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

Bacteroides spp., Propionibacterium, Peptococcus) are sensitive to
doxycycline, but other antibiotics (e.g., chloramphenicol, clindamycin,
metronidazole, and certain β-lactam antibiotics) have better activity.
Tetracycline is active against Actinomyces and is a drug of choice for
treating actinomycosis.
Currently established breakpoints for tigecycline susceptibility
vary by organism: for S. aureus ≤0.5 μg/mL; for Streptococcus,
Haemophilus, and Enterococcus species, ≤0.25 μg/mL; for S. pneumoniae,
≤0.06 μg/mL; for Enterobacteriaceae ≤2 μg/mL; and for anaerobic
organisms ≤4 μg/mL. In general, tigecycline is equally or more
active in vitro against bacteria than the tetracyclines (Table 55–1),
including activity against tetracycline-resistant organisms, especially
gram-negative organisms. There are a few exceptions where other
tetracyclines may be more active against certain organisms, such as
Stenotrophomonas and Ureaplasma. There is currently a lack of
clinical experience with tigecycline for infections caused by organisms
such as Burkholderia, Brucella, Yersinia, Francisella, and
Pasteurella. Notable holes in the spectrum of activity of tigecycline
(as with the tetracyclines) include Pseudomonas, Proteus, and
Providencia spp.
Mechanism of Action. Tetracyclines and glycylcyclines
inhibit bacterial protein synthesis by binding to the 30S
bacterial ribosome and preventing access of aminoacyl
tRNA to the acceptor (A) site on the mRNA-ribosome
complex (Figure 55–1). These drugs enter gramnegative
bacteria by passive diffusion through the
hydrophilic channels formed by the porin proteins of
the outer cell membrane and by active transport via an
energy-dependent system that pumps all tetracyclines
Nascent
polypeptide
chain
P site
50S
30S
A site
aa
Aminoacyl
tRNA
Transferase
site
Tetracycline
mRNA
template
Figure 55–1. Inhibition of bacterial protein synthesis by tetracyclines.
Messenger RNA (mRNA) attaches to the 30S subunit of
bacterial ribosomal RNA. The P (peptidyl) site of the 50S ribosomal
RNA subunit contains the nascent polypeptide chain; normally,
the aminoacyl tRNA charged with the next amino acid
(aa) to be added to the chain moves into the A (acceptor) site,
with complementary base pairing between the anticodon
sequence of tRNA and the codon sequence of mRNA.
Tetracyclines inhibit bacterial protein synthesis by binding to the
30S subunit and blocking tRNA binding to the A site.
across the cytoplasmic membrane. Entry of these drugs
into gram-positive bacteria requires metabolic energy,
but the process is not as well understood.
Resistance to Tetracyclines and Glycylcyclines. Resistance is primarily
plasmid mediated and often inducible. The three main resistance
mechanisms are (1) decreased accumulation of tetracycline as a
result of either decreased antibiotic influx or acquisition of an
energy-dependent efflux pathway; (2) production of a ribosomal protection
protein that displaces tetracycline from its target, a “protection”
that also may occur by mutation; and (3) enzymatic inactivation
of tetracyclines. Cross-resistance, or lack thereof, among tetracyclines
depends on which mechanism is operative. For example,
S. aureus strains that are tetracycline resistant on the basis of efflux
mediated by tetK still may be susceptible to minocycline.
Tetracycline resistance due to a ribosomal protection mechanism
(tetM) produces cross-resistance to doxycycline and minocycline
because the target site protected is the same for all tetracyclines.
The glycylamido moiety characteristic of tigecycline reduces
its affinity for most efflux pumps, restoring activity against many
organisms displaying tetracycline resistance due to this mechanism.
Binding of glycyclines to ribosomes is also enhanced, improving
activity against organisms that harbor ribosomal protection proteins
that confer resistance to other tetracyclines (Petersen et al., 1999).
Absorption, Distribution, and Excretion
Absorption. Oral absorption of most tetracyclines is incomplete. The
percentage of an oral dose that is absorbed with an empty stomach is
modest for demeclocycline and tetracycline (60-80%) and high for
doxycycline (95%) and minocycline (100%). The percentage of unabsorbed
drug rises as the dose increases. Tigecycline is not appreciably
absorbed from the gastrointestinal (GI) tract and is only available for
parenteral administration. Absorption of orally administered tetracyclines
mostly takes place in the stomach and upper small intestine and
is greater in the fasting state. Absorption may be impaired by the concurrent
ingestion of divalent and trivalent cations (e.g., Ca 2+ , Mg 2+ ,
Al 3+ , Fe 2+/3+ , and Zn 2+ ). Thus, dairy products, antacids, aluminum
hydroxide gels; calcium, magnesium, and iron or zinc salts; bismuth
subsalicylate (e.g., PEPTO-BISMOL), and dietary Fe and Zn supplements
can interfere with absorption of tetracyclines. The decreased
absorption apparently results from chelation with these cations and formation
of complexes with poor solubility. Doxycycline and minocycline
are less affected than tetracyclines and administration with milk
or calcium-containing foods is unlikely to impair absorption substantially,
but co-administration of antacids or mineral supplements should
be avoided.
Variable absorption of orally administered tetracyclines leads
to a wide range of plasma concentrations in different individuals.
Tetracycline is incompletely absorbed. After a single oral dose, the
peak plasma concentration is attained in 2-4 hours. These drugs have
half-lives in the range of 6-12 hours and frequently are administered
two to four times daily. The administration of 250 mg tetracycline
every 6 hours produces peak plasma concentrations of 2-2.5 μg/mL.
Increasing the dosage above 1 g every 6 hours does not further
increase plasma concentrations. Demeclocycline, which also is
incompletely absorbed, can be administered in lower daily dosages
than the congeners just mentioned because its t 1/2
of 16 hours provides
effective plasma concentrations for 24-48 hours.
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CHAPTER 55
PROTEIN SYNTHESIS INHIBITORS AND MISCELLANEOUS ANTIBACTERIAL AGENTS