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Purchasing Power for Healthcare Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust Purchasing Group Gita Wasan Patel, Pharm D Clinical Pharmacy Coordinator Medical Center of Plano

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Page 1: Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust

Purchasing Power for HealthcarePurchasing Power for Healthcare

Institutional Approaches to Antimicrobial Stewardship

John Theobald, Pharm D

Director of Clinical Pharmacy Services

HealthTrust Purchasing Group

Gita Wasan Patel, Pharm D

Clinical Pharmacy Coordinator

Medical Center of Plano

Page 2: Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust

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Objectives

• Describe the rationale for the development of antimicrobial stewardship programs

• Provide core strategies to assist in the development and implementation of antimicrobial stewardship programs

• Explore the ways that antimicrobial stewardship interventions can be tailored to improve outcomes

Page 3: Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust

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Rationale for Antimicrobial Stewardship Programs

Page 4: Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust

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High Rates of NosocomialInfections in the United States

Variable

No. of admissions (millions)

No. of patient days (millions)

Average length of stay (days)

No. of inpatient surgical procedures (millions)

No. of nosocomial infections (millions)

Incidence of nosocomial infections (no. per 1000 patient-days)

1975

37.7

299.0

7.9

18.3

2.1

7.2

1995

35.9

190.0

5.3

13.3

1.9

9.8

Year

Nosocomial Infections in the United States

Adapted with permission from Burke JP. N Engl J Med. 2003;348:651-656.

Page 5: Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust

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Changing Resistance/Decreased Susceptibilities Over Time

Ceftazidime- and Imipenem-Resistant Acinetobacter (NNIS 1986-2003)

1986 1988 1990 1992 1994 1996 1998 2000

Year

20020

1020304050607080

Imipenem

Ceftazidime

% o

f Res

ista

nt Is

olat

es

2004

Resistance to Third-Generation Cephalosporins AmongKlebsiella Pneumoniae and Escherichia Coli (NNIS 1986-2003)

1986 1988 1990 1992 1994 1996 1998 2000

Year

20020

5

10

15

20

25

E Coli

K Pneumoniae

% o

f Res

ista

nt Is

olat

es

2004

NNIS = National Nosocomial Infections Surveillance System.Results of Cochran-Armitage 2 tests for trend were significant for both organisms and for both drugs (P<.001).

Adapted with permission from Gaynes R et al. Clin Infect Dis. 2005;41:848-854.

Page 6: Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust

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Increasing Resistance: Gram-Positive Pathogens Also a Problem

Note: Data refer to infections in intensive care unit (ICU) patients only.

Sources: VRE and MRSA data, 1998-2000, 2002-2003 (CDC 1999; CDC 2000; CDC 2001; CDC 2003; CDC 2004); data for 2001 are for the average of 2000 and 2002 data. MRSA data from 1987-1997 are estimated from Lawy 1998. VRE data for 1989 and 1993 are from CDC 1993. VRE data for 1990-1992 and 1994-1997 are interpolated based on geometric mean.Available at: http://www.extendingthecure.org/downloads/ETC_FULL.pdf. Accessed April 30, 2007.

70

60

50

40

30

20

10

01987 1989 1991 1993 1995 1997 1999 2001 2003

Proportion of Methicillin-Resistant Staphylococcus Aureus (MRSA) and Vancomycin-Resistant Enterococcal (VRE) Infections Is

Increasing (1987-2003)

MRSA

VRE

% o

f R

esis

tan

t Is

ola

tes

Page 7: Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust

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1. Stein GE. Pharmacotherapy. 2005;25:44S-54S.2. South M et al. Med J Aust. 2003;178:207-209.3. McGowan JE Jr. Clin Infect Dis. 2004;38:939-942.4. Levy SB. J Antimicrob Chemother. 2002;49:25-30.

Factors Encouraging the Development of Antimicrobial-Resistant Pathogens

• High severity of illness in patients once hospitalized1

• Inappropriate antibiotic use2

– Prolonged use or inadequate antimicrobial exposure

• Institutional factors3

• Agricultural use of antimicrobials4

Page 8: Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust

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Increased Antibiotic Use Drives Resistance

Increasing fluoroquinolone resistance in Gram-negative bacilli correlates with increased fluoroquinolone use in patients from 43 states (numbers of isolates from 1994-2000=35,790). The 1990 to 1993 data points represent composite susceptibility and quinolone use for those 4 years.

Adapted with permission from Neuhauser MM et al. JAMA. 2003;289:885-888.

