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Practice Guidelines for Implementing Antimicrobial

Stewardship

Conducted during the 41st ASHP Midyear Clinical Meeting Anaheim, California

Practice Guidelines for Implementing Antimicrobial Stewardship

PROGRAM FACULTY Robert P. Rapp, Pharm.D., FCCP Professor of Pharmacy University of Kentucky Hospital Department of Pharmacy Services Lexington, Kentucky

CONTINUING EDUCATION ACCREDITATION

The American Society of Health-System Pharmacists is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This program provides 1 hour (0.1 CEU) of continuing education credit (program number 204-000-06-441-H01). After successful

completion of the CE post test, participants can print the CE statement online at www.ashpadvantage.com.


PROGRAM DESCRIPTION Inappropriate antimicrobial use is strongly associated with the emergence of antimicrobial-resistant pathogens. An effective antimicrobial stewardship program, with appropriate drug product selection, dosing, route of administration, and duration of antimicrobial therapy, in conjunction with a comprehensive infection control program has been shown to limit the emergence and transmission of antimicrobial-resistant microorganisms. The goals of antimicrobial stewardship are to optimize safe and appropriate use of antibiotics, enhance clinical outcomes while minimizing unintended consequences of antimicrobial use (e.g., toxicity, resistance), and reduce healthcare costs without adversely affecting quality of care. This program will describe the relationship between inappropriate antimicrobial use and the emergence of antimicrobial-resistant pathogens, the goals of antimicrobial stewardship programs in the hospital setting, and new evidence-based guidelines from the Infectious Diseases Society of America (IDSA) for developing programs to enhance antimicrobial stewardship in the hospital setting. The prominent role of pharmacists in antimicrobial stewardship programs called for in the new IDSA guidelines, with a clinical pharmacist who has infectious diseases training serving as a core member of a multidisciplinary antimicrobial stewardship team, will be discussed. The two proactive core strategies that provide the foundation for an antimicrobial stewardship program will be emphasized: (1) prospective auditing of antimicrobial utilization with direct interaction and feedback to the prescriber, and (2) formulary restriction and pre-authorization requirements to immediately reduce antimicrobial use and cost. Various additional elements (e.g., education, antimicrobial cycling, antimicrobial order forms, parenteral-to-oral conversion plans) that may be considered as part of the stewardship program based on local practice patterns and resources also will be described. The rationale for, potential impact of, and vital role that pharmacists play in the two core strategies and additional elements will be addressed in this program. LEARNING OBJECTIVES At the conclusion of this presentation, participants should be able to:

• Explain the relationship between inappropriate antimicrobial use and the emergence of antimicrobial-resistant pathogens.

• Describe the goals of antimicrobial stewardship programs in the hospital setting and the

role of pharmacists in these programs.

• Name the two proactive core strategies that provide the foundation for an antimicrobial stewardship program in the hospital setting and explain the rationale for use of these core strategies.

• Identify an additional element that may be considered as part of an antimicrobial

stewardship program and explain the potential impact of use of the element.


ROBERT P. RAPP, PHARM.D., FCCP Professor of Pharmacy University of Kentucky Hospital Department of Pharmacy Services Lexington, Kentucky Robert P. Rapp, Pharm.D., FCCP, is Professor of Pharmacy in the College of Pharmacy and

Professor of Surgery in the College of Medicine. Dr. Rapp also serves as Associate Director for

Clinical Services in the Department of Pharmacy Services at University Hospital. Dr. Rapp has

been a consultant to the pharmaceutical industry and is a member of the American Society of

Microbiology, the Society of Infectious Disease Pharmacists, and American Society of Health-

System Pharmacists (ASHP), the American College of Clinical Pharmacy (charter member), and

the Society for Healthcare Epidemiology of America. Dr. Rapp is also a Fellow of the American

College of Clinical Pharmacy.

