US Pharm. 2006;10:47-54.
Fluoroquinolones evolved from nalidixic acid,
which was approved by the FDA in 1963. Nalidixic acid was reasonably effective
against many gram-negative organisms; however, it did not possess adequate
activity against many gram-positive, anaerobic, or other important
gram-negative organisms, such as Pseudomonas aeruginosa.1,2
This narrow spectrum of activity limited the use of nalidixic acid to the
extent that it was indicated only for the use of urinary tract infections
After the introduction of nalidixic acid, the
addition of a fluoride atom was found to yield quinolones with a greater
spectrum of activity, thus leading to "fluoroquinolones." Second-generation
fluoroquinolones possessed improved activity against gram-negative organisms
but still had limited activity against gram-positive organisms. With the
release of the third- and fourth-generation fluoroquinolones, greater activity
against gram-positive organisms, particularly Streptococcus pneumoniae,
was gained, but activity against P. aeruginosa subsequently decreased.
3-10 The spectrum of in vitro activity for available fluoroquinolones is
listed in TABLE 1.
Mechanism of Action
Fluoroquinolones are bactericidal
anti-infectives that work by inhibiting DNA synthesis through the formation of
a complex with either DNA gyrase or topoisomerase IV--the enzymes responsible
for removing coils in the DNA and separating the daughter strands. This
three-way complex between the DNA molecule, fluoroquinolone, and
gyrase/topoisomerase IV prevents DNA replication from occurring at the
replication fork, leading to cell death.11
Current fluoroquinolones may have common, mild
side effects (e.g., nausea, dizziness, and headache) or other more serious
side effects (e.g., phototoxicity, hepatotoxicity, QT prolongation, and
tendinitis) and are not recommended for children. Yet, as a class, the
fluoroquinolones are generally well tolerated.
Rates of Fluoroquinolone Prescribing
Over the years, the
susceptibility of microorganisms has been changing, possibly due to the misuse
of antimicrobial agents. Misuse not only refers to incorrect use of a drug for
a certain indication or microorganism but also applies to inappropriate
treatment duration and/or the use of doses that are too low, which may result
in the selection of mutant isolates.
Widespread use of fluoroquinolones may also
contribute to the developing resistance of microorganisms. According to data
published in the American Journal of Medicine, fluoroquinolones became
the most frequently prescribed antibiotics in the United States between 1995
and 2002. During this time, there was a threefold increase in fluoroquinolone
use: Prescriptions rose from seven million in 1995 to 22 million in 2002. This
is a dramatic increase, particularly since the percentage of overall
antibiotic prescriptions did not vary significantly during this period (12% in
1995; 11% in 2002). In addition to the increase in number of fluoroquinolone
prescriptions, it was also found that 42% of these prescriptions were for
Based on research from a study conducted in
Belgium, the rate of fluoroquinolone use nearly doubled from 1993 to 2003 with
the introduction of levofloxacin and moxifloxacin. The majority of the
fluoroquinolone consumption was used to treat UTIs, followed by lower
respiratory infections, and to a lesser degree, upper respiratory tract
The information gained from these studies is
fundamental in determining the impact of widespread use of fluoroquinolones,
especially since evidence indicates there is a relationship between increasing
microorganism resistance and the rising use of antibiotics. Thus, prudent use
of fluoroquinolones is crucial, because resistance may increase with broad
misuse of this class of agents.14-16
Mechanisms of Fluoroquinolone Resistance
Resistance to fluoroquinolones
can occur through several mechanisms. First, alterations can occur in the
target enzymes, to the extent that fluoroquinolones are unable to bind DNA
gyrase or topoisomerase IV. Second, alterations can occur in the permeability
of the cell, making it difficult for fluoroquinolones to enter and access the
target enzymes. Third, chromosomal mutations may occur that could affect the
affinity, or confer resistance, of the target enzymes for fluoroquinolones. In
addition, multidrug resistance (MDR) efflux pumps found in the membranes of
some bacteria may also confer resistance to fluoroquinolones.17,18
In China, there have been reports of resistance to quinolones in
Escherichia coli introduced through plasmid-mediated transfers.19
Several studies have been
published regarding the evolving resistance of certain organisms to
fluoroquinolones. Of particular importance is the growing resistance of S.
pneumoniae. The CDC has already reported the organism's resistance to the
newest fluoroquinolone antimicrobials. S. pneumoniae is one of the most
common respiratory pathogens found in lower respiratory tract infections, such
as acute bronchitis, acute exacerbations of chronic obstructive pulmonary
disease, and pneumonia.20 Because treatment of lower respiratory
tract infections is based on empirical therapy, and due to their excellent
coverage of S. pneumoniae, the newer fluoroquinolones--levofloxacin,
moxifloxacin, gatifloxacin, and gemifloxacin (often termed the respiratory
fluoroquinolones)--have been pushed to the forefront in infections
involving this organism. This may add to the growing resistance seen in this
class of antibiotics. The mechanisms of resistance for S. pneumoniae
are thought to be due to chromosomal mutations and/or efflux pumps. Although
S. pneumoniae resistance to fluoroquinolones is currently low, news of
clinical failures and increasing resistance have already been reported.
Haemophilus influenzae is another important
pathogen involved in respiratory tract infections, particularly pneumonia.
