Review

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Antimicrobial stewardship
programs: interventions and
associated outcomes
Expert Rev. Anti Infect. Ther. 6(2), 209–222 (2008)

Dimple Patel,
Wendy Lawson and
B Joseph Guglielmo†
† hospital epidemiologists is considered optimal. Recommended stewardship interventions
Author for correspondence
University of California,
San Francisco School of
Pharmacy, 521 Parnassus
Avenue, C-152,
San Francisco, CA 94143,
USA
Tel.: +1 415 476 2354
Fax: +1 415 476 6632
guglielmoj@
pharmacy.ucsf.edu
Guidelines regarding antimicrobial stewardship programs recommend an infectious diseases-
trained physician and an infectious diseases-trained pharmacist as core members. Inclusion of
clinical microbiologists, infection-control practitioners, information systems experts and
include prospective audit and intervention, formulary restriction, education, guideline
development, clinical pathway development, antimicrobial order forms and the de-escalation
of therapy. The primary outcome associated with these interventions has been the associated
cost savings; however, few published investigations have taken into account the overall cost of
the intervention. Over the past 5 years, there has been an increased focus upon interventions
intended to decrease bacterial resistance or reduce superinfection, including infections
associated with Clostridium difficile colitis. Few programs have been associated with a
reduction in antimicrobial drug adverse events. Antimicrobial stewardship programs are
becoming increasingly associated with clear benefits and will be integral in the in-patient
healthcare setting.

KEYWORDS: adverse reaction • antimicrobial stewardship • cost • outcome • resistance • superinfection

Considering the substantial antimicrobial programs. In addition, it is recommended that

acquisition costs, adverse reactions, bacterial
resistance and superinfections, the formation
of antimicrobial stewardship programs has
been recommended. The Infectious Diseases
Society of America/Society for Healthcare Epi-
demiology of America (IDSA/SHEA) Guide-
lines for Antimicrobial Stewardship were pub-
lished in 2007 [1]. According to these
guidelines, an institutional antimicrobial
stewardship program should include an infec-
tious diseases-trained physician and an infec-
tious diseases-trained pharmacist as core mem-
bers, with the inclusion of a clinical
microbiologist, an infection control practi-
tioner, an information systems expert and a
hospital epidemiologist considered optimal.
The guidelines consider the following factors
to be essential: a strong link between infection
control and the pharmacy and therapeutics
committee, the support of hospital administra-
tion, medical-staff leadership and local pro-
viders, as well as support from hospital
administration in the development and ongo-
ing maintenance of antimicrobial stewardship
the infectious diseases physician and the direc-
tor of pharmacy negotiate with hospital
administration for sufficient monetary sup-
port. In general, the guidelines recommend
two general approaches toward antimicrobial
stewardship. These include prospective audit
with intervention and feedback and formulary
restriction and pre-authorization. Potential
supplemental activities include education,
development of clinical guidelines and path-
ways, and the use of antimicrobial order
forms. Additional supplemental activities
include antimicrobial cycling, decreased use of
combination antibacterial therapy, streamlin-
ing or de-escalation of empirical therapy, dose
optimization and parenteral-to-oral conver-
sion. Healthcare information technology,
computer-based surveillance and a strong role
of the clinical microbiology laboratory are all
integral. Finally, process and outcomes meas-
ures should be used to determine the impact
of the stewardship intervention. The
IDSA/SHEA review summarizes the
cost–benefit of such programs to be associated

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 Review Patel, Lawson & Guglielmo
with a 22–36% reduction in antimicrobial use and an associ-
ated decrease of US$200,000–900,000 in institutions, ranging
from small community healthcare settings to large university
teaching hospitals.
Previous reviews have summarized the impact of various
stewardship interventions on antimicrobial use [2,3]. These
reviews include recommendations regarding the optimal com-
position of the stewardship team, associated roles within the
team and potential strategies to optimize antimicrobial use.
These recommendations are consistent with those expressed by
the IDSA/SHEA. Improvement in antimicrobial usage has
been stated in a number of published studies. A Cochrane
review has been completed regarding the interventions
intended to improve antimicrobial-prescribing practices [4].
The objective of this review was to estimate the effectiveness of
interventions in the promotion of prudent antimicrobial use
and to evaluate the impact of these interventions in reducing
the incidence of bacterial resistance, Clostridium difficile-
associated disease (CDAD) and other associated outcomes. Of
the 66 eligible studies, 51 (77%) showed an improvement in a
minimum of one outcome. Of these studies, six intended to
increase antibiotic use to prevent infection, 57 intended to
reduce antibiotic use and three intended to both increase and
decrease antibiotic use. Intervention targets included the deci-
sion to prescribe antimicrobials, the timing of the first dose,
the regimen (e.g., drug and dosing interval) and the duration
of treatment. In most instances, the target was the drug regi-
men, including the choice of agent and dose modification.
The most frequently reported outcome was associated with
changes in antimicrobial prescribing; changes in other out-
comes were reported less often. Of the six studies that
intended to increase treatment, five reported an improvement
in drug outcomes and one reported an improvement in clinical
outcome. Of the 60 studies aiming to reduce treatment, 47
reported drug outcomes (i.e., the decision to prescribe anti-
biotics, choice of drug, dose, route, frequency and duration of
therapy), of which, 38 (81%) significantly improved. A total
of 16 of the 60 studies reported microbiologic outcomes and
12 out of the 16 (75%) showed a significant improvement.
Nine studies reported clinical outcomes, of which, two signifi-
cantly deteriorated and three significantly improved. Of the
five studies intended to reduce the rate of CDAD, three dem-
onstrated improvement. While differences in study design lim-
ited the authors’ ability to perform metaregression, they con-
clude that interventions intended to improve antimicrobial
prescribing can be successful and may also reduce antimicro-
bial resistance or hospital-associated infection, including
CDAD. This review intends to update the status of antimicro-
bial stewardship programs (i.e., evaluate those investigations
that have been completed in the past 5 years). More specifi-
cally, the intent is to review the association of stewardship
interventions with specific outcomes, including those associ-
ated with cost, bacterial resistance and superinfection and
adverse drug events.
210
Methods
A search of the PubMed database was conducted to identify
published studies regarding antimicrobial stewardship inter-
ventions assessing costs, antimicrobial resistance, superinfec-
tion and adverse event outcomes. Previously published reviews
have reported the impact of antimicrobial stewardship pro-
grams, particularly upon antimicrobial usage. Our objective
was to review the impact of stewardship interventions, specifi-
cally with respect to the outcomes of interest (cost, resistance,
superinfection and adverse events). The time period of the
search was from January 2002 to November 2007. Search
terms included antimicrobial, antibiotic, management, con-
trol, stewardship, intervention, education, guidelines, restric-
tion, feedback, cost, savings, resistance, susceptibility, Clostrid-
ium difficile, superinfection, allergy, adverse events,
nephrotoxicity, pancytopenia, myalgia, arthralgia, hepatotoxic-
ity and seizure. Additional studies were identified by a review
of references of review papers and other publications. Each
identified study was included in the review if the full text was
readily accessible via PubMed and/or the University of Califor-
nia library system. Multicenter studies were excluded to
improve the assessment of the intervention effects as a func-
tion of the individual health-system model. Included studies
were subsequently categorized according to the following out-
comes: costs, resistance/superinfection and/or adverse events.
Specific data extracted from each study included hospital
demographics, members of the antimicrobial stewardship
team, specific intervention(s) and their impact upon on the
outcome of interest. When hospital demographics were una-
vailable in the study text, the institution website was searched
to obtain the relevant information. Stewardship interventions
were categorized as follows: education, guideline development,
restriction requiring approval, review and feedback, computer
assistance, and antimicrobial cycling.
Costs
TABLE 1 includes those studies [5–33] that evaluated the impact of
the stewardship intervention on cost outcomes. Cost data were
expressed as a reduction or increase in antimicrobial costs dur-
ing the intervention period. When the data were available, the
costs associated with the implementation and maintenance of
the intervention were also included.
Antimicrobial resistance & superinfection
TABLE 2 summarizes the studies that evaluated the impact of
the intervention on antimicrobial resistance or superinfec-
tion [8,10,12,13,16,19,21,22,24,25,28,29,32–41]. Changes in the rate of
antimicrobial resistance or superinfection were calculated as a
relative (as opposed to an absolute) change between the pre-
and postintervention time periods. In those instances in
which changes in resistance patterns were presented for mul-
tiple pathogens, only pathogens or antimicrobials that were
specifically targeted by the intervention were reported.
Expert Rev. Anti Infect. Ther. 6(2), (2008)

