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

1538 Indiscriminant use and overuse will hasten selection of resistant
strains and the eventual loss of this valuable newer agent.
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Untoward Effects
Hematological Toxicity. Myelosuppression, including anemia,
leukopenia, pancytopenia, and thrombocytopenia, has been reported
in patients receiving linezolid. Thrombocytopenia or a significant
reduction in platelet count has been associated with linezolid in 2.4%
of treated patients, and its occurrence is related to duration of therapy.
Platelet counts should be monitored in patients with risk of
bleeding, preexisting thrombocytopenia, or intrinsic or acquired disorders
of platelet function (including those potentially caused by
concomitant medication) and in patients receiving courses of therapy
lasting beyond 2 weeks.
Other Toxic and Irritative Effects. The drug seems to be well tolerated,
with generally minor side effects (e.g., GI complaints,
headache, rash). Patients receiving long-term (e.g., >8 weeks) treatment
with linezolid have developed peripheral neuropathy, optic neuritis,
and lactic acidosis (Narita et al., 2007). It is believed that these
toxicities may originate from effects of linezolid on the mitochondria.
Because these effects have not always been reversible, linezolid
should be generally not be used for long-term therapy if there are
alternative agents.
Drug Interactions. Linezolid is a weak nonspecific inhibitor of
monoamine oxidase. Patients receiving concomitant therapy with an
adrenergic or serotonergic agent (including selective serotonin reuptake
inhibitors [SSRIs]) or consuming >100 mg of tyramine a day
may experience serotonin syndrome, characterized by palpitations,
headache, or hypertensive crisis. Co-administration of these agents
is best avoided if possible. However, in patients receiving SSRIs who
acutely require linezolid therapy for short-term (10-14 days) treatment,
co-administration with careful monitoring is reasonable
because SSRIs generally require tapering to avoid discontinuation
syndrome. Linezolid is neither a substrate nor an inhibitor of CYPs.
AMINOCYCLITOLS (SPECTINOMYCIN)
Spectinomycin is an antibiotic produced by
Streptomyces spectabilis. The drug is an aminocyclitol:
CH 3 OH
HN
HO
O
CH 3
O
OH
NH O
CH 3
Antimicrobial Activity, Mechanism of Action, and Resistance to
Spectinomycin. Spectinomycin is active against a number of gramnegative
bacterial species, but it is inferior to other drugs to which
such microorganisms are susceptible. Its only therapeutic use is in the
treatment of gonorrhea caused by strains resistant to first-line drugs
or if there are contraindications to the use of these drugs.
Spectinomycin selectively inhibits protein synthesis in gram-negative
bacteria. The antibiotic binds to and acts on the 30S ribosomal subunit.
Its action is similar to that of the aminoglycosides, but spectinomycin
O
SPECTINOMYCIN
is not bactericidal and does not cause misreading of messenger
RNA. Bacterial resistance may be mediated by mutations in the
16S ribosomal RNA or by modification of the drug by adenylyltransferase
(Clark et al., 1999).
Absorption, Distribution, and Excretion. Spectinomycin is rapidly
absorbed after intramuscular injection. A single dose of 2 g
produces peak serum concentrations of 100 μg/mL at 1 hour.
Eight hours after injection, the concentration is ~15 μg/mL. The
drug is not significantly bound to plasma protein, and all of an
administered dose is recovered in the urine within 48 hours.
Therapeutic Uses and Dosage. The Centers for Disease Control and
Prevention recommends ceftriaxone or cefixime for the treatment of
uncomplicated gonococcal infection (Workowski and Berman,
2006). Fluoroquinolones are no longer recommended because of
increasing resistance. Spectinomycin is recommended as an alternative
regimen in patients who are intolerant or allergic to β-lactam
antibiotics; however, the drug is not currently available in the U.S.
Spectinomycin also is useful in pregnancy when patients are intolerant
to β-lactams. The recommended dose for men and women is a
single deep intramuscular injection of 2 g. One of the disadvantages
of this regimen is that spectinomycin has no effect on incubating or
established syphilis, and it is not active against Chlamydia spp. It
also is less effective for pharyngeal infections, and follow-up cultures
to document cure should be obtained.
Untoward Effects. Spectinomycin, when given as a single intramuscular
injection, produces few significant untoward effects. Urticaria,
chills, and fever have been noted after single doses, as have dizziness,
nausea, and insomnia. The injection may be painful.
POLYMYXINS
The polymyxins, discovered in 1947, are a group of
closely related antibiotics elaborated by various strains
of Bacillus polymyxa. Colistin (polymyxin E) is produced
by Bacillus (Aerobacillus) colistinus. These
drugs, which are cationic detergents, are relatively simple
basic peptides with molecular masses of ~1000 Da.
Polymyxin B is a mixture of polymyxins B 1
and B 2
:
R
L-DAB
L-Thr
L-DAB
L-DAB
L-DAB
L-Thr
Polymyxin B 1 : R = (+)-methyloctanoyl
Polymyxin B 2 : R = 6-methylheptanoyl
DAB = α,γ-diaminobutyric acid
Colistin has a similar structure.
D-Phe
L-DAB
L-Leu
L-DAB
Antimicrobial Activity, Mechanism of Action, and Resistance to
Polymyxins. The antimicrobial activities of polymyxin B and colistin
are similar and restricted to gram-negative bacteria, including
Enterobacter, E. coli, Klebsiella, Salmonella, Pasteurella, Bordetella,
and Shigella, which usually are sensitive to concentrations of 0.05-
2 μg/mL. Most strains of P. aeruginosa and Acinetobacter are inhibited
by <8 μg/mL in vitro. Proteus and Serratia spp. are intrinsically
resistant.
Polymyxins are surface-active amphipathic agents. They interact
strongly with phospholipids and disrupt the structure of cell