Transcript Antimicrobial Stewardship: An Important Consideration for

ANTIMICROBIAL STEWARDSHIP:
A CONCERN FOR ALL PRACTITIONERS
David J. Feola, Pharm.D., Ph.D., BCPS
Assistant Professor
University of Kentucky College of Pharmacy
Modern Healthcare, August 7, 2006, page 36 – Protesting infections from MRSA
Hospital Acquired Infections:
Pennsylvania 2007
 Patients without infection
 Mortality = 2.0%
 Length of stay = 4.7 days
 Average Charge = $37,943
 Patients with hospital-acquired infection
 Mortality = 12.2%
 Length of stay = 19.7 days
 Average Charge = $191,872
PA Health Care Cost Containment
Council, November 2008
Learning Objectives
 1. Summarize the impact of antimicrobial resistance on
clinical and economic outcomes in various patient
populations.
 2. Summarize the goals of antimicrobial stewardship
programs in health-systems and the role of health care
practitioners in such programs.
 3. Explain two core strategies essential for the
implementation of antimicrobial stewardship initiatives.
Presentation Overview
 Why antimicrobial management is essential
 What is antimicrobial stewardship
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IDSA Guidelines: Definition
The Antimicrobial Management Team
 How to implement/role of practitioners
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Recommendations
The University of Kentucky experience
Why Stewardship is Needed
 Antimicrobial resistance results in
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Increased morbidity/mortality
Increased healthcare costs
 Practices in antimicrobial use often inadequate, not
routinely implemented
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Up to 50% antimicrobial prescribing inappropriate
Causal relationship between antimicrobial use and
emergence of resistance
A Disturbing Trend
Sulfa, BL, AG,
Chloramphenicol
TCN, MAC, Vanc,
RIF, FQ, TMP
No new classes.
Modification of existing agents.
LZD, CBP; DAL;
DAP, New Entities
Limited
TIG
PCN-resistant S. aureus
MRSA
VRE
VISA in 7 states
MDR Pseudomonas and Acinetobacter, metallo-beta-lactamases, carbapenemases
LZD-R S. aureus
VRSA
Half of US and Japanese companies END
drug discovery
1930
1940
1950
1960
1970
1980
1990
2000
2010
The Critical Balance
Importance of appropriate
empiric therapy
Mortality increases
when initial therapy
is inappropriate
Effect of broad-spectrum
therapy on resistance
Resistance increases
when broad-spectrum
agents are needed;
Resistance has a
negative impact on
outcomes
“Collateral damage”
Appropriate Initial Therapy Affects Outcomes
Effect of broad-spectrum
therapy on resistance
Importance of appropriate
empiric therapy
*Difference in mortality not significant.
LOS significantly increased
Antimicrobial Use and Resistance
 Changes in use parallel changes in resistance
 Resistance higher in healthcare-associated infections
 Patients with resistant infections more likely to have
received prior antimicrobials
 Hospital areas of highest resistance associated with
highest antimicrobial use
 Increased duration of therapy increase likeliness of
colonization with resistant organisms
Shales DM et al. CID 1997;25:584-99.
ESBL Production and Outcomes
 Non-urinary tract isolates of
Importance of appropriate
empiric therapy
Klebsiella, E. coli
 Length of stay

21 days vs. 11 days (P=0.006)
Effect of broad-spectrum
therapy on resistance
and outcomes
 Clinical success
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48% vs. 86% (P=0.027)
Lee, et al. Inf Cont Hosp Epi 2006;27:1226-32
MRSA and Outcomes
 MRSA vs. MSSA bacteremia
Clinical Failure:
59.6% vs. 33% (P<0.001)
 Length of Stay (infectionrelated):
20.1 vs. 13.7 days (P<0.001)
 Mortality (infection-related):
30.6% vs. 15.3% (P=0.001)
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Importance of appropriate
empiric therapy
Effect of broad-spectrum
therapy on resistance
and outcomes
Lodise T and McKinnon P. Diag Microbiol Inf Dis 2005;52.