Table 1. Cost outcomes.
Setting
600-bed university-affiliated
teaching hospital
Pediatric department of Aker
University Hospital, Oslo,
Norway
860-bed private teaching
hospital
Hartford Hospital, Hartford,
CT, USA
900-bed university-affiliated
teaching hospital
Ninewells Hospital, Tayside,
Scotland, UK
250-bed public teaching
hospital
Hospital San Martin, Parana,
Argentina
470-bed veterans affairs
teaching hospital
Edward Hines Jr Veterans
Affairs Hospital, Hines, IL, USA
200-bed community teaching
hospital
Carney Hospital, Boston, MA,
USA
140-bed private general
hospital
Hospital Santa Luzia, Brazil
600-bed veterans affairs
teaching hospital
Louis Stokes Cleveland
Veterans Affairs Medical
Center, Cleveland, OH, USA
11-bed ICU of an 860-bed
general teaching hospital
Font Pre Hospital, Toulon,
France
464-bed teaching hospital
Cook County Hospital,
Chicago, IL, USA
120-bed community
nonteaching hospital
Regional Medical Center, West
Monroe, LA, USA
600-bed teaching hospital
Centre Hospitalier
Intercommunal de Creteil,
Creteil Cedex, France
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Key team members
Infection Control Committee
Pediatricians
Infectious diseases physician
Microbiologist
Infectious diseases physicians
Pulmonary physicians
Clinical pharmacists
Clinical pharmacists
Infectious diseases physician
Clinical microbiologist
Laboratory microbiologist
Pharmacists (two)
Internal medicine specialist
Computerized system analyst
Infectious diseases pharmacist
Infectious diseases physician
(quarter-time)
Infectious diseases pharmacist
(full-time)
Infectious diseases physicians
Infectious diseases physician
Infectious diseases pharmacist
ICU physicians
Infectious diseases pharmacist
Infectious diseases physician
Clinical pharmacists
Infection control members
Microbiologists
Infectious diseases physician
Pharmacist
Bacteriologist
Antimicrobial stewardship programs Review
Intervention Effect on Ref.
antimicrobial-related costs
Guideline development Outcome: 82% reduction in [5]
Education1 antimicrobial costs over 5 years
Cost of program: not provided
Guideline development Outcome: US$3267 reduction in total [6]
Review (automatic iv.- drug-related costs, costs related to
to-oral conversion)2 adverse effects and costs of hospital-
stay savings per patient eligible for
conversion
Cost of program: US$5.10/patient
Guideline development Outcome: GB£133,296 reduction in [7]
Education antibiotic costs over 2 years
Review and feedback3 Cost of program: GB£20,133 over
2 years
Education Outcome: US$913,236 reduction in [8]
Review (authority to antimicrobial costs over 18 months
modify orders)4 Cost of program: not provided
Education Outcome: US$68,931.61 (16%) [9]
Computer assistance reduction in antimicrobial costs
Automatic stop order per year
Restriction requiring Cost of program: not provided
approval5
Review and feedback6 Outcome: US$243,000–293,000 [10]
reduction in antimicrobial costs
per year
Cost of program: US$43,000 per year
Review and feedback7 Outcome: US$29,282 reduction in [11]
antimicrobial costs per year
Cost of program: not provided
Education Outcome: US$48,000 reduction in [12]
Guideline development antimicrobial costs over 3 years
Review and feedback8 Cost of program: not provided
Guideline development Outcome: 35% relative reduction in [13]
Education9 antibiotic costs over 4 years
Cost of program: not provided
Computer assistance Outcome: US$60,000 reduction in [14]
Review and feedback10 antimicrobial costs per year
Cost of program: US$11,520 per year
Review and feedback11 Outcome: $177,000 (19%) reduction [15]
in antimicrobial costs per year
Cost of program: not provided
Guideline development Outcome: 25% relative reduction in [16]
Education antibiotic costs over 4 years
Review and feedback12 Cost of program: not provided
211
 Review Patel, Lawson & Guglielmo

Table 1. Cost outcomes (cont.).

Setting Key team members Intervention Effect on Ref.
antimicrobial-related costs
250-bed pediatric Pediatric infectious Guideline Outcome: US$103,431 reduction in [17]
teaching hospital diseases physician development13 Third-generation cephalosporin costs
Royal Children’s Hospital, per year
Melbourne, Australia Cost of program: ∼US$2 per guideline
card
120-bed university-affiliated Clinical pharmacist Education Outcome: No reduction in [18]
teaching hospital Infectious diseases physician Guideline development antimicrobial costs per 12 weeks
Central Institute of the Valais Review and feedback14 Cost of program: not provided
Hospitals, Sion, Switzerland
730-bed community teaching Infectious diseases physician Restriction requiring Outcome: 20% relative reduction in [19]
hospital Infectious diseases pharmacist approval antimicrobial costs per month over
Pitt County Memorial Hospital, Review and feedback15 3 years
Greenville, NC, USA Cost of program: not provided
300-bed university hospital for Infectious diseases physician Guideline development Outcome: 545 Swiss franc (54%) [20]
geriatrics Hospital pharmacist Education reduction in antimicrobial costs per day
University Hospitals of Clinical pharmacologist Review and feedback16 Cost of program: not provided
Geneva, Geneva, Switzerland
80-bed rural teaching hospital Staff physician (head of Restriction requiring Outcome: US$100.20 (53%) reduction [21]
Department of Internal Department of Internal approval in antimicrobial-related costs per
Medicine of the Kantonsspital Medicine) Education patient
Schaffhausen, Schaffhausen, Guideline development Cost of program: US$20,000
Switzerland Review and feedback17 (development per implementation),
US$20,000 per year (maintenance)
Two community hospitals of a Infection Control Committee Antimicrobial cycling18 Outcomes: 31% increase per [22]
health system: Pharmacy & Therapeutics 1000 patient days during a 2-year
150-bed teaching Committee cycling period
The Cambridge Hospital, Cost of program: not provided
Cambridge, MA, USA
180-bed nonteaching
Somerville Hospital,
Somerville, MA, USA
279-bed university-affiliated, Infectious diseases pharmacist Education Outcome: US$110 reduction in [23]
urban teaching hospital Review and feedback19 antimicrobial acquisition costs
Detroit Receiving Hospital and per patient
University Health Center, Cost of program: not provided
Detroit, MI, USA
470-bed university-affiliated Infectious diseases physician Formulary change Outcome: US$1,401,126 reduction in [24]
teaching hospital Antimicrobial subcommittee – Restriction requiring antimicrobial costsper 4 years
University of Kentucky formulary decisions (members approval Cost of program: not provided
Chandler Medical Center, from surgery, pediatrics, Automatic stop order20
Lexington, KY, USA internal medicine,
transplantation, critical care,
infectious diseases, pharmacy
and nursing)
350-bed university-affiliated Infectious diseases physicians Education Outcome: US$32,231 reduction in [25]
teaching hospital Clinical microbiologist Review and feedback21 antimicrobial costs per year
Thammasart University Pharmacists (4) Cost of program: not provided
Hospital, Thailand Internists (2)
Hospital epidemiologist
Infection control specialist
Computer system analyst
110-bed veterans affairs Infectious diseases physicians Review and feedback22 Outcome: US$7.36 (9%) reduction in [26]
teaching hospital antimicrobial costsper
Veterans Affairs Hospital, patient admission
Louisville, KY, USA Cost of program: not provided

