ANTIMICROBIAL STEWARDSHIP:

A CONCERN FOR ALL PRACTITIONERS

David J. Feola, Pharm.D., Ph.D., BCPSAssistant ProfessorUniversity 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 IDSA Guidelines: Definition The Antimicrobial Management Team

How to implement/role of practitioners Recommendations The University of Kentucky experience

Why Stewardship is Needed

Antimicrobial resistance results in Increased morbidity/mortality Increased healthcare costs

Practices in antimicrobial use often inadequate, not routinely implemented Up to 50% antimicrobial prescribing

inappropriate Causal relationship between antimicrobial

use and emergence of resistance

A Disturbing Trend

1930 1940 1950 1960 1970 1980 1990 2000 2010

Sulfa, BL, AG, Chloramphenicol

TCN, MAC, Vanc, RIF, FQ, TMP

No new classes. Modification of existing agents.

LZD, DAP,TIG

CBP; DAL;New Entities

Limited

PCN-resistant S. aureus

MRSA

VRE

VISA in 7 states

VRSA

LZD-R S. aureus

MDR Pseudomonas and Acinetobacter, metallo-beta-lactamases, carbapenemases

Half of US and Japanese companies END drug discovery

The Critical Balance

Importance of appropriate empiric therapy

Effect of broad-spectrum therapy on resistance

Mortality increases when initial therapy is inappropriate

Resistance increases when broad-spectrum

agents are needed; Resistance has a

negative impact on outcomes

“Collateral damage”

Appropriate Initial Therapy Affects Outcomes

*Difference in mortality not significant. LOS significantly increased

Importance of appropriate empiric therapy

Effect of broad-spectrum therapy on resistance

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 Klebsiella, E. coli

Length of stay 21 days vs. 11 days

(P=0.006) Clinical success

48% vs. 86% (P=0.027)

Lee, et al. Inf Cont Hosp Epi 2006;27:1226-32

Effect of broad-spectrum therapy on resistance

and outcomes

Importance of appropriate empiric therapy

MRSA and Outcomes

MRSA vs. MSSA bacteremia Clinical Failure:

59.6% vs. 33% (P<0.001) Length of Stay (infection-

related):20.1 vs. 13.7 days (P<0.001)

Mortality (infection-related):30.6% vs. 15.3% (P=0.001)

Lodise T and McKinnon P. Diag Microbiol Inf Dis 2005;52.

Effect of broad-spectrum therapy on resistance

and outcomes

Importance of appropriate empiric therapy

VRE and Outcomes

VRE bacteremia Decreased survival:

24% vs. 59% Length of Stay:

34.8 vs. 16.7 days Attributable cost: $27,190

VRE bloodstream meta-analysis 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.

Effect of broad-spectrum therapy on resistance

and outcomes

Importance of appropriate empiric therapy

P. aeruginosa Resistance

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.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) Pseudomonas aeruginosa (All

fluoroquinolones) Methicillin-susceptible Staph aureus Streptococcus pneumoniae

Garcia-Rey C et al. Clin Microbial Infect 2006;12:55-66Jacobi GA. Clin Infec Dis 2005;41:S120-6Cook PP et al. J Hosp Infect 2006:54:341-58.

Pseudomonas aeruginosaCiprofloxacin Resistance Trends (1989-1999)

Source: The Surveillance Network (TSN), Focus TechnologiesAnd for 2003, NNIS Survey. AJIC 2003

3rd Generation Cephalosporins Cause/associated with several different

problems in the hospital (oximinocephalosporins) 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/colitisDancer 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

Unknown pathogen

OximinocephalosporinsESBL production

ESBL-producing E. coli,K. pneumo, SPACE

ESBL-producingbacteria

CarbapenemsCarbapenemase development

KPC

KPC-producinginfection

?????

Economic Impact of Resistance

S. aureus bacteremia Methicillin resistance: 100% greater cost of

therapy

Klebsiella and E. coli infections ESBL production: 66% greater cost of

therapy

Pseudomonas aeruginosa infections Imipenem resistance: 68% greater cost of

therapyLodise 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 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

Centers for Disease Control Management of Multidrug-Resistant Organisms in

Healthcare Settings http://www.cdc.gov/ncidod/dhqp/pdf/ar/

mdroGuideline2006.pdf

ASM and SHEA Antimicrobial Resistance Prevention Initiative—An Update Moellering RC et al. Am J of Inf Contr 2007;35:S1-23

Role of Infection Control

Infection control trumps everything else Hand hygiene – must have hand washing

police Barrier precautions

Devotion to all aspects of strict infection control Nursing staff Medical staff Medical staff leadership

Infection Control – is it cost effective?

Infection Cost Savings VAP $25,072 Bacteremia $23,242 Surgical Site infection $10,443 Urinary Tract Infection $ 758

Anderson, et al. Infect Control Hosp Epidem 2007;28:767-73

Goals of Antimicrobial Stewardship

Primary goal Optimize clinical outcome/minimize unintended

consequences of antimicrobial use Unintended consequences:

Toxicity Selection of pathogenic organisms Emergence of resistant pathogens

Secondary goal 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

Kish MA et al. CID 2001; 32: 851 - 4

Category, Grade Definition

Strength of recommendationA

Good evidence to support

B Moderate evidence to support

C Poor evidence to support

Quality of evidenceI ≥ 1 randomized, controlled trials

II ≥ 1 clinical trial unrandomized, cohort or case-controlled studies, dramatic results from uncontolled experiments

III Opinion of experts, clinical experience, descriptive studies

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 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 Antimicrobial appropriate Cure vs. failure

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) When the patient’s condition allows

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) Based on culture results and elimination of

redundant therapy Decreases antimicrobial exposure and cost

Dose optimization (A-II) 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) Provides foundation of knowledge

Guidelines and clinical pathways – seek multi-disciplinary involvement and approval (A-I) 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) Shown to be effective component of the program

and can facilitate implementation into practice

Combination therapy 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 Create Public Health Advisory Board Create Antimicrobial Resistance Research and Strategic Plan

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

Control prescribing Vancomycin Reduce 3rd generation cephalosporin use Select a single fluoroquinolone (not ciprofloxacin) Select a single carbapenem

Antimicrobial Management Team Physician , Pharmacist hired (2001) Data collection

Pathways for empirical antimicrobial use

ICU specific antibiograms

Minimize the use of TPN

The University of Kentucky Experience: Antimicrobial Stewardship 1998-2008

Martin, et al. AJHP 2005; 62: 732 - 738

Prevalence of MRSAUniversity of Kentucky Hospital

AMT program begins

Antibiotic Cost/Patient DayUniversity Hospital Consortium: Top 7

InstitutionCost/Patient

Day Yale New Haven* 10.75

University of Kentucky* 11.25

Northeast UHC Hospital* 11.33

Southeast UHC Hospital 12.06

UC Davis* 12.33

Northeast UHC Hospital* 15.65

Northeast UHC Hospital* 15.69

* Active Antimicrobial Team – ID Physician and Pharmacist

AMT versus No AMT

UHC antibiotic cost/patient day No antimicrobial management team -

$19.80 With antimicrobial management team -

$12.83

$19.80 - $12.83 = $6.97/patient day 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 No data proving better than vancomycin Multinational trial in progress

Acinetobacter Clonal outbreak Back to baseline—rolling ICU shutdown

MRSA Rates increasing CA-MRSA responsible

Where to Begin

Chief of ID, Director of Pharmacy 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