Dr. Rapp received his Bachelor of Science in Pharmacy and Doctor of Pharmacy degrees at the

University of Kentucky. During his academic career, Dr. Rapp has published over 225 papers in

the professional and scientific literature and has been a primary author on numerous textbook

chapters in infectious diseases and microbiology. He currently serves on the editorial board for

Annals of Pharmacotherapy, and as a reviewer for the American Journal of Health-System

Pharmacy (AJHP), Pharmacotherapy, Journal of the Joint Commission on Hospital

Accreditation, and others. At the University of Kentucky College of Pharmacy, Dr. Rapp

teaches microbiology, infectious disease pharmacotherapy, and serves as a preceptor in

infectious diseases for both residents and undergraduate students.

1

Practice Guidelines for Implementing

Antimicrobial Stewardship

41st ASHP Midyear Clinical MeetingAnaheim ~ Orange County, California

Robert P. Rapp, Pharm.D., FCCPProfessor of Pharmacy College of Pharmacy

Associate Director – Pharmacy Services University Hospital

University of Kentucky Medical CenterLexington, Kentucky

The Answer Is:

An activity that is a JCAHO patient safety goal, takes 15

seconds to complete, is done before donning gloves and

after removing gloves, before and after patient contact, and

before & after

restroombreak.

UK Jeopardy

The Question Is:

What is hand washing?

2

Role of Infection Control

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

police.– Barrier precautions. – Nursing staff devoted to all aspects of strict

infection control.– Medical Staff devoted to all aspects of strict

infection control.– Medical Staff leadership willing to enforce

infection control strategies.

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

Half of US and Japanese companies end drug discovery

(BMS,Lilly,Wyeth,GSK,PG,etc)

A Disturbing Trend

1930 1940 1950 1960 1970 1980 1990 2000 2010

Sulfa,BLs,AGs,Chloramphenicol

TCN,MAC,Vanc,RIF, FQs,TMP

No new classes. Modification of existing agents.

LZD, DAP

Tigecycline

PCN-resistant S. aureus

MRSA

VRE

VISA in 7 states

VRSA

LZD-R S. aureus

Guidelines for Developing an Institutional Program to Enhance

Antimicrobial Stewardship

• Recommendation from the Infectious Diseases Society of America (IDSA).

• Endorsed by the ASHP Board of Directors in March of 2006.

• Includes the IDSA Ranking System for Clinical Guidelines.

• Official journal of the IDSA - Clinical Infectious Diseases.

3

A New Guideline and Press Release from the CDC

• New Guideline • Management of Multidrug-Resistant Organisms

in Healthcare Settings, 2006. http://www.cdc.gov/ncidod/dhqp/pdf/ar/mdroGuideline2006.pdf

• Press Release: CDC Urges Hospitals and Healthcare Facilities to Increase Efforts to Reduce Drug-Resistant Infections. http://www.cdc.gov/od/oc/media/pressrel/r061019

What is Antimicrobial Stewardship?• A marriage of infection control and antimicrobial

management.• Mandatory infection control compliance.• Selection of antimicrobials from each class of drugs that

does the least collateral damage.• Collateral damage issues include:

– MRSA– ESBLs– C. difficile– Stable derepression– Metallo-beta-lactamases and other carbapenemases– VRE

• Appropriate de-escalation when culture results are available.

IDSA Guidelines – Definition of Antimicrobial Stewardship

• Antimicrobial Stewardship is an activity that promotes:– The appropriate selection of antimicrobials. – The appropriate dosing of antimicrobials.– The appropriate route and duration of

antimicrobial therapy.

4

The Primary Goal of Antimicrobial Stewardship

• The primary goal of antimicrobial stewardship is to:– Optimize clinical outcomes while minimizing

unintended consequences of antimicrobial use.– Unintended consequences include the following

• Toxicity. • The selection of pathogenic organisms such as

Clostridium difficile.• The emergence of resistant pathogens.

Other Aspects of Antimicrobial Stewardship

• The appropriate use of antimicrobials is an essential part of patient safety.