212 Expert Rev. Anti Infect. Ther. 6(2), (2008)

 Antimicrobial stewardship programs Review

Table 1. Cost outcomes (cont.).

Setting Key team members Intervention Effect on Ref.
antimicrobial-related costs
88-bed teaching hospital Staff pharmacists Automatic stop order23 Outcome: US$157,112.04 (28%) [27]
Sanatorio Adventista del Plata, Infection control department reduction in antimicrobial costs
Entre Rios, Argentina over 3 years
Cost of program: not provided
650-bed university-affiliated Infectious diseases physician Computer assistance Outcome: US$84,194 (22.8%) [28]
urban teaching hospital (0.5 full-time employee) Review and feedback24 reduction in antimicrobial costs per
University of Maryland Clinical pharmacist (0.8 full- 3 months for intervention arm
Medical Center, Baltimore, time employee) Cost of program: not provided
MD, USA
900-bed community teaching Infectious diseases physician: Education Outcome: US$1,841,203 reduction in [29]
hospital 30 h/month Review (automatic iv.- antimicrobial acquisition costs over
Presbyterian Hospital of Dallas, Clinical pharmacists (two): one to-oral conversion) 3 years
Dallas, TX, USA full-time employee Automatic stop order25 Cost of program: salaries for
Microbiologist: 0.25 full-time pharmacist, microbiologist
employee and physician
410-bed government-owned Infection control physician Review (automatic iv.- Outcome: € 66,190 (18%) reduction in [30]
acute secondary-care hospital Pharmacy services director to-oral conversion) antibiotic acquisition costs over 3 years
Hillel Yaffe Medical Center, Review and feedback Cost of program: not provided
Hadera, Israel Restriction
requiring approval26
960-bed university-affiliated Infectious diseases physicians Guideline development Outcome: € 4039.40 reduction in [31]
teaching hospital Education antimicrobial costs per 100 people
Hôpital Henri Mondor, Creteil, Review and feedback27 treated
France Cost of program: € 55.40 per
intervention
500-bed general hospital Clinical pharmacists Guideline development Outcome: € 29,288 (31%) reduction in [32]
Breclav Hospital, Breclav, Education antibiotic costs per year
Czech Republic Restriction requiring Cost of program: not provided
approval
28
Review and feedback
12-bed neurosurgical ICU in a Intensive-care physician Guideline Outcome: € 5.85 (44%) reduction in [33]
university-affiliated teaching Infection-control physician development29 antibiotic costs per patient day
hospital Microbiologist Cost of program: not provided
Neurosurgical Intensive Care Pharmacist
Unit of Freiburg University
Hospital, Freiburg, Germany
1
Guidelines were developed for the empirical treatment of common infectious diseases.
2
Criteria were developed for iv.-to-oral conversion of levofloxacin. Patients receiving iv. levofloxacin were identified by a pharmacy computer and followed daily. Pharmacists
automatically converted patients meeting criteria without contacting their physician.
3
Alert Antibiotics Policy was developed by a multidisciplinary team headed by a surgeon targeting carbapenems, iv. amphotericin, glycopeptides, iv. ciprofloxacin, linezolid,
piperacillin/tazobactam and third-generation cephalosporins. Clinical pharmacists disseminated guidelines for prescribing, identified inappropriate prescribing in their wards
and provided concurrent feedback to physicians when necessary.
4
Stepwise implementation of the program included the education of physicians on resistance associated with the overuse of 3rd generation cephalosporins and carbapenems,
mandatory use of an antibiotic order form and bedside reviews of antimicrobial prescribing with an authority to modify inappropriate orders.
5
Antimicrobial restriction was enforced, requiring approval via pager. The policy was enforced via dissemination of educational material and computerized alerts at the time of
physician order entry. A 7-day automatic stop order was imposed on all antimicrobials.
6
All antibiotic orders for iv. third-generation cephalosporins, aztreonam, fluoroquinolones and imipenem were evaluated daily. Recommendations for therapy changes were
placed in the chart.
7
Every patient in the 14-bed medical–surgical ICU with the suspicion of infection was evaluated daily by the infectious diseases physician, with the ICU physician.
Recommendations for therapy changes were provided in person.
8
Guidelines were developed to encourage appropriate use of iv. fluoroquinolones and vancomycin, and to decrease duplicative Gram-negative coverage with iv.
fluoroquinolones. Medicine house staff and students were educated monthly or semimonthly by the infectious diseases physician and pharmacist at a midday conference on
general principles in infectious diseases and on the guidelines. Each patient receiving iv. fluoroquinolones or vancomycin greater than 48 h was evaluated. Recommendations
for therapy changes were provided in person.
9
Guidelines for rational antibiotic use in the ICU were developed, requiring the reassessment of antibiotic use on days 3, 7 and 10, the use of oral route for fluoroquinolones for
patients meeting criteria and the limited use of aminoglycoside dual therapy. Educational meetings were held frequently for the ICU staff.
10
Computerized surveillance for redundant antibiotic combinations was instituted. Recommendations for therapy changes were made via telephone to the ordering prescriber.
11
Charts were concurrently reviewed 3 days per week for patients receiving multiple, prolonged or high-cost antimicrobials. Recommendations for therapy changes were
placed in the chart or made via telephone. A total of 8–12 h/week was required to provide this service for all identified patients.
12
Prescribing guidelines were developed and educational sessions were held for all physicians. The use of antibiotic order forms was implemented. All orders inconsistent with
the order forms were reviewed.
13
Laminated 9 × 6 cm cards suitable to clip on a hospital identification badge, which contained guidelines for appropriate antibiotic prescribing for 20 common and important
pediatric infections, were disseminated.