Currently, fluoroquinolone resistance rates for this organism are low but not
unheard of.23 Notably, one case report involves a 71-year-old woman
with community-acquired pneumonia who died secondary to an infection involving
H. influenzae, which was resistant to levofloxacin, ciprofloxacin,
moxifloxacin, and gatifloxacin. The mechanism of resistance observed in this
organism was due to mutations in the target enzymes.24
UTIs are very common and can be found in both the
inpatient and outpatient settings. Some of the most typical urinary pathogens
associated with UTIs are E. coli, Proteus mirabilis,
Klebsiella pneumoniae, and the Enterobacter species. However, over
the years, the susceptibility of these pathogens has been changing.
Trimethoprim-sulfamethoxazole has been the mainstay of therapy for UTIs, but
fluoroquinolones have now become first-line empirical therapy in some regions.
This change may be a contributing factor to the growing resistance of these
organisms to fluoroquinolones.25
In one study that evaluated the rising resistance
rates of E. coli to fluoroquinolones in UTIs, resistance to
ciprofloxacin and ofloxacin rose from 4.1% and 5.2% in 1996, to 25.3% and
27.6% in 2002, respectively.16 Additionally, another study that was
conducted over a 12-year period found comparable increasing fluoroquinolone
resistance rates in both the inpatient and outpatient settings, not only for
E. coli but for P. mirabilis and Enterobacter cloacae as
well. Similar increasing inpatient resistance rates were also reported for
Combating Antimicrobial Resistance
Resistance is on the rise even in
organisms with low-level resistance to fluoroquinolones. Fluoroquinolones are
an important class of antibiotics, and if resistance to these antimicrobials
becomes problematic, treatment options for certain infectious diseases will be
limited. In addition, resistance leads to the need for new antimicrobials;
however, the number of new antimicrobial agents produced over the years has
decreased. Research has shown that FDA approvals of antibacterial drugs have
declined by 56% from 1998 to 2002, compared to the period between 1983 and
1987. Of the 225 new molecular entities approved from 1998 to 2002, only seven
of those agents were antimicrobials. Furthermore, even though development of
new antibiotics within an existing class is advantageous, because it can lead
to enhancement of the spectrum of activity and safety data, new classes of
antimicrobials with differing mechanisms of action are imperative to combat
the increasing rise of multidrug-resistant organisms.14
Recently, the CDC, FDA, and National Institutes of
Health teamed up with other key health organizations to form the Interagency
Task Force on Antimicrobial Resistance, which is dedicated to creating a
public health action plan to combat antimicrobial resistance.20
This plan comprises four areas of focus: surveillance, prevention and control,
research, and product development. These four areas form the "blueprint" for
measures that can be undertaken to address rising antimicrobial resistance.
Surveillance: According to
the Task Force, "unless antimicrobial problems are detected as they emerge--and
actions are taken quickly to contain them--the world may soon be faced with
previously treatable diseases that have again become untreatable, as in the
preantibiotic era."20 Thus, the Task Force considers it
necessary to monitor patterns of antimicrobial use, as well as to enhance the
current beliefs of the link between antimicrobial use and resistance.
Prevention and Control:The Task
Force defines effective antimicrobial use as "use that maximizes therapeutic
impact while minimizing toxicity and the development of resistance, and it is
overuse and misuse that must be decreased to reduce the selective pressure
favoring the spread of resistance."20 As stated earlier,
effective use entails using the correct drug for the specific indication and
microorganism, using the appropriate treatment duration and dosage, and using
antimicrobial therapy only when it is beneficial to the patient. The Task
Force concludes that strategies to endorse appropriate use involve informing
health care providers and consumers about the recommendations and limitations
surrounding antimicrobial agents, improving diagnostic techniques, carrying
out a public health educational crusade, and employing educational and
behavioral interventions that will aid health care providers in choosing the
correct antimicrobial therapy for each patient.
Research: The basis for each
of the focus points listed is research. There are three concentrated areas:
identifying gaps and needs in the understanding of resistance, supporting a
vigorous research community, and producing new antimicrobials from results of
Product Development:As indicated
previously, antimicrobial approvals have decreased over the years, which is
another concern of the Task Force. They recognize that the reduced rate of new
antimicrobial approvals is not sufficient to address the escalating rate of
microbial resistance. They attribute the lower rate to reluctant
pharmaceutical companies, scientific limitations, and lack of awareness of the
need for new antimicrobial agents. Thus, the focus of product development is
to address these deficits by recognizing and publicizing the need for new
agents and providing incentives to encourage the development of new
Fluoroquinolone resistance is an
increasing problem not only in the U.S. but also worldwide, potentially due to
the widespread misuse of this class of antimicrobials. The Interagency Task
Force on Antimicrobial Resistance suggests that enhanced surveillance of
antimicrobial resistance is critical to extend the therapeutic use of
antimicrobials, including fluoroquinolones. In addition, the production of new
agents is vital to combat this mounting rate of resistance. However, until new
agents can be produced, stricter guidelines should be initiated to preserve
this broad class of antibiotics and others as well. Furthermore, the public
and health care providers should be educated on the impact of inappropriate
antimicrobial use.Fluoroquinolone resistance is an increasing problem not only
in the U.S. but also worldwide, potentially due to the widespread misuse of
this class of antimicrobials. The Interagency Task Force on Antimicrobial
Resistance suggests that enhanced surveillance of antimicrobial resistance is
critical to extend the therapeutic use of antimicrobials, including
fluoroquinolones. In addition, the production of new agents is vital to combat
this mounting rate of resistance. However, until new agents can be produced,
stricter guidelines should be initiated to preserve this broad class of
antibiotics and others as well. Furthermore, the public and health care
providers should be educated on the impact of inappropriate antimicrobial use.
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