clostridium difficile.ppt

8/11/2019 clostridium difficile.ppt

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Evolving Challenges in

Clostridium difficileInfection (CDI):

From Risk Assessment to InnovativeTreatments


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Disclosure of Conflicts of Interest

Linda M. Mundy, MD, Ph.D

Dr. Linda M. Mundy, has affiliations withGenentech, Inc. (Patent holder - spouse) and

GlaxoSmithKline (Consultant).


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Educational Objectives

Discuss the pathophysiology of Clostridium difficileinfection (CDI) as it relates to clinical disease

Identify important risk factors for initial CDI and

recurrence

Apply therapeutic strategies for improved patient

outcomes

Implement methods to prevent CDI in high-risk patients


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CDI Overview: 60 Years of Research

Evolution of C. difficileknowledge over past 60years 1950: Staphylococcusenterocolitis

1974: Clindamycin colitis

1978: C. difficileas agent of pseudomembranous colitis

1981: Vancomycin approved by FDA for CDI

1982: Metronidazole introduced for CDI

1984: Enzyme immunoassays for CDI

2000: Outbreak in Pittsburgh, PA

2003: Outbreak in Quebec

2005: Outbreaks in United States and Europe


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CDI Epidemiology Incidence of CDI appears to be increasing in the US

Healthcare Cost and Utilization Project (HCUP). http://hcupnet.ahrq.gov.

138,954

348,950


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CDI Epidemiology

Severity of CDI appears to be increasing1-2 Increased morbidity and mortality

Increased infection in low-risk populations1-3

Emergence of novel, hypervirulent strain nowreported across the US, Canada, and Europe

Increased toxin production and sporulation may

contribute to widespread disease4,5

1. McDonald LC, et al. Emerg Infect Dis. 2006;12(3):409-415.

2. Loo VG, et al. N Engl J Med.2005;353:2442-2449.

3. Kuijper EJ, et al. Euro Surveill. 2007;12(6):E1-E2.

4. Tucker ME. http://www.ehospitalistnews.com/news/infectious-diseases/single-article/ic-difficilei-epidemic-still-poses-clinical-

challenges/01e37c081f.html

5. Merrigan M, et al.J Bacteriol. 2010;192:4904-4911.


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CDI Epidemiology

Characteristics of novel epidemic strain:

Typed BI/NAP1/027

Highly virulent

Produces 16-fold higher levels of Toxin A and

23-fold higher levels of Toxin B

Produces binary toxin CDT

Highly resistant to fluoroquinolones

Denve C, et al. Int J Antimicrob Agents. 2009;33:S24-S28.


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CDI Pathophysiology

Primary virulence factors:

Toxin A (TcdA)

Toxin B (TcdB)

Toxins A and B are potent cytotoxic enzymes

that damage the human colonic mucosa

Binary toxin (CDT) was previouslyidentified in

~6% of C. difficileisolates, but is present in all

isolates of the hypervirulent strain May potentiate toxicity of TcdAand TcdBand lead

to more severe disease

Denve C, et al. Int J Antimicrob Agents. 2009;33:S24-S28.


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Economic Burden of CDIStudy Patient

Population

Per-Episode

Costs

Increase in

Length of Stay

US Cost

Kyne 19981 -2 medical

wards

-40 cases

$3,669 3.6 days $1.1 billion

OBrien 20002

-MA dischargedatabase

-3,692 cases

Primarydiagnosis:

$10,212

Secondary

diagnosis:

$13,675

3.0 days $3.2 billion

Dubberke 20033 -Nonsurgicalpatients

-439 cases

$2,454$3,240

2.8 days $1.3 billion

1. Kyne L, et al. Clin Infect Dis. 2002;34:346-353.

2. OBrien JA, et al. Infect Control Hosp Epidemiol. 2007;28:1219-1227.

3. Dubberke ER, et al. Clin Infect Dis. 2008;46:497-504.


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Economic Burden of CDI

Limitations of current data Primarily hospitalized patients with CDI

Few studies determined costs associated withtreatment of CDI complications

Most data obtained prior to outbreak of epidemicstrain

Difficult to extrapolate and apply to current

epidemiology and management Economic burden expected to accumulate

1. Dubberke ER, Wertheimer AI. Infect Control Hosp Epidemiol. 2009;30:57-66.2. Ghantoji SS, et al.J Hosp Infect. 2010;74:309-318.


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Pathogenesis of CDI

From Poutanen SM, Simor AE. Can Med Assoc J. 2004;171(1):51-58; with permission.


