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

Drug Interactions. Chloramphenicol inhibits hepatic CYPs and
thereby prolongs the half-lives of drugs that are metabolized by this
system, including warfarin, dicumarol, phenytoin, chlorpropamide,
antiretroviral protease inhibitors, rifabutin, and tolbutamide. Severe
toxicity and death have occurred because of failure to recognize such
effects. Conversely, other drugs may alter the elimination of chloramphenicol.
Concurrent administration of phenobarbital or rifampin,
which potently induce CYPs, shortens the t 1/2
of the antibiotic and
may result in subtherapeutic drug concentrations.
MACROLIDES AND KETOLIDES
Erythromycin was discovered in 1952 by McGuire and
coworkers in the metabolic products of a strain of
Streptomyces erythreus. Clarithromycin (BIAXIN, others)
and azithromycin (ZITHROMAX, others) are semisynthetic
derivatives of erythromycin. Ketolides are semisynthetic
derivatives of erythromycin with activity against some
macrolide-resistant strains. Telithromycin (KETEK) is the
only ketolide currently approved in the U.S. Although the
ketolides are promising agents against drug-resistant organisms,
substantial hepatotoxicity seen with telithromycin has
limited their use.
Macrolide antibiotics contain a many-membered lactone ring
(14-membered rings for erythromycin and clarithromycin and a
15-membered ring for azithromycin) to which are attached one or
more deoxy sugars. Clarithromycin differs from erythromycin only
by methylation of the hydroxyl group at the 6 position, and
azithromycin differs by the addition of a methyl-substituted nitrogen
atom into the lactone ring. These structural modifications improve acid
stability and tissue penetration and broaden the spectrum of activity.
CH 2
H 3 C
H 3 C
H 3 C
HO
O
CH 3
N
OH
H 3 C
O
CH 3
H 3 C
OH OH H 3 C CH 3
OH CH 3 N
HO
H 3 C
O O CH 3
CH 2
O
CH 3 O O OCH 3
CH 3
O
CH 3
OH
CH 3
ERYTHROMYCIN
CH 3
OH H 3 C CH
CH 3
3 N
HO
O O CH 3
CH 3 O O OCH 3
CH 3
O
CH 3
OH
CH 3
AZITHROMYCIN
Telithromycin differs from erythromycin in that a 3-keto
group replaces the α-L-cladinose of the 14-member macrolide ring,
and there is a substituted carbamate at C11-C12. These modifications
render ketolides less susceptible to methylase-mediated (erm)
and efflux-mediated (mef or msr) mechanisms of resistance.
Ketolides therefore are active against many macrolide-resistant
gram-positive strains. The structural formula of telithromycin is:
Antimicrobial Activity. Erythromycin usually is bacteriostatic
but may be bactericidal in high concentrations
against susceptible organisms. The antibiotic is
most active in vitro against aerobic gram-positive
cocci and bacilli (Table 55–2). Staphylococci are considered
susceptible at ≤0.5 μg/mL and streptococci at
≤0.25 μg/mL. Macrolide resistance among S. pneumoniae
often co-exists with penicillin resistance
Staphylococci are not reliably sensitive to erythromycin,
especially methicillin-resistant strains. Macrolideresistant
strains of S. aureus are potentially
cross-resistant to clindamycin and streptogramin B
(quinupristin). Gram-positive bacilli also are sensitive
to erythromycin; typical MICs are 1 μg/mL for
Clostridium perfringens, from 0.2 to 3 μg/mL for
Corynebacterium diphtheriae, and from 0.25 to 4 μg/mL
for Listeria monocytogenes.
Erythromycin is inactive against most aerobic enteric gramnegative
bacilli. It has modest activity in vitro against other gramnegative
organisms, including H. influenzae (MIC, 1-32 μg/mL) and
N. meningitidis (MIC, 0.4-1.6 μg/mL), and good activity against most
strains of N. gonorrhoeae (MIC, 0.12-2 μg/mL). Useful antibacterial
activity also is observed against Pasteurella multocida, Borrelia spp.,
and Bordetella pertussis. Resistance is common for B. fragilis (the
MIC ranging from 2-32 μg/mL). Macrolides are usually active against
Campylobacter jejuni (MIC, 0.5-4 μg/mL). Erythromycin is active
against M. pneumoniae (MIC, 0.004-0.02 μg/mL) and Legionella
pneumophila (MIC, 0.01-2 μg/mL). Most strains of C. trachomatis
are inhibited by 0.06-2 μg/mL of erythromycin. Some of the atypical
mycobacteria, including M. scrofulaceum, are sensitive to erythromycin
in vitro; M. kansasii and M. avium-intracellulare vary in
sensitivity. M. fortuitum is resistant. Macrolides have no effect on
viruses, yeasts, or fungi.
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CHAPTER 55
PROTEIN SYNTHESIS INHIBITORS AND MISCELLANEOUS ANTIBACTERIAL AGENTS