0. 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

1. 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
Objectives
Nosocomial infections are the most common complication affecting hospitalized patients
Up to 70% are due to resistant organisms, and mortality rates correlate with multidrug-resistant organisms
Both nosocomial infections and resistance are rising, which represents an emerging public health threat and a call to action to institute or evolve programs to control it
One such opportunity is antimicrobial stewardship programs, programmatic approaches to minimize inappropriate antimicrobial use and the development of antimicrobial resistance in the hospital setting
This kind of management is, therefore, a critical component of patient safety
Stewardship interventions can be tailored to improve outcomes at the local level
Burke JP. Infection control — a problem for patient safety. N Engl J Med. 2003;348:

2. Rationale for Antimicrobial Stewardship Programs

3. High Rates of Nosocomial Infections in the United States
Year
Variable
1975
1995
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)
37.7
299.0
7.9
18.3
2.1
7.2
35.9
190.0
5.3
13.3
1.9
9.8
High Rates of Nosocomial Infections in the United States
Key point: Despite a decrease in the overall number of hospitalizations and
surgical procedures and the average length of stay, nosocomial infections are
the most common complications affecting hospitalized patients and continue to
have an impact on mortality, morbidity, and treatment costs.1
Up to 10% of hospitalized patients acquire at least one infection1
Risks have increased over time
In 2002, hospital-associated infections occurred in an estimated 1.7 million patients in the United States2
Nearly 100,000 infection-related deaths
Approximately $4.5 billion in excess healthcare costs each year3
As health care has evolved, lowering the rate of nosocomial infections has been a challenge1
Advances in medical treatments have led to an increase in the population of patients with decreased immune function or chronic disease
A shift in health care to the outpatient setting (more patients managed as outpatients) means that those who are hospitalized are sicker and more susceptible to infection and more vulnerable once infected
Of particular danger are the resistant strains of bacteria that have developed
Adapted with permission from Burke JP. N Engl J Med. 2003;348:
1. Burke JP. Infection control—a problem for patient safety. N Engl J Med. 2003;348:
2. Klevens RM, Edwards JR, Richards CL Jr, et al. Estimating health care–associated infections and deaths in U.S. hospitals, Public Health Rep. 2007;122:
3. McKibben L, Horan T, Tokars JI, et al. Guidance on public reporting of healthcare-associated infections: recommendations of the Healthcare Infection Control Practices Advisory Committee. Am J Infect Control. 2005;33:

4. Changing Resistance/Decreased Susceptibilities Over Time
Resistance to Third-Generation Cephalosporins Among Klebsiella Pneumoniae and Escherichia Coli (NNIS )
1986
1988
1990
1992
1994
1996
1998
2000
Year
2002 5 10 15 20 25
E Coli
K Pneumoniae
% of Resistant Isolates
2004
Ceftazidime- and Imipenem-Resistant Acinetobacter (NNIS )
1986
1988
1990
1992
1994
1996
1998
2000
Year
2002 10 20 30 40 50 60 70 80
Imipenem
Ceftazidime
% of Resistant Isolates
2004
Changing Resistance/Decreased Susceptibilities Over Time
Key point: There has been a trend toward increasing antimicrobial resistance
over the last two decades.
Surveillance of intensive care units between 1986 and 2003 reported a sharp rise in Klebsiella pneumoniae isolates showing resistance to third-generation cephalosporins in the early 1990s. Rates of resistance remained high over a 10-year period
Rates of Acinetobacter resistance to ceftazidime and imipenem rose significantly between 1986 and 2003
NNIS = National Nosocomial Infections Surveillance System. Results of Cochran-Armitage 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: 
Gaynes R, Edwards JR, and the National Nosocomial Infections Surveillance System. Overview of nosocomial infections caused by Gram-negative bacilli. Clin Infect Dis. 2005;41:

5. Increasing Resistance: Gram-Positive Pathogens Also a Problem
Proportion of Methicillin-Resistant Staphylococcus Aureus (MRSA) and Vancomycin-Resistant Enterococcal (VRE) Infections Is Increasing ( ) 70 60 50
MRSA 40
% of Resistant Isolates 30 20
VRE
Increasing Resistance: Gram-Positive Pathogens Also a Problem
Key point: The incidence of methicillin-resistant Staphylococcus aureus
(MRSA) and vancomycin-resistant enterococcal (VRE) infections has
drastically increased over the last 15 to 20 years.
Methicillin-resistant Staphylococcus aureus (MRSA) is an example of a Gram-positive organism for which antibiotic resistance has increased over the years
Between 1987 and 2004, resistance to methicillin increased from 2% to more than 50%
Since the early 1990s, VRE infection prevalence has risen significantly 10
1987
1989
1991
1993
1995
1997
1999
2001
2003
Note: Data refer to infections in intensive care unit (ICU) patients only.
Sources: VRE and MRSA data, , (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 are estimated from Lawy VRE data for 1989 and 1993 are from CDC VRE data for and are interpolated based on geometric mean. Available at: Accessed April 30, 2007.
Available at: Accessed April 30, 2007.

6. 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
Factors Encouraging the Development of Antimicrobial-Resistant
Pathogens
Key point: A combination of inadequate infection control, changing patient
demographics, and inappropriate antibiotic use has contributed to rising
antimicrobialresistance.
Factors contributing to the emergence of antibiotic-resistant pathogens include the following
High severity of illness in hospitalized patients1
Inappropriate antibiotic use
Increased use of antimicrobial prophylaxis1
The use of antibiotics in cases where bacterial infection is unlikely (eg, the common cold)2
The use of antibiotics for bacterial infections that are likely to resolve on their own (eg, acute otitis media in children)2
Inappropriate dose or duration of antimicrobial use3
Institutional factors
Inadequate infection control (eg, hand washing)1
Patient movement within and among medical institutions4
Poor adherence to environmental cleaning in high-risk venues4
Agricultural use of antimicrobials4
1. Stein GE. Pharmacotherapy. 2005;25:44S-54S. 2. South M et al. Med J Aust. 2003;178: McGowan JE Jr. Clin Infect Dis. 2004;38: Levy SB. J Antimicrob Chemother. 2002;49:25-30.
1. Stein GE. Antimicrobial resistance in the hospital setting: impact, trends, and infection control measures. Pharmacotherapy. 2005;25(suppl):44S-54S.
2. South M, Royle J, Starr M. A simple intervention to improve hospital antibiotic prescribing. Med J Aust. 2003;178:
3. McGowan JE Jr. Minimizing antimicrobial resistance: the key role of the infectious diseases physician. Clin Infect Dis. 2004;38:
4. Levy SB. Factors impacting on the problem of antibiotic resistance. J Antimicrob Chemother. 2002;49:25-30.