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Identifying Patients at Risk

for Recurrence and Poor Outcomes

Elderly

Administration of antibiotics after initial

treatment of CDI Prolonged hospitalization or stay in long-term

care facility (LTCF)

Defective immune response to toxin A Gastric acid suppression

1. Johnson S. J Infect.2009;58:403-410.

2. Hookman P, Barkin JS. World J Gastroenterol.2009;15(13):1554-1580.

3. Zilberberg M, et al. Crit Care Med. 2009;37:2583-2589.

4. Garey KW, et al.J Hosp Infect. 2008;70:298-304.


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Elderly

20.4/1,000 discharges



2.97/1,000

discharges

Healthcare Cost and Utilization Project (HCUP). http://hcupnet.ahrq.gov.


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Administration of Antibiotics

After Initial CDI Therapy Continued use of non-C. difficileantibiotic after

diagnosis of CDI associated with an odds ratio of 4.23(P


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Prolonged Hospitalization or Stay in LTCF

Risk related to transmission of C. difficile spores

Primary source from healthcare workers Staff may carry C. difficile spores on their hands (not likely

fecal carriers)

Environmental contamination important secondary

source Up to 50% of LTCF residents and 40% of

hospitalized patients have been found to becolonized with C. difficileor its toxin

Infection control and preventions strategies (ie,hand hygiene, isolation precautions) can reducethis risk

1. McFarland LV, et al. N Engl J Med. 1989;320:204-210. 2. Bartlett JG, Gerding DN. Clin Infect Dis. 2008;46(Suppl 1):S12-S18. 3. Simor AE, etal. Infect Control Hosp Epidemiol. 2002;23:696-703. 4. Hookman P, Barkin JS. World J Gastroenterol. 2009;15:1554-1580.


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CDI Diagnostic ChallengesTest Advantage(s) Disadvantage(s)

Toxin testing

Enzyme

immunoassay

Rapid, simple,

inexpensive

Least sensitive method, some

detect only toxin A (some strains

only produce toxin B)

Tissue culture

cytotoxicity

Organism identification

More sensitive than

enzyme immunoassay

Labor intensive; requires 2448

hours for a final result, special

equipment; not as sensitive as

generally thought

Detection of

glutamate

dehydrogenase

Rapid, sensitive, may

prove useful as a triage

or screening tool

Not specific, toxin testing required

to verify diagnosis; may not be

100% sensitive

PCR Rapid, sensitive,

detects presence of

toxin gene

Cost, special equipment, may be

too sensitive

Stool culture Most sensitive test

available when

performed

appropriately

May be associated with false-

positive results if isolate is not

tested for toxin; labor-intensive;

requires 48

96 hours for results


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CDI Diagnostic Challenges

Two- and three-step testing algorithms havebeen proposed

Initial screen: EIA for glutamate dehydrogenase

Confirmatory: Cell cytotoxicity assay (or culture)or polymerase chain reaction (PCR)

Results appear to differ based on the GDH kitused

Optimal universal strategy remains continuoussource of debate

1. Hansen G, et al. Clin Laboratory News. 2010 July:10-13.2. Cohen SH, et al. Infect Control Hosp Epidemiol.2010;31(5):431-455.


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SHEA/IDSA 2010 Guidelines

for Diagnosis Testing for C. difficileor its toxins should be

performed only on unformed stool (unless

ileus is suspected)

Testing asymptomatic patients not clinicallyuseful and not recommended outside of

epidemiological studies

Stool culture with confirmation of isolatetoxigenicity (toxigenic culture) provides the

standard against which other clinical test

results should be comparedCohen SH, et al. Infect Control Hosp Epidemiol.2010;31(5):431-455.


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SHEA/IDSA 2010 Guidelines

for Diagnosis (Cont.) EIA considered a suboptimal alternative approach

for diagnosis

2-step testing can help to overcome low

sensitivity of toxin testing; this approach remainsan interim recommendation

More data on the utility of PCR testing isnecessary before it can be recommended for

routine testing Repeat testing during same episode of diarrhea is

discouraged

Cohen SH, et al. Infect Control Hosp Epidemiol.2010;31(5):431-455.


