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

1534 gastric emptying in patients with gastroparesis (Chapter 46). The
GI symptoms are dose related and occur more commonly in children
and young adults; they may be reduced by prolonging the infusion
time to 1 hour or by pretreatment with glycopyrrolate (Bowler
et al., 1992). Intravenous infusion of 1-g doses, even when dissolved
in a large volume, often is followed by thrombophlebitis. This can
be minimized by slow rates of infusion. Clarithromycin,
azithromycin, and telithromycin also may cause GI distress, but typically
to a lesser degree than that seen with erythromycin.
Cardiac toxicity. Erythromycin, clarithromycin, and telithromycin
have been reported to cause cardiac arrhythmias, including QT prolongation
with ventricular tachycardia. Most patients have had
underlying risk factors, such as prolonged QT syndrome, uncorrected
hypokalemia or hypomagnesemia, profound bradycardia, or
in patients receiving certain antiarrhythmics (e.g., quinidine, procainamide,
amiodarone) or other agents that prolong QTc (e.g., cisapride,
pimozide).
Other Toxic and Irritative Effects. Among the allergic reactions
observed are fever, eosinophilia, and skin eruptions, which may
occur alone or in combination; each disappears shortly after therapy
is stopped. Transient auditory impairment is a potential complication
of treatment with erythromycin; it has been observed to
follow intravenous administration of large doses of the gluceptate
or lactobionate (4 g per day) or oral ingestion of large doses
of the estolate. Visual disturbances due to slowed accommodation
have been reported to occur in ~1% of treatment courses
with telithromycin, and they include blurred vision, difficulty
focusing, and diplopia. Telithromycin is contraindicated in
patients with myasthenia gravis due to reports of exacerbation
of neurological symptoms by the antibiotic in these patients.
Loss of consciousness and visual disturbances are associated
with telithromycin.
Drug Interactions. Erythromycin, clarithromycin, and telithromycin
inhibit CYP3A4 and are associated with clinically significant drug
interactions (Periti et al., 1992). Erythromycin potentiates the effects
of carbamazepine, corticosteroids, cyclosporine, digoxin, ergot alkaloids,
theophylline, triazolam, valproate, and warfarin, probably by
interfering with CYP-mediated metabolism of these drugs (Chapter
6). Clarithromycin, which is structurally related to erythromycin,
has a similar drug interaction profile. Telithromycin is both a substrate
and a strong inhibitor of CYP3A4. Co-administration of
rifampin, a potent inducer of CYP, decreases the serum concentrations
of telithromycin by 80%. CYP3A4 inhibitors (e.g., itraconazole)
increase peak serum concentrations of telithromycin.
Azithromycin, which differs from erythromycin and clarithromycin
because of its 15-membered lactone ring structure, and
dirithromycin, which is a longer-acting 14-membered lactone ring
analog of erythromycin, appear to be free of these drug interactions.
Caution is advised, nevertheless, when using azithromycin in conjunction
with drugs known to interact with erythromycin.
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
LINCOSAMIDES (CLINDAMYCIN)
Clindamycin is a lincosamide, a derivative of the amino
acid trans-L-4-n-propylhygrinic acid, attached to a
sulfur-containing derivative of an octose. It is a congener
of lincomycin:
CH 3 CH 3
C NH CH
CH 3 CH 2 CH 2
O HO
O H
H
H
N H
H C Cl
H
OH H
SCH 3
H OH
CLINDAMYCIN
Antimicrobial Activity. Bacterial strains are susceptible to clindamycin
at MICs of ≤0.5 μg/mL. Clindamycin generally is similar
to erythromycin in its in vitro activity against susceptible strains of
pneumococci, S. pyogenes, and viridans streptococci (Table 55–2).
Methicillin-susceptible strains of S. aureus usually are susceptible
to clindamycin, but methicillin-resistant strains of S. aureus and
coagulase-negative staphylococci frequently are resistant.
Clindamycin is more active than erythromycin or clarithromycin
against anaerobic bacteria, especially B. fragilis;
some strains are inhibited by <0.1 μg/mL, and most are inhibited by
2 μg/mL. The MICs for other anaerobes are as follows: Bacteroides
melaninogenicus, 0.1 to 1 μg/mL; Fusobacterium, <0.5 μg/mL
(although most strains of Fusobacterium varium are resistant);
Peptostreptococcus, <0.1-0.5 μg/mL; Peptococcus, 1-100 μg/mL
(with 10% of strains resistant); and C. perfringens, <0.1-8 μg/mL.
From 10-20% of clostridial species other than C. perfringens are
resistant. Resistance to clindamycin in Bacteroides spp. increasingly
is encountered (Hedberg and Nord, 2003). Strains of Actinomyces
israelii and Nocardia asteroides are sensitive. Essentially all aerobic
gram-negative bacilli are resistant.
With regard to atypical organisms and parasites, M. pneumoniae
is resistant. Chlamydia spp. are variably sensitive, although the
clinical relevance is not established. Clindamycin plus primaquine
and clindamycin plus pyrimethamine are second-line regimens for
Pneumocystis jiroveci pneumonia and T. gondii encephalitis, respectively.
Clindamycin has been used for treatment of babesiosis.
Mechanism of Action. Clindamycin binds exclusively to the 50S subunit
of bacterial ribosomes and suppresses protein synthesis.
Although clindamycin, erythromycin, and chloramphenicol are not
structurally related, they act at sites in close proximity (Figures 55–2
and 55–3), and binding by one of these antibiotics to the ribosome
may inhibit the interaction of the others. There are no clinical indications
for the concurrent use of these antibiotics.
Resistance to Clindamycin. Macrolide resistance due to ribosomal
methylation by erm-encoded enzymes also may produce resistance
to clindamycin. Because clindamycin does not induce the methylase,
there is cross-resistance only if the enzyme is produced constitutively.
However, strains with inducible resistance may develop
constitutive production of the methylase during therapy. Thus, many
clinicians avoid use of clindamycin in the treatment of deep-seated
infections due to organisms displaying an inducible resistance phenotype.
Detection of this phenotype can be accomplished by approximating
erythromycin and clindamycin on an agar plate with a lawn
of the organism; a blunting of the zone of inhibition between clindamycin
and erythromycin suggests inducible resistance (this is
known as the “D-test”) (Lewis & Jorgensen, 2005). Clindamycin is
not a substrate for macrolide efflux pumps; thus strains that are resistant
to macrolides by this mechanism are susceptible to clindamycin.