7. Increased Antibiotic Use Drives Resistance35
250 30
200 25
150 20
% of Strains Resistant to Ciprofloxacin
Quinolone Use (kg x 103) 15
100 10
Pseudomonas
Gram-Negative 50 5
Fluoroquinolone use
Increased Antibiotic Use Drives Resistance
Key point: Resistance is associated with increased antibiotic use.
Increased antibiotic use is associated with increased resistance in Gram-negative bacteria1
Increased use of fluoroquinolones between 1994 and 2000 is commensurate with a substantial increase in the proportion of fluoroquinolone-resistant Gram-negative bacilli, especially Pseudomonas aeruginosa1
Resistance to one antibiotic class may be associated with resistance to other antibiotic classes, such as third-generation cephalosporins2
1994
1995
1996
1997
1998
1999
2000
Increasing fluoroquinolone resistance in Gram-negative bacilli correlates with increased fluoroquinolone use in patients from 43 states (numbers of isolates from =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:
1. Neuhauser MM, Weinstein RA, Rydman R, et al. Antibiotic resistance among Gram-negative bacilli in US intensive care units: implications for fluoroquinolone use. JAMA. 2003;289:
2. McGowan JE. Resistance in nonfermenting gram-negative bacteria: multidrug resistance to the maximum. Am J Infect Control. 2006;34:S29-S37.

8. 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
Causal Associations Between Antimicrobial Use and Emergence of
Antimicrobial Resistance
Key point: Inappropriate use of antimicrobial therapies correlates with
increased selection of resistant pathogens.
Causal associations have been established between the use of antibiotics and 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:
Dellit TH, Owens RC, McGowan JE Jr, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis. 2007;44:

9. 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 rates exceeding 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
Mortality Rates Correlate With Presence of Multidrug-Resistant
Organisms
Key point: Patients with multidrug-resistant infections have poorer
clinical outcomes.1
A recent study showed the correlation between fluoroquinolone resistance in Pseudomonas aeruginosa and adverse clinical outcomes2
Patients experienced a greater delay in receiving effective treatment
Patients experienced poorer outcomes, including a higher incidence of infection-related mortality
Enterococcal bacteremia has been associated with mortality rates exceeding 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-S McGowan JE Jr. Am J Infect Control. 2006;34:S29-S Lautenbach E et al. Clin Infect Dis. 2003;36: Cosgrove SE et al. Clin Infect Dis. 2003;36:53-59.
1. Cosgrove SE. The relationship between antimicrobial resistance and patient outcomes: mortality, length of hospital stay, and health care costs. Clin Infect Dis. 2006;42(suppl 2):S82-S89.
2. McGowan JE Jr. Resistance in nonfermenting gram-negative bacteria: multidrug resistance to the maximum. Am J Infect Control. 2006;34(suppl 1):S29-S37.
3. Lautenbach E, LaRosa LA, Marr AM, et al. Changes in the prevalence of vancomycin-resistant enterococci in response to antimicrobial formulary interventions: impact of progressive restrictions on use of vancomycin and third-generation cephalosporins. Clin Infect Dis. 2003;36:
4. Cosgrove SE, Sakoulas G, Perencevich EN, et al. Comparison of mortality associated with methicillin-resistant and methicillin-susceptible staphylococcus aureus bacteremia: a meta-analysis. Clin Infect Dis. 2003;36:53-59.

10. Fewer Antibiotics to Address Increased Resistance
Fewer New Antibiotics Are Being Brought to Market as More Companies Leave the Anti-Infectives Business 16 14 12 10
New Antimicrobials Approved 8 6 4
Fewer Antibiotics to Address Increased Resistance
Key point: Despite rising resistance rates, fewer and fewer new antibiotics are
being brought to the market.
The pace of new antibiotic development is inadequate to address the emergence of antimicrobial resistance 2
Antibacterial Agents Approved by FDA,
FDA = Food and Drug Administration.
Available at: Accessed April 30, Source: (Spellberg et al. 2004), (Bosso 2005).
Available at: Accessed April 30, 2007.

11. 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
Economic Impact of Increased Resistance
Key point: Increased resistance results in higher costs throughout the
health care system.
During 2004, an estimated $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: Accessed April 30, Scott D II et al. In: Owen RC Jr et al, eds. Antibiotic Optimization: Concepts and Strategies in Clinical Practice. Marcel Dekker Publishers
1. Available at: Accessed April 30, 2007.
2. Scott D II, Solomon SL, Cordell R, et al. Measuring the attributable costs of resistant infections in hospital settings. In: Owen RC Jr, Ambrose PG, Nightingale CH, eds. Antibiotic Optimization: Concepts and Strategies in Clinical Practice. New York, NY: Marcel Dekker Publishers; 2005.

12. 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
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 left in 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 staphylococcus aureus (MRSA)
11. Surgical site infections
12. Serious preventable event—wrong surgery
13. Falls
Other Economic Impacts of Increased Resistance
Key point: Increased resistance can lead to higher rates of hospital-acquired
infections; Medicare rule changes are proposed to pay lower rates for certain
hospital-acquired conditions.
The Department of Health and Human Services is proposing changes in the structure of Medicare payments for certain conditions
Hospital-acquired conditions, including specific infections, are considered comorbidities related to the initial reason for hospitalization
Proposed changes to Medicare indicate that treatment of certain hospital-acquired infections will be paid at a lower rate
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, Available at: /CMSProposedRuleHAQ.pdf. Accessed June 28, 2007.
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, Available at: DOWNLOADFILENAME/ /CMSProposedRuleHAQ.pdf. Accessed June 28, 2007.

13. Antimicrobial Stewardship Programs

14. 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.
Antimicrobial Stewardship
Key point: Antimicrobial stewardship optimizes the use of antimicrobials to
take clinical outcomes and risk of resistance into account.
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 the development of subsequent resistance.
Owens RC, Ambrose PG. Diagn Microbiol Infect Dis. 2007;57(suppl 3):S77-S83.
Owens RC Jr, Ambrose PG. Antimicrobial stewardship and the role of pharmacokinetics–pharmacodynamics in the modern antibiotic era. Diagn Microbiol Infect Dis. 2007;57(suppl 3):S77-S83.

15. 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
Antimicrobial Stewardship: Overview
Key point: Antimicrobial stewardship is a program that combines judicious
use of antibiotics with efforts to provide the best clinical outcome for the
patient.
The primary goal of antimicrobial stewardship is to optimize clinical outcomes while minimizing the unintended consequences of antibiotic use
Toxicity
Selection of pathogenic bacteria
Emerging antibiotic resistance
The secondary goal of antimicrobial stewardship is to 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:
Dellit TH, Owens RC, McGowan JE Jr, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis. 2007;44:

16. Antimicrobial Stewardship Teams
Multidisciplinary Team Approach to Optimizing Clinical Outcomes
Hospital Administrator
Hospital Epidemiologist
Infectious Diseases Division
Infection Control
Director,
Outcomes Research
ASP Directors • ID PharmD • ID Physician
Medical Information Systems
Chairman, P&T Committee
Partners in Optimizing Antimicrobial Use Such as Pulmonologists and Surgeons
Microbiology Laboratory
Clinical Pharmacy Specialists
Antimicrobial Stewardship Teams
Key point: A comprehensive program with collaboration among multiple
disciplines is key to the success of antimicrobial stewardship.
The core members of an antimicrobial stewardship team should include an infectious disease physician and a clinical pharmacist with infectious disease training
Additional members will help the team function optimally
Clinical microbiologist
Information systems specialist
Infection control professional
Hospital epidemiologist
The program should function under the auspices of quality assurance and/or patient safety
Collaborations are crucial to the success of antimicrobial stewardship teams
Teams should collaborate with hospital infection control and with the pharmacy/therapeutics committee
Collaboration with hospital administrators, medical staff leaders, and local providers is also important
Decentralized Pharmacy Specialist
ASP = Antimicrobial Stewardship Program, ID = infectious disease, P&T = Pharmacy and Therapeutics. Dellit TH et al. Clin Infect Dis. 2007;44: and Fishman N. Am J Med. 2006;119:S53-S61.
Dellit TH, Owens RC, McGowan JE Jr, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis. 2007;44:

17. Core Strategies For Antimicrobial Stewardship
Prospective audit with intervention and feedback
Formulary restriction/preauthorization
Core Strategies for Antimicrobial Stewardship
Key point: Two core strategies and locally applicable supplemental strategies
may be used for an optimal antimicrobial stewardship program.
Facilities initiating an antimicrobial stewardship program will usually choose 1 of 2 core strategies
This is an important first step if a formal stewardship program does not yet exist
Each of the core strategies is based upon robust levels of evidence
The choice will depend on local resistance patterns and which strategy will best impact the individual facility
There may be cross-collaboration within or between the 2 strategies to optimize local stewardship programs
A series of supplemental strategies may also be used
These can be combined in several ways to tailor the antimicrobial stewardship program to individual situations
For existing programs, tailoring substrategies or adding new strategies may help with ongoing success
Dellit TH et al. Clin Infect Dis. 2007;44: and Fishman N. Am J Med. 2006;119:S53-S61.
Dellit TH, Owens RC, McGowan JE Jr, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis. 2007;44:

18. 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
Core Strategy 1: Prospective Audit With Intervention and Feedback
Key point: Prospective audit of antimicrobial use with direct interaction and
feedback to the prescriber, usually performed by an infectious disease
specialist or a clinical pharmacist with infectious disease training, can result
in reduced inappropriate use of antimicrobials.1
Involves review of antimicrobial orders2
Inappropriate orders initiate contact between an antimicrobial team member and the prescriber
Provides an opportunity to optimize therapy
Advantages to prospective audit with intervention and feedback
Prescribers still have autonomy in the antibiotics they prescribe2
This strategy can create incentives for physicians to improve their performance3
Disadvantages to conducting a prospective audit with intervention and feedback
Compliance is voluntary2
This strategy must distinguish between appropriate and inappropriate prescribing to be effective3
1. MacDougall C, Polk RE. Clin Microbiol Rev. 2005;18: Available at: Accessed April 30, 2007.
1. Dellit TH, Owens RC, McGowan JE Jr, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis. 2007;44:
2. MacDougall C, Polk RE. Antimicrobial stewardship programs in health care systems. Clin Microbiol Rev. 2005;18:
3. Available at: Accessed April 30, 2007.

19. Prospective Audit With Intervention and Feedback: Example 1
Decrease in Amoxicillin/Clavulanate Use
Decrease in Cephalosporin Use 2 4 6 8 10 12 14
7-Day Cephalosporin Courses per 100 Admissions 60 50 40
7-Day Courses per 100 Admissions 30 20 10
Jan 03
July 02
Jan 02
July 01
Jan 01
July 00
Jan 00
Sept 99
Jan 03
July 02
Jan 02
July 01
Jan 01
July 00
Jan 00
Sept 99
Increased Benzyl Penicillin Use
Lower Rates of Clostridium Difficile Infection 45 14
Prospective Audit with Intervention and Feedback: Example 1
Key point: Intervention and feedback can result in lower overall rates
of infection.
Fowler evaluated the effectiveness of conducting a prospective audit with feedback and intervention as an antimicrobial stewardship strategy
Four end points were evaluated
Change in use of amoxicillin/clavulanate use (expected to decrease)
Change in cephalosporin use (expected to decrease)
Change in benzyl penicillin use (expected to increase)
Rate of Clostridium difficile infection (expected to decrease)
There was a significant reduction in the use of amoxicillin/clavulanate and cephalosporins, both immediately and long-term after initiation of prospective audit with intervention and feedback (P<.05)
There was a significant increase in the long-term trends indicating increased use of benzyl penicillin (P=.012)
The level of C difficile infection fell significantly (P=.009) over the intervention period 40 12 35 10 30
7-Day Courses per 100 Admissions 25
Number of CDI Cases per Month 8 20 6 15 4 10 5 2
Jan 03
July 02
Jan 02
July 01
Jan 01
July 00
Jan 00
Sept 99
Jan 03
July 02
Jan 02
July 01
Jan 01
July 00
Jan 00
Sept 99
Vertical dashed line = program begun.
Adapted with permission from Fowler S et al. J Antimicrob Chemother. 2007;59:
Fowler S, Webber A, Cooper BS. Successful use of feedback to improve antibiotic prescribing and reduce Clostridium difficile infection: a controlled interrupted time series. J Antimicrob Chemother. 2007;59:

20. Prospective Audit With Intervention and Feedback: Example 2
Parenteral Antibiotic Use, Cost Decreased*
Rates of Resistant Enterobacteriaceae Infections Decreased 20 10
-10
-20
-30
-40
1991
1992
1993
1994
1995
1996
1997
1998
Cost
Use
Illness Severity
% of Preintervention Observations
1989
1990
1991
1992
1993
1995
1998 4 6 5 3 2 1
1994
1996
1997
Cases per 1000 Patient Days
Prospective Audit With Intervention and Feedback: Example 2
Key point: A prospective audit with intervention and feedback can
significantly decrease overall antibiotic use and resistant infections.
A community teaching hospital established a program (in 1991) with prospective antibiotic monitoring, which led to individualized therapeutic recommendations
Overall antibiotic use decreased over the 6-year period starting from 1991
Especially the use of third-generation cephalosporins and aztreonam
Admission of patients colonized with vancomycin-resistant enterococci (VRE) during 1996 and 1997 increased the level of VRE isolates within the hospital
However, rates began to decrease after a 2-year period ( ), falling to 6%, significantly less than the 24% seen in comparable hospitals
Resistant Enterobacteriaceae infections decreased significantly (P=.02)
*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:
Carling P, Fung T, Killion A, et al. Favorable impact of a multidisciplinary antibiotic management program conducted during 7 years. Infect Control Hosp Epidemiol. 2003;24:

21. 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 for off-hour approvals1
May discourage appropriate antibiotic use3
May delay receiving appropriate therapy initially
Core Strategy 2: Formulary Restriction/Preauthorization
Key point: Formulary restriction/preauthorization that limits use of antibiotics
based on considerations of therapeutic efficacy, toxicity, and cost while limiting
redundant new agents with no significant additional benefit, can reduce costs
and decrease antibiotic resistance.1,2
Added step of restriction or preauthorization may be enough to limit antimicrobial use1
Advantages to formulary restriction/preauthorization
This strategy provides the most direct control over antimicrobial use1
This is an alternative to providing incentives for appropriate prescribing3
Disadvantages to formulary restriction/preauthorization
Prescribers may feel they have lost the autonomy to prescribe appropriate antibiotics1
Consultants may be needed at all hours to authorize appropriate antibiotics1 May discourage use of appropriate antibiotics3
May delay initiation of appropriate therapy
May interfere with the relationship between physician and patient3
1. Dellit TH et al. Clin Infect Dis. 2007;44: MacDougall C, Polk RE. Clin Microbiol Rev. 2005;18: Available at: Accessed April 30, 2007.
1. Dellit TH, Owens RC, McGowan JE Jr, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis. 2007;44:
2. MacDougall C, Polk RE. Antimicrobial stewardship programs in health care systems. Clin Microbiol Rev. 2005;18:
3. Available at: Accessed April 30, 2007.