35

0

5

10

15

20

25

30

250

0

200

150

100

50% o

f S

trai

ns

Res

ista

nt

to C

ipro

flo

xaci

n Qu

ino

lon

e Use

(kg x 10

3)

1990-1993 1994 1995 1996 1997 1998 1999 2000

PseudomonasGram-NegativeFluoroquinolone use

Page 9: Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust

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Causal Associations Between Antimicrobial Use and Emergence of Antimicrobial Resistance

• Changes in antimicrobial use are paralleled by changes in prevalence of resistance

• Antimicrobial resistance is more prevalent in health care–associated infections compared with community-acquired infections

• Patients with health care–associated infections caused by resistant strains are more likely than control patients to have prior antibiotic exposure

• Areas within hospitals with the highest rates of antimicrobial resistance also have the highest rates of antimicrobial use

• Increased length of exposure to antimicrobials increases the likelihood of colonization with resistant organisms

Dellit TH et al. Clin Infect Dis. 2007;44:159-177.

Page 10: Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust

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Mortality Rates Correlate With Presence of Multidrug-Resistant Organisms

• Association between development of antimicrobial resistance in Staphylococcus aureus, enterococci, and Gram-negative bacilli and mortality1

• Pseudomonas aeruginosa is increasingly resistant to fluoroquinolones, with a number of consequences, including infection-related mortality2

• Enterococcal infections have been associated with mortality ratesexceeding 30%3

• A meta-analysis of published studies found that patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia had an increased risk of mortality compared with patients who had methicillin-sensitive Staphylococcus aureus (MSSA) bacteremia (OR = 1.93; P<.001)4

1. Cosgrove SE. Clin Infect Dis. 2006;42(suppl 2):S82-S89.2. McGowan JE Jr. Am J Infect Control. 2006;34:S29-S37.3. Lautenbach E et al. Clin Infect Dis. 2003;36:440-446.4. Cosgrove SE et al. Clin Infect Dis. 2003;36:53-59.

Page 11: Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust

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FDA = Food and Drug Administration.

Available at: http://www.extendingthecure.org/downloads/ETC_FULL.pdf. Accessed April 30, 2007.Source: 1983-2002 (Spellberg et al. 2004), 2003-2005 (Bosso 2005).

Fewer Antibiotics to Address Increased Resistance

16

14

1086420

1983-1987

12

New

An

tim

icro

bia

ls A

pp

rove

d

1988-1992 1993-1997 1998-2002 2003-2005

Antibacterial Agents Approved by FDA, 1983-2005

Fewer New Antibiotics Are Being Brought to Market as More Companies Leave the Anti-Infectives Business

Page 12: Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust

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Economic Impact of Increased Resistance

• During 2004, it was estimated that at least $20 billion was billed nationally to Medicare for hospital-acquired infections1

• Many were resistant to one or more classes of antibiotics

• Increased cost can come from periodic switches to newer, more expensive antibiotics1

• Costs have increased with increased prophylactic use of antibiotics, and their use in immunocompromised patients1

• Direct excess medical cost due to resistant infections comprises only a small portion of the potential cost to society2

1. Available at: http://www.extendingthecure.org/downloads/ETC_FULL.pdf. Accessed April 30, 2007.2. Scott D II et al. In: Owen RC Jr et al, eds. Antibiotic Optimization: Concepts and Strategies in Clinical Practice. Marcel Dekker Publishers. 2005.

Page 13: Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust

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Other Economic Impacts of Increased Resistance

Medicare payments adjusted for hospital-acquired conditions, including infections

Medicare will pay a lower rate for hospital-acquired infections

Adapted from US Department of Health and Human Services. 42 CFR Parts 411, 412, 413, and 489 Medicare Program; Proposed Changes to the Hospital Inpatient Prospective Payment Systems and Fiscal Year 2008 Rates; Proposed Rule. Effective October 1, 2007. Available at: http://www.asm.org/ASM/files/LeftMarginHeaderList/DOWNLOADFILENAME/000000002404/CMSProposedRuleHAQ.pdf. Accessed June 28, 2007.

