SUPPLEMENT ARTICLE

A Call to Arms: The Imperative for Antimicrobial

Stewardship
John G. Bartlett
Department of Medicine and Epidemiology, Johns Hopkins University School of Medicine, Baltimore, Maryland

Antimicrobial resistance is a major public health crisis. The prevalence of drug-resistant organisms, such as
the emerging NAP1 strain of Clostridium difficile, now highly resistant to fluoroquinolones, Acinetobacter
species, Klebsiella pneumoniae carbapenemase-producing organisms, and methicillin-resistant Staphylococcus
aureus, is increasing nationwide. The sources of antimicrobial resistance are manifold, but there is a well-
documented causal relationship between antimicrobial use and misuse and the emergence of antimicrobial-

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resistant pathogens. As the development of new antimicrobial agents is on the decline, the medical community,
across all specialties and in conjunction with public health services, must develop and implement programs and
strategies designed to preserve the integrity and effectiveness of the existing antimicrobial armamentarium.
Such strategies are collectively known as antimicrobial stewardship programs and have the potential to
minimize the emergence of resistant pathogens.

Two of the major health care challenges that face the
medical practice are the rapidly evolving problems of
Clostridium difficile infection (CDI) and the crisis of
antimicrobial resistance. These 2 issues are related by the
following observations: they are driven by antimicrobial
use, and they reflect, to some extent, the abuse of these
drugs. Both are epidemics in the US and much of the
world, both are focused primarily in hospitals and
chronic care facilities with spillage into the community,
andpossibly most important for the purposes of this
supplementboth are in desperate need for effective
programs of antibiotic stewardship.
CLOSTRIDIUM DIFFICILE INFECTION
Clostridium difficile was identified as the agent of antibi-
otic- associated colitis in 1978 [1], which was followed by
Correspondence: John G. Bartlett, MD, Dept of Medicine and Epidemiology,
Johns Hopkins University School of Medicine, 1830 East Monument St, Rm 447,
Baltimore, MD 21205 (jb@jhmi.edu).
Clinical Infectious Diseases 2011;53(S1):S4S7
The Author 2011. Published by Oxford University Press on behalf of the
Infectious Diseases Society of America. All rights reserved. For Permissions,
please e-mail: journals.permissions@oup.com.
1058-4838/2011/53S1-0001$14.00
DOI: 10.1093/cid/cir362
the rapid evolution of information about its epidemiol-
ogy, clinical features, diagnostic testing with the cytotoxin
assay, and treatment with either oral vancomycin or
metronidazole. It was known at that time that almost any
antibiotic with an antibacterial spectrum of activity could
be responsible for this antibiotic-associated colitis, but the
major offenders in the first 25 years were clindamycin and
broad-spectrum antibiotics. During this period, CDI was
regarded as a severe and potentially life-threatening
complication of antibiotic use, but management guide-
lines were well established, and mortality rates were rel-
atively low. In the early 2000s, there was a surge of cases of
CDI that was first recognized in Quebec, Canada [2],
which was followed by an increase in cases in the United
States and much of Europe [3]. There was not only an
increase in the number of cases but also a substantial
increase in attributable mortality. It now appears that this
surge of more disease and more serious disease due to
CDI was possibly associated with a new strain identified as
the NAP1 strain. The emergence of this organism was
thought to be at least partially due to resistance by
C. difficile to the fluoroquinolones, which was very
uncommon in the historic strains, and the widespread use
of these drugs was thought to contribute substantially to
the surge in incidence of the aforementioned cases [4].
The NAP1 strain was also noted to produce several-fold

S4 d CID 2011:53 (Suppl 1) d Bartlett

more toxin in vitro, which possibly accounted for the increase in
severity [5]. Substantial study of the epidemic in Quebec showed
a 5- to 10-fold increase in rates of infection and attributable
mortality rates of close to 17% [2, 6]. The response in Quebec was
aggressive and largely successful because of infection control and
antibiotic control.
The 30-year history of CDI has been characterized by important
observations that led to the guidelines that are now available from
the Infectious Diseases Society of America/Society for Heathcare
Epidemiology of America (IDSA/SHEA) [7], as well as guidelines
from Europe [8], which are similar to those from IDSA/SHEA.
CDI is primarily associated with antibiotic use in hospitals and
chronic care facilities. This epidemiology reflects the fact that
these facilities harbor large populations of elderly patients (who
are most vulnerable). Use rates of the antibiotics that induce the
disease are high, and the pathogen is widespread in the hospital
environment (eg, walls, floors, air, the hands of health care
workers) [7, 9], Hospitals have high rates of colonization with
these spore-forming bacteria, which can survive on hard surfaces
for years. The role of antibiotic control for prevention includes
restraint in unnecessary abuse and, in outbreaks, the sometimes
successful intervention of banning use of some agents based on
epidemiologic data that define the major offending agent [10].
EMERGING RESISTANCE TO ANTIBIOTICS
Antibiotic resistance is an inevitable consequence of bacterial
evolution and would occur even in the absence of antibiotic
exposure. Nevertheless, these drugs clearly select for these more
resistant bacteria by a simple Darwinian principle. The problem
now encountered in the US and in most of the developed world is
escalating resistance reflecting the obvious selective pressure of
antimicrobial drugs, particularly in the health care environment
where antibiotic use is concentrated. However, in contrast to the
earlier part of the more than 3 decades of using these drugs, there
is a dramatic decrease in the development of new antibiotics to
deal with these resistant bacteria. In prior years, there was an
evolution of resistant bacteriaprimarily within hospitals and
chronic care facilitiesthat was controlled by new drugs from
the pharmaceutical industry, which was extremely adept at new
drug development. However, that resource is now almost totally
closed because of economic realities indicating limited markets
and a difficult regulatory environment for antibiotic de-
velopment compared with alternative health care markets that
are far more profitable [11]. It should be noted that the lifetime of
an antibiotic is often relatively limited, and antibiotics comprise
one of the few segments of the health care market where extensive
use of a product leads to a loss of benefit (ie, resistance). The
impending crisis of limited new antibiotics was predicted in 2004
with the establishment of IDSAs Antibiotic Availability Task
Force, as well as in the document Bad Bugs, No Drugs [12].
The data from that report have been beautifully updated in the
technical report The Bacterial Challenge: Time to React, issued
by the European Centre for Disease Prevention and Control and
the European Medicines Agency [13]. This document notes that
the last new class of drugs active against Gram-negative bacilli
was trimethoprim in the 1970s. More worrisome was their ex-
tensive review of the antibiotic pipeline for drugs in phase 2
development or beyond, indicating that there were no new classes
of antimicrobials in the foreseeable future. The implication of this
observation is that there will be no new drugs that can deal with
the multiply resistant Gram-negative bacilli until 2018 at the
earliest. This crisis is now so well recognized that the World
Health Organization has identified antibiotic resistance as one of
the major threats to human health [14].
The specific organisms identified as having evolving problems
with resistance are summarized by the acronym ESKAPE (ie,
Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumo-
niae, Acinetobacter baumannii, Pseudomonas aeruginosa, and
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Enterobacter species) [15]. Five to ten years ago, attention was
focused largely on S. aureus, most particularly on the USA300
strain that caused widespread epidemics in diverse settings in the
US and similar problems in Europe [16]. More recently, there has
been greater attention on the rapid evolution of highly resistant
Gram-negative bacilli, accounting for 4 of the ESKAPE organisms,
especially extended-spectrum b-lactamaseproducing and carba-
penemase-producing Enterobacteriaceae [17]. Most recently, we
have seen the rapid spread of the New Delhi carbapenemase in
ACA Enterobacteriaceae that is now generally resistant to all
antibiotics except for tigecycline and colistin [18].
Colistin serves as a reasonable surrogate to use for extremely
drug-resistant Gram-negative bacilli because it is generally
reserved for cases where alternative antibiotics with activity are
not available. It has been extremely difficult to get national sales
data for colistin, but use rates at Johns Hopkins Hospital are
probably representative of the use trend. There were 96 courses in
68 patients in the calendar year 2009. Based on use during the
past 5 years, the projection is for more than 1600 courses by 2014.
It should be noted that history has taught us that an average of 8
years is required to bring a drug to market from start to finish,
which accounts for the dire predictions of no new antibiotic
classes until after 2018. The intent here is to emphasize the
need to plan our response in the face of escalating resistance to
very limited options and the predictable future problems
including colistin in terms of both nephrotoxicity and resistance
[19, 20].
STEWARDSHIP
Most important for our discussion is the development of ade-
quate plans for prevention to the extent possible as noted,
a medical discipline, and effectiveness based on rates of usage.
Imperative for Antimicrobial Stewardship d CID 2011:53 (Suppl 1) d S5
Thus, antibiotic stewardship becomes a pivotal issue in our
ability to better cope with increasing resistance, which is an
inevitable consequence of bacterial evolution but heavily influ-
enced by our use of antibiotics.
ANTIBIOTIC STEWARDSHIP
Antibiotic stewardship is an important component for our
challenges in both microbial resistance and CDI. For resistance,
the issue is the need to conserve the effectiveness of the currently
available antibiotics by limiting their use based on basic and
evolving principles; for CDI, the need is development of data to
document institutional epidemiologic patterns with both broad
and targeted interventions. Guidance in establishing appropriate
stewardship programs is available, and effectiveness of these
programs is well documented [21]. Specifically, the collected ex-
perience documented in this guideline review showed reduction
in antibiotic use of 22%36% and resulted in annual cost savings
of $200 000$900 000. Specifics of these programs will vary by
resources, hospital size, and local experiences, but some recent
reports with specific opportunities include the following:
d A review of management of infections of skin and soft
tissue in hospitalized patients showed extensive over-
prescribing of antibiotics that are active against Gram-
negative bacteria despite culture data showing Streptococcus
or S. aureus in 97% of patients with positive cultures,
extensive use of imaging with positive results in only 4%,
and excessive duration of antibiotics [22]. The authors
specifically called for the need for antibiotic stewardship in
managing these infections.
d Microbiology is in a state of transition with the rapid
evolution of new tests that require expertise in selection of
methods and interpretation of results. An example is the rapid
polymerase chain reaction to detect methicillin-resistant
S. aureus (MRSA) in blood cultures. Use of this technology at
Ohio State University Medical Center showed that antibiotic
adjustments were made 1.7 days earlier, the mean length of stay
averaged 6.2 days shorter, and mean costs were reduced by
$21 387 per patient [23].
d The new guidelines for vancomycin dosing represent
a radical change in the use of this antibiotic [24], which
represents the most common antibiotic used in US hospitals.
Further, these guidelines call for substantial increases in dosing
for a drug that now has a tight toxicity:therapeutic ratio and
emphasizes the need for alternative agents that target MRSA.
Vancomycin issues are further complicated by recent data
showing variable in vivo activity based on relative quality of
different generic supplies [25].
d Many studies now show that antibiotic conservation can be
notably improved by using shorter courses of these drugs than
is customary practice in certain diseases. Examples are
S6 d CID 2011:53 (Suppl 1) d Bartlett
ventilator-associated pneumonia [26], community-acquired
pneumonia [27], and septic arthritis [28].
These examples are a minor component of the total needs of
a good antibiotic stewardship program, but they serve to illus-
trate the magnitude of both the need and the opportunities in
this area.
Acknowledgments
Supplement sponsorship. This article was published as part of a sup-
plement entitled Antimicrobial Stewardship for the Community Hospital:
Practical Tools and Techniques for Implementation, jointly sponsored by
the University of Cincinnati and Rockpointe Corporation, ACPE credit
provided by Potomac Center for Medical Education, and supported by an
educational grant from Ortho-McNeil.
Potential conflict of interest. The author reported no conflicts.
All authors have submitted the ICMJE Form for Disclosure of Potential
Conflicts of Interest. Conflicts that the editors consider relevant to the con-
tent of the manuscript have been disclosed in the Acknowledgments section.
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