VRE and Outcomes
 VRE bacteremia
Decreased survival:
24% vs. 59%
 Length of Stay:
34.8 vs. 16.7 days
 Attributable cost: $27,190
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Importance of appropriate
empiric therapy
Effect of broad-spectrum
therapy on resistance
and outcomes
 VRE bloodstream meta-analysis
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Mortality increase: 30%
Stoser V et al. Arch Int Med 1998;158:522-7
DiazGranados CA et al. CID 2005;41:327-33.
Salgado CD et al. Inf Contr Hosp Epid 2003;24:690-8.
P. aeruginosa Resistance
35
Percent Resistance
30
25
Imipenem
Ceftazidime
Cefepime
Pip/Tazo
Ciproflox
20
15
10
5
0
1993 1994 1995 1996 1997 1998 1999 2000 2001 2002
Obritsch MD, et al. Antimicrob Agents Chemother. 2004;48:4606-4610
Correlation: Use and Resistance
Lepper PM et al. Antimicrob Agents Chemother 2002;46:2920-5.
Fluoroquinolones
 Ciprofloxacin—selection of resistant isolates when
appropriate pharmacodynamic parameters are not
met (AUC/MIC)
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Pseudomonas aeruginosa (All fluoroquinolones)
Methicillin-susceptible Staph aureus
Streptococcus pneumoniae
Garcia-Rey C et al. Clin Microbial Infect 2006;12:55-66
Jacobi GA. Clin Infec Dis 2005;41:S120-6
Cook PP et al. J Hosp Infect 2006:54:341-58.
Pseudomonas aeruginosa
Ciprofloxacin Resistance Trends (1989-1999)
Source: The Surveillance Network (TSN), Focus Technologies
And for 2003, NNIS Survey. AJIC 2003
rd
3
Generation Cephalosporins
 Cause/associated with several different problems in
the hospital (oximinocephalosporins)
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Extended-spectrum beta-lactamases
Selection of stably derepressed isolates in SPACE
bacteria
Selection of vancomycin-resistant enterococcus –
particularly E. faecium
Contribution to MRSA
Increased cases of Clostridium difficile associated
diarrhea/colitis
Dancer SJ. J Antimcirobial Chemother 2001; 48: 463-478
Carbapenems: Emerging Resistance
 Meropenem and P. aeruginosa
 Up-regulation of MexA-MexB-Oprm (efflux pump)
 Loss of the OprD protein (porin channel)
 Both mutations needed for resistance development
 MIC 0.12–0.5 µg/ml (before mutation)
 MIC 2-4 µg/ml (with one mutation)
 MIC >8 µg/ml (with both mutations)
Livermore D. JAC 2001; 47: 247-250
Perilous Cycle: KPC Example
Resistant Pathogen
ESBL-producing E. coli,
K. pneumo, SPACE
Infection
Unknown pathogen
ESBL-producing
bacteria
KPC
KPC-producing
infection
Antimicrobial
Resistance
Antimicrobial Use
Oximinocephalosporins
ESBL production
Carbapenemase development
Carbapenems
?????
Economic Impact of Resistance
 S. aureus bacteremia
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Methicillin resistance: 100% greater cost of therapy
 Klebsiella and E. coli infections
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ESBL production: 66% greater cost of therapy
 Pseudomonas aeruginosa infections
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Imipenem resistance: 68% greater cost of therapy
Lodise T and McKinnon P. Diag Microbiol Inf Dis 2005;52.
Lee, et al. Inf Cont Hosp Epi 2006;27:1226-32.
Lautenbach, et al. Inf Cont Hosp Epi 2006;27:893-90.