www.future-drugs.com 213
 Review Patel, Lawson & Guglielmo

14
Antimicrobial guidelines for iv.-to-oral switch were developed and physicians from selected wards were educated. Guidelines were reinforced by clinical pharmacists during
rounds for patients meeting the switch criteria.
15
An antimicrobial classification was developed whereby restricted agents required approval before dispensing and controlled agents were reviewed for their appropriateness
by an infectious disease pharmacist 2 days after being ordered. Recommendations for therapy changes were placed in the patient’s chart. The ordering physician was given a
24 h period to reject or accept. If the 24 h time period was exceeded, acceptance was assumed.
16
Guidelines (pocket cards) for appropriate antimicrobial use, with emphasis on urinary and respiratory infections, were disseminated, lectures on geriatric infectious diseases
were presented, and team members made weekly ward rounds, targeting individual physicians to provide counseling on antimicrobial therapy.
17
Mandatory approval by a staff physician was required for restricted drugs (ceftriaxone, ceftazidime, piperacillin/tazobactam, imipenem/cilastatin and vancomycin). An
educational program was developed for the medical staff, focusing on antimicrobial cost data, appropriate use, indications for early iv.-to-oral switch, and diagnosis and
treatment of common infectious diseases, weekly rounds with medical staff to evaluate antimicrobial therapy, biannual feedback to medical staff regarding antimicrobial costs,
and yearly provision of antimicrobial susceptibilities. Antimicrobial guidelines were disseminated via handbooks and the hospital intranet.
18
An antibiotic cycling protocol was implemented, whereby fluoroquinolones and β-lactams were alternatively cycled every 3 months for empiric therapy of all infections,
except meningitis, endocarditis, sexually transmitted infections or infections with pathogens presumed resistant. Protocol was distributed four-times annually by email to all
medical and pharmacy staff, posted on the hospital intranet and nursing stations. Educational sessions were held for medical, surgical and pharmacy staff prior to
implementation.
19
Education was provided to internal medicine and emergency medicine physicians on the treatment of community-acquired pneumonia and on the potential benefits of
conversion to oral therapy. Patients receiving iv. antibiotics for community-acquired pneumonia were identified daily. Pharmacist recommended or automatically converted
patients meeting criteria for oral therapy to an oral fluoroquinolone.
20
Ceftazidime and cefotaxime were removed from the formulary. The use of ceftriaxone, carbapenems and lipid formulations of amphotericin B was restricted and required
approval by the infectious diseases physician. Cefepime was added to the formulary. An automatic 72-h stop order was placed on vancomycin orders. Ciprofloxacin was
replaced by levofloxacin on the formulary.
21
A hospital antibiogram was introduced. Antibiotic prescription forms were developed. All orders for Third-generation cephalosporins, β-lactam/β-lactamase inhibitors,
glycopeptides and carbapenems were reviewed by the infectious diseases physician and rated for their appropriateness. Feedback was provided to each specialty service at
educational sessions. Educational training sessions were performed monthly for all medical students and residents, and every 4 months for all physicians.
22
All antimicrobial orders by internal medicine residents and general surgery residents were evaluated to determine compliance with hospital guidelines and the AMT provided
recommendations for noncompliant orders. The AMT provided feedback to physicians, including weekly reports on compliance with institutional guidelines and prescriber
acceptance of AMT recommendations, quarterly department-specific reports on compliance and a monthly newsletter outlining the feedback reports.
23
An automatic stop prophylaxis form was implemented for surgery, with extensive education of each surgeon as well as operating room, nursing and pharmacy staff. The
physician could call the pharmacy to request the continuation of an antibiotic if he deemed it necessary.
24
Computerized clinical decision support was added, allowing for modification of existing antimicrobial management program where patients on restricted antimicrobials were
identified and recommendations for therapy changes made if necessary. The software additionally alerted the team of patients with potential for iv.-to-oral conversion, of
potentially unnecessary double coverage or to organisms potentially resistant to current therapy.
25
Education was provided to the medical staff regarding the purpose and objectives of the antimicrobial management program. Pharmacists automatically converted eligible
patients from iv.-to-oral routes for highly bioavailable antimicrobials. Perioperative antimicrobial prophylaxis at 24 h for clean and clean-contaminated surgical procedures was
automatically discontinued. Use of antimicrobials with high risk for adverse events, high cost, high potential for promoting resistance, or drugs of last resort was restricted. All
restricted antimicrobials continued for greater than 48 h required infectious diseases consultation.
26
Eligible patients were automatically converted from iv.-to-oral routes for fluoroquinolones, clindamycin and metronidazole after 24 h. Conversion of iv. antibiotics to oral
antibiotics with similar spectra was recommended by the clinical pharmacists via direct interaction with the prescriber if patients met criteria for switching. The restricted
antibiotic authorization system was reorganized. The pharmacy director reviewed restricted antibiotic orders twice daily with the infection controller.
27
Recommendations on aminoglycoside use were updated, including dosing regimens, indications, and timing of drug level monitoring. Updates were disseminated to all staff
and junior physicians via educational sessions at each ward. Each aminoglycoside order was reviewed, and interventions were provided via counseling to the prescriber when
appropriate.
28
New guidelines for antibiotic prophylaxis were developed. An antibiotic restriction requiring approval of hospital antibiotic center was implemented. All new restricted
antibiotic orders were reviewed by clinical pharmacists. Interventions for inappropriate use were performed via education of prescribers on antimicrobial use and cost, microbial
susceptibilities and conversion to oral agents.
29
Guidelines were revised for duration of treatment of nosocomial pneumonia from 7–14 days and for community-acquired pneumonia from 10–14 days to 5 days.
Carbapenems were removed from recommendations for nosocomial pneumonia to encourage use of piperacillin/tazobactam.
ICU: Intensive-care unit; iv.: Intravenous.

Adverse events
TABLE 3 sumarizes those studies that showed the impact of
stewardship intervention on antimicrobial-related adverse events
[22,31]. Changes in the rates of adverse events were expressed
as a relative change between the pre- and postintervention
time periods.
Results
Outcomes associated with antimicrobial stewardship inter-
ventions are summarized in TABLES 1, 2 & 3. A total of 36 studies
were identified from the time period of interest and, subse-
quently, included in the analysis. Some studies evaluated
more than one of the outcomes of interest. In reviewing the
included studies, the composition of the stewardship team
could be determined. In 26 out of the 36 included investiga-
tions, a pharmacist was part of the stewardship team (USA:
15 out of 17; Europe: six out of 11; others: five out of eight).
Physicians were key members of the stewardship interven-
tions in 31 out of 36 of the studies (USA: 15 out of 17;
Europe: ten out of 11; others: six out of eight). Clinical
microbiologists and infection-control practitioners were
included less frequently (in seven and eight out of 36 of
reported studies, respectively). A total of 29 studies evaluated
the impact of the intervention on cost outcomes, and 22
assessed the impact upon bacterial resistance and/or super-
infection due to C. difficile. Of note, only two studies evalu-
ated the impact on the rate of adverse drug events. TABLE 1 dis-
plays these studies associated with evaluation of cost
outcomes. Of the identified studies, the majority of studies
examining cost outcomes originated from the USA or
Europe. Interestingly, only seven listed studies provided
information regarding the costs associated with the imple-
mentation and development of the stewardship intervention
program. Of the 29 identified studies, 27 reported a reduc-
tion in costs specifically associated with the intervention. In
most instances, cost savings were generally reported using a
decrease in total antimicrobial acquisition costs over time,
while some presented their findings per patient or patient day.
One study evaluating the effectiveness of a parenteral-to-oral

214 Expert Rev. Anti Infect. Ther. 6(2), (2008)

 Antimicrobial stewardship programs Review

Table 2. Antimicrobial resistance and superinfection outcomes.