22. 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
250 12 10
200 8
150
% Ceftazidime-Resistant K Pneumoniae Isolates
Grams per 1000 Patient Days 6
100 4 50 2
Formulary Restriction: Example
Key point: Formulary restriction and preauthorization may improve
rates of antimicrobial use and resistance.
The impact of formulary restriction was evaluated in a university hospital as part of an antimicrobial stewardship program
Selected antimicrobials with potential for inappropriate use or documented inappropriate use were restricted or removed from formulary
Results for the first 5 years of the program showed that antimicrobial use, pharmacy expenditures, and antimicrobial resistance patterns for many important pathogens all decreased
1998
1999
2000
2001
2002
Year
Third-Generation Cephalosporins
Cefepime
Ceftazidime-Resistant K Pneumoniae
Originally published in Martin C et al. Am J Health Syst Pharm. 2005;62: ©2005, American Society of Health-System Pharmacists, Inc. All rights reserved. Reprinted with permission. (R0727).
Martin C, Ofotokun I, Rapp R, et al. Results of an antimicrobial control program at a university hospital. Am J Health Syst Pharm. 2005;62:

23. Supplemental Strategies For Antimicrobial Stewardship
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
Supplemental Strategies for Antimicrobial Stewardship
Key point: Supplemental strategies can be used in combination with the core
strategies to optimize antimicrobial stewardship.
Dellit TH et al. Clin Infect Dis. 2007;44:
Dellit TH, Owens RC, McGowan JE Jr, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis. 2007;44:

24. 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
Clinical Pathways and Guidelines
Key point: Development of multidisciplinary, evidence-based practice
guidelines utilizing local microbiology and resistance patterns can be an
effective part of antimicrobial stewardship.1
Clinical guidelines should be developed within a multidisciplinary team, with input from as many members as possible
Advantages to clinical pathways and guidelines2
Increased awareness of pathways and guidelines may alter prescribing behavior
The prescriber still has autonomy to prescribe antibiotics
Disadvantages to clinical pathways and guidelines2
Passive education (providing guidelines without active intervention and/or feedback) may not be as effective
MacDougall C, Polk RE. Clin Microbiol Rev. 2005;18:
1. Dellit TH, Owens RC, McGowan JE Jr, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis. 2007;44:
2. MacDougall C, Polk RE. Antimicrobial stewardship programs in health care systems. Clin Microbiol Rev. 2005;18:

25. Clinical Pathways and Guidelines: Example
100
P=.028
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 90 92
P=.001
P<.001 80
P=.7 81 70 77 78 71 60 66
P<.11
% of Cases 50 48 50 40 30 30 20 19 10 — —
Clinical Pathways and Guidelines: Example
Key point: Implementation of clinical pathways and guidelines has been effective in
decreasing cost and improving rates of appropriate antibiotic treatment.
A study using a physician-accessible list of antibiotic guidelines was conducted in an Australian pediatric hospital1
Physicians were provided with guidelines on plastic cards that clipped to their identification badges
Over two 6-month periods (pre- and post-intervention), the choice and dosage of antibiotics were evaluated, as well as the antibiotic cost, for patients with tonsillitis, pneumonia, or orbital/periorbital cellulitis
Appropriate choice of antibiotic increased by 5% to 59%
Appropriate dose of antibiotic increased by 20% to 33%
Annualized costs of third-generation cephalosporins were reduced by more than $100,000
Optional for the speaker: Another study evaluated the impact of clinical guidelines in improving outcomes in ventilator-associated pneumonia (VAP)2
Guidelines were developed based on the authors’ prior experience
Initial administration of adequate antimicrobial treatment was significantly greater after implementation of clinical guidelines (94% vs 48%)
Patients who received initial treatment after implementation of clinical guidelines were less likely to experience a recurrence of VAP
Pre-Card
Post-Card
Pre-Card
Post-Card
Appropriate CHOICE of Antibiotic
Appropriate DOSE of Antibiotic*
Tonsillitis
Pneumonia
Orbital/Periorbital Cellulitis
*Includes only those cases in which the appropriate antibiotic was chosen.
= insufficient data.
South M et al. Med J Austr. 2003;178: —
1. South M, Royle J, Starr M. A simple intervention to improve hospital antibiotic prescribing. Med J Austr. 2003;178:
2. Ibrahim EH, Ward S, Sherman G, et al. Experience with a clinical guideline for the treatment of ventilator-associated pneumonia. Crit Care Med. 2001;29:

26. Streamlining/De-escalation: Therapy
Serious Nosocomial Infection Suspected
Begin Empirical Antibiotic (Abx) Treatment With a Combination of Agents Targeting the Most Common Pathogens Based on Local Data
Yes No
Pathogen Identified?
Deescalate Antibacterials Based on Results of Clinical Microbiology Data
Continue Initial Treatment
Reassess After Appropriate Time Frame
Streamlining/De-escalation: Therapy
Key point: Streamlining/de-escalation therapy can decrease antimicrobial
exposure by utilizing the strategy of replacing excessively broad empirical
antimicrobial therapy with more targeted therapy once culture results become
available.1
Physicians in consultation with pharmacists can select targeted therapy for their patients
When culture results are available, streamlining/de-escalation of empirical therapy may allow for more targeted therapy1
May also include discontinuation of empirical antibiotic therapy if culture results and clinical signs indicate absence or eradication of infection1
Potential advantages to streamlining/de-escalation therapy
Decreases antimicrobial exposure1
Reduces risk of antibiotic resistance2
Contains cost1
Potential decrease in toxicity and superinfection
Disadvantages to streamlining/de-escalation therapy2
Time delay for culture results
Perceived difficulty in switching from broad-spectrum antibiotics to narrow-spectrum antibiotics
Significant Clinical Improvement After Hours of Antibacterial Treatment?
Yes No
Search for Superinfection, Abscess Formation, Noninfectious Cause of Symptoms, Inadequate Tissue Penetration of Abx
Discontinue Abx After 7-14 Days Based on Site of Infection and Clinical Response
Adapted with permission from Kollef MH. Drugs. 2003;63:
1. Dellit TH, Owens RC, McGowan JE Jr, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis. 2007;44:
2. Available at Accessed April 30, 2007.