Definition: Antimicrobial Stewardship
 Infection control plus antimicrobial management
 Appropriate antimicrobial selection, dosing, route,
and duration
 System selection of antimicrobials that cause the
least collateral damage
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MRSA
ESBLs
Clostridium difficille
Stable derepression
Metallo-beta-lactamases and other carbapenemases
VRE
Guideline Resources
 IDSA and SHEA
Guidelines for Developing an Institutional Program to Enhance
Antimicrobial Stewardship
 Dellit TH et al. CID 2007;44:159-77
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 Centers for Disease Control
Management of Multidrug-Resistant Organisms in Healthcare
Settings
 http://www.cdc.gov/ncidod/dhqp/pdf/ar/mdroGuideline2006.pdf
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ASM and SHEA
Antimicrobial Resistance Prevention Initiative—An Update
 Moellering RC et al. Am J of Inf Contr 2007;35:S1-23
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Role of Infection Control
 Infection control trumps everything else
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Hand hygiene – must have hand washing police
Barrier precautions
 Devotion to all aspects of strict infection control
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Nursing staff
Medical staff
Medical staff leadership
Infection Control – is it cost effective?
Infection
VAP
Bacteremia
Surgical Site infection
Urinary Tract Infection
Cost Savings
$25,072
$23,242
$10,443
$ 758
Anderson, et al. Infect Control Hosp Epidem
2007;28:767-73
Goals of Antimicrobial Stewardship
 Primary goal
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Optimize clinical outcome/minimize unintended
consequences of antimicrobial use
Unintended consequences:
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Toxicity
Selection of pathogenic organisms
Emergence of resistant pathogens
 Secondary goal
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Reduce healthcare costs without adversely impacting quality
of care
Core Members of the Team
 Infectious disease physician (Director or Co-director)
 Clinical pharmacist with infectious disease training
(Co-director or core member)
 Other members of the team
 Microbiologist
 Information system specialist
 Infection control professional
 Hospital epidemiologist
IDSA Grading System for Ranking Recommendations in
Clinical Guidelines
Category, Grade
Definition
Strength of recommendation
A
Good evidence to support
B
Moderate evidence to support
C
Poor evidence to support
Quality of evidence
I
≥ 1 randomized, controlled trials
II
≥ 1 clinical trial unrandomized, cohort or casecontrolled studies, dramatic results from
uncontolled experiments
III
Opinion of experts, clinical experience,
descriptive studies
Kish MA et al. CID 2001; 32: 851 - 4
Active Core Strategies
 Prospective audit with intervention and feedback to
reduce inappropriate antimicrobial use (A-I)
 Formulary restriction and pre-authorization leading
to reductions in antimicrobial use and cost (A-II)
NOTE – neither of these strategies
are mutually exclusive
Assessments
 Antimicrobial consumption
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Defined daily dose
Cost
Days of treatment
 Antimicrobial adverse events
 Resistance patterns/development
 Intervention monitoring
Patel D et al. Exp Rev Anti Infect Ther 2008; 6:209-22
Assessments
 Clinical outcomes measurements
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Antimicrobial appropriate
Cure vs. failure
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Clinical
Microbiologic
Superinfections
Reinfection
Resistance development
Fishman N. Am J Inf Contr 2006;34:S55-63
Elements for Consideration and Prioritization
 Parenteral to oral conversion (A-I)
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When the patient’s condition allows
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Decrease length of stay
Decrease healthcare costs
Development of clinical criteria and guidelines allowing
conversion to use of oral agents (A-III)
Elements for Consideration and Prioritization
 Streamlining or de-escalation therapy (A-II)
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Based on culture results and elimination of redundant
therapy
Decreases antimicrobial exposure and cost
 Dose optimization (A-II)
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Based on PK/PD parameters and includes patient
characteristics, causative organism, site of infection, in
addition to PK/PD characteristics of the drug
Elements for Consideration and Prioritization
 Educational programs, active intervention (A-III, B-II)
