Evidence-based Synthesis Program 

(ESP)

Antimicrobial Stewardship 

Programs in Inpatient Settings

A Systematic Review of the Evidence

Gregory Filice, MD

Nancy Greer, PhD

Minneapolis VA Medical Center

December 16, 2013
Evidence-based Synthesis Program 

(ESP)

Acknowledgements

Co-Authors/Collaborators

o Dimitri Drekonja, MD, MS

o Timothy J. Wilt, MD, MPH

o Mary Butler, PhD, MBA

o Brittin Wagner, PhD

o Roderick MacDonald, MS

o Maureen Carlyle, MPH

o Indulis Rutks, BS

Expert Panel/Reviewers

o Matthew Goetz, MD

o Melinda Neuhauser, PharmD,

MPH 

o Allison Kelly, MD, MSOH

o Gary Roselle, MD

o Sanjay Saint, MD, MPH

o Kelly Echevarria, PharmD

o Chris Graber, MD

o Karl Madaras-Kelly, PharmD
Evidence-based Synthesis Program 

(ESP)

Disclosure

This report is based on research conducted by the Evidence-based 

Synthesis Program (ESP) Center located at the Minneapolis VA Medical 

Center, Minneapolis, MN funded by the Department of Veterans Affairs, 

Veterans Health Administration, Office of Research and Development, 

Quality Enhancement Research Initiative (QUERI). The findings and 

conclusions in this document are those of the author(s) who are 

responsible for its contents; the findings and conclusions do not 

necessarily represent the views of the Department of Veterans Affairs or 

the United States government. Therefore, no statement in this article 

should be construed as an official position of the Department of Veterans 

Affairs. No investigators have any affiliations or financial involvement 

(e.g., employment, consultancies, honoraria, stock ownership or options, 

expert testimony, grants or patents received or pending, or royalties) that 

conflict with material presented in the report.
Evidence-based Synthesis Program 

(ESP)

VA Evidence-based Synthesis (ESP)

Program Overview

• Sponsored by VA Office of R&D and Quality Enhancement 

Research Initiative (QUERI).

• Established to provide timely and accurate 

syntheses/reviews of healthcare topics identified by VA 

clinicians, managers and policy-makers, as they work to 

improve the health and healthcare of Veterans. 

• Builds on staff and expertise already in place at the 

Evidence-based Practice Centers (EPC) designated by AHRQ. 

Four of these EPCs are also ESP Centers: 

o Durham VA Medical Center; VA Greater Los Angeles Health Care 

System; Portland VA Medical Center; and Minneapolis VA Medical 

Center.
Evidence-based Synthesis Program 

(ESP)

• Provides evidence syntheses on important clinical practice 

topics relevant to Veterans, and these reports help:

o develop clinical policies informed by evidence, 

o the implementation of effective services to improve patient 

outcomes and to support VA clinical practice guidelines and 

performance measures, and 

o guide the direction for future research to address gaps in 

clinical knowledge.

• Broad topic nomination process – e.g. VACO, VISNs, field – 

facilitated by ESP Coordinating Center (Portland) through 

online process: 

 http://www.hsrd.research.va.gov/publications/esp/TopicNomination.cfm
Evidence-based Synthesis Program 

(ESP)

• Steering Committee representing research and operations 

(PCS, OQP, ONS, and VISN) provides oversight and guides 

program direction.

• Technical Expert Panel (TEP)

o Recruited for each topic to provide content expertise.

o Guides topic development; refines the key questions.

o Reviews data/draft report.

• External Peer Reviewers & Policy Partners

o Reviews and comments on draft report

• Final reports posted on VA HSR&D website and disseminated 

widely through the VA. 

http://www.hsrd.research.va.gov/publications/esp/reports.cfm
Evidence-based Synthesis Program 

(ESP)

Current Report

Antimicrobial Stewardship Programs in 

Inpatient Settings

A Systematic Review of the Evidence

(September, 2013)

Full-length report available on ESP website (VA INTRANET only):

http://www.hsrd.research.va.gov/publications/esp/reports.cfm
Evidence-based Synthesis Program 

(ESP)

Background

• More than 3 million kilograms of antimicrobials 

administered to human patients in the United 

States in 2009 (Spellberg 2013)

• Antimicrobial use influences the patient being 

treated AND the surrounding ecosystem (Fleming 

1945, Avorn 2000, CDC 2010)
Evidence-based Synthesis Program 

(ESP)

Background

• Inappropriate/excessive antimicrobial use associated 

with:

• Increasing microbial resistance

• Higher incidence of antimicrobial associated 

Clostridium difficile infection (CDI)

• Other drug related toxicities and increased 

healthcare costs (Jacob 2010)

• Inadequate antimicrobial use associated with 

increased mortality (Kollef 1999, Ibrahim 2000, Micek

2010)
Evidence-based Synthesis Program 

(ESP)

