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

Protein Synthesis Inhibitors
and Miscellaneous Antibacterial
Agents
Conan MacDougall and Henry F. Chambers
The antimicrobial agents discussed in this chapter may
be assigned to three groups:
• Bacteriostatic, protein-synthesis inhibitors that target
the ribosome, such as tetracyclines and glycylcyclines,
chloramphenicol, macrolides and
ketolides, lincosamides (clindamycin), streptogramins
(quinupristin/dalfopristin), oxazolidinones (linezolid),
and aminocyclitols (spectinomycin).
• Agents acting on the cell wall or cell membrane such
as polymyxins, glycopeptides (vancomycin and
teicoplanin), and lipopeptides (daptomycin).
• Miscellaneous compounds acting by diverse mechanisms
with limited indications: bacitracin and
mupirocin.
TETRACYCLINES AND GLYCYLCYCLINES
Sources and Chemistry. The tetracyclines are close
congeners of polycyclic naphthacenecarboxamide.
Structural formulas of the tetracyclines are shown in
Table 55–1.
Chlortetracycline, the prototype of this class, was introduced
in 1948 but is no longer marketed in the U.S. Oxytetracycline is a
natural product elaborated by Streptomyces rimosus. Tetracycline is
a semisynthetic derivative of chlortetracycline. Demeclocycline is
the product of a mutant strain of S. aureofaciens, and methacycline
(not available in the U.S.), doxycycline, and minocycline all are
semisynthetic derivatives.
Because of their activity against Rickettsia, aerobic and anaerobic
gram-positive and gram-negative bacteria, and Chlamydia,
tetracyclines became known as “broad-spectrum” antibiotics. The
spread of antimicrobial resistance has eroded the activity of tetracyclines
against many gram-positive and gram-negative organisms. A
new group of tetracycline derivatives, the glycyclines, have regained
much of this activity. The glycylcyclines are synthetic analogs of the
tetracyclines; the glycycline currently approved is tigecycline, the
9-tert-butyl-glycylamido derivative of minocycline.
Antimicrobial Activity. Tetracyclines are bacteriostatic
antibiotics with activity against a wide range of aerobic
and anaerobic gram-positive and gram-negative bacteria.
They also are effective against some microorganisms, such
as Rickettsia, Coxiella burnetii, Mycoplasma pneumoniae,
Chlamydia spp., Legionella spp., Ureaplasma, some atypical
mycobacteria, and Plasmodium spp., that are resistant to cell-wallactive
antimicrobial agents. The tetracyclines are active against many
spirochetes, including Borrelia recurrentis, Borrelia burgdorferi
(Lyme disease), Treponema pallidum (syphilis), and Treponema
pertenue. Tetracyclines are active against Chlamydia and
Mycoplasma. Some nontuberculosis strains of mycobacteria (e.g.,
M. marinum) also are susceptible. They are not active against fungi.
Demeclocycline, tetracycline, minocycline, and doxycycline are
available in the U.S. for systemic use. Other derivatives are available
in other countries. The more lipophilic drugs, minocycline and
doxycycline, usually are the most active by weight, followed by
tetracycline. Resistance of a bacterial strain to any one member of
the class may or may not result in cross-resistance to other tetracyclines.
Tigecycline is generally, although not universally, active
against organisms that are susceptible to tetracyclines as well as
those with acquired resistance to tetracyclines (Gales et al., 2008).
Bacterial strains with tetracycline minimum inhibitory concentrations
(MICs) ≤4 μg/mL are considered susceptible except for
Haemophilus influenzae and Streptococcus pneumoniae, whose susceptibility
breakpoints (defined as the upper limit of the concentration
at which bacteria are still considered susceptible to a given drug)
are ≤2 μg/mL, and Neisseria gonorrhoeae, with a breakpoint of
≤0.25 μg/mL. The MIC breakpoint for susceptible anaerobic bacteria
is 8 μg/mL. Tetracyclines intrinsically are more active against
gram-positive than gram-negative microorganisms, but acquired
resistance is common. Recent data from the U.S. on the activity of
tetracycline and other agents discussed in this chapter against
selected gram-positive aerobes are displayed in Table 55–2.
However, prevalence of resistant strains varies in different regions.
For example, ~10% of S. pneumoniae isolates in the U.S. are resistant