27. 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
Clinical Outcome Measures
Before Period (n=50)
After Period (n=52)
Outcome
P Value
Streamlining/De-escalation: Example
Key point: Although initial experiences with streamlining/de-escalation are
limited, available data suggest that outcomes can be improved with its use,
including decreased antibiotic use, fewer secondary episodes of pneumonia,
decreased resistance, shorter duration of therapy, and decreased mortality.
A study of patients with VAP attempted to reduce unnecessary antibiotic administration1
Antibiotic treatment was modified based on culture results and patient clinical outcome
Antibiotics were discontinued after 7 days if patients met clinical criteria
Duration of antibiotic therapy was decreased from 15 days to 9 days (P<.001)
No significant difference in mortality was observed
Implementation of the clinical guidelines, which included de-escalation therapy, resulted in patients being less likely to have a recurrence of pneumonia
In a review of de-escalation therapy in VAP2
De-escalation was defined as using antimicrobiologic and clinical data to change from an initial broad-spectrum, multidrug, empiric therapy to therapy with fewer antibiotics and agents of narrow spectrumAvailable data suggest that it is a promising strategy for optimizing responsible use of antibiotics while allowing delivery of prompt appropriate empiric VAP therapy
Mortality, no. (%)
ICU length of stay, days
Hospital length of stay, days
Secondary VAP, no. (%)
21 (42.0)
23.1 ± 17.4
39.3 ± 33.1
12 (24.0)
27 (51.9)
21.7 ± 12.9
34.2 ± 26.2
4 (7.7)
.102
.987
.379
.030
Adapted with permission from Ibrahim EH et al. Crit Care Med. 2001;29:
1. Ibrahim EH, Ward S, Sherman G, et al. Experience with a clinical guideline for the treatment of ventilator-associated pneumonia. Crit Care Med. 2001;29:
2. Niederman MS. De-escalation therapy in ventilator-associated pneumonia. Curr Opin Crit Care. 2006;12:

28. Dose Optimization Takes several factors into account
Pharmacokinetic/pharmacodynamic (PK/PD) characteristics of the antibiotic
Patient characteristics
Causative organism
Site of infection
Dose Optimization
Key point: Dose optimization utilizes factors unique to each patient to achieve
the best clinical outcome. Optimizing dosing of antibiotics based upon their
pharmacokinetic/pharmacodynamic (PK/PD) properties can increase the
likelihood of clinical success, pathogen eradication, and prevention of
resistance.
Dose optimization is dependent upon several other factors as well1
Patient characteristics (eg, age, weight, disease state, renal function)
Causative organism
Site of infection (eg, heart, lung)
Dose optimization follows different pathways depending on whether the antibiotic exhibits concentration-dependent or time-dependent killing2
Concentration-dependent antibiotics show increased activity over a wide range of concentrations
Maximizing the concentration can potentially improve bacteriologic response
Time-dependent antibiotics show optimal activity over a narrower range of concentrations
The focus for these drugs is maximizing the time the drug concentration is above the organism’s minimum inhibitory concentration (T>MIC) for optimal therapeutic benefit
Dellit TH et al. Clin Infect Dis. 2007;44:
1. Dellit TH, Owens RC, McGowan JE Jr, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis. 2007;44:
2. Owens RC Jr, Ambrose PG. Antimicrobial stewardship and the role of pharmacokinetics-pharmacodynamics in the modern antibiotic era. Diagn Microbiol Infect Dis. 2007;57(suppl 3):S77-S83.

29. Dose Optimization: PK/PD Parameters
Applicable Antimicrobial(s)
Cmax/MIC
Aminoglycosides
%T>MIC
β-Lactams Tetracycline Oxazolidinones
AUC/MIC
Fluoroquinolones Macrolides Ketolides Cyclopeptides
Cmax
Cmax/MIC
Antibiotic Concentration
AUC/MIC
%T>MIC
MIC
Dose Optimization: PK/PD Parameters
Key point: Though many factors are involved in choosing a dose, the principal
focus is to optimize PK/PD to achieve optimal drug exposure, thus minimizing
resistance.
Three PK/PD parameters can help predict antibiotic effectiveness
Ratio of maximum serum concentration to the minimum inhibitory concentration (Cmax/MIC)
Ratio of the area under the curve to the MIC (AUC/MIC)
Percentage of time in a dosing interval that the plasma drug concentrations remain above the MIC (%T>MIC)
These 3 parameters best, albeit loosely, describe the ability of the antibiotic to eradicate bacteria and contain infection
Different classes of antibiotics are associated with different parameters, though information may conflict between individual antibiotics within a class
Beta-lactams exhibit time-dependent killing
Aminoglycoside activity is best associated with Cmax/MIC
Fluoroquinolones, macrolides, ketolides and glycopeptides are associated with AUC/MIC
The efficacy of macrolides, oxazolidinones, and β-lactams is most predicted by the %T>MIC
Time
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.
Rybak MJ. Pharmacodynamics: relation to antimicrobial resistance. Am J Infect Control. 2006;34(5 suppl 1):S38-S45.

30. 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
Combination Therapy
Key point: A rationale for the use of combination therapy is that drugs with
different mechanisms of action may act additively or synergistically.1 However,
data are insufficient to recommend routine use to prevent antimicrobial
resistance.2
Combination therapy has a role in certain clinical contexts2
Used for empirical therapy in critically ill patients at risk of multidrug- resistant pathogens
Increase coverage and improve likelihood of adequate initial therapy
A study evaluated combination therapy versus monotherapy in patients with ventilator-associated pneumonia1
74 Patients received either cefepime alone or in combination with amikacin or levofloxacin1
No significant differences were observed in any outcome (clinical signs, ventilator-free days, mortality)1
Monotherapy was as effective as combination therapy1
Damas P et al. Crit Care. 2006;10:1-7. Dellit TH et al. Clin Infect Dis. 2007;44:
1. Damas P, Garweg C, Monchi M, et al. Combination therapy versus monotherapy: a randomised pilot study on the evolution of inflammatory parameters after ventilator associated pneumonia [ISRCTN ]. Crit Care. 2006;10:R52-R58.
2. Dellit TH, Owens RC, McGowan JE Jr, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis. 2007;44:

31. 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, )
Treatment failure was numerically more common for combination therapy than for monotherapy (OR, 0.62; 95% CI, )
No difference in mortality rates between monotherapy and combination therapy groups (OR, 0.70; 95% CI, )
Combination Therapy: Example
Key point: Compared with β-lactam monotherapy, aminoglycoside/β-lactam
combination therapy is not protective against the emergence of antimicrobial
resistance.
A meta-analysis of 8 trials evaluating aminoglycoside/β-lactam combination therapy versus β-lactam monotherapy and reporting data regarding the emergence of resistance was conducted
Combination therapy was associated with more superinfections than treatment with β-lactam monotherapy (OR, 0.62; 95% CI, )
Treatment failure was numerically more common for combination therapy than for monotherapy (OR, 0.62; 95% CI, )
No difference in mortality rates between monotherapy and combination therapy groups (OR, 0.70; 95% CI, )
Bliziotis IA, Samonis G, Vardakas KZ. Clin Infect Dis. 2005;41:
Bliziotis IA, Samonis G, Vardakas KZ, et al. Effect of aminoglycoside and β-lactam combination therapy versus β-lactam monotherapy on the emergence of antimicrobial resistance: a meta-analysis of randomized, controlled trials. Clin Infect Dis. 2005;41:

32. Switch From Parenteral to Oral Therapy
120
100
Vancomycin (IV only)
Linezolid (PO, or IV to PO switch) 80
% of Patients Remaining in Hospital 60 40
Switch From Parenteral to Oral Therapy
Key point: Switching from parenteral to oral therapy can have clinical
and cost benefits for the patient and the institution.
The study shown here evaluated length of stay in patients with soft tissue infections treated with linezolid (IV or PO) versus IV vancomycin1
Patients switched from IV to PO linezolid had a significantly shorter length of stay than those receiving vancomycin (P<.01)
A multicenter, prospective, randomized study evaluated the therapeutic outcome and cost-benefit of abbreviated IV therapy with early switch to oral antibiotic therapy in hospitalized patients with community-acquired pneumonia2
95 Patients were randomized to receive either conventional intravenous (IV) therapy with cefamandole for 7 days or abbreviated IV therapy with cefamandole for 2 days followed by early oral (PO) therapy with cefaclor for 5 days
Clinical response rates were similar for conventional IV therapy and IV to PO therapy (97% vs 95%)
Length of stay was significantly reduced in the IV to PO therapy group (P<.01)
Total patient costs were significantly decreased in the IV to PO therapy group (P<.05) 20 14 21 28 35
P<.01 7
Days From Study Medication Start Date
Adapted with permission from Itani KMF et al. Int J Antimicrob Agents. 2005;26:
1 Itani KMF, Weigelt J, Li JZ, Duttagupta S. Linezolid reduces length of stay and duration of intravenous treatment compared with vancomycin for complicated skin and soft tissue infections due to suspected or proven methicillin-resistant Staphylococcus aureus (MRSA). Int J Antimicrob Agents. 2005;26:
2. Omidvari K, De Boisblanc BP, Karam G, et al. Early transition to oral antibiotic therapy for community-acquired pneumonia: duration of therapy, clinical outcomes, and cost analysis. Respir Med. 1998;92:

33. 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

34. 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

35. 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

36. Targeted High-use Antimicrobials for Automatic Renal Adjustment
Cefepime
Fluconazole
Levofloxacin
Piperacillin/Tazobactam
Imipenem/Cilastatin
Meropenem
Automatic adjustment requires physician approved policies and procedures

37. No Active Intervention
Education: Example 1
No Active Intervention
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
2000
2001
2002
2003
Minneapolis-St. Paul and Milwaukee-Waukesha MSA
Other Counties in Minnesota and Wisconsin
0.7
0.8
0.9
1.0
1.1
1.2
1.3
Prescribing Ratio (WI : MN)
Education: Example 1
Key point: Although education is the most frequently used supplemental strategy for
antimicrobial stewardship, evidence underscores the need for active intervention (participant is
notified when not adhering to what he was educated about) in order for education to be
effective at changing both knowledge and attitudes about antibiotic prescribing.1
Education should be considered a cornerstone for antimicrobial stewardship2
But education should only be considered a starting point within a stewardship program3
Advantages to education:
Prescribers may alter behavior when they are aware of current guidelines3
Prescribers are still free to prescribe appropriate antibiotics3
Educational initiatives can be inexpensive and simple to initiate4
Disadvantages to education:
Passive interactions are often ineffective3
Education alone may not be sufficient to produce optimal results4
A 5-year educational campaign (including mailings, reports, guidelines presentations, and posters, but not active intervention) to reduce outpatient antimicrobial prescribing was introduced in Wisconsin in 19995
Antimicrobial prescribing rates were compared with Minnesota, which had no comparable campaign in place at that time
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:
1. Dellit TH, Owens RC, McGowan JE Jr, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis. 2007;44:
2. Fishman N. Antimicrobial stewardship. Am J Med. 2006;119(suppl 6A):S53-S61.
3. MacDougall C, Polk RE. Antimicrobial stewardship programs in health care systems. Clin Microbiol Rev. 2005;18:
4. Available at Accessed April 30, 2007.
5. Belongia EA, Knobloch MJ, Kieke BA Jr, et al. Impact of statewide program to promote appropriate antimicrobial drug use. Emerg Infect Dis. 2005;11:

38. Inappropriate Antibiotic
Education: Example 2
Active Intervention
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]
100
Intervention
Control 90 80
P=.001 70 60
Inappropriate Antibiotic
Discontinuation, % 50 40 30
Education: Example 2
Key point: Active educational strategies can have a significant impact on
prescribing behavior.
A large teaching hospital instituted a multitiered educational campaign to improve rates of appropriate antibiotic use
Distributed hospital-developed guidelines for proper antimicrobial use
Actively intervened to educate physicians who wrote inappropriate antibiotic orders
Measured appropriate use of 2 target antibiotics (ceftazidime and levofloxacin) in medical services randomized to receive educational intervention versus those with no intervention
Intervention reduced unnecessary (target) antibiotic use by 37% from baseline (P<.001)
Inappropriate antibiotics were discontinued at a higher rate in the educational intervention compared with controls (70% vs 30%) 20 10
Target Antibiotics
Adapted with permission from Solomon DH et al. Arch Intern Med. 2001;161:
Solomon DH, Van Houten L, Glynn RJ, et al. Academic detailing to improve use of broad-spectrum antibiotics at an academic medical center. Arch Intern Med. 2001;161:

39. 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
Work Closely With the Microbiologist
Key point: Data obtained from the microbiologist is crucial to informed decision-making by the
antimicrobial stewardship team.
The clinical microbiology lab is a key part of antimicrobial stewardship programs1
Data on resistance patterns can aid the antimicrobial stewardship team in formulary and treatment guideline decisions1
Benefit of microbiology labs:
Treatment based on culture results encourages the use of narrow-spectrum antibiotics if appropriate2
The Clinical and Laboratory Standards Institute (CLSI) published updated guidelines (2007) for analysis and reporting of antibiograms
Some considerations
Frequency of data analysis and reports3
Recommend at least annual analysis and reporting
Number of isolates3
Combine data from sites in the same geographic area or use a longer time period if insufficient isolates are available, to decrease risk of reporting errors
Susceptibility testing3
Quantitative and qualitative test results are both important
Group distribution and review3
Allows for modification of local guidelines and formulary decisions
The CLSI also established guidelines for testing infrequently isolated pathogens4
Involvement of infectious disease specialists can determine necessity of testing and interpretation of results
In general, only isolates involved in serious infections would be tested; however, testing can also be considered in the following situations
Persistent infection
Clinical failure
Allergy or intolerance to standard therapy
Potential antibiotic resistance
Dellit TH et al. Clin Infect Dis. 2007;44:
1. MacDougall C, Polk RE. Antimicrobial stewardship programs in health care systems. Clin Microbiol Rev. 2005;18:
2. Available at Accessed April 30, 2007.
3. Hindler JF, Stelling J. Analysis and presentation of cumulative antibiograms: a new consensus guidelines from the Clinical and Laboratory Standards Institute. Clin Infect Dis. 2007;44:
4. Jorgensen JH, Hindler JF. New consensus guidelines from the Clinical and Laboratory Standards Institute for antimicrobial susceptibility testing of infrequently isolated or fastidious bacteria. Clin Infect Dis. 2007;44:

40. Antimicrobial Order Forms
Can help implement practice guidelines1
Portion of Antibiotic Order Form Demonstrating How Vancomycin Is Ordered by the Prescriber2
Vancomycin (PO) [$251] mg/Dose
Vancomycin (IV) [$81] mg/kg/DAY PO IV
12A: Treatment of Clostridium difficile diarrhea after failure of metronidazole or if life threatening
q6h
q6h q8h q_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 back of 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
Dose adjusted based on levels and renal function
Antimicrobial Order Forms
Key point: Antimicrobial order forms (AOFs) can be an effective part of antimicrobial
stewardship and can help implement practice guidelines.
An Argentine teaching hospital implemented AOFs as part of a hospitalwide antimicrobial stewardship program1
To optimize antibiotic use within the hospital, a sequential intervention program was developed by an antimicrobial treatment committee (ATC)
Program included 4 successive 6-month intervention periods
Period 1 (baseline): introduction of optional AOF, collection of baseline data
Period 2 (initial intervention): feedback from baseline findings, conversion of optional AOF to mandatory
Period 3 (education phase): similar to period 2 but with added policy activity for every antibiotic prescription; bedside discussion among the infectious disease (ID) physicians, the clinical microbiologist, and the attending physicians
Period 4 (active control): similar to period 3 but with any necessary prescription modification by the ATC
Mandatory AOFs, as part of a multifaceted antimicrobial usage program, resulted in a significant reduction in overall antibiotic use between the baseline period and the initial intervention period (P<.05)
This trend continued during the remaining periods (adjusted R2=0.6885; P=.01)
In contrast, a study of AOFs was conducted in a 325-bed pediatric tertiary care teaching hospital2
Compliance with AOFs ranged from 30% to 80%
Increased inappropriate use of vancomycin observed after implementation of AOF (P<.01 for the pre-AOF period compared with the improved compliance period)
PO = orally; qxh = every x hours; IV = intravenously; CVL = central venous catheter.
1. Dellit TH et al. Clin Infect Dis. 2007;44: Bolon MK et al. Pediatr Infect Dis J. 2005;24:
1. Bantar C, Sartori B, Vesco E, et al. A hospitalwide intervention program to optimize the quality of antibiotic use: impact on prescribing practice, antibiotic consumption, cost savings, and bacterial resistance. Clin Infect Dis. 2003;37:
2. Bolon MK, Arnold AD, Feldman HA, et al. An antibiotic order form intervention does not improve or reduce vancomycin use. Pediatr Infect Dis J. 2005;24:

41. 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
Antibiotic Cycling/Switch
Key point: Antibiotic cycling/switch is a controversial part of antimicrobial
stewardship.
Antibiotic cycling/switch refers to scheduled cycling of antibiotics (either individually or by class)1
Goal is to reduce resistance
Antibiotic is usually reintroduced at a predefined time
Advantages to antibiotic cycling/switch
May reduce resistance2,3
Theoretically, resistance to a specific drug will decline while it is out of use2
Disadvantages to antibiotic cycling/switch:
Adherence to this strategy is difficult to control2
Mathematical models of resistance development suggest that this approach is a poor strategy for the prevention of resistance2
1. Dellit TH et al. Clin Infect Dis. 2007;44: MacDougall C, Polk RE. Clin Microbiol Rev. 2005;18:
1. Dellit TH, Owens RC, McGowan JE Jr, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis. 2007;44:
2. MacDougall C, Polk RE. Antimicrobial stewardship programs in health care systems. Clin Microbiol Rev. 2005;18:
3. Available at: Accessed April 30, 2007.

42. Local Computer Surveillance and Decision 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
Local Computer Surveillance and Decision Support
Key point: Additional strategies can provide benefits to existing antimicrobial
stewardship programs.
Physician order entry (POE) refers to a variety of computer-based systems of ordering medications that share the common features of automating the medication ordering process. These systems can integrate antibiotic surveillance data with clinical decision support
Physician order entries include interfaces with clinical decision–support systems that provide advice on drug selection, dose, and duration
This strategy is based on local surveillance of resistance patterns
Timing and types of antibiotics can be impacted by this strategy
For example, surveillance programs can report broad-spectrum in vitro activity against both Gram-positive and Gram-negative bacteria in an area
Especially important in centers that prescribe broad-spectrum agents
These data can be used to help develop appropriate prescribing algorithms
Can help prescribers determine which antibiotic to use as well as appropriate timing and route of administration
1. King WJ et al. BMC Pediatrics. 2007;7: Fischer MA et al. Arch Intern Med. 2003;163:
King WJ, Le Saux N, Sampson M, et al. Effect of point of care information on inpatient management of bronchiolitis. BMC Pediatrics. 2007;7:4-10.

43. Physician Order Entry: Example
Reduced antibiotic use
Average defined daily dose of IV anti-infectives decreased, ranging from 9% to 23%, after initiation of 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
Physician Order Entry: Example
Key point: Physician order entry programs can help reduce antibiotic use and
prescription errors, with a potential for positive impact on mortality rates.
Reduced intravenous anti-infective use after implementation of a physician order entry (POE) system1
In a pediatric setting, incorporation of a clinical evidence module for bronchiolitis management into a computerized POE decreased the percentage of children receiving antibiotics in a condition where antimicrobial use is not routinely recommended2
Studies in internal medicine and intensive care unit (ICU) settings showed decreased prescription errors3,4
Some increases in administrative errors were seen (missing dates, signatures), but clinically significant errors were reduced
A study in critically ill pediatric patients showed lower mortality after implementation of a physician order entry system, but the differences were not statistically significant5
These results contradicted an earlier report of increased mortality associated with physician order entry systems6
1. Fischer MA et al. Arch Intern Med. 2003;163: King WJ et al. BMC Pediatrics. 2007;7: van Gjissel-Wiersma DG et al. Drug Safety. 2005;28: Colpaert K et al. Crit Care. 2006;10: Keene A et al. Pediatr Crit Care Med. 2007;8:
1. Fischer MA, Solomon DH, Teich JM, Avorn J. Conversion from intravenous to oral medications: assessment of a computerized intervention for hospitalized patients. Arch Intern Med. 2003;163:
2. King WJ, Le Saux N, Sampson M, et al. Effect of point of care information on inpatient management of bronchiolitis. BMC Pediatrics. 2007;7:4-10.
3. van Gjissel-Wiersma DG, van den Bemt PMLA, Walenbergh-van Veen MCM. Influence of computerised medication charts on medication errors in a hospital. Drug Safety. 2005;28:
4. Colpaert K, Claus B, Somers A, et al. Impact of computerized physician order entry on medication prescription errors in the intensive care unit: a controlled cross-sectional trial. Crit Care. 2006;10:R21.
5. Keene A, Ashton L, Shure D, et al. Mortality before and after initiation of a computerized physician order entry system in a critically ill pediatric population. Pediatr Crit Care Med. 2007;8:
6. Han YY, Carcillo JA, Venkataraman ST, et al. Unexpected increased mortality after implementation of a commercially sold computerized physician order entry system. Pediatrics. 2005;116:

