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Department of Infectious Diseases, Indiana University School of Medicine, Indiana University, Indianapolis, Indiana, USA;
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.
b
KEYWORDS:
Antibiotic therapy
resistance
Antibiotics
Antimicrobials
In response to the overuse and misuse of antibiotics, leading to increasing bacterial resistance and
decreasing development of new antibiotics, the Council for Appropriate and Rational Antibiotic
Therapy (CARAT) has developed criteria to guide appropriate and accurate antibiotic selection. The
criteria, which are aimed at optimizing antibiotic therapy, include evidence-based results, therapeutic
benefits, safety, optimal drug for the optimal duration, and cost-effectiveness.
2005 Elsevier Inc. All rights reserved.
0002-9343/$ -see front matter 2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.amjmed.2005.05.007
the development of increasing antibiotic resistance among existing 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 indications in which their use is not warranted, or an incorrect
or suboptimal antibiotic is prescribed. Although the population- and visit-based prescribing rates for antimicrobials in
ambulatory care settings declined 23% and 25%, respectively, between 1992 and 2000 in the United States, many
prescriptions for antibiotics in ambulatory patients are
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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 bacterial 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 actively 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
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 provide the highest quality information for making decisions.
Slama et al
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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)
Level II (moderate)
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 therapeutic 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
Safety
In treating patients with a particular drug, safety must be
weighed against efficacy. Clinically applicable treatment
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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 established as those that have been in use for many years. In a
study of the period between 1975 and 2000, 548 new chemical 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, temafloxacin 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.
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, particularly if hospitalization is required.24
Using an optimal course of antibiotics can have economic as well as clinical advantages. Outpatients may experience 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 concentrations attained during therapy.8 Among these properties
are the time for which nonprotein-bound serum concentration 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 outcome.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
Summary
Infectious diseases are still a serious problem, compounded by the development of antibiotic resistance in
many bacteria and the relative lack of newer antimicrobial 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 costeffectiveness). Appropriate aggressive short-course
treatment is recommended for ensuring clinical and microbiologic cure, optimal patient adherence, and minimal
generation of antibiotic resistance. Ideally, institution of
the 5 CARAT criteria will optimize safe and well-tolerated treatment regimens, curb unnecessary prescribing of
antibiotics, decrease treatment costs, and increase adherence.
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