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Basic Principles of CDI Therapy

Discontinue offending antimicrobial agent (ifpossible)

Send stool specimen for C. difficile testing

Initiate CDI therapy either empirically or

following confirmation of diagnosis (dependingon clinical urgency) Pharmacotherapy

Vancomycin (only FDA-approved treatment for CDI)

Metronidazole

Other Supportive treatment

Monitor for symptom resolution and be awareof recurrence after treatment discontinuation



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SHEA/IDSA Treatment

Recommendations

Severity-based management

SHEA/IDSA recommends stratification of

treatment based on disease severity

Risk-stratification method has not yet been

validated

Criteria based on expert opinion and/or

retrospective data


SHEA/IDSA T t t


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SHEA/IDSA Treatment

Recommendations


Clinical scenario Supportive clinical data Recommended treatment

Mild to moderate Leukocytosis (WBC < 15,000

cells/uL) or SCr level < 1.5

times premorbid level

Metronidazole 500 mg 3

times per day PO for 10-

14 days

Severe Leukocytosis (WBC 15,000

cells/uL) or SCr level 1.5

times premorbid level

Vancomycin 125 mg 4

times per day PO for 10-

14 days

Severe, complicated Hypotension or shock, ileus,

megacolon

Vancomycin 500 mg 4

times per day PO or by

nasogastric tubeplusmetronidazole 500 mg IV

q 8 hrs

Additional Management of


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Additional Management of

Severe, Complicated CDI Prompt recognition of severe, complicated CDI and

early surgical evaluation is critical*

Indications of severe, complicated disease course: Elevated and rising white blood cell count (WBC)

Elevated serum creatinine (SCr) level

Elevated serum lactate Clinical and/or radiographic evidence of severe ileus,

impending toxic megacolon

Consider vancomycin per rectum if ileus is severe

*Colectomy may be lifesaving, but is associated withincreased risk of mortality if WBC is > 50,000 and lactate is>5 mg/dL

1. Cohen SH, et al. Infect Control Hosp Epidemiol.2010;31(5):431-455.

2. Pepin J, et al. Dis Colon Rectum. 2009;52:400-405.


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Management of Recurrent CDI

CDI recurrence is a significant challenge

Rates of recurrent CDI:

20% after first episode

45% after first recurrence

65% after two or more recurrences

Clinical scenario Recommended treatment

First recurrence Treat as first episode according to

disease severitySecond recurrence Treat with oral vancomycin taper

and/or pulse dosing

1. Cohen SH, et al. Infect Control Hosp Epidemiol.2010;31(5):431-455.

2. Johnson S.J Infect. 2009;58(6):403-410.


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Multiple Recurrent CDI

Several empirical approaches have been advocated

but most have no controlled data1-3

Metronidazole should not be used beyond first

recurrence or for prolonged course, ie, >14 days(concerns for hepatotoxicity and polyneuropathy)1-3

Best data with vancomycin taper regimen4,5

1. Aslam S, et al. Lancet Infect Dis.2005;5:549-557. 2. McFarland LV, et al.Am J Gastroenterol.2002:97:1769-1775. 3. McFarland LV, et

al.JAMA. 1994;271:1913-1918. 4. Kyne L, Kelly CP. Gut.2001;49:152-153. 5. Tedesco FJ, et al.Am J Gastroenterol. 1985;80:867-868.

Oral Vancomycin Taper

125 mg QID x 10-14 days

125 mg BID x 7 days

125 mg daily x 7 days125 mg once every 2 days x 8 days

125 mg once every 3 days x 15 days


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Alternative CDI Therapies: Rifaximin Rifaximin chaser therapy for multiple recurrent

CDI1

Rifaximin 400 mg BID for 14 days immediately

following last course of vancomycin

Seven of eight patients had no further diarrhearecurrence

Single case of rifaximin resistance with recurrent CDIafter a second course of rifaxmin

Follow up experience with 6 patients 2 recurred, rifaximin resistance identified in one

Issues with resistance2 Rifampin resistance observed in 36.8% of 470

recovered isolates and 81.5% of 205 epidemic cloneisolates

1. Johnson S, et al. Clin Infect Dis. 2007;44:846-848.

2. Curry SR, et al. Clin Infect Dis. 2009;48:425-429.3. Johnson S, et al. Anaerobe. 2009; 15:290-1


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Alternative CDI Therapies: Tigecycline Adjunctive treatment for severe CDI

Lu CL, et al. Int J Antimicrob Agents.2010;35:311-312. Single case study

CDI refractory to metronidazole and vancomycin successfullytreatedwith IV tigecycline

Herpers BL, et al. Clin Infect Dis. 2009;48:1732-1735. 4 pts with severe, refractory CDI

Successful treatment with IV tigecycline therapy

Kopterides P, et al.Anaesth Intensive Care.