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Provides foundation of knowledge
 Guidelines and clinical pathways – seek multi-
disciplinary involvement and approval (A-I)
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Incorporate local antimicrobial resistance patterns (A-I)
Provide education and feedback to practitioners (A-III)
Elements for Consideration and Prioritization
 Antimicrobial order forms (B-II)
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Shown to be effective component of the program and can
facilitate implementation into practice
 Combination therapy
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Insufficient data for routine use (C-II)
Has a role to increase coverage in empiric therapy in
patients at risk for multi-drug resistant pathogens
 Antimicrobial cycling – is not recommended because
of insufficient data (no ranking)
Research Priorities/Future Directions
 Antimicrobial Cycling
 Validation of mathematical models of resistance
 Long-term impact of formulary restrictions
 Focusing interventions on “collateral damage issues”
 Development of more rapid susceptibility tests
 Bad bugs/no drugs – stimulate research
 Counteract inappropriate detailing
Critical Success Factors Identified
 Collegial and educational relationship
 Daily review of antimicrobial orders by a consistent
accountable team
 Support of hospital/medical leadership
 FTE’s dedicated to program (Pharm.D. and MD)
 Development of criteria and guidelines for anti-
infective use
 Formulary restriction
 Education of prescribers to insure compliance
STAAR
 The Strategies to Address Antimicrobial Resistance Act
 Develop an Office of Antimicrobial Resistance within DHHS
 Coordinate a plan for addressing the problem of antimicrobial
resistance
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Create Public Health Advisory Board
Create Antimicrobial Resistance Research and Strategic Plan
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Collection of antimicrobial drug utilization data in humans and animals
Development of a clinical research and public health network
Award grants
 Endorsed by SIDP, IDSA, SHEA, PIDS, AMA, APHA, APIC, NFID,
APUA, and ACP
The University of Kentucky Experience:
Antimicrobial Stewardship 1998-2008
 Control prescribing
Vancomycin
 Reduce 3rd generation cephalosporin use
 Select a single fluoroquinolone (not ciprofloxacin)
 Select a single carbapenem
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 Antimicrobial Management Team
Physician , Pharmacist hired (2001)
 Data collection
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 Pathways for empirical antimicrobial use
 ICU specific antibiograms
 Minimize the use of TPN
Martin, et al. AJHP 2005; 62: 732 - 738
Prevalence of MRSA
University of Kentucky Hospital
AMT program begins
Antibiotic Cost/Patient Day
University Hospital Consortium: Top 7
Institution
Cost/Patient Day
Yale New Haven*
University of Kentucky*
Northeast UHC Hospital*
10.75
11.25
11.33
Southeast UHC Hospital
12.06
UC Davis*
Northeast UHC Hospital*
12.33
15.65
Northeast UHC Hospital*
15.69
* Active Antimicrobial Team – ID Physician and Pharmacist
AMT versus No AMT
 UHC antibiotic cost/patient day
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No antimicrobial management team - $19.80
With antimicrobial management team - $12.83
 $19.80 - $12.83 = $6.97/patient day
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UKMC in 2004 had 114,983 patient days
Est. cost savings = $801,438/year
Antimicrobial Costs at UK
$8,188,456
$1,793,723
UKMC: Current Challenges
 Linezolid prescribing
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No data proving better than vancomycin
Multinational trial in progress
 Acinetobacter
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Clonal outbreak
Back to baseline—rolling ICU shutdown
 MRSA
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Rates increasing
CA-MRSA responsible
Where to Begin
 Chief of ID, Director of Pharmacy
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Develop initial budget proposal
Present to hospital administration
Include financial and microbiology goals
 Form Antimicrobial Subcommittee to P&T
 Hire physician and pharmacist
 Develop practice guidelines/pathways
 Buy in and implement
Summary and Conclusions
 Antimicrobial Stewardship programs show great
promise and offer new opportunities for patient care
and cost impact
 Recommendation by both IDSA/ASHP and the CDC
offer firm foundations to obtain support and funding
for antimicrobial stewardship programs
 Huge opportunity for advancement of clinical
pharmacy practice