Background

• Antimicrobial Stewardship Programs 

• Effort to optimize antimicrobial use

• selection, dose, route, duration

• Goals:

• Improve patient outcomes

• Prevent/reduce antimicrobial resistance

• Reduce adverse antimicrobial effects

• Deliver cost-effective therapy 

(Avorn 2000, Fishman 2006, Dellit 2007, Jacob 2010, Ohl 2011) 
Evidence-based Synthesis Program 

(ESP)

Background

• Antimicrobial Stewardship Programs may involve:

• Multidisciplinary teams (infectious disease physicians, 

clinical pharmacists, clinical microbiologists, infection 

control specialists, epidemiologists)

• Support and collaboration of hospital leadership and 

administration

• Computer systems for decision making and tracking 

antimicrobial use, infections, adverse drug events

(Avorn 2000, Fishman 2006, Dellit 2007, Jacob 2010, Ohl 2011) 
Evidence-based Synthesis Program 

(ESP)

Background

• Intervention types include:

• Prospective audit with feedback

• Formulary restriction and preauthorization

• Education

• Guidelines and clinical pathways

• Antimicrobial cycling

• Order forms

• Streamlining or de-escalation of therapy

• Dose optimization

• Parenteral to oral conversion

(Dellit 2007) 
Evidence-based Synthesis Program 

(ESP)

Purpose of Review

Synthesize evidence about effectiveness & 

harms of antimicrobial stewardship 

programs implemented in adult 

inpatient settings
Evidence-based Synthesis Program 

(ESP)

Key Questions

• Key Question #1

What is the effectiveness of inpatient antimicrobial 

stewardship programs on the following: 

a. Primary Outcome: Patient centered outcomes 

(mortality, readmission, CDI, length of stay)

b. Secondary Outcomes: 

 1) Antimicrobial prescribing 

 2) Microbial outcomes 

 3) Costs
Evidence-based Synthesis Program 

(ESP)

Key Questions

• Key Question #2

What are the key intervention components 

associated with effective inpatient antimicrobial 

stewardship? 

• Key Question #3

Does effectiveness vary by:

a) hospital setting

b) suspected patient condition?
Evidence-based Synthesis Program 

(ESP)

Key Questions

• Key Question #4

What are the harms of inpatient antimicrobial 

stewardship programs? 

• Key Question #5

Within the included studies, what are the barriers to 

implementation, sustainability, and scalability of 

inpatient antimicrobial stewardship programs?
Evidence-based Synthesis Program 

(ESP)

Methods 

• Cochrane review (Davey 2005) with search to 2003 partially 

addressed key questions

• MEDLINE search 2000 to June 2013, based on Cochrane 

search strategy, limited to English language

• Additional citations from systematic reviews, reference lists 

of retrieved articles, and suggestions from technical expert 

panel and peer reviewers

• During our review process, Cochrane review updated (Davey 

2013) with search to 2009 

• we included only studies not in this review
Evidence-based Synthesis Program 

(ESP)

Methods 

• Excluded

• Conducted in nursing homes or long-term care facilities

• Pediatric population

• Antimicrobials for medical or surgical prophylaxis

• Viral or fungal infections, tuberculosis

• Provider education only or community/public health campaigns

• Descriptions of interventions with no outcome assessment

• Design other than randomized controlled trial, controlled clinical 

trial, controlled before and after study, or interrupted time series

• Setting not relevant to medicine in the US (e.g., antimicrobials 

available without prescription) or involving a population or 

infectious disease not relevant to US population

• Did not report outcomes of interest
Evidence-based Synthesis Program 

(ESP)

 

Methods 

• Standard methods for data extraction 

• Assessed risk of bias of individual studies (Cochrane Effective 

Practice and Organization of Care method) and strength of 

evidence for patient-centered outcomes

• Categorized studies by intervention type

• Difficult for some studies - multiple interventions, hybrid 

interventions 

• Unable to pool data due to heterogeneity of interventions, 

study designs, patient populations, and outcomes reporting
Evidence-based Synthesis Program 

(ESP)

 Literature Flow 

 Abstracts Triaged: 6,334

 Abstracts Excluded: 5,775

 Full Text Review: 559 Articles

 Excluded: 539 Articles

Not an included study design: 260

 No intervention: 108

 Outpatient setting: 71

 Not stewardship: 57

 Other: 43

Hand Search: 15 Articles

 Included: 35 Studies 

 
Evidence-based Synthesis Program 

(ESP)

Results

 

• Existing Cochrane Review (Davey 2013)

• Included 89 studies published through 2009

• Focused on prescribing outcomes

• Categorized interventions as:

• Persuasive (education, reminders, audit and feedback)

• Restrictive (order forms, formulary restriction)

• Structural (EMR, decision support systems)
Evidence-based Synthesis Program 

(ESP)