2010;38:755-758. Single case study Treatment failure with tigecycline combined with

vancomycin, metronidazole, and intravenousimmunoglobulin (IVIG)

Alt ti CDI Th i IVIG


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Alternative CDI Therapies: IVIG

Study Type N Population Potential Benefit

of IVIG?

Yes No

McPherson 20061 Retrospective

Review

14 Severe,

refractory,

recurrent CDI

X

Abougergi 20102 Observational

study and

literature review

21 Severe C. difficile

colitis

X

Wilcox 20043 Descriptive study 5 Intractable,

severe C. difficile

diarrhea

X

OHoro20094 Systematic

review

-- CDI inconclusive inconclusive

Hassoun 20075 Case review 1 Severe C. difficile

colitis

X

Inconclusive evidence regarding the benefit of

intravenous immunoglobulin (IVIG) in CDI

1. McPherson S, et al. Dis Colon Rectum. 2006;49:640-645. 2. Abougergi MS, et al.J Hosp Med. 2010;5:E1-E9. 3. Wilcox MH. J Antimicrob

Chemother. 2004;53:882-884. 4. OHoro J, Safdar N. Int J Infect Dis. 2009;13:663-667. 5. Hassoun A, Ibrahim F.Am J Geriatr Pharmacother.

2007;5:48-51.

F l Fl R i


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Fecal Flora Restoration

Theory: Restoration of fecal flora and colonization

resistance

Data:

1958 to 2000: 9 reports (68 patients); cure rate ~90%.

2003: 18 patients; fecal filtrate (stool transplant); 1 of 16survivors had a single subsequent recurrence; pre-treated

with vancomycin and omeprazole; instilled through

nasogastric tube.

Test donor: enteric pathogens, C. difficile, ova andparasites, HAV, HBV, HCV, HIV, RPR

1. Persky SE, Brandt LJ.Am J Gastroenterol. 2000;95:3283-3285.

2. Borody TJ.Am J Gastroenterol. 2000;95:3028-3029.3. Palmer R. Nat Med. 2011;17:150-152.


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Potential Future CDI Therapies: Fidaxomicin

Similar conclusions reached in second phase 3

study Equivalent cure

rates were

achieved with

FDX and VAN

Significantly fewer

recurrences were

seen after FDX(50% less than VAN)

resulting in higher global cures

91.7

12.8

79.6

90.6

25.3

65.5

91.1

19.1

72.3

0

10

20

30

40

50

60

70

80

90

100

Clinical Cure Recurrence Global cure

*

FDX VAN Total FDX VAN Total FDX VAN Total

198

216213

235

411

451

23

180

46

182

69

362172

216

154

235

326

451

FDX, fidaxomicin; VAN, vancomycin; *P= NS; P= .002; P< .001

Johnson S, et al. DDW 2010; Abstract 711c.

Potential Future CDI Therapies:


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Nontoxigenic C. difficile

Nontoxigenic C. difficilestrainsoccur naturally

Natural asymptomatic C. difficilecolonization (toxigenic ornontoxigenic) decreases risk of

infection Nontoxigenic C. difficilecan be

administered orally as spores toprovide protection against CDI Mechanism by which nontoxigenic

C. difficileprevents colonization bytoxigenic strains not yet elucidated

Human Phase I trials completed inearly 2010

1. Gerding DN, Johnson S. Clin Infect Dis. 2010;51:1306-1313.2. Sambol SP, et al.J Infect Dis. 2002;186:1781-1789; with permission

Non-toxigenic C. difficile

prevented CDI in 87%-97%

of hamsters

P ti f F t l I f ti ith T i i C


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Prevention of Fatal Infection with Toxigenic C.

difficile (J9) by Prior Colonization of Hamsters

with Non-toxigenic C. difficile (M3)

M3 J9

ControlJ9 XX -dead

Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day..

Clindamycin



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Potential Future CDI Therapies:C. difficileToxoid Vaccine

Seroconversion rates in young vs elderly healthysubjects (50 g dose)

Foglia G, et al. Anarobe Society of Americas 2010; Abstract CD 1093.