• The frequency of inappropriate antimicrobial use is often used as a surrogate marker for the avoidable impact on antimicrobial resistance.

• The combination of antimicrobial stewardship and comprehensive infection control has been shown to limit the emergence and transmission of antimicrobial resistant bacteria.

A Secondary Goal of Antimicrobial Stewardship

• To reduce healthcare costs without adversely impacting the quality of care.

5

Guidelines Focus on the Development of Effective Hospital-based Stewardship

Programs

• Do not include any outpatient recommendations.• Antimicrobial stewardship programs are

financially self-supporting.• Antimicrobial stewardship programs improve

patient care.• Antimicrobial stewardship programs should be

evidence-based.

Core Members of the Antimicrobial Stewardship 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

Infectious Disease Pharmacist Specialist

• Qualifications:– Pharm. D. degree – Pharmacy Practice Residency – Infectious Disease Specialty Residency

(preferred)– Maintains competency in infectious diseases

and microbiology

6


• Responsibilities– Provides cost-effective pharmaceutical care to

patients receiving select/targeted antimicrobial therapy.

– Discuss antimicrobial order changes with ID Physician or prescriber.

– Document changes and inform others of those changes.

– Monitor antimicrobial therapy to evaluate appropriateness of use.

– Provide PK/PD services as required.– Facilitate discharge planning.– Provide inservice programs to all hospital staff.– Review yearly antibiogram with appropriate

individuals on a regular basis.


• Responsibilities (Continued)– Provide financial forecasts for the ID physician and

the Department of Pharmacy Services for new and investigational antimicrobials and related pharmaceuticals.

– Precept College of Pharmacy students. – Precept and mentor pharmacy practice and ID

specialty residents. – Provide presentations, publications at the local, state,

regional, and national level.– Conduct collaborative research to test the

effectiveness of new methods of antimicrobial control/restriction/reporting that may increase the effectiveness of antimicrobial stewardship.

Antimicrobial Stewardship Team: Statement on Collaboration

• Essential collaboration must be established with the Infection Control Committee

• Essential collaboration must be established with the Pharmacy and Therapeutics Committee – a committee of the medical staff.– Approval of pathways – Review of budgetary issues – Approval of restriction policies and procedures – Review of yearly antibiogram

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Antimicrobial Stewardship Team:Statement on Collaboration (Cont)

• Essential collaboration and support of hospital administration to fully fund the team.– Director of Pharmacy and ID physician, as

appropriate should negotiate with hospital administration to obtain adequate authority, compensation, and expected outcomes for the program.

• Essential collaboration with the medical staff via the Chief-of-Staff, or other individuals with budgetary and medical authority is mandatory.

IDSA Grading System for Ranking Recommendations in Clinical Guidelines

Category, Grade DefinitionStrength of Recommendation

A Good evidence to support a recommendation for useB Moderate evidence to support a recommendation for use

C Poor evidence to support a recommendation for use

Quality of EvidenceI Evidence from > 1 properly randomized, controlled trial

II Evidence from > 1 well-designed clinical trial without randomization; from cohort or case controlled studies

III Evidence from opinions or respected authorities, based onclinical experience, descriptive studies or expert committees

Kish MA, Guide to development of practice guidelines. CID 2001; 32: 851 – 4.

Antimicrobial Stewardship Team:Potential Active Core Strategies

• Prospective audit with intervention and feedback that can result in reduced inappropriate antimicrobial use (A-I)

• Formulary restriction and pre-authorization –can lead to significant and immediate reductions in antimicrobial use and cost (A-II)

NOTE – neither of these strategies are mutually exclusive

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Prospective Audit with Intervention and Feedback

• Report on a regular basis the results of audits and interventions to the Pharmacy and Therapeutics Committee and other hospital groups as appropriate.– Provide targeted feedback to physicians

individually or to physician services based on the results of prospective audits.

• Plan additional prospective audits and seek help from others when antimicrobials are not used appropriately.

• Report on the financial impact of interventions and feedback.

Formulary Restriction and Pre-authorization

• Report rates of resistance designed to show the effects of formulary restriction and pre-authorization.

• Examples of this would include:– ESBL rates in key bacteria (Klebsiella pneumoniae for

example).– CDAD hospital rates compared to previous rates.– MRSA rates compared to previous rates. – SPACE bacteria rates of resistance to key antimicrobials

(Acinetobacter species and Pseudomonas aeruginosaresistance rates to cefepime, imipenem/meropenem, fluoroquinolones).

– Monitor for transferable resistance in Gram-negative bacteria (MBLs and KPC 1-3 for example).

ESBL = extended-spectrum beta lactamases CDAD = Clostridium difficile associated diseaseSPACE = Serratia marcescens, Pseudomonas aeruginosa, Acinetobacter species, Citrobacter species, and Enterobacter species KPC = Klebsiella pneumoniae carbapenemase (1,2, and 3)

There is a Causal Association between Antimicrobial Use and the Emergence of

Antimicrobial Resistance

• Changes in antimicrobial usage are paralleled by changes in the prevalence of resistance.

• Resistance is more prevalent in healthcare-associated bacterial infections compared with those from community-acquired infections.

• Patients with healthcare-associated infections caused by resistant strains are more likely than control patients to have received prior antimicrobials.

• Areas within hospitals that have the highest rates of resistance also have the highest rates of use.

• Increasing duration of patient exposure to antimicrobials increases the likelihood of colonization with resistant organisms.

9

Antimicrobial Stewardship Team:Elements for Consideration and

Prioritization

• Educational programs – but with active intervention (A-III, B-II).

• 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).


Prioritization• Antimicrobial cycling – is not recommended because

of insufficient data (no ranking).• Antimicrobial order forms (B-II)

– Shown to be effective component of the program and can facilitate implementation of practice guidelines.

• Combination therapy– Insufficient data for routine use (C-II).– Has a role to increase coverage in empiric therapy in

patients at risk for multidrug-resistant pathogens.


Prioritization

• Streamlining or de-escalation therapy (A-II)– Based on culture results and elimination of redundant

therapy can decrease antimicrobial exposure and decrease 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.

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Dose Optimization: Considerations for Pharmacists

• Bactericidal activity of beta-lactams correlates with amount of time > MIC for the bacteria.

• Fluoroquinolones and aminoglycosides –concentration dependent agents –– Cmax:MIC (extended interval aminoglycosides)– AUC:MIC ratio for fluoroquinolones – high-dose

short-course therapy for community-acquired pneumonia.


Prioritization

• Parenteral to oral conversion (A-I).– When the patient’s condition allows

• Decrease in length of stay.• Decrease in healthcare costs.

– Development of clinical criteria and guidelines allowing conversion to use of oral agents can facilitate implementation at the institutional level (A-III).

Research Priorities and Future Directions (11 areas)

• Antimicrobial Cycling• Clinical validation of mathematical models regarding

antimicrobial 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.• Influence of pharmaceutical industry marketing on

antimicrobial prescribing and strategies to counteract inappropriate detailing.

A partial list of research priorities from the Guidelines

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Antimicrobial Stewardship:University of Kentucky Program – 1998 - 2006

• Restriction of the oximinocephalosporins– VRE– C. difficile– ESBLs– ampC hyperproduction

• Use vancomycin according to HICPAC guidelines– VRE– VISA– VRSA

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

HICPAC = Hospital Infection Control Practitioner Advisory Committee


• Fluoroquinolones – judicious use – Elimination of ciprofloxacin

• Association with MRSA • Association with C. difficile• Cost benefit with a single fluoroquinolone

formulary

• Carbapenems – restriction– Metallo-beta-lactamases– Other carbapenemases (KPC 1 – 3, OXA)

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


• Antifungals– Amphotericin B lipid formulation

• Requires approval by ID Physician– Echinocandins

• All three declared as equivalents• Dramatic reduction in costs

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

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Antimicrobial Costs at UK

$8,188,456

$1,793,723

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

$0

$1,000,000

$2,000,000

$3,000,000

$4,000,000

$5,000,000

$6,000,000

$7,000,000

$8,000,000

$9,000,000

1998 1999 2000 2001 2002 2003 2004$0

$1,000,000

$2,000,000

$3,000,000

$4,000,000

$5,000,000

$6,000,000

$7,000,000

$8,000,000

$9,000,000

Inflated (10% rate)ActualCum. Savings (baseline)Cum. Savings (inflated)

Prevalence of Methicillin-resistant Staphylococcus aureus at the University of Kentucky Hospital

University of Kentucky Clinical Microbiology.

17%11%11%11%

15%16%22%23%

33%40%

37%34%

31%35%

42%

0%5%

10%15%20%25%30%35%40%45%50%

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

Perc

ent M

RSA

C. difficile Rates at UK Hospital(based on toxin + patients)

Rate mean 1999 – 2002 - 6.27 cases per 1000 admissions Rate mean 2003 – 2005 – 5.05 cases per 1000 admissions

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Figure 1. Box plot showing rates of CDAD by quarter in 100 - 119 UHC hospitals. The 10, 25, 50 (median), 75 and 90th percentiles are illustrated. The solid line connects the means.

Polk RE, Oinonen, M and Pakyz A. Epidemic Clostridium difficile. New Eng J Med 2006; 354:1200-1201.

CDAD = Clostridium difficile associated disease

C. difficileRates (cont’d)

Training Requirements for Pharmacists ?

*****– Pharmacy Practice Residency + Specialty Residency

in Infectious Diseases.****

– Pharmacy Practice Residency + 6 months additional training in microbiology and infectious diseases.

***– Pharmacy Practice Residency with at least 2 months

of training in microbiology and infectious diseases during the residency.

**– Pharm.D. degree with some clinical experience.

Where Do You Begin?• Chief of ID and Director of Pharmacy develop initial

budget proposal.• Present proposal to hospital administration with financial

and microbiology goals from latest antibiogram.• Form an Antimicrobial Subcommittee of the Pharmacy

and Therapeutics Committee.• Hire the physician and the pharmacist. • Develop practice guidelines and pathways.• Educate all services in the hospital on the guidelines and

pathways.• Obtain “buy-in” from all services.• Begin implementation of the guidelines and collection of

data.

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Summary and Conclusions• Antimicrobial Stewardship programs show great promise

and offer new opportunities for hospital-based pharmacists.

• Recommendation by IDSA and ASHP and the CDC offer firm foundations to obtain support and funding for antimicrobial stewardship programs.

• Determine the appropriate training requirements for ID Pharmacists who are members of the Antimicrobial Stewardship Team.– Specialty Residency training versus clinical experience– Competency requirements– Need for board certification

• We welcome your questions.

• Staff will collect written question cards.

• Please approach a standing microphone in the aisle.

• Please complete the program evaluation located in your handout and leave with staff as you exit.

• Thank you for your attention.

• Join us again for CE in the Mornings.

Questions and Discussion


FACULTY DISCLOSURE STATEMENT ASHP Advantage requires that faculty members disclose any relationships (e.g., shareholder, recipient of research grant, consultant or member of an advisory committee) that the faculty may have with commercial companies whose products or services may be mentioned in their presentations. The existence of these relationships is provided for the information of attendees and should not be assumed to have an adverse impact on faculty presentations. The faculty reports the following relationships: Robert P. Rapp, Pharm.D., FCCP Dr. Rapp reports that he is a speaker for Pfizer, Wyeth Pharmaceuticals, and Ortho-McNeil, Inc., and he has received research support from AstraZeneca.

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