Setting Key team members Intervention Effect on rates of antimicrobial resistance Ref.
and/or superinfection (expressed as relative
changes during intervention period)
250-bed public teaching Infectious diseases Education Third-generation cephalosporin resistance: [8]
hospital physician Review (authority to - Escherichia coli: NS/18 months
Hospital San Martin, Clinical microbiologist modify orders)1 - Klebsiella spp.: NS/18 months
Parana, Argentina Laboratory - Proteus mirabilis: 32.5% reduction/18 months
microbiologist - Enterobacter cloacae: 80% reduction/18 months
Pharmacists (two) Ampicillin/sulbactam resistance:
Internal-medicine - E. coli: NS/18 months
specialist Imipenem/cilastatin resistance:
- Pseudomonas aeruginosa: 100%
reduction/18 months
Cefepime resistance:
- P. aeruginosa: NS/18 months
Methicillin resistance:
- Staphylococcus aureus: 36.2%
reduction/18 months
200-bed community Infectious diseases Review and feedback2 Ceftazidime resistance: [10]
teaching hospital physician (quarter-time) - Enterobacteriaceae: ~60% reduction/7 years
Carney Hospital, Boston, Infectious diseases Clostridium difficile superinfection:
MA, USA pharmacist (full-time) - 36.4% reduction/7 years
600-bed veterans affairs Infectious diseases Education Ciprofloxacin resistance: [12]
teaching hospital physician Guideline development - P. aeruginosa: NS/3 years
Louis Stokes Cleveland Infectious diseases Review and feedback3
Veterans Affairs Medical pharmacist
Center, Cleveland, OH,
USA
11-bed ICU of an ICU physicians Guideline development Methicillin resistance: [13]
860-bed general teaching Education4 - S. aureus: 79% reduction/4 years
hospital Ceftazidime resistance:
Font Pre Hospital, Toulon, - Enterobacteriaceae: 52% reduction/4 years
France - P. aeruginosa: NS/4 years
Extended-spectrum β-lactamase-producing
organisms:
- Enterobacteriaceae: NS/4 years
800-bed hospital system Formulary change C. difficile superinfection: [34]
Preston Acute Hospitals iv.-to-oral conversion - NP (>50% reduction/5 years)
Trust, Preston, UK encouraged5
725-bed university- Infectious diseases Restriction requiring Vancomycin resistance: [35]
affiliated teaching physician approval6 - Enterococcus spp.: 70% increase/10 years
hospital Infectious diseases
Hospital of the University pharmacist
of Pennsylvania,
Philadelphia, PA, USA
600-bed teaching hospital Infectious diseases Guideline development Methicillin resistance: [16]
Centre Hospitalier physician Education - S. aureus: NS/4 years
Intercommunal de Creteil, Pharmacist Review and feedback7 Extended-spectrum β-lactamase-producing
Creteil Cedex, France Bacteriologist organisms:
- Enterobacteriaceae: 71% reduction/4 years
Ceftazidime resistance:
- P. aeruginosa: NS/4 years

www.future-drugs.com 215
 Review Patel, Lawson & Guglielmo

Table 2. Antimicrobial resistance and superinfection outcomes (cont.).

Setting Key team members Intervention Effect on rates of antimicrobial resistance Ref.
and/or superinfection (expressed as relative
changes during intervention period)
730-bed community Infectious diseases Restriction requiring Piperacillin/tazobactam, cefepime, ciprofloxacin, [19]
teaching hospital; physician approval gentamicin and imipenem/cilastatin resistance:
Pitt County Memorial Infectious diseases Review and feedback8 - E. coli: NS/3 years
Hospital, Greenville, NC, pharmacist - P. aeruginosa: NS/3 years
USA - K. pneumoniae: NS/3 years
- Serratia marcescens: NS/3 years
- Enterobacter spp.: NS/3 years
Oxacillin resistance:
- S. aureus (ICU): 15.3% reduction/3 years
- S. aureus (non-ICU): 20.5% increase/3 years
580-bed university- Elderly care service Guideline development C. difficile superinfection [36]
affiliated teaching Education9 31% reduction/10 months
hospital;
Elderly Care Service at
Cork University Hospital,
Cork, Ireland
80-bed rural teaching Staff physician (head of Restriction requiring NS/7 years for all organisms and all [21]
hospital; Department of Internal approval antimicrobials reported
Department of Internal Medicine) Education
Medicine of the Guideline development
Kantonsspital Review and feedback10
Schaffhausen,
Schaffhausen,
Switzerland
Two community hospitals Infection Control Antimicrobial cycling11 The Cambridge Hospital [22]
in a health system: Committee Ceftazidime resistance:
150-bed teaching Pharmacy & - Gram-negative organisms: 63%
The Cambridge Hospital, Therapeutics Committee reduction/2 years
Cambridge, MA, USA Cefotaxime resistance:
180-bed nonteaching - Gram-negative organisms: 44%
Somerville Hospital, reduction/2 years
Somerville, MA, USA Levofloxacin, piperacillin/tazobactam and
ticarcillin/clavulanate resistance:
- Gram-negative organisms: NS/2 years
Vancomycin resistance:
- Enterococcus spp.: 80% reduction/2 years
Methicillin resistance:
- S. aureus: NS/2 years
C. difficile superinfection: NS/2 years
Somerville Hospital:
NS/2 years for all organisms and all antimicrobials
reported
560-bed university- Infectious diseases Automatic stop order Vancomycin-resistant Enterococcus infection: [37]
affiliated teaching physician Review and feedback - hospital-wide: NS/5 years
hospital Infectious diseases Guideline - ICU: 65% reduction/5 years
University of California pharmacists development 12
San Francisco Medical
Center, San Francisco,
CA, USA
470-bed university- Infectious diseases Formulary change Piperacillin/tazobactam resistance: [24]
affiliated teaching physician Restriction requiring - P. aeruginosa: NP (17% reduction/4 years)
hospital Antimicrobial approval Ceftazidime resistance:
13
University of Kentucky subcommittee – Automatic stop order - P. aeruginosa: NP (5% reduction/4 years)
Chandler Medical Center, formulary decisions - K. pneumoniae: NP (91% reduction/4 years)
Lexington, KY, USA (members from surgery, Carbapenem resistance:
pediatrics, internal - P. aeruginosa: NP (36% reduction/4 years)
medicine, Fluoroquinolone resistance:
transplantation, critical - P. aeruginosa: NP (13% increase/4 years)
care, infectious diseases, Methicillin resistance:
pharmacy and nursing) - S. aureus: NP (23% reduction/4 years)

216 Expert Rev. Anti Infect. Ther. 6(2), (2008)

 Antimicrobial stewardship programs Review

Table 2. Antimicrobial resistance and superinfection outcomes (cont.).