Proposed Changes Effective in 2007

Proposed Changes Open for Comment in 2008

1. Catheter-associated urinary tract infections

2. Pressure ulcers (decubitus ulcers)

3. Serious preventable event—object leftin surgery

4. Serious preventable event—air embolism

5. Serious preventable event—blood incompatibility

6. Staphylococcus aureus septicernia

7. Ventilator-associated pneumonia (VAP)/pneumonia

8. Vascular catheter–associated infections

9. Clostridium difficile–associated disease (CDAD)

10. Methicillin-resistant staphylococcusaureus (MRSA)

11. Surgical site infections

12. Serious preventable event—wrong surgery

13. Falls

Page 14: Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust

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Antimicrobial Stewardship Programs

Page 15: Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust

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Antimicrobial Stewardship

The optimal selection, dose, and duration of an antimicrobial that results in the best clinical outcome for the treatment of infection, with minimal toxicity to the patient and minimal impact on subsequent development of resistance.

Owens RC, Ambrose PG. Diagn Microbiol Infect Dis. 2007;57(suppl 3):S77-S83.

Page 16: Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust

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Antimicrobial Stewardship: Overview

• Updated guidelines for developing programs to enhance antimicrobial stewardship published in 2007

• IDSA/SHEA*consensus guidelines endorsed by• American Academy of Pediatrics• American Society of Health-System Pharmacists• Infectious Diseases Society for Obstetrics and Gynecology• Pediatric Infectious Diseases Society• Society for Hospital Medicine• Society of Infectious Diseases Pharmacists

• Primary goal• Optimize clinical outcomes while minimizing unintended consequences

of antibiotic use– Toxicity– Selection of pathogenic bacteria (eg, Clostridium difficile)– Emerging resistance

• Secondary goal• Reduce health care cost without compromising quality of care

*Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA).

Dellit TH et al. Clin Infect Dis. 2007;44:159-177.

Page 17: Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust

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Antimicrobial Stewardship Teams

ASP = Antimicrobial Stewardship Program, ID = infectious disease, P&T = Pharmacy and Therapeutics.Dellit TH et al. Clin Infect Dis. 2007;44:159-177 and Fishman N. Am J Med. 2006;119:S53-S61.

Multidisciplinary Team Approach to Optimizing Clinical Outcomes

HospitalHospitalEpidemiologistEpidemiologist

HospitalHospitalEpidemiologistEpidemiologist

InfectionInfectionControlControl

InfectionInfectionControlControl

MedicalMedicalInformationInformation

SystemsSystems

MedicalMedicalInformationInformation

SystemsSystems

MicrobiologyMicrobiologyLaboratoryLaboratory

MicrobiologyMicrobiologyLaboratoryLaboratory

InfectiousInfectiousDiseases Diseases DivisionDivision

InfectiousInfectiousDiseases Diseases DivisionDivision

Director,Director,OutcomesOutcomesResearchResearch

Director,Director,OutcomesOutcomesResearchResearch

Chairman,Chairman,P&TP&T

CommitteeCommittee

Chairman,Chairman,P&TP&T

CommitteeCommittee

Partners in Partners in OptimizingOptimizing

Antimicrobial Use SuchAntimicrobial Use Suchas Pulmonologistsas Pulmonologists

and Surgeonsand Surgeons

Partners in Partners in OptimizingOptimizing

Antimicrobial Use SuchAntimicrobial Use Suchas Pulmonologistsas Pulmonologists

and Surgeonsand Surgeons

HospitalHospitalAdministratorAdministrator

HospitalHospitalAdministratorAdministrator

ASP DirectorsASP Directors•• ID PharmD ID PharmD•• ID Physician ID Physician

ClinicalClinicalPharmacyPharmacySpecialistsSpecialists

ClinicalClinicalPharmacyPharmacySpecialistsSpecialists

DecentralizedDecentralizedPharmacyPharmacySpecialistSpecialist

DecentralizedDecentralizedPharmacyPharmacySpecialistSpecialist

Page 18: Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust

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Core Strategies For Antimicrobial Stewardship

• Prospective audit with intervention and feedback

• Formulary restriction/preauthorization

Dellit TH et al. Clin Infect Dis. 2007;44:159-177 and Fishman N. Am J Med. 2006;119:S53-S61.

Page 19: Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust

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Core Strategy 1: Prospective Audit With Intervention and Feedback

• Involves concurrent review of patients receiving antimicrobials

• Inappropriate orders initiate interaction between antimicrobial team members and the prescriber1

• Goal is to enhance antimicrobial stewardship (optimize selection, dose, duration, route)

• Advantages

• Avoids loss of autonomy for prescribers1

• Creates incentives for physicians to improve performance2

• Disadvantages

• Compliance is voluntary1

• Less effective unless it distinguishes between appropriate and inappropriate prescribing2

1. MacDougall C, Polk RE. Clin Microbiol Rev. 2005;18:638-656.2. Available at: http://www.extendingthecure.org/downloads/ETC_FULL.pdf. Accessed April 30, 2007.

