Transcript Clos diff Feb 2006

Clostridium difficile
Associated Diarrhea (CDAD)
What’s going on?
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
Background
Clostridia
• Gram +, spore forming, obligate anaerobes
• Worldwide distribution
• Infections range from localized wound
infection to overwhelming systemic disease
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
C. difficile Pathogenesis
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; 294:2989
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
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
Epidemiology
Annual CDAD rates, hospitals >500 beds,
unit surveillance component, National Nosocomial Infections Surveillance system, 1987-2001
ICU surveillance component, NNIS
Figure 1. Annual Clostridium difficile-associated diarrhea rates, hospitals >500 beds, intensive care
6.5
Cases/10,000 pt- days
6.0
5.5
5.0
4.5
r = 0.61
4.0
P <.01
3.5
3.0
19
87
19
88
19
89
19
90
19
91
19
92
19
93
19
94
19
95
19
96
19
97
19
98
19
99
20
00
20
01
19
86
2.5
Year
Archibald LK, et. al. J Infect Dis 2004; 189:1585–9
National Estimates of U.S. Short stay Hospital Discharges with C. difficile Listed as
First-listed or Any Diagnosis
Discharges
80
70
Discharges per 100,000 population
60
50
Any Diagnosis
40
Primary
30
20
10
0
1996
1997
1998
1999
2000
2001
2002
2003
Year
McDonald et al. 14th Annual Scientific Meeting of the
Society for Healthcare Epidemiology of America, Philadelphia, PA. 2004
Overall rates of any listed CDAD discharge diagnosis by
various demographic factors, 1996-2003
Demographics:
Category
Estimated rate*
95% CI*
Geographic
region
Northeast
68
56-79
Midwest
49
36-61
0.03
Southern
36
27-45
<0.001
Western
31
26-37
<0.001
<100
0.30%
0.23-0.36%
100-200
0.42%
0.37-0.47%
0.004
>300
0.38%
0.35-0.40%
0.03
Hospital size by
number of
beds
*Per 100,000 population
McDonald et al. 14th Annual Scientific Meeting of the
Society for Healthcare Epidemiology of America, Philadelphia, PA. 2004
P value
PFGE: Epidemic Strain
Dice (Opt:0.50%) (Tol 1.3%-1.3%) (H>0.0% S>0.0%) [0.0%-100.0%]
Pfsma
95
90
85
80%
100
Pfsma
.C.DIFF 101 III
Maine,
Hospital A
.C.DIFF 163 III
Pennsylvania
.C.DIFF 164 III
Pennsylvania
.C.DIFF
207 III
Maine,
Hospital
B
.C.DIFF
210 III
Maine,
Hospital
B
.C.DIFF 212 III
Illinois
.C.DIFF 213 III
Illinois
.C.DIFF 5 A/IIII
Georgia
.C.D.201
TYPE I I I A
Maine,
Hospital
.C.DIFF
106 III
New
Jersey
.C.DIFF
108 III
New
Jersey
.C.DIFF 204 III
Oregon
.C.DIFF 217
III
Historic,
1988-1991
.C.DIFF 220
III
Historic,
1993
.C.DIFF 221
III
Historic,
1993-2000
Oregon
.C.DIFF 203 III
.C.DIFF 219 III
Historic,
1990-1991
.C.DIFF 218 III
Historic, 1984-1991
“BI” strain by REA
“BI” strain by REA
McDonald et al. 42nd Annual Meeting of the Infectious Diseases
Society of America, Boston, Massachusetts. 2004
US Map
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)
187
96 (51%)
Total
McDonald et al. 42nd Annual Meeting of the Infectious Diseases
Society of America, Boston, Massachusetts. 2004
Fluoroquinolones as a risk factor in outbreaks
involving the epidemic strain, 2001-2004
Fluoroquinolone
N
Any
1570
Moxifloxacin
27
Levofloxacin
368
Ciprofloxacin
1153
Gatifloxacin
22
Pepin et al. CID Nov 1, 2005;41
Ratio
3.4
2.0
2.5
3.7
6.1
95% CI
2.7-4.4
0.5-8.3
1.7-3.8
2.8-5.0
2.2-16.7
CDAD Rate in Relation to
Fluoroquinolone Use in a LTCF
1.4
1.2
1
0.8
Gatifloxacin
Levofloxacin
0.6
0.4
p < 0.002
0.2
0
Jan-Sep 2001
2nd Qtr
3rd Qtr
Gaynes et al. CID 2004;38:640
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
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
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 1999;341:1645-51
Treatment
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
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
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)
Response Time for Treatment of CDAD
with Metronidazole or Vancomycin
8
Number of patients
7
Vancomycin
Metronidazole
6
5
4
3
2
1
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16
Number of days until diarrhoea cessation
Wilcox MH, Howe R. J Antimicrob Chemother 1995; 36: 673-9
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
Response to treatment of
Clostridium difficile associated diarrhea
Year of publication
Metronidazole
Year of publication
Vancomycin
2005
2005
1996
2005
1994
Failure
Recur
1992
2004
1989
2001
1989
1996
1986
1985
Failure
Recur
1994
1984
1983
1983
1981
1982
1980
0
10
20
30
40
50
% treated subjects
20% Recurrence
13% Failure
Aslam et al. Lancet, 2005
60
0
10
20
30
40
50
% treated subjects
19% Recurrence
4% Failure
60
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 2002:97:1769
Saccharomyces boulardii
Saccharomyces boulardii
• Specific strain of Saccharomyces cervesiae
• Survives passage through human GI tract
• Caution: fungemia in immunosuppressed patients
S. boulardii plus High Dose Vancomycin
for Recurrent C. difficile Disease
50%
*p=0.05
% CDD recurrences
50
40
16.7%*
30
20
10
0
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 2000;31:1012-7.
Current Treatment Controversies
• Is metronidazole still effective therapy for CDAD?
• Is metronidazole-resistance clinically important?
• What, if any, are the alternative therapies
Recent Reports of Poor CDAD
Responses to Metronidazole
• Musher et al. CID. 2005;40:1586-1590
• 207 CDAD patients at Houston VAMC
• Historical controls
• Reduced response rates and higher recurrence rates with
metronidazole
• Pepin et al. CID. 2005;40:1591-1597
• 438 Quebec patients treated in 2003-2004
• 688 Quebec patients treated from 1991-2002
• Reduced response rates and higher recurrence rates with
metronidazole
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
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
MIC (g/ml)
MTR Failure
0.23
Sanchez J, et al. Anaerobe 1999
MTR success
0.29
Prospective Randomized Trials for CDAD
Johnson S, Gerding DN. In: Antimicrobial Therapy & Vaccines, 2nd Ed.
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 1994;15:371-381
Vancomycin Enemas
•Adjunct treatment for severe C. difficile
• Non-randomized open trials
• Inf Cont Hosp Epidemiol 1994;15:371-381
– 6/8 patients with ileus responded in 4-17 days
– 2 patients died, one following colectomy
•Apisarnthanarak et al Clin Inf Dis 2002;35:690-96
– 8/9 cases resolved
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
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
Alcohol vs Chlorhexidine
C. difficile Transferred by
Handshaking
Pair
1
2
3
4
5
Donor PostAlcohol Rub*
406
665
180
885
1547
* Colony forming units
Recipient PreHandshake*
0
0
0
0
1
Recipient PostHandshake*
128
369
33
317
151
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 manufacturer’s instructions for
disinfection of endoscopes and other devices
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
Reasons for New Requirements
• The emergence of a new strain of C. difficileassociated 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
New Reporting Requirements
• ODH Director’s 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
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
Case Definitions
• Health Care-Associated (Initial)
– Positive result > 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 < 48
after admission)
– No healthcare-associated episodes in past 6 months
– Regardless of recent hospitalizations
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
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
Questions