The American Journal of Medicine (2005) Vol 118 (7A), 1S 6S

A clinicians guide to the appropriate and accurate use

of antibiotics: the Council for Appropriate and Rational
Antibiotic Therapy (CARAT) criteria
Thomas G. Slama, MD,a Alpesh Amin, MD, MBA,b Stephen A. Brunton, MD,c
Thomas M. File, Jr, MD,d Gary Milkovich, RPh,e Keith A. Rodvold, PharmD,f
Daniel F. Sahm, PhD,g Joseph Varon, MD,h David Weiland, Jr, MD,i for the Council
for Appropriate and Rational Antibiotic Therapy (CARAT)

a
Department of Infectious Diseases, Indiana University School of Medicine, Indiana University, Indianapolis, Indiana, USA;
b
Department of Medicine, University of California, Irvine Medical Center, Orange, California, USA;
c
Department of Family Medicine, Carolinas Medical Center, Charlotte, North Carolina, USA;
d
Department of Internal Medicine, Northeastern Ohio Universities, College of Medicine, Akron, Ohio, USA;
e
RJM and Associates, Woodbridge, Virginia, USA;
f
Colleges of Pharmacy and Medicine, University of Illinois at Chicago, Chicago, Illinois, USA;
g
Focus Technologies, Inc., Herndon, Virginia, USA;
h
The University of Texas Health Sciences Center at Houston, Houston, Texas, USA;
i
Department of Family Medicine, University of South Florida, Largo, Florida, USA.

KEYWORDS: In response to the overuse and misuse of antibiotics, leading to increasing bacterial resistance and
Antibiotic therapy decreasing development of new antibiotics, the Council for Appropriate and Rational Antibiotic
resistance Therapy (CARAT) has developed criteria to guide appropriate and accurate antibiotic selection. The
Antibiotics criteria, which are aimed at optimizing antibiotic therapy, include evidence-based results, therapeutic
Antimicrobials benefits, safety, optimal drug for the optimal duration, and cost-effectiveness.
2005 Elsevier Inc. All rights reserved.

Antibiotics were hailed as miracle drugs after their initial
introduction in the 1940s. Their widespread availability and
success led to such dramatic reductions in the morbidity and
mortality caused by infectious diseases that in 1967 US Sur-
geon General William H. Stewart reportedly declared that it
was time to close the book on infectious diseases.1,2 How-
ever, the subsequent emergence of new infectious diseases and
Requests for reprints should be addressed to Thomas M. File, Jr., MD,
Internal Medicine Division, Northeastern Ohio Universities, College of
Medicine, 75 Arch Street, Suite 105, Akron, Ohio 44304.
E-mail address: filet@summa-health.org.
the development of increasing antibiotic resistance among ex-
isting bacterial diseases underscore the continued importance
of treating infectious diseases.
Although increased bacterial resistance to antibiotics has
several causes, 2 key factors are the overuse and misuse of
antibiotics.3 6 Antibiotics are frequently prescribed for in-
dications in which their use is not warranted, or an incorrect
or suboptimal antibiotic is prescribed. Although the popu-
lation- and visit-based prescribing rates for antimicrobials in
ambulatory care settings declined 23% and 25%, respec-
tively, between 1992 and 2000 in the United States, many
prescriptions for antibiotics in ambulatory patients are

