605
Antimicrobial Stewardship
51  Conan MacDougall
Issues associated with use of antibiotics were recognized shortly after
their introduction into clinical medicine in the early 1940s. The intro-
duction of new antibiotics during the next decade saw increasing and
often inappropriate use of these agents. In his review of the subject in
1956, Jawetz1 was one of the first to recognize the problems caused by
the attractiveness of new antibiotics to physicians, the exaggerated
claims by the pharmaceutical industry, and the enormous impact
that promotion by the drug companies had on medical practice.
The problem has only worsened. In 2010, 258 million courses of anti-
biotics were prescribed to outpatients in the United States, a rate of
833 per 1000 population.2 Approximately 60% of all hospitalized
patients in the United States receive at least one dose of an antibacterial
drug during hospitalization.3 About 50% of this use is considered
unnecessary or otherwise inappropriate.4,5 Among the unwanted con-
sequences of antimicrobial therapy are adverse reactions, increased
morbidity and mortality, increased length of stay, increased cost of
hospitalization, predisposition to secondary infections, and the emer-
gence of drug-resistant microorganisms.6 Antimicrobial drug use is
at least partially responsible for the rising incidence of serious infec-
tions caused by methicillin- and glycopeptide-resistant Staphylococcus
aureus, vancomycin-resistant enterococci (VRE), extended-spectrum
β-lactamase–producing Enterobacteriaceae, multidrug-resistant Pseu-
domonas aeruginosa and Acinetobacter spp., and Klebsiella spp. express-
ing Klebsiella pneumoniae carbapenemases, as well as the proliferation
of more virulent strains of Clostridium difficile.7-9 Development of
novel antimicrobial agents active against these resistant organisms
has not kept pace with their proliferation; thus, more effective use of
current agents is essential to preserve the value that antimicrobials
provide to modern medicine.10
ANTIMICROBIAL STEWARDSHIP
The ideas that antimicrobial drugs are in a different class from all other
pharmaceuticals because their use in one patient has the potential for
adverse consequences in other patients who have not received them,
and that the usefulness of these drugs is declining as their use increases,
gave rise to the term “stewardship” in 1996 to draw attention to these
unique characteristics.11 Programs designed to increase the appropri-
ateness of antimicrobial use in hospitals had been described since the
1970s and were commonly referred to as antimicrobial “management”
or “control” programs.12,13 The focus of these programs tended to be
financial because antibiotic expenditures accounted for as much as
30% to 50% of a hospital’s total drug budget.14 The currently preferred
term, antimicrobial stewardship, serves to emphasize the special status
of this class of drugs.
The focus of these programs is improvement in the quality of
patient care, with the primary goals of improving clinical outcomes
and stabilizing or reducing rates of resistance. Support for antimicro-
bial stewardship programs (ASPs) in hospitals received a major boost
in 2007 with the publication of stewardship guidelines from the Infec-
tious Diseases Society of America (IDSA) and the Society for Health-
care Epidemiology of America (SHEA).15 This chapter reviews
antimicrobial stewardship strategies that have been reported in the
literature, summarizes their goals and the clinical and institutional
outcomes of these efforts, and ends with recommendations for the
development, implementation, and funding of a successful ASP.
PHILOSOPHY OF
ANTIMICROBIAL USE
To address the problem of inappropriate antimicrobial usage, we first
must understand the constraints under which physicians work and the
pressures that are exerted on them to prescribe drugs. The prescription
of antibiotics has become as much of a psychological or philosophical
endeavor as a scientific exercise.16,17 Physicians must balance the risks
of not treating or inadequately treating a patient with antimicrobials
against the risks of antimicrobial use in terms of adverse effects, drug
costs, and contribution to antimicrobial resistance. Because the last
consequence (antimicrobial resistance) is typically removed in time
and place from the original prescribing decision, it often receives
little weight. Indeed, a study by Metlay and colleagues18 found that
“risk of contributing to antimicrobial resistance” ranked last among
seven factors that physicians were asked to weigh when deciding
which antimicrobial to prescribe for a hypothetical patient. In the same
study, patient expectations to receive antimicrobials when they visit a
physician for a condition they perceive is infectious was identified as
a key factor in overprescribing of antimicrobials. Although studies
have demonstrated that patients can be successfully dissuaded from
demanding unnecessary antimicrobials without adverse effects on sat-
isfaction with their physician, these interventions may be more time-
consuming and require more training relative to simply prescribing an
antimicrobial.19 Diagnostic tests for infections may be perceived as
overly expensive, invasive, or time-consuming relative to simply pre-
scribing an antimicrobial for a suspected infection. When diagnostic
tests for infections are ordered, they are often slow to turn around and
limited in their sensitivity. Prescribers may be unwilling to take the
risks of not prescribing an antimicrobial or prescribing a narrower-
spectrum antimicrobial because of malpractice and litigation concerns
if a patient truly has an infection. Clinicians may lack adequate knowl-
edge of infectious disease diagnostics and management, especially in
the face of a growing population of immunocompromised patients
(human immunodeficiency virus, stem cell and solid-organ transplan-
tation). All of these factors may lead physicians to fall back on the rela-
tive “comfort” of broad-spectrum antimicrobial use.20
In this environment, some physicians believe that ASPs impose
unnecessary or even deleterious constraints on the practice of medi-
cine.21 Prescribers fail to appreciate that antimicrobial use has signifi-
cant ecologic consequences that extend beyond the individual patient
under their care and can affect their entire practice population. Their
skepticism may arise from the perception that there is a lack of docu-
mented efficacy of ASPs across varied health care settings, a paucity of
direct evidence demonstrating an improvement in clinical outcomes,
limited physician time or incentive to pursue such efforts, and a weak
causal link between the emergence of resistance and antibiotic use
patterns. Although there are no large multicenter, randomized con-
trolled trials to address all of these questions, the preponderance
of evidence and recent publication of the IDSA/SHEA stewardship
guidelines15 supports the implementation of antimicrobial stewardship
efforts.
ANTIMICROBIAL STEWARDSHIP
STRATEGIES
Many strategies have been used to curb soaring antimicrobial expen-
ditures and to limit the adverse consequences of inappropriate anti­
microbial therapy (Table 51-1). In a 1983 survey of 112 hospitals
associated with medical schools, Klapp and Ramphal22 found that 62
of 108 respondents had some form of direct control of antimicrobial
usage, either through requirements for authorization by a specialist
or through restriction of acceptable indications for the use of particu-
lar agents. A 2009 survey of 357 hospital practitioners at teaching
(55%) and nonteaching hospitals found that although only 48% had an
existing antimicrobial stewardship program, an additional 26% were
605
 605.e1
KEYWORDS
adverse effects; antibiotic formulary; antimicrobial costs;
antimicrobial resistance; antimicrobial restriction; antimicrobial

Chapter 51  Antimicrobial Stewardship

stewardship; benchmarking; Clostridium difficile; education; quality
improvement
 606

TABLE 51-1  Antimicrobial Stewardship Strategies an effective method to achieve a long-term impact on prescribing
practices.
Antibiotic order forms Educational programs are difficult to assess because of the complex
Antibiotic rotation
nature of educational variables, the diversity of efforts, the lack of
Part I  Basic Principles in the Diagnosis and Management of Infectious Diseases

Antimicrobial formulary restriction

Automatic stop orders standardized feedback, and the intricacy of the infectious diseases
Clinical practice guidelines decision-making process. Nonetheless, several generalizations can be
Computer-assisted management programs culled from the existing literature. Individual instruction by an
Costing of items in clinical microbiology laboratory
Direct interaction antibiotic-utilization expert appears to be the most successful educa-
Educational programs tional strategy, whereas utilization review is less useful.14,16 Contempo-
Formal seminars raneous interventions have a greater impact than those removed from
Multidisciplinary approaches the original antibiotic order by space and time. However, in the absence
Newsletters
Performance evaluation of continuous reinforcement, all results extinguish rapidly.34,35 There-
Prior-approval programs fore, although education should be the cornerstone of any ASP, this
Purchase plans approach should not be used as the sole strategy.15
Simple chart entry
Telephone approval
Therapeutic substitution and streamlining programs Antimicrobial Formulary  
Restriction Strategies
Limiting the availability of agents on formulary is the most direct
method to influence antimicrobial utilization; it is a simple way to
prohibit the use of newer, more expensive antibiotics in favor of older,
Hospital equally effective drugs.36 One of the landmark studies in this area was
Infection
Control
Epidemiologist Hospital published by Woodward and colleagues37 in 1987. Use of a restricted
Professional Director formulary resulted in cost savings of $34,597 per month for restricted
agents and $24,620 per month for all antibiotics (P < .03), with no
Director, Managed-Care
Organization
adverse impact on the clinical outcomes of patients with bacteremia or
Information
Systems Representative a variety of other infections. Before implementation, unnecessarily
Director,
Antimicrobial expensive agents were prescribed 37% of the time, compared with just
Management 2% of the time during the study period. The researchers were able to
Program
Director,
demonstrate that the restriction of certain agents could result in sig-
Infectious
Clinical Diseases
nificant cost savings without decreasing the quality of patient care.
Microbiology Faculty Conversely, a study by Himmelberg and associates38 evaluated the
Infectious impact of removing long-standing formulary restrictions at a univer-
Director,
Diseases
Chairman, Outcomes sity hospital. Antimicrobial expenditures escalated by 103% during the
Clinical
Pharmacist
P and T Management study. Imipenem-cilastatin accounted for the greatest proportion of the
Committee
increase, with costs rising from $44,423 to $126,332 annually, whereas
expenditures for unrestricted drugs did not change appreciably.
FIGURE 51-1  Organizational structure of a comprehensive antimi- Although the study was not designed to test this hypothesis, the results
crobial management program. P and T, pharmacy and therapeutics. implied that the increase was due to unnecessary use of formerly
(Modified from John JF Jr, Fishman NO. Programmatic role of the infectious
restricted agents and not to substitution of drugs. Antimicrobial for-
diseases physician in controlling antimicrobial costs in the hospitals. Clin
Infect Dis. 1997;24:471-485.) mulary restriction is a simple and effective means of controlling drug
costs without increasing adverse patient outcomes and should be
included in most antimicrobial stewardship schemes.
Beyond the issue of cost, exercising control over which antimicrobi-
developing an antimicrobial stewardship program.23 The most common als are available for physicians to prescribe also may strongly influence
strategies used among the institutions represented were restrictive for- the development of antimicrobial resistance in a health care institution.
mularies (80%), prescriber education (77%), prospective audit and There is debate as to whether certain antibiotic classes or agents have
feedback (66%), and antimicrobial prior-approval programs (38%). a lower intrinsic risk of selecting for antimicrobial resistance. Patterson
Almost 500 infectious diseases physicians who participated in the and Rice39 argued that third-generation cephalosporins may be most
Emerging Infections Network of the IDSA responded to a question- likely to result in resistance problems, and it is possible that selection
naire that assessed their roles in antimicrobial management programs.12 of a different class of antibiotic for routine use may forestall resistance.
Overall, half indicated that the hospitals in which they worked required Similarly, some have argued that preferential use of the most potent
approval of an infectious disease physician before restricted antimicro- fluoroquinolone for treatment of respiratory tract infections caused by
bials could be dispensed, but payment for such services was rare (18%). Streptococcus pneumoniae (e.g., moxifloxacin instead of levofloxacin)
John and Fishman14 published a critical review of ASPs that summa- will delay or prevent the emergence of resistant strains.40 Livermore41,42
rized the results of 37 strategies and evaluated the strengths and weak- noted that resistance in Pseudomonas spp. was more difficult to achieve
nesses of each approach.14 The emphasis of the programs that were with meropenem than with imipenem because two mutations were
reviewed is illustrated in Figure 51-1. required rather than one. In addition to intrinsic differences in potency
In the following sections, we consider the data supporting major among agents for a particular pathogen, it is also possible that dose
strategies. The reader is referred to many excellent reviews of steward- optimization using pharmacodynamic principles may help delay emer-
ship programs for additional details.24-31 gence of resistance during therapy for some organisms.43
A restricted formulary tends to result in more homogeneous anti-
Educational Strategies microbial use, because fewer drugs are available for selection. Clinical
Although education has long been considered one of the hallmarks of practice guidelines that encourage use of specific drug therapies for an
the activities of the infectious diseases physician, it is the least rigor- infection also promote less variability in antimicrobial use. Two differ-
ously studied intervention. A variety of approaches have been used, ent methods of formulary manipulation attempt to increase the het-
including staff conferences, lectures by visiting professors (grand erogeneity of the antimicrobials to which patients are exposed, albeit
rounds), clinical pharmacy consultations, drug-utilization evaluations, using very different approaches. The first approach is termed antimi-
newsletters, and the development of clinical pathways or guidelines. crobial “cycling”—alternating the predominant antimicrobial used for
Inasmuch as there are significant ongoing deficiencies in physicians’ empirical therapy for all patients in a particular patient care area in
knowledge concerning antibiotic actions, pharmacology, and inappro- a regular pattern over time.44 The rationale behind cycling is that,
priate use,32,33 it is reasonable to assume that education alone is not as bacteria in an intensive care unit (ICU) or hospital acquire new

resistance genes directed against a predominant antibiotic, a new anti-
biotic to which the organism is susceptible will be introduced into the
environment and will eradicate the emerging pathogens that are resis-
tant to the prior antibiotics. The identification of the optimal antibiot-
ics to be cycled, the duration of cycles, and the preferred order of
rotation are key variables.
Since the initial quasi-experimental studies of aminoglycoside
cycling by Gerding and colleagues,45,46 there have been a number of
studies of cycling interventions, primarily in the ICU but also in
hematology-oncology and transplantation wards. Outcomes of these
studies included the percentage of pathogens resistant to study antimi-
crobials, infection rates, and mortality. Study results have been posi-
tive,47-49 negative,50-52 and mixed.53 Frequent methodologic limitations
of these studies include co-interventions (including enhanced infec-
tion control measures), nonrandomized designs, and incomplete deliv-
ery of the intervention (compliance to cycling protocols was frequently
50% or less). Mathematical models suggest that the standard antibiotic
cycling designs (where there is heterogeneity in antimicrobials used
over time but homogeneous use at any given time) ultimately will lead
to greater rates of resistance than strategies that promote heterogeneity
in antimicrobial use at any given time (either “mixing” protocols or
cycling protocols with very short cycles).54,55 Some studies suggest that
institutions with greater diversity in the types of antimicrobial used
(but without cycling protocols) have a lower burden of antimicrobial
resistance.56 Interventional studies of mixing protocols are limited57 but
may become more feasible with the widespread adoption of computer-
ized provider order entry systems that could promote heterogeneity in
antimicrobial use at a patient level, rather than the unit level.
Prior-Approval and   excessive or inadequate doses to more appropriate doses (dose optimi-
Justification Strategies
At a level below institution-wide decisions about which antimicrobials
are available are strategies that require physicians to justify their use of
antimicrobials in some way. These stretch across a spectrum from less
restrictive (requiring use of antimicrobial order forms, mandating an
indication accompany every antimicrobial order) to more restrictive
(requiring physicians to obtain approval from an infectious disease
clinician before restricted antimicrobial release, mandating formal
infectious disease consultation for use of specific agents).
McGowan and Finland58 were the first to use telephone calls to
provide for justification by prescribers and for approval by infectious
diseases physicians to limit the use of systemic antimicrobial agents.
Most approvals were given by telephone, and formal consultation
usually was not required. Chloramphenicol prescription rates demon-
strated the most dramatic alteration in this program, with annual usage
decreasing from 20,000 to 3000 g. Recco and colleagues59 were first
to demonstrate the economic impact of a prior-approval program.
They also used a telephone-approval mechanism, but disagreements
necessitated consultation with an infectious disease physician, and an
educational program was implemented concomitantly. Antimicrobial
expenditures decreased by $131,826 during the first year, and savings
were sustained during the initial 3 years reported in the study. In addi-
tion, inappropriate use of antibiotics was curtailed significantly. Anti-
biotic order forms also have effected similar improvements in the use
of anti-infective agents for empirical and prophylactic purposes.60
However, order forms should be used in conjunction with a restricted
formulary, and the forms should be reviewed regularly to document
reporting accuracy.
The final landmark study in this category was conducted by
Coleman and colleagues61 and was the first effort to critically analyze
long-term reductions in antibiotic expenditures among many different
clinical syndromes. The authors collected baseline data for 18 months
before instituting four categories of restricted usage (cephalosporins,
penicillins, aminoglycosides, and miscellaneous agents) and maximal
dosage guidelines for seven drugs. In addition, a review of treatment
plans was required before the pharmacy could distribute drugs. The
program yielded savings of $7600 per month ($91,200 annually). The
doses and cost of antibiotics decreased for pneumonia, urinary tract
infection, and septicemia but increased for cellulitis. The cost per treat-
ment day, cost per admission, and total number of doses all differed
significantly from those in the prestudy period. The length of therapy
607
did not differ between the prerestriction and postrestriction periods.
The most significant decreases in use were seen with cefoxitin and
clindamycin, whereas the largest increases were demonstrated with
ticarcillin-clavulanate and cefotetan.
Chapter 51  Antimicrobial Stewardship
Enforcement of a prior-approval program can be difficult, and the
process may be viewed as a punitive exercise. In a survey of residents
in a teaching hospital, a majority agreed that a restrictive antimicrobial
program was a “good idea” and that such a program “improved indi-
vidual patient care,” but a majority also agreed that the requirement for
call approval led to delays in patient receipt of antimicrobial agents and
that calling for approval was frustrating.62 In private practices, infec-
tious disease physicians are not enthusiastic about restricting antibiot-
ics because of concerns that the policies will place them in a policing
role and thereby damage their traditional referral patterns.12 Although
these strategies are the most onerous to prescribing physicians, they
undoubtedly are the most effective single interventions to change or
improve usage patterns and to control the antimicrobial budget.14
Prospective Audit and  
Feedback Strategies
Prospective audit of antimicrobial prescribing (usually accomplished
by daily review of prescriptions of targeted antimicrobials), coupled
with feedback to physicians to improve antimicrobial use, is an impor-
tant stewardship strategy. Feedback should be educational and evi-
dence based, with the goal of appropriate individualized therapy.
Interventions occurring as part of an audit and feedback strategy
include switching patients from intravenous to oral therapy (switch or
step-down therapy), from broad-spectrum and combination therapy to
more narrow-spectrum therapy (also called streamlining), and from
zation strategies). Prescribers tend to view audit and feedback strate-
gies as less onerous than prior-approval programs. The most effective
antibiotic stewardship programs will at least incorporate components
of prospective audit and feedback along with other efforts such as
restriction and prior approval.
The feasibility of switch therapy has been investigated primarily in
the management of pulmonary infections. Early studies demonstrated
significant savings in drug costs as well as decreased lengths of stay63
and a decreased incidence of catheter-related infections.64 The largest
and most ambitious study of switch therapy produced somewhat more
modest results.65 A seven-hospital, cluster randomized trial evaluated
outcomes of patients admitted for treatment of community-acquired
pneumonia. The intervention was designed to switch patients to oral
therapy, to discharge as early as medically feasible, and to assess
medical outcomes. The physicians responsible for treatment of patients
randomized to the control arm of 325 patients received only a practice
guideline via the mail. In the intervention arm of 283 patients, physi-
cians received a “multifaceted guideline intervention,” consisting of
daily monitoring of the patients’ status to meet criteria for conversion
to oral therapy and early discharge; verbal and written interventions
were made daily to the responsible physician as appropriate. There
were nonsignificant trends toward earlier conversion to oral therapy
(P = .06) and earlier discharge (P = .11), and medical complications
were significantly fewer in the intervention group (P = .04). There were
no differences in mortality between the groups.
Using an interrupted time-series design, Elligsen and colleagues66
studied the impact of a prospective audit and feedback program on
streamlining broad-spectrum antimicrobial use in three ICUs. Initial
review of prescriptions for broad-spectrum antimicrobials was per-
formed by a pharmacist; cases that were considered opportunities for
intervention were discussed with an infectious diseases physician
before contacting the treating physician with recommendations.
During the intervention period, suggestions for drug optimization
were given in relation to 34% of broad-spectrum antimicrobial orders;
of these, 82% were accepted. The most common suggestions involved
antimicrobial discontinuation (56%), change to an alternative agent
(26%), and change of antimicrobial dose (8%). Compared with the
prior 12 months before the intervention, the mean monthly use of
targeted antimicrobials decreased by 22% during the intervention
period. Use of nontargeted antimicrobials did not increase during the
intervention, leading to an overall reduction in antimicrobial use. The
 608
TABLE 51-2  Comparison of Antimicrobial Treatment Managed by an AMT or by ID Fellows
OUTCOME OF PATIENTS WHOSE TREATMENT
WAS MANAGED BY
Part I  Basic Principles in the Diagnosis and Management of Infectious Diseases
AMT (n = 87) ID Fellows (n = 93)
Appropriate 76 44
Cure 49 35
Failure 13 26
AMT, antimicrobial management team; CI, confidence interval; ID, Division of Infectious Diseases; n, number of patients; OR, odds ratio.
From Gross R, Morgan AS, Kinky DE, et al. Impact of a hospital-based antimicrobial management program on clinical and economic outcomes. Clin Infect Dis.
2001;33:289-295.
percentage of drug-resistant isolates was similar between the two
periods, except for a reduction in meropenem resistance among gram-
negative organisms. The monthly rate of Clostridium difficile infections
was decreased by 31% during the intervention period. Hospital and
ICU length of stay and mortality were similar between the two study
periods.
Although the streamlining component of prospective audit with
feedback is usually considered to emphasize a change to a more
narrow-spectrum agent, discontinuation of therapy when none is indi-
cated is an important goal of any program.39 Hecker and colleagues4
reviewed 1941 days of antimicrobial therapy in 129 patients and
reported that 30% of the days represented unnecessary therapy, mostly
related to excessive treatment duration or treatment for nonbacterial
syndromes. In addition, drugs with activity against anaerobes were
often prescribed when an anaerobic spectrum was not indicated. Singh
and colleagues67 described an innovative and aggressive program to
limit the duration of therapy to 3 days in patients with suspected
ventilator-associated pneumonia but with less severe infection scores.
There were significantly fewer superinfections in the short-duration
arm and a lower mortality rate that neared significance (P = .06). There
is an urgent need to better define the duration of therapy for many
infections.31
Computer-Assisted   had as their primary outcome the amount of aggregate antimicrobial
Stewardship Programs
Information systems have the potential to be outstanding methods for
antibiotic stewardship and education. Computer order entry affords a
unique opportunity for instantaneous feedback, education, and altera-
tion in prescription patterns.68 The best demonstration of the potential
of computer assistance in stewardship was performed by the group at
the LDS Hospital in Salt Lake City, Utah. They developed a computer-
ized decision-support program that is linked to computer-based
patient records.69,70 The program presents epidemiologic data, detailed
information, and warnings and assists in the selection of anti-infective
regimens and courses of therapy for patients. The system was prospec-
tively studied for 1 year in a 12-bed ICU.70 When compared with
management in the same ICU during the 2 years before the interven-
tion period, computer-assisted antimicrobial selection led to signifi-
cant reductions in orders for drugs to which patients had reported
allergies (35 vs. 146; P < .01), excess drug dosages (87 vs. 405; P < .01),
and mismatches of antibiotic susceptibility (12 vs. 206, P < .01). There
were also marked reductions in the mean number of days of excessive
drug dosage and in adverse events caused by antimicrobial agents. In
addition, those patients treated with regimens that were recommended
by the computer program demonstrated significant reductions in anti-
infective costs, total hospital costs, and length of stay, compared with
controls. This computer-assisted stewardship program is one of several
commercially available and is designed to be integrated into the hos-
pital information system. In addition, systems for computerized physi-
cian order entry (CPOE) are beginning to integrate their own clinical
decision support, creating the potential for effective antimicrobial
stewardship interventions at the point and time of prescribing.
Multidisciplinary and   also demonstrated increased cure rates and decreased failure rates
Multistrategy Approaches
The review by John and Fishman14 demonstrated that multidisciplinary
programs offer the best potential for sustained improvements in both
clinical and economic outcomes. DeLisle and Perl71 described the
UNADJUSTED OR (95% CI) P VALUE
7.7 (3.7-16.2) <.001
2.4 (1.3-4.5) .007
0.5 (0.2-0.9) .03
framework needed to develop a multidisciplinary ASP. Approaches
that used four or more strategies appeared to be the most effective. For
example, the ASP at Hartford Hospital emphasized formulary stream-
lining reinforced by formulary restriction and review, antibiotic order
forms, and educational efforts.36 Such programs also tend to be more
readily accepted because they involve input from a variety of hospital
services, including the departments of infectious diseases, clinical
pharmacy, infection control, clinical microbiology, nursing, and hos-
pital administration. The team approach supports the implementation
of multiple strategies and offers the best option for sustained success.
OUTCOMES OF ANTIMICROBIAL
STEWARDSHIP PROGRAMS
In assessing whether comprehensive ASPs are effective, one must con-
sider both clinical and institutional (economic) outcomes. Although
the preponderance of evidence supports the positive impact of such
efforts, the literature is of “limited strength.” A systematic review of the
quality of the literature describing methods to improve antibiotic use
in hospitals found that only 30% of 306 papers published by 2003 met
the minimal inclusion criteria for a Cochrane review.72
Clinical Outcomes
Most studies of the impact of antimicrobial stewardship programs have
use, antimicrobial costs, or rates of antimicrobial resistance.* When
clinical outcomes such as clinical cure rate, length of hospital stay, or
mortality have been examined, there has typically been no difference
between the stewardship group and control, although many of these
studies are underpowered to detect these differences.† The best evi-
dence supporting improved clinical outcomes resulting from an anti-
microbial stewardship strategy comes from the computerized antibiotic
assistant at LDS Hospital discussed earlier.70 Additional data come
from a retrospective review before and after the initiation of a prior-
approval program at Indiana University Medical Center (Indianapolis,
IN).73 In this review, Frank and co-workers found statistically signifi-
cant decreases in the rates of enterococcal bacteremia (0.34 vs. 0.16
events per 1000 patient-days), selected gram-negative bacteremias
(0.26 vs. 0.11), methicillin-resistant S. aureus (MRSA) colonization or
infection (0.66 vs. 0.20), and Stenotrophomonas colonization or infec-
tion (0.35 vs. 0.17). The program also resulted in a decrease in yearly
antimicrobial expenditures, from $2,486,902 to $1,701,522. The effort
resulted in improved clinical outcomes in the form of significant
decreases in rates of selected nosocomial infections caused by resistant
organisms, coupled with substantial cost savings.
Further support can be found in the results of a randomized, con-
trolled trial designed to assess the clinical and economic outcomes
of a comprehensive ASP compared with required approval by the
Infectious Disease Fellow at the Hospital of the University of Pennsyl-
vania.74 A summary of this univariate analysis is shown in Table 51-2.
The program resulted in an improved cure rate, a decreased failure
rate, and more appropriate use of antimicrobial agents, as judged by
adherence to institutional guidelines. A more recent, albeit small,
randomized controlled trial performed at the same institution24
when comparing usual practice to use of antimicrobial stewardship
*References 34, 37, 38, 47, 51, 61, 63, 67, 70.
†
References 37, 56, 61, 63, 67, 70.

interventions. Although a large multicenter trial of the impact of
various interventions on clinical outcomes is lacking, the majority
of published evidence demonstrates a beneficial or neutral impact of
ASPs on these outcomes.
Economic Outcomes
It is clear from the discussion of antimicrobial stewardship strategies
that most published reports have demonstrated successful cost con-
tainment. However, if savings are calculated as a function of pharmacy
expenditures, they tend to plateau over time, probably as a function of
improved antimicrobial utilization practices and sustained benefits
of the program. To address this issue, Gross and colleagues74 devel-
oped a probability pathway model to calculate both the direct and
the indirect cost savings of a stewardship program. In this model,
total cost was defined as the sum of drug expenditures, microbiology
costs, bed costs, and the costs of infectious diseases consultations;
additional costs accrued if the initial antibiotic regimen failed. The
median drug costs per recommendation were $50 lower for the ASP
compared with usual practice, and total costs were $379 lower per
recommendation. Based on the probability pathway model, the annu-
alized savings were $363,000 in antibiotic expenditures and $2.7
million in total costs.
More recent studies have indicated that more significant savings
may result from improved clinical outcomes rather than decreased
antimicrobial expenditures. For instance, the bulk of cost savings in
several studies24,68 appeared to be attributable to decreased length of
stay in the ICU. With antimicrobial pressure driving C. difficile infec-
tion rates, reductions in usage would be expected to lower such noso-
comial infections.
DO ANTIMICROBIAL
STEWARDSHIP PROGRAMS ALTER
RESISTANCE IN THE HOSPITAL?
The effectiveness of antimicrobial stewardship as a means to prevent
the emergence of resistance has been reviewed in detail.75,76 Available
studies are suggestive but not conclusive concerning the efficacy of this
approach. The shortcomings of published studies include the presence
of selection biases, small sample sizes, limitation to single institutions,
and failure to control for confounding variables.76 The relationship
between antibiotic use in the hospital and rates of antimicrobial resis-
tance is complex, and further work is needed to evaluate the relative
impact of infection control interventions to limit transmission, impor-
tation of resistant organisms from long-term care facilities and other
health care settings, and antimicrobial changes within the acute care
institution.12 In addition, most studies used a “before and after” design
and did not follow trends in antibiotic use or resistance for sufficiently
long periods before and after the intervention to establish a causal
relationship.72 A recent systematic review of the literature on ASPs in
pediatric settings reached similar conclusions.77
A significant development in efforts to link an intervention, such
as a new stewardship program, to changes in antimicrobial use or
changes in resistance has been the application of quasi-experimental
studies, such as interrupted time series (ITS) analysis, to these data, as
initially described by Monnet and López-Lozano.78,79 A number of
investigators have reported on the use of ITS to link interventions to
changes in drug use and isolation of resistant orgranisms.80-83 New
guidelines for investigators that recommend standards for the conduct
and analysis of quasi-experimental interventions to reduce nosocomial
infections have been published. Called the ORION Statement (out-
break reports and intervention studies of nosocomial infection), the
recommended statistical procedure for assessment of intervention out-
comes is the ITS.84
ITS has been used in systematic reviews to provide additional rigor
to assess the effects of stewardship interventions on outcomes. Davey
and colleagues76 performed a systematic review of reports published
from 1980 through 2003 that were designed to improve the quality of
antimicrobial prescribing and reanalyzed the original reports using
segmented time series regression. Among the 10 investigations that
met their criteria for sound study methodology, the strongest evidence
supported interventions that reduced infections caused by C. difficile.
Less consistent evidence was found for a beneficial effect on infections
609
caused by gram-negative bacilli and gram-positive organisms, includ-
ing VRE and MRSA.
Future studies should be multicenter investigations with random
allocation to the interventions studied and appropriate outcome mea-
Chapter 51  Antimicrobial Stewardship
sures that have minimal potential confounders. Clearly, much work
needs to be done to determine which specific changes in drug use
convincingly produce a beneficial effect on rates of resistance. However,
this is an emerging field of study, and the appropriate methodology is
still evolving, including basic statistical procedures. An ASP that is
planning to monitor the effects of an intervention on antimicrobial use
or rates of resistance should give serious consideration to performing
ITS by consulting the previous references and a statistician familiar
with these methods.
DESIGN AND IMPLEMENTATION
As discussed earlier, IDSA and SHEA have published evidence-based
guidelines for developing an institutional program to enhance antimi-
crobial stewardship.15 These guidelines are summarized in Table 51-3.
A detailed discussion of recommendations for the design and imple-
mentation of a successful ASP follows.
1. Define the philosophy of the program. This may seem to be a
trivial step, but the initial approach defined at this early time is
likely to form the foundation for the success or failure of the
program. Although most physicians generally understand that
resistance is important, increasing in scope, and costly, they do not
necessarily agree that the care of individual patients affects this
issue. However, antibiotic misuse more often results from inade-
quate information than from inappropriate behavior.85 Therefore,
physicians are more likely to respond to a program designed to
“improve” antibiotic use or patient care rather than an effort to
“restrict” or “control” antimicrobials or solely to decrease costs.
Most physicians will alter their behavior to improve the quality of
patient care.
2. Gather baseline data concerning antimicrobial expenditures, anti-
microbial utilization patterns, and susceptibilities of nosocomial
and community pathogens. Benchmark the antimicrobial budget
and antimicrobial use to similar institutions, if possible. There is
no agreement on the best metric to assess antimicrobial use. The
most often recommended measures of hospital antibiotic use are
defined daily doses per 1000 patient-days (DDD/1000 PD)86 or
days of therapy (DOT) per 1000 PD.2
3. Define the structure of participation in the ASP. An example of a
comprehensive program is diagrammed in Figure 51-1.
4. Develop a budget for all official positions and operating costs.
5. Involve hospital administrators early in the design and implemen-
tation process and clarify budgetary issues. Agree on a formula to
calculate cost savings. It may be prudent to involve managed-care
organizations in these discussions if they are at risk for pharmacy
TABLE 51-3  IDSA/SHEA Guidelines for
Developing an Institutional Program to Enhance
Antimicrobial Stewardship
Core members
  Infectious diseases physician
  Clinical pharmacist with infectious diseases training
  Health care epidemiologist
  Infection preventionist
  Clinical microbiologist
  Information systems specialist
Close collaboration with the hospital infection prevention and control program
and the pharmacy and therapeutics committee
Support and collaboration of:
  Hospital administration
  Quality assurance and patient safety programs
Negotiate for adequate authority, compensation, and expected outcomes
Hospital administrative support for necessary infrastructure
Use both process and outcome measures to monitor impact
IDSA, Infectious Diseases Society of America; SHEA, Society for Healthcare
Epidemiology of America.
Data from Dellit TH, Owens RC, McGowan JE, 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;44:159-177.
 610
costs. The support of key officials is critical to the success of the
program. Physicians are more likely to comply with a health
system effort rather than with an infectious diseases or pharmacy
program that may be perceived to have predominantly financial
Part I  Basic Principles in the Diagnosis and Management of Infectious Diseases
motives. Maintain an open dialogue with chief administrative per-
sonnel, and update them frequently concerning the progress of the
program.
6. Evaluate the antimicrobial formulary for redundancy and seek
competitive bidding between therapeutic equivalents.
7. Develop and publish guidelines for antibiotic use and empirical
antimicrobial therapy. Recommendations should be based on local
susceptibility profiles. In addition, establish appropriate dosing
and dosage intervals based on disease-state and pharmacokinetic
principles. This step is critical to the success of the program.
Involve key personnel from all departments when designing the
guidelines, to build consensus for the program. Be willing to com-
promise on certain issues, but demand that all recommendations
be evidence based. It is also worthwhile to consider multimedia
formats. For example, we have posted University of Pennsylvania
guidelines on the Internet and have included links to relevant
articles, as well as other educational materials.87 It is also useful to
publish reports of antimicrobial susceptibility and price lists along
with the clinical guidelines.
8. Define the strategies that the program will use. As previously dis-
cussed, multidisciplinary efforts offer the greatest potential for
sustained improvements. However, interventions must be tailored
to the character of the institution. For example, telephone-approval
mechanisms are less likely to be successful at a community hospital
staffed by busy private practitioners. Begin with a focus on the
most frequently used and most costly agents.
9. Develop mechanisms to arbitrate disagreements. A discussion
between the prescriber and the director of the program is usually
sufficient if the director has administrative time to handle these
issues. A mandatory infectious diseases consultation is another
option.
10. Develop innovative educational methods. The Internet can be a
useful tool in this regard.87 Information systems personnel may be
helpful in incorporating guidelines, recommendations, or remind-
ers into the hospital computer network.
11. Develop and maintain a database to monitor clinical and institu-
tional outcomes.
12. Continually reevaluate the program, paying particular attention to
changes in susceptibility profiles and patterns of use. Drug utiliza-
tion evaluations should be a part of this process. Reformulate the
program as indicated to address problems as they arise. This
should be a dynamic process that is responsive to the needs of
prescribers and their patients.
THE FUTURE
Health care is constantly changing. Providers are challenged to deliver
high-quality care in an increasingly cost-constrained environment. This
requires limiting cost-increasing technology while improving patient
and population health outcomes. Although the data are still evolving,
Key References
The complete reference list is available online at Expert Consult.
12. Sunenshine RH, Liedtke LA, Jernigan DB, et al. Role
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2. Hicks LA, Taylor TH Jr. U.S. outpatient antibiotic prescrib-
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4. Hecker MT, Aron DC, Patel NP, et al. Unnecessary use
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15. Dellit TH, Owens RC, McGowan JE, et al. Infectious Dis-
2003;163:972-978.
6. Cosgrove S, Carmeli Y. The impact of antimicrobial resis-
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2003;36:1433-1437.
9. Spellberg B, Guidos R, Gilbert D, et al, for the Infectious
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18. Metlay JP, Shea JA, Crossette LB, et al. Tensions in antibiotic
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10. Talbot GH, Bradley J, Edwards JE, et al. Bad bugs need
drugs: an update on the development pipeline from the
comprehensive ASPs have the potential to decrease costs while improv-
ing both patient and institutional outcomes. However, further work is
needed to clearly identify the relationship between antimicrobial use
and the emergence of resistance in a way that colleagues will appreciate
and accept.88 Relevant studies will require sufficient statistical power to
characterize baseline resistance, to deal with random variation, and to
control for a multitude of confounding variables.
We also must begin to focus on issues of antimicrobial use and the
emergence of resistance throughout the entire health care system. As
these systems expand and become a prominent feature of medical
practice in the United States, it is no longer sufficient to consider infec-
tion solely in the context of the academic teaching hospital, from which
most reports of antimicrobial stewardship programs originate. Rather,
health care must be viewed in the larger context of community and
tertiary acute care settings, extended-care facilities, and especially
ambulatory practices, where most of the usage occurs.89 A number of
recent studies have demonstrated the feasibility and effectiveness of
antimicrobial stewardship programs in these settings.90-94 Future efforts
to improve the use of antimicrobial agents and studies to document
efficacy must be expanded to include these arenas.
The high cost of antimicrobial drugs remains an important reason
to implement stewardship procedures, as described in this chapter.
However, the rising prevalence of resistance and its clinical and eco-
nomic impacts are being recognized as critical by clinicians, adminis-
trators, and increasingly by health care regulatory bodies. The state of
California has recently mandated that all acute care hospitals enact
programs to evaluate and promote the judicious use of antimicrobi-
als.95 Recently, a joint statement by leading United States infectious
diseases societies recommended that the Centers for Medicare and
Medicaid Services require participating hospitals to put in place anti-
microbial stewardship programs.96 Because it is likely that few new
drugs will become available for these multidrug-resistant pathogens
during the next 5 to 10 years, therapeutic options will become increas-
ingly limited. The focus on antimicrobial stewardship strategies must
continue to shift from cost containment to efforts to limit resistance.
It is likely that the increasingly sophisticated information systems
being deployed in all hospitals will play a more prominent role in
antimicrobial stewardship. Several companies currently market prod-
ucts that can either assist in monitoring antimicrobial therapy and
evaluating interventions or actually offer computer decision support
for antimicrobial selection and dosing. A report of an Internet-based
ASP developed and studied at the Johns Hopkins Children’s Medical
and Surgical Center demonstrated improved communication, more
timely antimicrobial administration, increased user satisfaction, and
significant cost savings.97 However, the current crisis of antimicrobial
resistance and the lack of viable therapeutic options mandate that,
regardless of how antimicrobial stewardship may be defined or imple-
mented, the types of measures summarized in this chapter will increas-
ingly become the responsibility of all clinicians.
ACKNOWLEDGMENT
The author and editors wish to thank Drs. Ronald E. Polk and Neil O.
Fishman for their contributions to prior editions of this chapter.
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