Day

Study 009

65 yrs; median age = 70

Study 008

1855 yrs; median age = 26

0 10 20 30 40 50 60 70 800

25

50

75

100

Ser

oconversionRate(%)

Toxin A Toxin B Both toxins

Ser

oconversionRate(%)100%

75%

75%

42%

25%

0 10 20 30 40 50 60 70 800

20

40

60

80

100

Day

100%


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Prevention of CDI

Transmission between patients and healthcareprofessionals within hospitals represents majorsource of C. difficileacquisition

Survey reports inconsistencies among infectioncontrol measures

Hand hygiene policies

Duration of isolation

Environmental cleaning practices

Antimicrobial stewardship programs

APIC 2010 Clostridium difficilePace of Progress Survey. Available at:

http://www.apic.org/Content/NavigationMenu/ResearchFoundation/NationalCDiffPrevalanceStudy/CDI_Pace_of_Progress_Survey_Report.pdf.Accessed January 31, 2011.


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Minimize Transmission among

Healthcare Personnel: Hand Hygiene Appropriate hand hygienearea of

controversy

In routine settings, alcohol-based hand hygiene in

conjunction with isolation precautions usinggloves may be acceptable

In setting of outbreak or increased rates, consider

washing hands with soap and water after caring

for patients with C. difficileHCWs = healthcare workers.

1. Cohen SH, et al. Infect Control Hosp Epidemiol.2010;31:431-455.

2. Dubberke ER, et al. Infect Control Hosp Epidemiol. 2008;29:S81-S92.

3. APICGuide to the Elimination of Clostridium difficile in Healthcare Settings, Association for Professionals in Infection Control and

Epidemiology, Inc. November 2008.

ff f d h d f l


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Efficacy of Hand Hygiene Methods for Removal

of C. difficileContamination from Hands

*Different from AHR (P


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Healthcare Personnel: Hand Hygiene

C. difficile spores generally resistant tobactericidal effects of alcohol

Clinical correlation of CDI and alcohol-based

disinfectants? Several studies have failed to demonstrate an

increase in CDI rates with alcohol-based hand

hygiene

No studies have found a decrease in CDI rates withsoap and water

1. Gordin FM, et al. Infect Control Hosp Epidemiol. 2005;26:650-653.

2. Boyce JM, et al. Infect Control Hosp Epidemiol. 2006;27:479-483.

3. Knight N, et al.Am J Infect Control 2010;38:523-528.

4. Vernaz N, et al. J Antimicrob Chemother. 2008; 62:601-607.5. Kaier K, et al. Infect Control Hosp Epidemiol. 2009;30:346-353.


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Minimize Transmission Among Healthcare

Personnel: Contact Precautions

Patients with CDI placed in private rooms

when possible

Full barrier precautions (gown and gloves) forcontact with CDI patient

Use of dedicated patient care items and

equipment

1. Dubberke ER, et al. Infect Control Hosp Epidemiol. 2008;29:S81-S92.2. Cohen SH, et al. Infect Control Hosp Epidemiol.2010;31(5):431-455.



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Healthcare Personnel: Use of Gloves

Four wards randomized

Intervention

Education: gloves when

handling body substances(stool)

Gloves placed at bedside

Reduction in CDI and

colonization on glovewards

P = 0.015

Johnson S, et al.Am J Med. 1990;88:137-140.

Mi i i T i i f


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Minimize Transmission from

Environment: Disinfection

Use of sodium hypochlorite (at least 5,000 ppmavailable chlorine) for environmental contamination,during outbreak areas

Inconsistent efficacy in endemic settings

Areas in question:

Concentration of bleach? [Available chlorine: 5,000 ppm(1:10), 1,000 ppm, or 500ppm]

Where to clean? [CDI rooms only, all rooms, entire ward]

How frequent? [Daily or upon discharge]

How to implement? [Mix fresh daily, premixed, orprepackaged wipes; wipe or spray]

Perez. J, et al. Am J Infect Control. 2005;33:320-325.


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R d Ri k f CDI A i i i


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Reduce Risk of CDI Acquisition:

Antimicrobial Stewardship

Reduce use of high

risk antimicrobials

Reduce unnecessary

antimicrobial use Effective in outbreak

and non-outbreak

settings

1. Valiquette L. Clin Infect Dis. 2007;45:S112-121; with permission.2. Fowler S.J Antimicrob Chemother. 2007;59:990-995.


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CDI: Future Direction

Optimal diagnostic algorithm for CDI

Prompt recognition of severe CDI

Validation of risk-stratified treatment for CDI Expanding armamentarium for CDI (both

antibiotic and non-antibiotic approaches)

Successful implementation of CDI bundle ofinfection control measures

clostridium difficile.ppt

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