0002-9343/$ -see front matter 2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.amjmed.2005.05.007
2S
written to treat acute respiratory tract infections (RTIs),
including the common cold, acute bronchitis, and acute
uncomplicated rhinosinusitis.79
The overuse and misuse of antibiotics has contributed to
an increase in bacterial resistance patterns, which may differ
by locality.8 In addition, antibiotics are now included in
many animal feeds, which are given to promote growth in
animals not otherwise known to be bacterially infected.
Many of these antibiotics are then ingested by humans
through consuming animal products. Taken together, these
factors enhance the risk of developing strains of bacteria
that are resistant to most common classes of antibiotics.
Furthermore, the development of new antibiotics has
stalled10,11 as a result of (1) fewer novel compounds in the
pipelines of pharmaceutical companies and (2) decisions
that have been made by the same companies to develop
drugs for chronic conditions such as arthritis, depression,
pain syndromes, lipid disorders, hypertension, and other
disorders rather than infectious diseases because of the
higher potential for profit.12 This may, in turn, lead to a
situation in which it will be more difficult to combat bac-
terial infections. Consequently, approaches that preserve the
efficacy of currently used antibiotics are needed.
The US Centers for Disease Control and Prevention
(CDC) and the World Health Organization (WHO) are ac-
tively addressing the primary issues associated with the
overuse and/or misuse of antibiotics. Less attention has been
paid, however, to the accurate use of antibiotics, defined as
choosing the correct drug at the correct dose for the correct
duration of treatment. The available evidence suggests that,
when antibiotic use is warranted, choosing the therapy most
likely to achieve clinical cure and treating for the shortest
length of time to achieve clinical and microbiologic efficacy
will result in lower incidence of retreatment, as well as a
lower incidence of antibiotic resistance.3,4,8
The Council for Appropriate and Rational
Antibiotic Therapy
The Council for Appropriate and Rational Antibiotic Ther-
apy (CARAT) is an independent, multidisciplinary panel of
healthcare professionals, clinicians as well as scientists,
established to advocate the appropriate and accurate use of
antibiotics. CARAT has developed 5 criteria to assist
healthcare providers in selecting the most appropriate and
accurate treatment regimens (Table 1). These criteria are
designed to help guide healthcare practitioners in using
antibiotics where they are appropriately indicated. This ar-
ticle addresses issues of appropriate antibiotic therapy and
offers guidelines for the accurate use of antibiotics. It also
presents the rationale for treating infectious diseases with
shorter-course therapy using optimal agents when antibiotic
therapy is warranted, thus helping to reduce the develop-
ment of antibiotic resistance and improve outcomes.
The American Journal of Medicine, Vol 118 (7A), July 2005
Appropriate antibiotic therapy
The first consideration in choosing appropriate antibiotic
therapy should be whether there is an indication for an
antimicrobial agent. Indications for an antibiotic include the
unambiguous demonstration or the strong suspicion that the
etiologic agent is bacterial. In general, the latter should be
based on the signs and symptoms of infection, as well as on
other factors, including the age of the patient, the patients
medical history, and the presence or absence of comorbidi-
ties. There are several guidelines and appropriate use state-
ments in the literature that variably discuss this process.8,9,1319
Once it is decided that an antibiotic is warranted, accurate
use of the agent should be explored, including examining
issues of resistance, benefits, safety, and cost.
Many of the same factors that go into determining
whether or not an etiologic agent is bacterial should also be
considered when selecting an antibiotic. Several groups
have issued specific guidelines on the use of antimicrobials
for certain disease states. According to guidelines on the
treatment of community-acquired pneumonia (CAP) issued
by the American Thoracic Society (ATS), factors that
should be taken into account when choosing an antimicro-
bial include severity of illness, presence of comorbidities,
presence of identified clinical risk factors for drug-resistant
and unusual pathogens, place of therapy (e.g., outpatient vs.
in hospital), and presence of risk factors for drug-resistant
Streptococcus pneumoniae, among others.13
In the 2000 update of their practice guidelines for the
management of CAP, the Infectious Diseases Society of
America (IDSA) recommended that, when an etiologic di-
agnosis is established or strongly suspected, the antimicro-
bial agent that is most cost-effective, least toxic, and most
narrow in spectrum should be used. When etiologic diag-
nosis is not available and empiric antibiotic selection is
required, severity of illness, pathogen probabilities, resis-
tance patterns, and comorbid conditions should be consid-
ered.14
The Sinus Allergy and Health Partnership, a group spon-
sored by the American Academy of Otolaryngology and
Head and Neck Surgery, among others, has issued guide-
lines on the antimicrobial treatment of acute bacterial rhi-
nosinusitis that recommend considering severity, rate of
progression, and recent antibiotic exposure when selecting
antibiotic therapy.16
Evidence-based results
In choosing an antibiotic, clinicians should consider the
clinical evidence demonstrating that the drug is clinically
and microbiologically appropriate, the efficacy of that drug
in well-designed clinical trials, and the antibiotic resistance
patterns of the local region. Clinicians should then use their
professional judgment to choose the optimal antibiotic.
Well-conducted, randomized, controlled clinical trials pro-
vide the highest quality information for making decisions.
Slama et al A Clinicians Guide to the CARAT Criteria 3S

Table 1 Council for Appropriate and Rational Antibiotic Therapy (CARAT) criteria
for accurate use of antibiotic therapy

Evidence-based results
Therapeutic benefits
Safety
Cost-effectiveness
Optimal drug dose and duration
Shorter-course, more aggressive therapy

Table 2 American Thoracic Society simplified grading system for ranking evidence
in the treatment of community-acquired pneumonia