Setting Key team members Intervention Effect on rates of antimicrobial resistance Ref.
and/or superinfection (expressed as relative
changes during intervention period)
350-bed university- Infectious diseases Education Methicillin resistance: [25]
affiliated teaching physicians Review and feedback14 - S. aureus: 30% reduction/year
hospital Clinical microbiologist ESBL-producing organisms:
Thammasart University Pharmacists (four) - E. coli: 36% reduction/year
Hospital, Thailand Internists (two) - K. pneumoniae: 33% reduction/year
Hospital epidemiologist Third-generation cephalosporin resistance:
Infection-control - Acinetobacter baumannii: 30% reduction/year
specialist Imipenem resistance:
Computer-system - P. aeruginosa: NS/year
analyst Multidrug resistance
- A. baumannii: NS/year
920-bed teaching hospital Infectious diseases Guideline development Ciprofloxacin resistance: [38]
Shin Kong Wu Ho-Su physicians Restriction requiring - P. aeruginosa: 55% reduction/3 months
Memorial Hospital, Taipei, Infection control approval15 - Serratia spp.: 65% reduction/3 months
Taiwan professional NS/3 months for all other organisms and
Clinical pharmacist antimicrobials reported
650-bed university- Infectious diseases Computer assistance C. difficile superinfection: [28]
affiliated urban teaching physician (0.5 full-time Review and feedback16 - NS/3 months
hospital employee)
University of Maryland Clinical pharmacist
Medical Center, (0.8 full-time employee)
Baltimore, MD,USA
900-bed community Infectious diseases Education Ceftazidime resistance: [29]
teaching hospital physician: 30 h/month Review (automatic iv.- - K. pneumoniae: 73% reduction/3 years
Presbyterian Hospital of Clinical pharmacists to-oral conversion) - E. coli:
Dallas, Dallas, TX, USA (two): one full-time Automatic stop order17 - Urinary: 2% increase/3 years
employee Cefepime resistance:
Microbiologist: 0.25 - E. coli:
full-time employee - Nonurinary: 2% increase/3 years
Ceftriaxone resistance:
- K. pneumoniae: 75% decrease/3 years
Cefuroxime resistance:
- K. pneumoniae: 68% decrease/3 years
Levofloxacin resistance:
- K. pneumoniae: 78% decrease/3 years
NS/3 years for all other organisms and
antimicrobials reported
Geriatric wards of a Guideline development C. difficile superinfection: [39]
1200-bed teaching Feedback18 - 65% reduction/2 years
hospital
500-bed general hospital Clinical pharmacists Guideline development NS/3 years for all organisms and antimicrobials [32]
Breclav Hospital, Breclav, Education reported
Czech Republic Restriction requiring
approval
Review and feedback19
12-bed neurosurgical Intensive-care physician Guideline Oxacillin resistance: [33]
intensive care unit in a Infection-control development20 - S. aureus: 65% reduction/2 years
university-affiliated physician NS/2 years for all other organisms and
teaching hospital Microbiologist antimicrobials reported
Neurosurgical Intensive Pharmacist
Care Unit of Freiburg
University Hospital,
Freiburg, Germany

www.future-drugs.com 217
 Review Patel, Lawson & Guglielmo

Table 2. Antimicrobial resistance and superinfection outcomes (cont.).

Setting Key team members Intervention Effect on rates of antimicrobial resistance Ref.
and/or superinfection (expressed as relative
changes during intervention period)
683-bed university- Infectious diseases Education C. difficile superinfection: [40]
affiliated teaching physicians Guideline development - 60% reduction/2 years
21
hospital Infectious diseases Review and feedback
Centre Hospitalier pharmacists
Universitaire de
Sherbrooke, Quebec,
Canada
834-bed university- Infectious diseases Education C. difficile superinfection: [41]
affiliated teaching physicians Review and feedback - 58% reduction/6 years
hospital Infectious diseases Infection control
University of Pittsburgh pharmacists Restriction requiring
Medical Center- approval22
Presbyterian, Pittsburgh,
PA, USA
1
Stepwise implementation of the program included education of physicians on resistance associated with overuse of third-generation cephalosporins and carbapenems,
mandatory use of an antibiotic order form and bedside reviews of antimicrobial prescribing with authority to modify inappropriate orders.
2
All antibiotic orders for iv. third-generation cephalosporins, aztreonam, iv. fluoroquinolones and imipenem were evaluated daily. Recommendations for therapy changes were
placed in the patient’s chart.
3
Guidelines were developed to encourage the appropriate use of iv. fluoroquinolones and vancomycin and to decrease duplicative Gram-negative coverage with iv.
fluoroquinolones. Medicine housestaff and students were educated monthly or semimonthly by the infectious diseases physician and pharmacist at noon conference on
general principles in infectious diseases and on the guidelines. Each patient receiving iv. fluoroquinolones or vancomycin for greater than 48 h was evaluated.
Recommendations for therapy changes were provided in person.
4
Guidelines for rational antibiotic use in the ICU were developed, requiring reassessment of antibiotic use on days 3, 7 and 10, the use of oral route for fluoroquinolones for
patients meeting criteria and the limited use of aminoglycoside dual therapy. Educational meetings were held frequently for the ICU staff.
5
Cefotaxime was replaced by ceftriaxone. Implementation of an early iv.-to-oral switch policy was intended to minimize iv. cephalosporin use. A policy for restricted duration of
ceftriaxone was developed. Ceftriaxone was later replaced by levofloxacin.
6
A progressive restriction policy was implemented, eventually requiring approval for all uses of vancomycin and the full restriction of third-generation cephalosporins.
7
Prescriber guidelines were developed, and educational sessions were held for all physicians. The use of antibiotic order forms were implemented. All orders inconsistent with
the order forms were reviewed.
8
An antimicrobial classification was developed where restricted agents required approval before dispensing and controlled agents were reviewed for their appropriateness by an
infectious disease pharmacist 2 days after being ordered. Recommendations for therapy changes were placed in the patient’s chart. The ordering physician was given 24 h to
reject or accept. If 24 h was exceeded, acceptance was assumed.
9
The antibiotic policy was revised to restrict the use of iv. second- or third-generation cephalosporins to specific indications, discouraging their use when other agents
were available.
10
Mandatory approval by a staff physician was required for restricted drugs (ceftriaxone, ceftazidime, piperacillin–tazobactam, imipenem–cilastatin and vancomycin). An
educational program was developed for the medical staff focusing on antimicrobial cost data, appropriate use, indications for early iv.-to-oral switch and diagnosis and
treatment of common infectious diseases. Weekly rounds with medical staff to evaluate antimicrobial therapy, biannual feedback to medical staff regarding antimicrobial costs
and yearly provision of antimicrobial susceptibilities were included. Antimicrobial guidelines were disseminated via handbooks and the hospital intranet.
11
An antibiotic cycling protocol was implemented, where fluoroquinolones and β-lactams were alternatively cycled every 3 months for empiric therapy of all infections, except
meningitis, endocarditis, sexually transmitted infections or infections with presumed resistant pathogens. Protocol was distributed four-times anually by email to all medical and
pharmacy staff, posted on the hospital intranet and nursing stations. Educational sessions were held for all medical, surgical and pharmacy staff prior to implementation.
12
A 72-h automatic stop order was implemented on all empiric vancomycin orders in the absence of resistant Gram-positive infections or serious β-lactam allergies. All critically
ill patients receiving vancomycin for greater than 72 h were evaluated. Recommendations for therapy changes were made in person. A blood-culture protocol was developed
to minimize the inappropriate use of vancomycin.
13
Ceftazidime and cefotaxime were removed from the formulary. The use of ceftriaxone, carbapenems and lipid formulations of amphotericin B was restricted and required
approval by the infectious diseases physician. Cefepime was added to the formulary. An automatic 72-h stop order was placed on vancomycin orders. Ciprofloxacin was
replaced by levofloxacin on the formulary.
14
A hospital antibiogram was introduced. Antibiotic prescription forms were developed. All orders for third-generation cephalosporins, β-lactam/β-lactamase inhibitors,
glycopeptides and carbapenems were reviewed by the infectious diseases physician and rated for their appropriateness. Feedback was provided to each specialty service at
educational sessions. Educational training sessions were performed monthly for all medical students and residents and every 4 months for all physicians.
15
A guideline was implemented limiting the duration of use of any parenteral antimicrobials to 14 days and duration of use of postsurgery prophylactic antimicrobials to 3 days.
Approval was required for all prophylactic antibiotics for surgery required approval and for all second- and third-line parenteral antimicrobials.
16
Computerized clinical decision support was added, allowing for the modification of existing antimicrobial management programs where patients on restricted antimicrobials
were identified and recommendations for therapy changes were made if necessary. The software additionally alerted the team of patients with potential for iv.-to-oral
conversion, to potentially unnecessary double coverage, or to organisms potentially resistant to current therapy.
17
Education was provided for the medical staff regarding the purpose and objectives of the antimicrobial management program. Pharmacists automatically converted eligible
patients from iv.-to-oral routes for highly bioavailable antimicrobials. Perioperative antimicrobial prophylaxis at 24 h for clean and clean-contaminated surgical procedures was
automatically discontinued. Use of antimicrobials with high risk for adverse events, high cost, high potential for promoting resistance or drugs of last resort was restricted. All
restricted antimicrobials continued for greater than 48 h required infectious diseases consultation.
18
A new policy was developed recommending reduced use of amoxicillin/clavulanate and further restriction of cephalosporin use. Feedback of antibiotic usage, rates of
C. difficile infection and rates of methicillin-resistant S. aureus infection was provided to physicians every 8–12 weeks.
19
New guidelines for antibiotic prophylaxis were developed. An antibiotic restriction requiring approval of the hospital antibiotic center was implemented. All new restricted
antibiotic orders were reviewed by clinical pharmacists. Interventions for inappropriate use were performed via education of prescribers on antimicrobial use and cost, microbial
susceptibilities and conversion to oral agents.
20
Guidelines were revised for the duration of treatment of nosocomial pneumonia from 14 to 7 days and for community-acquired pneumonia from 10–14 days to 5 days.
Carbapenems were removed from recommendations for nosocomial pneumonia to encourage use of piperacillin/tazobactam.
21
Infection control procedures were strengthened. Local guidelines for empirical treatment of common infections were developed and disseminated via pocket cards and
educational lectures. The guidelines targeted reducing the use of second- and third-generation cephalosporins, ciprofloxacin, clindamycin and macrolides. Recommendations
for therapy changes were made via telephone.