44. Evaluating Antimicrobial Stewardship Programs
Key point: Strategies can be adapted to local areas, issues, and specialties to
improve antimicrobial use. Measurable goals should be established when
implementing/evolving an antimicrobial stewardship program.
Interventions can be tailored to improved antibiotic use at the local level for all involved
Goals should be developed before initiating/evolving an antimicrobial stewardship program
Outcomes should be easily measured and relevant
Clinical outcomes should always prevail over economic outcomes
Published outcome measures include
Acceptance/adherence rates
Clinical response
Length of stay
Mortality
Antibiotic use versus resistance
Antibiotic expenditures
Outcome measurement should be tailored to each institution
Measures should be agreed upon before initiation of the program
Fraser GL, Stogsdill P, Owens RC Jr. Antimicrobial stewardship initiatives: a programmatic approach to optimizing antimicrobial use. In: Owens RC Jr, Ambrose PG, Nightingale CH, eds. Antibiotic Optimization: Concepts and Strategies in Clinical Practice. New York, NY: Marcel Dekker; 2005:

45. Evaluating Stewardship Programs: Example 1—Clinical Outcomes
Comparing Antimicrobial Management by an AMT vs ID Fellows
Patients Whose Treatment Was Managed By
Outcome
AMT (n=87)
ID Fellows (n=93)
Unadjusted OR (95% CI)
P Value
Appropriate 76 44
7.7 ( )
<.001
Cure* 49 35
2.4 ( )
.007
Failure 13 26
0.5 ( )
.03
Evaluating Stewardship Programs: Example 1—Clinical Outcomes
Key point: Implementation of antimicrobial stewardship programs can
optimize the use of antimicrobials and significantly improve clinical outcomes.
A study at the Hospital of the University of Pennsylvania compared the effectiveness of antimicrobial management by the antimicrobial management team (AMT) versus antimicrobial management by infectious disease (ID) fellows
Compared antimicrobial use and clinical outcomes
Outcome measures included
Appropriateness of antimicrobial agents
Cure with first regimen
Failure of first regimen
Failure defined as change/addition of secondary antimicrobial agent to target isolated pathogens resistant to initial treatment
Cost of care
Better performance for all measured outcomes was observed in cases managed by the AMT compared with those managed by ID fellows
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:
Gross R, Morgan AS, Kinky DE, et al. Impact of hospital-based antimicrobial management program on clinical and economic outcomes. Clin Infect Dis. 2001;33:

46. Evaluating Stewardship Programs: Example 2—Financial Outcomes
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
112,000
2001
2002
2003
2004
Fiscal Year
Average Monthly Expenditure ($)
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
Evaluating Stewardship Programs: Example 2—Financial Outcomes
Key point: Increased vigilance in antimicrobial use can have financial benefits
for the institution.
A study of outcomes at the Maine Medical Center was undertaken after initiation of an antimicrobial stewardship program
Antimicrobial expenditures have decreased
Rates of oral antibiotic use have increased
This study was modified from a prospective, randomized study by Fraser et al evaluating clinical patient safety and economic outcomes following implementation of a concurrent review program
Adult inpatients receiving ≥1 of 10 designated antibiotics randomized to intervention group or control group after 3 days of therapy
Review of initial antimicrobial therapy by an ID physician fellow and a PharmD specializing in critical care
Intervention group received written or verbal treatment suggestions; the control group did not
Patient outcomes included clinical and microbiological response rates, adverse events, inpatient mortality, length of stay, readministration rates, and readmission rates
50% of patients receiving targeted regimens had their treatment refined at day 3, resulting in lower antimicrobial costs without adversely impacting clinical 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:
Fraser GL, Stogsdill P, Owens RC Jr. Antimicrobial stewardship initiatives: a programmatic approach to optimizing antimicrobial use. In: Owens RC Jr, Ambrose PG, Nightingale CH, eds. Antibiotic Optimization: Concepts and Strategies in Clinical Practice. New York, NY: Marcel Dekker; 2005:

47. 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

48. 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

49. 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

50. Evaluating 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 12 10
200 8
150
% Klebsiella pneumoniae Resistant Isolates
Grams per 1000 Patient Days 6
100
Evaluating Stewardship Programs: Example 3—Antimicrobial Resistance
Key point: Antimicrobial stewardship programs can result in decreased
antibiotic use with a concomitant reduction in antimicrobial resistance.
In response to antimicrobial stewardship committee recommendations, antibiotics with potential for inappropriate use were restricted or removed from formulary
Total antimicrobial expenditures decreased by 25% over the first 5 years of program implementation
Ceftazidime resistance in Klebsiella pneumoniae decreased significantly, while overall susceptibility of Pseudomonas aeruginosa to key antimicrobials remained constant or improved slightly over the 5-year period 4 50 2
1998
1999
2000
2001
2002
Year
Originally published in Martin C et al. Am J Health Syst Pharm. 2005;62: ©2005, American Society of Health-System Pharmacists, Inc. All rights reserved. Reprinted with permission. (R0727).
Martin C, Ofotokun I, Rapp R, et al. Results of an antimicrobial control program at a university hospital. Am J Health Syst Pharm. 2005;62:

51. Beyond Antimicrobial Stewardship
12 Steps to Prevent Antimicrobial Resistance in Hospitalized Adults
PREVENT INFECTION
1. Vaccinate
2. Get the catheters out
DIAGNOSE AND TREAT INFECTION EFFECTIVELY
3. Target the pathogen
4. Access the experts
Prevent Infection
Diagnose And Treat Infection
Use Antimicrobials Wisely
Prevent Transmission
USE ANTIMICROBIALS WISELY
5. Practice antimicrobial control
6. Use local data
7. Treat infection, not contamination
8. Treat infection, not colonization
9. Know when to say “no” to vanco
10. Stop treatment when infection is cured or unlikely
Beyond Antimicrobial Stewardship
Key point: Antimicrobial stewardship is one of many strategies to decrease
antimicrobial resistance. Other factors include many aspects of simple
infection control.
Infection control
The CDC has published a 12-step fact sheet to prevent antimicrobial resistance among hospitalized patients, including1
Infection prevention such as vaccinations and optimized care
Effective diagnosis and treatment
Targeted treatment with input from experts
Wise use of antimicrobials, including application of local antibiogram data
Transmission prevention, including infection control and hand hygiene
Importance of avoiding treatment when bacterial infection is unlikely, or present but likely to resolve without therapy2
Common cold
Coughs and bronchitis
Acute otitis media in children
PREVENT TRANSMISSION
11. Isolate the pathogen
12. Break the chain of contagion
CDC. Available at: Released November Accessed August 2, 2007.
1. Available at: Released November Accessed August 2, 2007.
2. South M, Royle J, Starr M. A simple intervention to improve hospital antibiotic prescribing. Med J Aust. 2003;178: