unknown
Nitazoxanide (abx) 14/19 Pts Phase II
Monoclonal Ab None Phase II
CD Vaccine Unknown Phase I
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Prevention of C. difficile

• Use antibiotics judiciously
• Use Contact Precautions for patients with known
  or suspected C. difficile-associated disease
• Place these patients in private rooms
• If private rooms are not available, patients can
  be cohorted
• Use soap and water for hand hygiene when caring
  for patients with C. difficile-associated disease
• Use gloves when entering patients rooms and
  during patient care
• Use gowns if soiling of clothes is likely
• Dedicate equipment whenever possible
• Continue precautions until diarrhea ceases

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Alcohol vs Chlorhexidine
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C. difficile Transferred by Handshaking

• Donor Post- Recipient Pre- Recipient Post-
• Pair Alcohol Rub Handshake Handshake
• 1 406 0 128
• 2 665 0 369
• 3 180 0 33
• 4 885 0 317
• 5 1547 1 151

Colony forming units
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Environmental Cleaning and Disinfection

• Ensure adequate cleaning and disinfection of
  environmental surfaces and reusable devices
• Use an EPA-registered hypochlorite-based
  disinfectant
• Alcohol-based disinfectants are not effective
  against C. difficile and should not be used to
  disinfect environmental surfaces
• Follow the manufacturers instructions for
  disinfection of endoscopes and other devices

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CDC Recommendations

• Hospitals should 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 important for
  reducing severe outcomes and should be emphasized
• Subset of epidemic isolates tested for
  metronidazole susceptibility
• Strict infection control
• Contact precautions for CDAD patients
• An environmental cleaning and disinfection
  strategy
• Hand washing with CDAD outbreak
• Further research needed

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Reasons for New Requirements

• The emergence of a new strain of C.
  difficile-associated disease associated with
  hospital outbreaks in several states has been
  reported by the Centers for Disease Control and
  Prevention (CDC) at scientific meetings
• The new strain appears to be more virulent, with
  ability to produce greater quantities of toxins A
  and B
• In addition, it is more resistant to the
  antibiotic group known as fluoroquinolones

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New Reporting Requirements

• ODH Directors Journal Entry December 28, 2005
• In effect January 1 through June 30, 2006
• Aggregate numbers of confirmed cases of C.
  difficile reported by hospitals and long term
  care facilities to the local health department
• Report by the close of each work week
• Only health care-associated infections reported
• Community onset infections are not reportable

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Case Definitions

• Diagnostic test for Clostridium difficile
• EIA
• Cytotoxin
• Antigen
• Culture (not a recommended test)
• Pseudomembranes seen on endoscopy
• Positive histology from surgical or autopsy
  specimen

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Case Definitions

• Health Care-Associated (Initial)
• Positive result gt 48 hours after admission to a
  health care facility
• No CDAD in past 6 months
• Health Care-Associated (Recurrent)
• Positive result
• Previous healthcare-associated positive within
  prior 6 months
• Clinical resolution after previous treatment
• Community-Onset Positive result as outpatient
  (or lt 48 after admission)
• No healthcare-associated episodes in past 6
  months
• Regardless of recent hospitalizations

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January Local Reporting

• 9 acute care hospitals reported 23 initial and 8
  recurrent cases
• 8 initial cases and 1 recurrent case not included
  in the ODH report (facilities not on the current
  ODH report)
• Thirty-seven nursing homes reported 6 initial
  cases and 1 recurrent case

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Summary

• CDAD rates are increasing
• An epidemic C. difficile strain has been found in
  the US, Canada, and Europe
• CDAD-associated mortality/morbidity is increasing
• New reporting requirements
• Better define the problem in Ohio
• Allow for design of ongoing surveillance

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Questions