Transcript Trends in Antimicrobial Resistance and Impact on Treatment

Clostridium difficile
David B. Blossom, MD MS
Division of Healthcare Quality Promotion
Coordinating Center for Infectious Diseases
Centers 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 antimicrobialassociated 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: 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 )
1. Bartlett JG, et al. Gastroenterology 1978; 75:778-82
Healthy
colon
Pseudomembranous
colitis
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
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
Biggest Risks
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
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
100,000
1.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; 353:2442-9
2 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;320:204-10
2. 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
Variable
Sum CDAD pressure
1 or less
2-8
More than 8
Mean CDAD pressure
Less than 0.3
0.3-1.4
More than 1.4
Rel. Risk
95% CI
Ref.
3.9
9.7
Ref.
2.8-5.5
7.1-13.1
Ref.
6.4
8.7
Ref.
4.6-8.9
6.3-12.0
Dubberke et al. Arch Int Med 2007; 167: 1092-7
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.Proportion
difficile-associated
Disease
of U.S. Acute Care Hospital
Discharges
with Clostridium
difficile Listed as
(CDAD)
in US Hospitals
Any Diagnosis
Proportion of All Discharges
0.50%
0.40%
0.30%
0.20%
0.10%
0.00%
1993
1994
1995
1996
1997
1998
1999
2000
Year
McDonald et al. 14th Annual Scientific Meeting of the
Society for Healthcare Epidemiology of America, Philadelphia, PA. 2004
2001
2002
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
McDonald LC, et al. Emerg Infect Dis. 2006;12(3):409-15
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 1997;39:537-41
2. Dallal RM, et al. Ann Surg. 2002;235:363-372.
Loo VG, et al. NEJM 2005;353:2442-2449
3. 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
No relationship between alcohol-based hand
rubs and increasing rates of CDAD
Boyce et al. Infect Control Hosp Epidemiol 2006; 27:479-483
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;341:1645-51
2 Warny M, et al. Lancet 2005; 366: 1079-84
Acute Care Hospitals with
CDAD Outbreaks* Between 2001-2004
2
1
2 1
1
1
*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.
Common (Epidemic) Strain by
PFGE
Dice (Opt:0.50%) (Tol 1.3%-1.3%) (H>0.0% S>0.0%) [0.0%-100.0%]
100
95
Pfsma
90
85
Pfsma
.C.DIFFHospital
101 III
Maine,
A
.C.DIFF 163 III
Pennsylvania
Pennsylvania
.C.DIFF 164 III
Maine,
B
.C.DIFFHospital
207 III
.C.DIFFHospital
210 III
Maine,
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
Historic,
1993-2000
.C.DIFF 221
III
Oregon
.C.DIFF 203 III
.C.DIFF 219 III
Historic,
1990-1991
.C.DIFF 218 III
Historic, 1984-1991
Toxinotype and Potential
Virulence Factors of Isolates
1
Characteristic:
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” isolates
2 32 (89%) were toxinotype 0 or wild type
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. 2005;366:1079-1084.
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. 2005;366:1079-1084.
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
HI
AK
PR
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)
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)
CDC. MMWR. 2005;54:1201-1205.
Severe CDAD in Populations Previously
at Low Risk—Four 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 < 3 doses of
antimicrobials
• Clindamycin most common exposure (10
cases)
CDC. MMWR. 2005;54:1201-1205.
Proportion of all cases
Community-associated CDAD may
be Increasing, Atlanta VA Hospital
35%
30%
25%
99 total
cases
20%
15%
10%
5%
73 total
cases
67 total
cases*
93 total
cases
0%
2003
2004
2005
Year
Gaynes, R et al. ICAAC 2006, San Francisco
2006
•Through July 31, 2006
•Chi-square for trend: P<0.05
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: 1-4
2Rodriguez-Palacios
3Arroyo
A, et al. EID 2007; 13: 485-7
LG, et al. J Med Microbiol 2005; 54: 163-6
Defining CDAD Below the
Waterline
Dramatic, Severe
Disease In Healthy,
Young Persons
Diarrhea in older
ambulatory
patients +/chronic conditions
Antibiotic-associated
Inpatient Disease
?
Antibiotics? NSAIDS? PPIs?
H2 blockers?
Source: Human-to-Human and ?
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 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
Community vs. Hospital
Hospitalization
Admission
Discharge
3 months after
Discharge
48 h
CA
HO
4 weeks
8 weeks
CO-HCFA
Indeterminate
McDonald LC, et al. ICHE 2007; 28: 140-45
CA
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
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/
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
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
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
Use
Antimicrobials
Wisely
Campaign to Prevent Antimicrobial Resistance in Healthcare Settings
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
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
[email protected]
http//:www.cdc.gov/ncidod/dhqp/index.html