218 Expert Rev. Anti Infect. Ther. 6(2), (2008)


22
A ‘bundle’ approach was implemented in response to a C. difficile outbreak. Education was provided by means of an electronic module. Primary-care nurses were given
authority to order C. difficile testing to expedite early case finding and therapy initiation. Infection-control measures were heightened. A C. difficile-management team was
established to evaluate all toxin-positive patients in near real time. In addition, a formal antimicrobial management program was developed, targeting restriction of clindamycin,
ceftriaxone and levofloxacin, requiring approval for use.
ESBL: Extended-spectrum β-lactamase; iv.: Intravenous; ICU: Intensive-care unit; NP: Not provided (regarding statistical signifcance); NS: Non-significant effect (statistically
significant difference not detected).
switch was unable to demonstrate a reduction in costs over a
12-week time period [18]. Notably, one study reported an
increase in antimicrobial acquisition costs associated with the
intervention [22]. In this latter investigation, antimicrobial
cycling was performed over a 2-year time period. The investi-
gators observed a 31% increase per 1000 patient-days in two
community hospitals in a healthcare system.
TABLE 2 summarizes those studies intended to change the rate
of bacterial resistance or superinfection. A total of 22 studies
were identified that evaluated this study outcome. The
majority of the included trials evaluated changes in bacterial
resistance, ranging from methicillin-resistant Staphylococcus
aureus to multidrug-resistant Gram-negative infections. In
most studies, changes in susceptibility were reported for mul-
tiple organisms. In six investigations, the primary outcome of
interest was the rate of CDAD. One study evaluated the
impact of the program for both CDAD and changes in the
rate of bacterial resistance. Of the listed studies, most
reported positive findings (i.e., a decrease in the rate of bacte-
rial resistance or CDAD was observed). When reduction in
the rate of CDAD was observed, the antimicrobial steward-
ship intervention was also generally associated with addi-
tional changes in infection control. As an example, one medi-
cal center noted an increase in the rate of CDAD from 2.7 to
7.2 per 1000 patient-days [41]. In response, a ‘bundle’ inter-
ventional approach took place, including education, early and
increased identification of patients, improved infection-con-
trol procedures, development of a CDAD control team and
antimicrobial control centered upon clindamycin, ceftriaxone
and levofloxacin. The results of this bundle approach
included a decrease of 41% in targeted antimicrobial therapy,
a reduction in the rate of CDAD to 3.0 per 1000 patient
days, and a decrease in the percentage of hypervirulent
C. difficile from 51% of all CDAD cases to 13%.
Interestingly, only two trials were identified that assessed the
impact of an intervention on antimicrobial adverse events; one
demonstrated no increase in the observation of adverse events
in a study of antimicrobial cycling, where the primary intent
was a reduction in bacterial resistance [22]. Only one trial used
adverse events as the primary outcome [31]. In this investiga-
tion, a team of infectious diseases physicians, using guideline
development, education, review and feedback, reduced the rate
of nephrotoxicity over 1 year.
In most studies, pharmacists and physicians were the key
members of the antimicrobial stewardship team. The major-
ity of trials utilized multiple interventions to achieve the pri-
mary outcome. In general, those techniques demonstrating
the most benefit in terms of reduction in antimicrobial-related
costs and antimicrobial resistance, and the incidence of CDAD
www.future-drugs.com
Antimicrobial stewardship programs Review
were prospective antimicrobial order reviews with concurrent
feedback, guideline development and regular physician edu-
cation. Of note, antimicrobial cycling was associated with a
substantial increase in antimicrobial costs [22].
Discussion
Numerous organizations, including the IDSA/SHEA, have
recommended the use of antimicrobial stewardship teams to
ensure the safe, effective and appropriate use of antimicrobi-
als. These recommendations, together with the findings of
our review document that infectious diseases-trained physi-
cians and infectious diseases-trained pharmacists are the most
commonly used members of the stewardship team. However,
it is clear that the contributions of microbiologists, infection-
control practitioners and computer-system support profes-
sionals are important as these members constitute the opti-
mal team. As others have suggested [2], publication bias prob-
ably exists with respect to the outcomes associated with
antimicrobial stewardship team interventions. In other
words, studies with negative results are less likely to be pub-
lished than those associated with positive outcomes. Thus, it
is not surprising that the majority of published investigations
report positive results. While the possibility of publication
bias probably exists, consistent cost savings, improvements in
bacterial resistance, and a decreased rate of CDAD have been
associated with such programs. While the published results
regarding cost outcomes are encouraging, in most instances
the true cost of the intervention is unknown. In order to
assess the true ‘net’ cost avoidance, associated with such stew-
ardship program interventions, it is clear that these associated
program costs must be included in the analysis. Similarly,
interventions intended to decrease bacterial resistance or hos-
pital-associated infections should take into account costs
associated with the intervention. The costs and resources
required to implement and maintain an intervention are
essential components of cost–benefit analysis; such analyses
are necessary in establishing sufficient hospital administra-
tion support to institute a successful stewardship program.
Resources that should be incorporated in these analyses
include stewardship team-member salaries, costs of required
equipment and computer programs and expenses associated
with the development and distribution of educational materi-
als. Changes in bacterial resistance or CDAD are difficult to
unequivocally link solely with antimicrobial stewardship
interventions. In most instances, changes in infection control
procedures were implemented at the same time as the antimi-
crobial interventions. As an example, the most recent investi-
gation regarding the successful control of the hypervirulent
219
 Review Patel, Lawson & Guglielmo

Table 3. Adverse event outcomes.