Page 20: Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust

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Jan 0

3

July 0

2

Jan 0

2

July 0

1

Jan 0

1

July 0

0

Jan 0

0

Sept 9

9

Vertical dashed line = program begun.

Adapted with permission from Fowler S et al. J Antimicrob Chemother. 2007;59:990-995.

Prospective Audit With Intervention and Feedback: Example 1

02468

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Page 21: Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust

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Prospective Audit With Intervention and Feedback: Example 2

*Parental antibiotic use, cost per 1000 patient-days, and Medicare Case Mix Index trends following implementation of an antibiotic management program.

Adapted with permission from Carling P et al. Infect Control Hosp Epidemiol. 2003;24:699-706.

Parenteral Antibiotic Use, Cost Decreased*

Rates of Resistant Enterobacteriaceae Infections Decreased

0

20

10

-10

-20

-30

-401991 1992 1993 1994 1995 1996 1997 1998

Cost

Use

Illness Severity

% o

f P

rein

terv

enti

on

Ob

serv

atio

ns

1989 1990 1991 1992 1993 1995 1998

4

6

5

3

2

11994 1996 1997

Cas

es p

er 1

000

Pat

ien

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ays

Page 22: Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust

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Core Strategy 2: Formulary Restriction/Preauthorization

• Effective method to control antibiotic use and cost; conflicting results on decreasing antimicrobial resistance1

• Advantages

• Provides the most direct control over antimicrobial use2

• Disadvantages

• Prescribers may feel loss of autonomy2

• Team members must have contingency plans foroff-hour approvals1

• May discourage appropriate antibiotic use3

– May delay receiving appropriate therapy initially

1. Dellit TH et al. Clin Infect Dis. 2007;44:159-177.2. MacDougall C, Polk RE. Clin Microbiol Rev. 2005;18:638-656.3. Available at: http://www.extendingthecure.org/downloads/ETC_FULL.pdf. Accessed April 30, 2007.

Page 23: Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust

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Formulary Restriction: Example

• After initiation of formulary restriction

• Prescribing of third-generation cephalosporins decreased

• Prescribing of cefepime remained relatively stable

• Rates of ceftazidime-resistant Klebsiella pneumoniae decreased

Originally published in Martin C et al. Am J Health Syst Pharm. 2005;62:732-738. ©2005, American Society ofHealth-System Pharmacists, Inc. All rights reserved. Reprinted with permission. (R0727).

250

01998

Gra

ms

per

100

0 P

atie

nt

Day

s

200

150

100

50

12

0

8

10

6

4

2

1999 2001 2002

% C

eftazidim

e-Resistan

tK

Pn

eum

on

iae Iso

lates

2000

Year

Third-Generation Cephalosporins

Cefepime

Ceftazidime-Resistant K Pneumoniae

Page 24: Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust

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Supplemental Strategies ForAntimicrobial Stewardship

• Supplemental strategies

• Clinical pathways and guidelines

• Streamlining/de-escalation

• Dose optimization

• Combination therapy

• Switch from parenteral to oral therapy

• Renal dose adjustments

• Education

• Antimicrobial order forms

• Antibiotic cycling/switch

• Other recommendations

• Working closely with microbiologists

• Physician order entry

Dellit TH et al. Clin Infect Dis. 2007;44:159-177.

Page 25: Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust

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Clinical Pathways and Guidelines

• Should be developed with a multidisciplinary team

• Advantages

• May alter prescribing behavior

• Maintains prescriber autonomy

• Disadvantages

• Must have active intervention (participant is notified when not adhering to clinical pathways and guidelines) to be maximally effective

MacDougall C, Polk RE. Clin Microbiol Rev. 2005;18:638-656.

Page 26: Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust

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Clinical Pathways and Guidelines: Example

*Includes only those cases in which the appropriate antibiotic was chosen.

= insufficient data.

South M et al. Med J Austr. 2003;178:207-209.

Appropriate CHOICEof Antibiotic

Appropriate DOSEof Antibiotic*

66

100

80

50

40

30

20

10

0Pre-Card

60

% o

f C

ases

70

90

Post-Card Pre-Card Post-Card

77

19

71

92

78

— —

48

30

81

50

P=.7

P=.028

P<.001P=.001

P<.11

Study in Australian pediatric hospital

Physicians received antibiotic guidelines on cards clipped to ID badges

Appropriate choice and dose of antibiotic was evaluated over two 6-month periods

Tonsillitis Pneumonia Orbital/Periorbital Cellulitis

Page 27: Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust

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Streamlining/De-escalation: Therapy

Serious Nosocomial Infection SuspectedSerious Nosocomial Infection Suspected

Begin Empirical Antibiotic (Abx) Treatment With a Begin Empirical Antibiotic (Abx) Treatment With a Combination of Agents Targeting the Most Common Combination of Agents Targeting the Most Common

Pathogens Based on Local DataPathogens Based on Local Data

Pathogen Identified?Pathogen Identified?

Reassess After Appropriate Time FrameReassess After Appropriate Time Frame

Continue Initial TreatmentContinue Initial Treatment

Significant Clinical Improvement After Significant Clinical Improvement After 48-96 Hours of Antibacterial Treatment?48-96 Hours of Antibacterial Treatment?

Deescalate Antibacterials Based on Deescalate Antibacterials Based on Results of Clinical Microbiology DataResults of Clinical Microbiology Data

Search for Superinfection, Abscess Search for Superinfection, Abscess Formation, Noninfectious Cause of Formation, Noninfectious Cause of

Symptoms, Inadequate Tissue Symptoms, Inadequate Tissue Penetration of AbxPenetration of Abx

Discontinue Abx After 7-14 Days Based Discontinue Abx After 7-14 Days Based on Site of Infection and Clinical Responseon Site of Infection and Clinical Response

No

Yes No

Yes

Adapted with permission from Kollef MH. Drugs. 2003;63:2157-2168.

Page 28: Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust

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Streamlining/De-escalation: Example

• Prospective before-and-after study in an intensive care unit (ICU)

• Implementation of a clinical guideline for administration of adequate initial antimicrobial treatment with subsequent reevaluation for potential de-escalation therapy in patients with VAP

Adapted with permission from Ibrahim EH et al. Crit Care Med. 2001;29:1109-1115.

Outcome

Mortality, no. (%)

ICU length of stay, days

Hospital length of stay, days

Secondary VAP, no. (%)

Before Period(n=50)

21 (42.0)

23.1 ± 17.4

39.3 ± 33.1

12 (24.0)

After Period(n=52)

27 (51.9)

21.7 ± 12.9

34.2 ± 26.2

4 (7.7)

Clinical Outcome Measures

P Value

.102

.987

.379

.030

Page 29: Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust

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Dose Optimization

• Takes several factors into account

• Pharmacokinetic/pharmacodynamic (PK/PD)characteristics of the antibiotic

• Patient characteristics

• Causative organism

• Site of infection

Dellit TH et al. Clin Infect Dis. 2007;44:159-177.

Page 30: Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust

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%T>MIC

Dose Optimization: PK/PD Parameters

AUC = area under the concentration-time curve; Cmax = maximum concentration; MIC = minimum inhibitory concentration; T = time.

Adapted with permission from Rybak MJ. Am J Infect Control. 2006;34(5 suppl 1):S38-S45.

Time

Cmax/MIC

An

tib

ioti

c C

on

cen

trat

ion

AUC/MIC

PK/PD Parameter Applicable Antimicrobial(s)

Cmax/MIC Aminoglycosides

%T>MIC%T>MIC β-LactamsTetracyclineOxazolidinones

AUC/MIC FluoroquinolonesMacrolidesKetolidesCyclopeptides

Cmax

MIC

Page 31: Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust

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Combination Therapy

• Role in certain clinical contexts

– Used for empirical therapy for critically ill patients at risk of infection with multidrug-resistant pathogens to increase breadth of coverage and likelihood of adequate initial therapy

• Insufficient data to recommend routine use to prevent emergence of resistance

Damas P et al. Crit Care. 2006;10:1-7.Dellit TH et al. Clin Infect Dis. 2007;44:159-177.

Page 32: Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust

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Combination Therapy: Example

• Meta-analysis of trials evaluating aminoglycoside/β-lactam combination therapy versus β-lactam monotherapy

• Combination therapy was associated with more superinfections than monotherapy (OR, 0.62; 95% CI, 0.42-0.93)

• Treatment failure was numerically more common for combination therapy than for monotherapy (OR, 0.62; 95% CI, 0.38-1.01)

• No difference in mortality rates between monotherapy and combination therapy groups (OR, 0.70; 95% CI, 0.40-1.25)

Bliziotis IA, Samonis G, Vardakas KZ. Clin Infect Dis. 2005;41:149-158.

Page 33: Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust

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Switch From Parenteral to Oral Therapy

Adapted with permission from Itani KMF et al. Int J Antimicrob Agents. 2005;26:442-448.

Days From Study Medication Start Date

Vancomycin (IV only)

Linezolid (PO, or IV to PO switch)

120

100

80

60

40

20

0 7

% o

f P

atie

nts

Rem

ain

ing

in H

osp

ital

14 21 28 35

P<.01

Page 34: Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust

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Renal Adjustment of Antimicrobials

Evaluating the Patient

• Age

• Body Weight

• Sex

• Dehydration (BUN:SCR ratio greater than 20:1)

• Low muscle mass

• Disease state

• Urine output

• Creatinine Clearance

Page 35: Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust

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Renal Adjustment of Antimicrobials

Assessment of Volume Depletion• Volume depletion can be caused by

-diarrhea, vomiting or diuretics

• Check patient’s BUN:SCr ratio

Normal= 15:1

• If BUN:SCr ratio >20 wait 24 hours and reassess patient

Page 36: Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust

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Creatinine Clearance (CrCl)

• Calculation of Creatinine Clearance can be used to assess renal function

• CrCl calculation is only an estimate of renal function

• Many different methods of calculating estimated CrCl

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Targeted High-use Antimicrobials for Automatic Renal Adjustment

• Cefepime

• Fluconazole

• Levofloxacin

• Piperacillin/Tazobactam

• Imipenem/Cilastatin

• Meropenem

• Automatic adjustment requires physician approved policies and procedures

Page 38: Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust

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Education: Example 1

• Five-year educational campaign to reduce outpatient antimicrobial prescribing introduced in Wisconsin in 1999

• Antimicrobial prescribing rates were compared with Minnesota, a state without a comparable campaign

• Antimicrobial use declined in both states during the study period

• Improved knowledge did not generate greater reductions in Wisconsin

MSA = metropolitan statistical area.Antimicrobial prescribing rate ratios by year and practice location, adjusted for specialty and baseline (1998) prescribing rate. Vertical bars show 95% confidence intervals. Ratio <1 indicates lower antimicrobial prescribing in WI relative to MN.

Adapted with permission from Belongia EA et al. Emerg Infect Dis. 2005;11:912-920.

No Active Intervention

2000 2001 2002 2003 2000 2001 2002 2003

Minneapolis-St. Paul andMilwaukee-Waukesha

MSA

Other Counties in Minnesota

and Wisconsin

0.7

0.8

0.9

1.0

1.1

1.2

1.3

Pre

scri

bin

g R

atio

(W

I : M

N)

Page 39: Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust

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Education: Example 2

• Multitiered campaign to improve rates of appropriate antibiotic use

• Compared the average number of days of unnecessary antibiotic use between the study groups

• Inappropriate antibiotics were discontinued more often in the educational intervention groups (70%) than in the control groups (30%) [no education]

Adapted with permission from Solomon DH et al. Arch Intern Med. 2001;161:1897-1902.

100

90

70

50

30

10

0Target Antibiotics

Inap

pro

pri

ate

An

tib

ioti

cD

isco

nti

nu

atio

n, %

80

60

40

20

Intervention

ControlP=.001

Active Intervention

Page 40: Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust

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Work Closely With the Microbiologist

• Role of microbiologist

• Provides patient-specific culture and susceptibility data to optimize individual antimicrobial management

• Assists infection control efforts in the surveillance of resistant organisms and in the molecular epidemiologic investigation of outbreaks

• Critical role in the timely identification of microbial pathogens and the performance of susceptibility testing

• Responsibilities

– Analyze and present data at least once per year

– Use a sufficient number of isolates to assure accurate data

– Perform and report quantitative and qualitative susceptibility testing

– Conduct group review of data

Dellit TH et al. Clin Infect Dis. 2007;44:159-177.

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Antimicrobial Order Forms

• Can help implement practice guidelines1

PO = orally; qxh = every x hours; IV = intravenously; CVL = central venous catheter.

1. Dellit TH et al. Clin Infect Dis. 2007;44:159-177.2. Bolon MK et al. Pediatr Infect Dis J. 2005;24:1053-1058.

Portion of Antibiotic Order Form Demonstrating How Vancomycin Is Ordered by the Prescriber2

Vancomycin (PO) [$251]125-250 mg/Dose

Vancomycin (IV) [$81]40-60 mg/kg/DAY

PO

IV

12A: Treatment of Clostridium difficile diarrhea after failure of metronidazole or if life threateningq6h

q6hq8hq_h

13A: Suspected pneumococcal meningitis or shunt infection

13B: Serious infections due to β-lactam–resistant Gram-positive organisms

13C: Infections due to Gram-positive organisms in patients with allergy to β-lactam agents

13D:Systemic bacterial endocarditis prophylaxis (see backof form)

13E: Empiric treatment for infection of prosthetic device

13F: Empiric treatment for CVL-related infection with suspicion of Gram-positive organism (eg, cellulitis, positive Gram stain of pus)

1 g

Doseadjustedbased on

levelsand renalfunction

Page 42: Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust

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1. Dellit TH et al. Clin Infect Dis. 2007;44:159-177.2. MacDougall C, Polk RE. Clin Microbiol Rev. 2005;18:638-656.

Antibiotic Cycling/Switch

• Not currently recommended as a routine part of an antimicrobial stewardship program by IDSA guidelines1

• Scheduled removal and substitution of antibiotics (individually or by class) to avoid localized resistance2

• Conflicting evidence on impact2

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1. King WJ et al. BMC Pediatrics. 2007;7:4-10.2. Fischer MA et al. Arch Intern Med. 2003;163:2585-2589.

Local Computer Surveillance andDecision Support

• Can impact antibiotic use1,2

• Can provide benefits to existing antimicrobial stewardship programs

• Key example: physician order entry

• A computer-based system of ordering medication

• Includes interfaces with clinical decision–support systems1

– Provides advice on drug selection, dose, duration

• Based on local surveillance of resistance patterns

Page 44: Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust

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Physician Order Entry: Example

• Reduced antibiotic use• Average defined daily dose of IV anti-infectives

decreased, ranging from 9% to 23%, after initiationof POE1

• 37% relative decrease in antibiotic use as a part of bronchiolitis management after introduction of a clinical evidence module into an existing POE system2

• Increased switch from parenteral to oral formulations1

• Decreased prescription errors3,4

• No increase in mortality rates5

1. Fischer MA et al. Arch Intern Med. 2003;163:2585-2589.2. King WJ et al. BMC Pediatrics. 2007;7:4-10.3. van Gjissel-Wiersma DG et al. Drug Safety. 2005;28:1119-1129.4. Colpaert K et al. Crit Care. 2006;10:1-9.5. Keene A et al. Pediatr Crit Care Med. 2007;8:268-271.

Page 45: Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust

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Evaluating Antimicrobial Stewardship Programs

Page 46: Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust

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Patients Whose Treatment Was Managed By

OutcomeAMT

(n=87)ID Fellows

(n=93)Unadjusted OR

(95% CI) P Value

Appropriate 76 44 7.7 (3.7-16.2) <.001

Cure* 49 35 2.4 (1.3-4.5) .007

Failure 13 26 0.5 (0.2-0.9) .03

Evaluating Stewardship Programs: Example 1—Clinical Outcomes

AMT = antimicrobial management team; ID = infectious disease.

*Ten subjects in each group for whom antimicrobial agents were requested for prophylaxis or in whom no evidence of infection was seen when the request was reviewed were excluded.

Adapted from Gross R et al. Clin Infect Dis. 2001;33:289-295.

Comparing Antimicrobial Management byan AMT vs ID Fellows

Page 47: Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust

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Evaluating Stewardship Programs: Example 2—Financial Outcomes

Adapted with permission from Fraser GL et al. In: Owens RC Jr et al, eds. Antibiotic Optimization: Concepts and Strategies in Clinical Practice. Marcel Dekker; 2005:261-326.

Durable Reduction in Antimicrobial Expenditures Associated With the Antimicrobial Stewardship Program at Maine Medical Center

157,000

152,000

142,000

132,000

122,000

117,000

112,0002001 2002 2003 2004

Fiscal Year

Ave

rag

e M

on

thly

Exp

end

itu

re (

$)

Projected Expenditure With 4.5% Inflation, Assuming Use Had Remained Stable

147,000

137,000

127,000

162,000

140,356

134,743

121,437

113,530

Page 48: Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust

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Pharmacoeconomics of Stewardship Programs

• Ruttimann et. al. studied the effects of a multifaceted antibiotic program at an 80-bed tertiary facility

• Over a 4 year time period, the proportion of patients receiving an antibiotic decreases from 46% to 30% (p<0.0001)

• Cost for antibiotics decreased by 56% and total cost of treatment was reduced by 53%

• In theory, the program cost about $20,000 to develop and $20,000 to maintain but no new positions were created

Page 49: Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust

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Pharmacoeconomics of Stewardship Programs

• Bantar et al also instituted and studied a multidisciplinary antimicrobial program over an 18 month period

• The use of antibiotics decreased significantly and yielded a $913,236 cumulative savings

• Decreasing resistance to ceftriaxone among Proteus mirabilis and Enterobacter cloacae and decreasing resistance to methicillin among S. aureus isolates were also observed

• Cost of the program was not studied

Page 50: Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust

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Pharmacoeconomics of Stewardship Programs

• Theobald et al prospectively examined the economic impact of pharmacist-initiated interventions on antibiotics and found approximately a $60/general medicine patient reduction in antibiotic costs (p<0.01).

• LaRocco et al examined the efficacy of concurrent antimicrobial review program at a 120 bed community hospital. This program resulted in an annualized expenditure reduction of $177,000

Page 51: Purchasing Power for Healthcare Institutional Approaches to Antimicrobial Stewardship John Theobald, Pharm D Director of Clinical Pharmacy Services HealthTrust

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Gra

ms

per

100

0 P

atie

nt

Day

sEvaluating Stewardship Programs:Example 3—Antimicrobial Resistance

Defined Daily Doses per 1000 Patient Days of Third-Generation Cephalosporins (orange bars) and Cefepime (green bars) Purchased Compared With Ceftazidime-Resistant

Klebsiella Pneumoniae Isolates (dashed line)

250

01998

200

150

100

50

12

0

8

10

6

4

2

1999 2001 2002

% K

leb

siel

la p

neu

mo

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e R

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2000

Year

Originally published in Martin C et al. Am J Health Syst Pharm. 2005;62:732-738. ©2005, American Society ofHealth-System Pharmacists, Inc. All rights reserved. Reprinted with permission. (R0727).

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Beyond Antimicrobial Stewardship12 Steps to Prevent Antimicrobial Resistance in Hospitalized Adults

USE ANTIMICROBIALS WISELYUSE ANTIMICROBIALS WISELY 5. Practice antimicrobial control5. Practice antimicrobial control 6. Use local data6. Use local data 7. Treat infection, not contamination 7. Treat infection, not contamination 8. Treat infection, not colonization8. Treat infection, not colonization 9. Know when to say “no” to vanco9. Know when to say “no” to vanco10. Stop treatment when infection10. Stop treatment when infection is cured or unlikely is cured or unlikely

USE ANTIMICROBIALS WISELYUSE ANTIMICROBIALS WISELY 5. Practice antimicrobial control5. Practice antimicrobial control 6. Use local data6. Use local data 7. Treat infection, not contamination 7. Treat infection, not contamination 8. Treat infection, not colonization8. Treat infection, not colonization 9. Know when to say “no” to vanco9. Know when to say “no” to vanco10. Stop treatment when infection10. Stop treatment when infection is cured or unlikely is cured or unlikely

PREVENT INFECTIONPREVENT INFECTION 1. Vaccinate1. Vaccinate 2. Get the catheters out2. Get the catheters out

PREVENT INFECTIONPREVENT INFECTION 1. Vaccinate1. Vaccinate 2. Get the catheters out2. Get the catheters out

DIAGNOSE AND TREATDIAGNOSE AND TREATINFECTION EFFECTIVELYINFECTION EFFECTIVELY 3. Target the pathogen3. Target the pathogen 4. Access the experts4. Access the experts

DIAGNOSE AND TREATDIAGNOSE AND TREATINFECTION EFFECTIVELYINFECTION EFFECTIVELY 3. Target the pathogen3. Target the pathogen 4. Access the experts4. Access the experts

PREVENT TRANSMISSIONPREVENT TRANSMISSION 11. Isolate the pathogen11. Isolate the pathogen 12. Break the chain of contagion12. Break the chain of contagion

PREVENT TRANSMISSIONPREVENT TRANSMISSION 11. Isolate the pathogen11. Isolate the pathogen 12. Break the chain of contagion12. Break the chain of contagion

CDC. Available at: www.cdc.gov/drugresistance/healthcare. Released November 2003.Accessed August 2, 2007.

Prevent InfectionPrevent Infection Diagnose And Treat InfectionDiagnose And Treat Infection

Use Antimicrobials WiselyUse Antimicrobials Wisely

Prevent TransmissionPrevent Transmission