DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1472 DNA via an ATP-dependent reaction requiring that both
strands of the DNA be cut to permit passage of a segment
of DNA through the break; the break then is
resealed.
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
The DNA gyrase of E. coli is composed of two 105,000 Da
A subunits and two 95,000 Da B subunits encoded by the gyrA and
gyrB genes, respectively. The A subunits, which carry out the strandcutting
function of the gyrase, are the site of action of the quinolones
(Figure 52–3). The drugs inhibit gyrase-mediated DNA supercoiling
at concentrations that correlate well with those required to inhibit
bacterial growth (0.1-10 μg/mL). Mutations of the gene that encodes
the A subunit polypeptide can confer resistance to these drugs
(Hooper, 2005a).
Topoisomerase IV is also composed of four subunits encoded
by the parC and parE genes in E. coli (Hooper, 2005a).
Topoisomerase IV separates interlinked (catenated) daughter DNA
molecules that are the product of DNA replication. Eukaryotic cells
do not contain DNA gyrase, but they do contain a conceptually and
mechanistically similar type II DNA topoisomerase that removes
positive supercoils from DNA to prevent its tangling during replication.
This enzyme is the target for some antineoplastic agents
(Chapters 60 and 61). Quinolones inhibit eukaryotic type II topoisomerase
only concentrations (100-1000 μg/mL) much higher than
those that inhibit bacterial DNA gyrase (Mitscher and Ma, 2003).
Antibacterial Spectrum. The fluoroquinolones are potent bactericidal
agents against E. coli and various species of Salmonella,
Shigella, Enterobacter, Campylobacter, and Neisseria (Hooper,
2005a). MICs of the fluoroquinolones for 90% of these strains
(MIC 90
) usually are <0.2 μg/mL. Ciprofloxacin is more active than
norfloxacin (NOROXIN) against P. aeruginosa; values of MIC 90
range
from 0.5-6 μg/mL. Fluoroquinolones also have good activity against
staphylococci, but not against methicillin-resistant strains (MIC 90
=
0.1-2 μg/mL).
Activity against streptococci is limited to a subset of the
quinolones, including levofloxacin (LEVAQUIN), gatifloxacin, and
moxifloxacin (AVELOX) (Hooper, 2005a). Several intracellular bacteria
are inhibited by fluoroquinolones at concentrations that can be
achieved in plasma; these include species of Chlamydia, Mycoplasma,
Legionella, Brucella, and Mycobacterium (including Mycobacterium
tuberculosis) (American Thoracic Society, 2003). Ciprofloxacin
(CIPRO, others), ofloxacin (FLOXIN), and pefloxacin have MIC 90
values
from 0.5-3 μg/mL for M. fortuitum, M. kansasii, and M. tuberculosis;
ofloxacin and pefloxacin (not available in U.S.) are active in animal
models of leprosy (Hooper, 2005a). However, clinical experience with
these pathogens remains limited.
Several fluoroquinolones, including garenoxacin (not available
in U.S.) and gemifloxacin, have activity against anaerobic bacteria
(Medical Letter, 2000, 2004).
Resistance to quinolones may develop during therapy via
mutations in the bacterial chromosomal genes encoding DNA gyrase
or topoisomerase IV or by active transport of the drug out of the bacteria
(Oethinger et al., 2000). No quinolone-modifying or -inactivating
activities have been identified in bacteria (Gold and Moellering,
1996). Resistance has increased after the introduction of fluoroquinolones,
especially in Pseudomonas and staphylococci. Increasing
fluoroquinolone resistance also is being observed in C. jejuni,
Salmonella, N. gonorrhoeae, and S. pneumoniae.
As mentioned in Chapter 48, the pharmacokinetic and pharmacodynamic
parameters of antimicrobial agents are important in
preventing the selection and spread of resistant strains and have led
to description of the mutation-prevention concentration, which is the
lowest concentration of antimicrobial that prevents selection of
resistant bacteria from high bacterial inocula. β-Lactams are timedependent
agents without significant post-antibiotic effects, resulting
in bacterial eradication when unbound serum concentrations
exceed MICs of these agents against infecting pathogens for >40-50%
of the dosing interval. By contrast, fluoroquinolones are concentrationand
time-dependent agents, resulting in bacterial eradication when
unbound serum area under the curve-to-MIC ratios exceed 25-30.
An extended release formulation of ciprofloxacin (PROQUIN XR)
exemplifies this principle.
Absorption, Fate, and Excretion. The quinolones are well absorbed
after oral administration and are distributed widely in body tissues.
Peak serum levels of the fluoroquinolones are obtained within 1-3 hours
of an oral dose of 400 mg, with peak levels ranging from 1.1 μg/mL
for sparfloxacin to 6.4 μg/mL for levofloxacin. Relatively low serum
levels are reached with norfloxacin and limit its usefulness to the
treatment of urinary tract infections. Food does not impair oral
absorption but may delay the time to peak serum concentrations.
Oral doses in adults are 200-400 mg every 12 hours for ofloxacin,
400 mg every 12 hours for norfloxacin and pefloxacin, and 250 to
750 mg every 12 hours for ciprofloxacin. Bioavailability of the fluoroquinolones
is >50% for all agents and >95% for several. The
serum t 1/2
is 3-5 hours for norfloxacin and ciprofloxacin. The volume
of distribution of quinolones is high, with concentrations of
quinolones in urine, kidney, lung and prostate tissue, stool, bile, and
macrophages and neutrophils higher than serum levels. Quinolone
Stabilize
positive node
(+)
Break
back segment
Reseal break
on front side
(–)
(–)
(–) (–)
1 2 3
Figure 52–3. Model of the formation of negative DNA supercoils by DNA gyrase. The enzyme binds to two segments of DNA (1), creating
a node of positive (+) superhelix. The enzyme then introduces a double-strand break in the DNA and passes the front segment
through the break (2). The break is then resealed (3), creating a negative (–) supercoil. Quinolones inhibit the nicking and closing activity
of the gyrase and, at higher concentrations, block the decatenating activity of topoisomerase IV. From Cozzarelli NR. DNA gyrase
and the supercoiling of DNA. Science, 1980, 207:953–960. Reprinted with permission from AAAS.