Results (Davey 2013)

• Patient-Centered Outcomes - Mortality

• Interventions to increase guideline compliance for 

patients with community acquired pneumonia reduced 

mortality:

• (4 studies, RR 0.89 [0.82, 0.97])

• Interventions to increase effective prescribing (3 studies) 

and interventions to decrease excessive prescribing (11 

studies) were not significantly associated with mortality

 
Evidence-based Synthesis Program 

(ESP)

Results (Davey 2013)

 

• Patient-Centered Outcomes - Other 

• Interventions to decrease excessive prescribing : 

• No effect length of stay 

• (6 studies, mean difference, -0.04 days [-0.34, 0.25])

• Associated with increased hospital readmissions 

• (5 studies, 1.26 [1.02, 1.57])

• Reduction in C. difficile infection: 

• 15% to 65% at one month post-intervention 

• 4 interrupted time series studies
Evidence-based Synthesis Program 

(ESP)

Results (Davey 2013)

 

• Prescribing Outcomes

• Calculated median effect size with all prescribing 

outcomes; positive sign = change in intended direction

• Persuasive, restrictive, and structural interventions:

• Associated with improved prescribing 

• Median change in prescribing ranged from 4% to 46% 

across intervention types and study design types 
Evidence-based Synthesis Program 

(ESP)

Results

• VA-ESP Evidence

o 9 RCTs, 4 CCTs, 2 CBAs, 20 ITS studies

o Categorized studies by intervention type:

• 14 audit and feedback 

• 5 formulary restriction and preauthorization 

• 4 guideline implementation with feedback

• 4 guideline implementation with no feedback

• 4 computerized decision support

• 4 protocol or policy implementation
Evidence-based Synthesis Program 

(ESP)

ASP Intervention

(# studies) Mortality Length of Stay Readmission CDI

Prospective Audit 

and Feedback (14) + 1 study

≈ 9 studies ≈ 9 studies + 1 study

≈ 2 studies p=NR, 1 study

Formulary 

Restriction and 

Preauthorization

(5)

≈ 3 studies ≈ 2 studies NR + 1 study

Guidelines with 

Feedback (4) ≈ 3 studies ≈ 3 studies NR + 2 studies

Guidelines without 

Feedback (4)

+ 1 study

≈ 1study

- 1 study

+ 1 study

≈ 1study

- 1 study

≈ 1 study NR

Computerized 

Decision Support (4) ≈ 3 studies + 1 study

≈ 2 studies ≈ 1 study + 1 study

≈ 1 study

Protocols (4) + 1 study

≈ 2 studies

+ 2 studies

≈ 1 study ≈ 1 study NR

KQ1 – Program Effectiveness: Clinical Outcomes
Evidence-based Synthesis Program 

(ESP)

KQ1 – Program Effectiveness: Prescribing Outcomes

ASP Intervention 

(# studies) Use Selection Timing Duration

Prospective Audit 

and Feedback (14)

Decreased: + 8 studies

Appropriate:

+ 1 study, ≈ 1 study

+ 1 study

≈ 1 study NR + 5 studies

Formulary 

Restriction and 

Preauthorization (5)

Decreased: + 4 studies NR NR + 1 study

Guidelines with 

Feedback (4)

Decreased: + 1 study

Compliant/appropriate: 

+ 2 studies

≈ 1 study + 1 study ≈ 2 studies

Guidelines without 

Feedback (4)

Decreased: + 1 study

Compliant/ 

appropriate:

+ 2 studies, ≈ 1 study

NR - 1 study + 1 study

≈ 1 study 

Computerized 

Decision Support (4)

Decreased: + 1 study,

≈ 1 study NR NR NR

Protocols (4) Appropriate: ≈ 1 study NR ≈ 1 study + 2 studies
Evidence-based Synthesis Program 

(ESP)

KQ1 - Program Effectiveness

• Microbial Outcomes (9 studies)

o 6 reported improvement 

 decreased infection or resistance

o 3 reported no differences

• Cost Outcomes (5 studies)

o 4 reported decreased costs

o 1 reported no difference
Evidence-based Synthesis Program 

(ESP)

KQ2 Results – Key Implementation 

Components

• All author opinion (6 studies)

o Consistent and persistent effort from qualified 

personnel 

o Effective communication skills 

o Support from electronic medical records or 

computerized decision support systems
Evidence-based Synthesis Program 

(ESP)

KQ3 Results – Effectiveness in Different 

Settings or Different Suspected Conditions

• Davey 2013 review

o 9 from VA Medical Centers

o Similar results (unchanged mortality [1], 

decreased CDI [2], mixed results prescribing [3], 

decreased infection [3])

• No recent studies from VA eligible 

• Most studies from University-affiliated hospitals
Evidence-based Synthesis Program 

(ESP)

KQ3 Results – Effectiveness in Different 

Settings or Different Suspected Conditions

• ICU programs (9 studies)

o Similar to overall results

• Most studies included “any suspected infection” 

• Respiratory infection (7 studies) 

o Similar to overall results
Evidence-based Synthesis Program 

(ESP)

KQ4 Results – Harms of Programs

• 2 studies reported possible harms (other than 

patient, prescribing, and microbial harms from 

KQ1)

o Anecdotal evidence of inappropriate switch to 

narrow-spectrum antimicrobial

o Termination of program speculated to be due 

to provider dissatisfaction with prescribing 

restrictions
Evidence-based Synthesis Program 

(ESP)

KQ5 Results – Barriers to Implementation, 

Sustainability, Scalability

• Barriers (4 studies; 2 with interview/survey data)

o Lack of familiarity, experience, awareness 

o Disagreement with guidelines/conflicting guidelines

o Lack of communication between professionals 

o Organizational constraints

• Sustainability (1 study)

o Use and costs decreased over 5 years of study and 

increased when study was terminated

• Scalability (No studies)
Evidence-based Synthesis Program 

(ESP)

Discussion

• Antimicrobial stewardship strategies can decrease 

antimicrobial prescribing and limit costs, without 

substantial harms

• Greatest body of recent evidence is from audit 

and feedback programs

• Systematic review of earlier studies provided 

evidence of comparable effects for persuasive and 

restrictive interventions 

• Evidence base for KQ1 was substantial; much less 

substantial for KQ2-5 
Evidence-based Synthesis Program 

(ESP)

Discussion

• Studies not designed to adequately assess impact 

on mortality or other clinical outcomes

• Suggestions for improving adherence to ASPs: 

o Involvement of stakeholders and opinion leaders in 

guideline and program development

o Addition of quality improvement cycles

o Understanding the prescribing culture

o Collaboration between physicians and pharmacists 

(mostly opinion rather than evidence-based) 
Evidence-based Synthesis Program 

(ESP)

Discussion

• Limitations:

• Quality of evidence: Low

• Few randomized controlled trials

• Limited ability to control for secular trends or 

other confounding variables

• Possibility of regression to the mean in C. 

difficile rates

• Findings for specific interventions have not 

been replicated

 
Evidence-based Synthesis Program 

(ESP)

Discussion

• Limitations (continued):

• Prescribing improvements often not sustained 

or long-term follow-up not reported

• Most studies done in academic medical centers; 

generalizability to other settings is difficult. 

 
Evidence-based Synthesis Program 

(ESP)

 

Discussion

• Limitations (continued):

• Within academic centers, substantial variation 

in settings, structures, patient bases, culture

o Strength: stewardship has impact in diverse 

settings 

o Weakness: Hard to be sure that each specific 

intervention works across all settings

• Few studies reported on harms of stewardship 

interventions; most not designed to identify 

harms, and most would not have been 

adequately powered to recognize them
Evidence-based Synthesis Program 

(ESP)

 

Future Research Needs

• Given the complexity of antimicrobial prescribing, 

conducting well-designed studies is difficult

• Large healthcare organizations should consider 

organizing stewardship activities (that are likely 

on-going within the organization) to provide 

useful information on comparative effectiveness 

of different intervention types
Evidence-based Synthesis Program 

(ESP)

 

Overall Conclusions

• Despite these many shortcomings, the overall 

evidence suggests that antimicrobial stewardship 

interventions are associated with improved 

intended outcomes, mostly antimicrobial usage, 

over short time periods (1-3 years)

• The literature supports hospital and healthcare 

system implementation of sensible, practical 

antimicrobial stewardship interventions to 

improve outcomes
Evidence-based Synthesis Program 

(ESP)

 

Recommendations

• Data on antimicrobial use by clinical unit, type of 

patients, provider groups, and by individual 

providers should be gathered to determine where 

antimicrobial use might be less than ideal or is in 

need of improvement 
Evidence-based Synthesis Program 

(ESP)

Recommendations

• Existing infection prevention programs, 

microbiology laboratories, pharmacy services, 

infectious disease physicians, electronic medical 

record systems, continuous improvement 

programs, and staff or trainee education and 

certification programs should be utilized to 

contribute to stewardship activities 

• Leadership should also be informed and involved 

in planning; leadership support is essential 

 
Evidence-based Synthesis Program 

(ESP)

Recommendations

• Formative evaluation should be used to identify 

effective stewardship programs and programs in 

need of modification 

 
Evidence-based Synthesis Program 

(ESP)

Questions?

If you have further questions, 

feel free to contact:

Nancy Greer, PhD

Minneapolis ESP Program Manager

612-467-5204

Nancy.Greer@va.gov

The full report and cyberseminar presentation is available on the ESP website 

(Intranet Only): 

http://www.hsrd.research.va.gov/publications/esp/