Setting Key team members Intervention Relative effect on adverse Ref.
antimicrobial events
Two community Infection Control Antimicrobial cycling* Adverse events: NS/2-year cycling period [22]
hospitals of a health Committee
system: Pharmacy & Therapeutics
150-bed teaching Committee
180-bed nonteaching
The Cambridge
Hospital, Cambridge,
MA, USA
Somerville Hospital,
Somerville, MA, USA
960-bed university- Infectious diseases Guideline development Nephrotoxicity: 73% reduction every year [31]
affiliated teaching physicians Education
hospital Review and feedback‡
Hôpital Henri Mondor,
Creteil, France
*
An antibiotic cycling protocol was implemented where fluoroquinolones and β-lactams cycled alternatively every 3 months for empiric therapy of all infections except
meningitis, endocarditis, sexually transmitted infections or infections with presumed resistant pathogens. Protocol was distributed quarterly by email to all medical and
pharmacy staff, posted on the hospital intranet and nursing stations. Educational sessions were held for medical, surgical and pharmacy staff prior to implementation.
‡
Recommendations on aminoglycoside use were updated, including dosing regimens, indications and timing of drug-level monitoring. Updates were disseminated to
all staff and junior physicians via educational sessions at each ward. Each aminoglycoside order was reviewed and interventions were provided via counseling to the
prescriber when appropriate.

strain of C. difficile used a combination of antimicrobial
interventions and enhanced infection control [41]. With
respect to interventions intended to reduce antimicrobial-
associated adverse events, only one investigation was found
and it centered upon aminoglycoside nephrotoxicity. The
paucity of investigations centered upon adverse events is
probably a result of the decreased use of the nephrotoxic and
ototoxic aminoglycoside antimicrobials in favor of β-lactams
and fluoroquinolones. However, over the more recent years
reliance upon these less toxic agents has also been associated
with increases in bacterial resistance and CDAD. In light of
these findings, the use of aminoglycosides may increase. As
noted previously, physician education was among those inter-
ventions reported to show the most benefit in terms of a
reduction in costs, antimicrobial resistance and incidence of
CDAD. One study sought to survey clinicians in order to
determine their perceptions of various issues related to anti-
microbial resistance. The results showed that clinicians per-
ceived antimicrobial resistance to be less pertinent to their
own institutions, but rather, a complicated problem on a
national level [42]. On the contrary, antimicrobial resistance is
a widespread issue at the institutional level and clinicians must
fully appreciate strategies in order to reduce antimicrobial
resistance selection pressure.
Conclusion
This review on the impact of antimicrobial stewardship pro-
grams underscores and reinforces the conclusions of the
IDSA/SHEA and others. The past 5 years have been associated
with additional studies demonstrating favorable outcome asso-
ciated with stewardship interventions. The most clearly linked
outcomes associated with such programs has been cost savings;
however, inclusion of the true costs of the implementation of
such interventions must also be part of any such analysis. Simi-
larly, intervention programs improve bacterial resistance and
reduce CDAD, but this is generally only in concert with infec-
tion-control procedures. Nonetheless, antimicrobial steward-
ship programs are associated with clear value and will be
increasingly integral in the inpatient healthcare setting.
Expert commentary
Antimicrobial stewardship programs should be considered
mandatory for any inpatient hospital setting. The optimal
stewardship team should include representatives from infec-
tious diseases, pharmacy, microbiology and infection con-
trol. Hospital administration support is essential in order to
establish such a team. Vigilant tracking of antimicrobial
costs, resistance pattern and the rate of CDAD, must take
place to allow the team to responsively address and inter-
vene. In addition, documentation of the associated out-
comes should consistently take place in order to confirm the
cost–benefit of such programs.
Five-year view
The use of antimicrobial stewardship teams will continue to
grow in the acute care setting. In larger hospitals, the likely
composition of the team will be infectious diseases-trained
physicians and infectious diseases-trained pharmacists.
However, in smaller facilities, cost efficiencies will probably
result in the use of internists and pharmacist generalists. In
contrast to the current situation, clinical microbiologists,

220 Expert Rev. Anti Infect. Ther. 6(2), (2008)

 Antimicrobial stewardship programs Review

infection-control practitioners and computer-support

experts will increasingly serve as core members of such
teams. Assessment of the costs associated with such a pro-
gram will be mandatory, particularly for those interventions
associated with cost avoidance. Antimicrobial stewardship
interventions intended to reduce bacterial resistance or hos-
pital-associated infections will probably be linked with
infection-control interventions.
Financial & competing interests
The authors have no relevant affiliations or financial involvement with
any organization or entity with a financial interest in or financial conflict
with the subject matter or materials discussed in the manuscript. This
includes employment, consultancies, honoraria, stock ownership or options,
expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.

Key issues
• Antimicrobial stewardship programs offer value to acute-care hospital settings.
• Professional societies have established guidelines regarding the development of stewardship programs.
• While the inclusion of microbiology, infection-control and systems-support experts is optimal, the most commonly included members
of the stewardship team are infectious diseases-trained physicians and infectious diseases-trained pharmacists.
• The most likely outcomes associated with stewardship programs are cost avoidance, a reduction in bacterial resistance and a decrease
in Clostridium difficile-associated disease.
• Interventions intended to reduce bacterial resistance and Clostridium difficile-associated disease optimally include concomitant
infection-control interventions.
• The cost of such programs must be included in assessing the value of the intervention as there is currently a paucity of data that clearly
demonstrate a reduction in overall hospital costs.
• The use of informatics will optimally identify antimicrobial usage and bacterial-resistance trends.

5 Berild D, Ringertz SH, Aabyholm G, program conducted during 7 years. Infect.

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Affiliations
• Dimple Patel, Pharm.D, BCPS
University of California, San Francisco School
of Pharmacy, 521 Parnassus Avenue, C-152,
San Francisco, CA 94143, USA
Tel.: +1 415 514 9323
Fax: +1 415 514 2680
dimple.patel@ucsf.edu
• Wendy Lawson, BSc Hons. (Pharm)
Lead Pharmacist, Infectious Diseases,
Hammersmith Hospitals NHS Trust, Du
Cane Road, London, W12 OHS, UK
Tel: +44 208 346 1000
Fax: +44 208 746 1160
wendy.lawson@imperial.nhs.uk
• B Joseph Guglielmo, Pharm.D
University of California, San Francisco School
of Pharmacy, 521 Parnassus Avenue, C-152,
San Francisco, CA 94143, USA
Tel.: +1 415 476 2354
Fax: +1 415 476 6632
guglielmoj@pharmacy.ucsf.edu
Expert Rev. Anti Infect. Ther. 6(2), (2008)