Evidence Level Definition

Level I (high) Evidence comes from well-conducted,
randomized, controlled trials.
Level II (moderate) Evidence comes from well-designed,
controlled trials without
randomization (including cohort,
patient series, and case-control
studies).
Level II studies also include any
large case series in which systematic
analysis of disease patterns and/or
microbial etiology was conducted, as
well as reports of new therapies that
were not collected in a randomized
fashion.
Level III (low) Evidence comes from case studies
and expert opinion. In some
instances, therapy recommendations
come from antibiotic susceptibility
data without clinical observations.
Adapted from Am J Respir Crit Care Med.13

Without it, providers may make decisions based on tradition
and anecdotal experience.20
Virtually all professional organizations have developed
guidelines for evaluating clinical evidence. For example, in
formulating guidelines for the treatment of CAP, the ATS
applied a simplified 3-level grading system for the types of
evidence used in evaluating medications (Table 2), a tool
that has been gaining widespread professional acceptance.13
These guidelines are similar to those recommended by the
IDSA.15
Therapeutic benefits
The key to applying evidence-based results and making
appropriate therapeutic choices for each patient involves
determining the correct diagnosis and analyzing the thera-
peutic benefits of possible treatments. To maximize patient
health and reduce unnecessary prescribing, the therapeutic
benefits of each drug should be considered relative to the
status of the patients infection. The clinician must consider
any evidence that a particular antibiotic can result in a
clinical and microbiologic cure, as well as the treatment
failures associated with the absence of drug treatment. If
possible, the clinician should identify the causative patho-
gen and use surveillance data on regional antibiotic resis-
tance patterns in selecting the optimal therapeutic agent.
When evaluating potential therapeutic choices, data on
regional antibiotic resistance patterns should be taken into
consideration. Although antibacterial susceptibility patterns
are based on the results of in vitro tests, they can be used as
guidelines to minimize the chances of clinical failure.
Therefore, regional resistance patterns should be used to
help direct prescribing practices. If there is substantial re-
sistance to a particular class of antibiotics in a particular
geographic area, a different class of drug should be consid-
ered.8,14
Safety
In treating patients with a particular drug, safety must be
weighed against efficacy. Clinically applicable treatment
4S
strategies should be chosen to maximize efficacy while
minimizing side effects.
Although antibiotics are generally considered safe and
well tolerated, they have been associated with a wide range
of adverse effects. Safety profiles vary for different classes
of antibiotics, as well as for antibacterial agents within each
class. In addition, it should be considered that the safety
profiles of newer medications may not be as well estab-
lished as those that have been in use for many years. In a
study of the period between 1975 and 2000, 548 new chem-
ical entities were approved for use in the United States; 45
of these (8.2%) acquired new black-box warnings and 16
(2.9%) were withdrawn from the market during this time.
Of the 16 withdrawn from the market, 8 were withdrawn
within 2 years after their introduction. For example, tema-
floxacin was withdrawn 0.3 years after introduction and
grepafloxacin was withdrawn 2.0 years after introduction.21
In general, the selected antibiotic should be the one that
satisfies all other criteria and has the lowest rate of known
adverse events.
Optimal drug for optimal duration
Optimal drug selection requires finding the antimicrobial
class and the specific member of that class that is best suited
to treat a particular infection. Because empiric therapy is
necessary in most cases, multiple factors have to be consid-
ered. Among these are whether the etiologic agent is likely
to be gram-positive or gram-negative, whether a narrow or
broad-spectrum agent should be chosen, the resistance pat-
terns of the likely pathogen to this drug, both nationally and
regionally, and the individual patients medical history, in-
cluding recent antibiotic exposure. Several governing bod-
ies, such as the ATS and the IDSA, have issued guidelines
for the use of antimicrobial therapy in CAP. The IDSA
guidelines for the treatment of outpatients with signs and
symptoms of CAP suggest considering previous health,
recent courses of antibiotic treatment, and comorbid condi-
tions when determining a treatment.15 Previously healthy
patients with no recent antibiotic therapy should be treated
with a macrolide (erythromycin, azithromycin, or clarithro-
mycin) or doxycycline, whereas previously healthy patients
recently treated with an antibiotic should be treated with a
respiratory fluoroquinolone alone or an advanced macrolide
(azithromycin or clarithromycin) plus high-dose amoxicillin
or high-dose amoxicillin-clavulanate. Outpatients with co-
morbiditiesincluding chronic obstructive pulmonary dis-
ease, renal or congestive heart failure, or a malignancy
should be treated with an advanced macrolide or a
respiratory fluoroquinolone if they had no recent antibiotic
therapy or a respiratory fluoroquinolone alone or an ad-
vanced macrolide plus a -lactam if they had a recent
course of antibiotic therapy.15
Optimal duration means prescribing the selected drug for
the shortest amount of time required for clinical and micro-
biologic efficacy. There are many reasons for reducing an-
timicrobial therapy to the shortest appropriate duration.
The American Journal of Medicine, Vol 118 (7A), July 2005
They include the potential for reduced occurrence of ad-
verse effects, increased patient adherence, decreased pro-
motion of resistance, and decreased costs.22
The rational use of medicines has been defined by the
WHO as requiring that patients receive medications appro-
priate to their clinical needs, in doses that meet their own
requirements, for an adequate time, and at the lowest cost to
them and their community.23 As part of its guidelines, the
WHO has recognized that antimicrobial resistance has be-
come a serious worldwide public health problem and has
formulated a global strategy of interventions to slow the
emergence and reduce the spread of antimicrobial-resistant
microorganisms.
Cost-effectiveness
Choosing inappropriate therapy is associated with increased
costs, including the cost of the antibiotic and increases in
overall costs of medical care because of treatment failures
and adverse events. Upper RTIs, while usually mild and not
life-threatening, are associated with significant healthcare
costs. Treatment failure results in increased costs, particu-
larly if hospitalization is required.24
Using an optimal course of antibiotics can have eco-
nomic as well as clinical advantages. Outpatients may ex-
perience a faster return to their normal daily routine and an
earlier return to work. In a study comparing 500-mg and
750-mg intravenous levofloxacin in 232 inpatients with
CAP (intention-to-treat population), the higher dose of drug
was associated with a more rapid intravenous-to-oral switch
(2.35 vs. 2.75 days), fewer doses of oral antibiotic (4.08 vs.
8.59 doses), and lower cost of levofloxacin (US$115.47 vs.
$150.65).25 Other studies have also supported the efficacy
of shorter courses of treatment in pneumonia.26 33 Similar
results have also been found for short courses of therapy for
bronchitis, sinusitis, and urinary tract infections.34 43
Pharmacokinetic considerations
Pharmacokinetic properties differentiate among classes of
antibiotics, and even among antibiotics within the same
class, in their ability to eradicate bacteria at drug concen-
trations attained during therapy.8 Among these properties
are the time for which nonprotein-bound serum concentra-
tion of drug exceeds its minimum inhibitory concentration
(MIC); the ratio between peak serum concentration (Cmax)
and MIC; and the ratio between drug exposure, measured as
area under the serum 24-hour concentration-time curve
(AUC24), and MIC (AUC24MIC) ratio. These parameters
have been shown to be coordinated with clinical out-
come.44 46 For example, at a free-drug AUC24MIC ratio
33.7, the microbiological response of S pneumoniae to
fluoroquinolones is 100%.47 An AUC24MIC ratio of 125
predicts an 85.4% microbiologic response to levofloxacin
and an 81.5% response to ciprofloxacin.48
Slama et al A Clinicians Guide to the CARAT Criteria
For several classes of antibiotics, including the -lactams
and macrolides, bacteriologic efficacy can be correlated
with the time during which drug concentration exceeds
MIC.49,50 Thus, for optimal reduction of bacterial load,
these agents should be administered such that drug concen-
trations exceed the MIC for 40% of the dosing interval.
In contrast to the time-dependent efficacy of the -lac-
tams, macrolides, and lincosamides, the aminoglycosides,
metronidazole, and fluoroquinolones exhibit concentration-
dependent bactericidal activity. The efficacy of these drugs
has been found to correlate with the CmaxMIC and AUC24
MIC ratios.44 46,51 For example, an AUC24MIC ratio of 25
to 40 is thought to predict optimal bactericidal activity for
fluoroquinolones against S pneumoniae.47,49,5254 Thus, for
this class of drug, administration of a maximum dose for a
shorter time would be optimal in the absence of adverse
effects resulting from high drug doses.
Summary
Infectious diseases are still a serious problem, com-
pounded by the development of antibiotic resistance in
many bacteria and the relative lack of newer antimicro-
bial agents to combat these multiresistant organisms. In
choosing appropriate and accurate antibiotic therapy, the
clinician should use the 5 criteria of CARAT described
herein (evidence-based results, therapeutic benefits,
safety, optimal drug for the optimal duration, and cost-
effectiveness). Appropriate aggressive short-course
treatment is recommended for ensuring clinical and mi-
crobiologic cure, optimal patient adherence, and minimal
generation of antibiotic resistance. Ideally, institution of
the 5 CARAT criteria will optimize safe and well-toler-
ated treatment regimens, curb unnecessary prescribing of
antibiotics, decrease treatment costs, and increase adher-
ence.
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