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

Lewis, 1999). The following species are also susceptible: M. gordonae,
M. marinum, M. scrofulaceum, M. szulgai. However, the majority
of M. xenopi, M. fortuitum, and M. chelonae have been reported
as resistant (Lewis, 1999).
Mechanisms of Resistance. In vitro, mycobacterial resistance to the
drug develops via mutations in the embB gene. In 30-70% of clinical
isolates that are resistant to ethambutol, mutations are encountered
at codon 306 of the embB gene. However, mutations in this
codon are also encountered in ethambutol-susceptible mycobacteria,
as though this mutation is necessary, but not sufficient, to confer
ethambutol resistance (Safi et al., 2008). In addition, enhanced
efflux pump activity may induce resistance to both isoniazid and
ethambutol in the laboratory.
Absorption, Distribution, Metabolism, and Excretion. The oral
bioavailability of ethambutol is ~80%. Approximately 10-40% of
the drug is bound to plasma protein. Ethambutol drug concentrations
have been modeled using a two-compartment open model, with firstorder
absorption and elimination (Peloquin et al., 1999; Zhu et al.,
2004). The decline in ethambutol is biexponential, with a t 1/2
of
3 hours in the first 12 hours, and a t 1/2
of 9 hours between 12 and
24 hours, due to redistribution of drug. Clearance and V d
are greater
in children than in adults on a per kilogram basis. Slow and incomplete
absorption is common in children, so that good peak concentrations
of drug are often not achieved with standard dosing (Zhu
et al., 2004). In addition, these C max
values are not very impressive
given the typical MIC values for most clinical isolates of mycobacteria.
See Table 56–2 for PK data on this drug.
Alcohol dehydrogenase oxidizes ethambutol to an aldehyde,
which is then oxidized by aldehyde dehydrogenase to dicarboxylic
acid. However, 80% of the drug is not metabolized at all and is
renally excreted. Therefore, in renal failure ethambutol should be
dosed at 15-25 mg/kg, three times a week instead of daily, even in
patients receiving hemodialysis.
Microbial pharmacokinetics-pharmacodynamics. Ethambutol’s
microbial kill of M. tuberculosis is optimized by AUC/MIC, while
that against disseminated MAC is optimized by C max
/MIC
(Srivastava et al., 2010; Deshpande et al., 2010). Thus, to optimize
microbial kill, high intermittent doses such as 25 mg/kg
every other day to 50 mg/kg twice a week may be superior to daily
doses of 15 mg/kg.
Therapeutic Uses. Ethambutol is available for oral administration
in tablets containing the D-isomer. It is used for the treatment
of TB, disseminated MAC, and in M. kansasii infection.
Ethambutol is administered at 15-25 mg/kg per day for both adults
and children.
Untoward Effects. Ethambutol produces very few serious untoward
reactions. Fewer than 2% of patients who receive daily doses of
15 mg/kg of ethambutol have adverse reactions: ~1% experience
diminished visual acuity, 0.5% a rash, and 0.3% drug fever. Other
side effects that have been observed are pruritus, joint pain, GI upset,
abdominal pain, malaise, headache, dizziness, mental confusion, disorientation,
and possible hallucinations. Numbness and tingling of
the fingers owing to peripheral neuritis are infrequent. Anaphylaxis
and leukopenia are rare. Therapy with ethambutol results in an
increased concentration of urate in the blood in ~50% of patients,
owing to decreased renal excretion of uric acid.
The most important side effect is optic neuritis, resulting in
decreased visual acuity and loss of ability to differentiate red from
green. The incidence of this reaction is proportional to the dose of
ethambutol and is observed in 15% of patients receiving 50
mg/kg/day, in 5% of patients receiving 25 mg/kg/day, and in <1%
of patients receiving daily doses of 15 mg/kg. The intensity of the
visual difficulty is related to the duration of therapy after the
decreased visual acuity first becomes apparent and may be unilateral
or bilateral. Tests of visual acuity and red-green discrimination
prior to the start of therapy and periodically thereafter are thus recommended.
Recovery usually occurs when ethambutol is withdrawn;
the time required is a function of the degree of visual
impairment.
Cases of ethambutol overdose are rare; drug interactions
involving ethambutol are not significant.
Aminoglycosides: Streptomycin,
Amikacin, and Kanamycin
The aminoglycosides streptomycin, amikacin, and
kanamycin are used for the treatment of mycobacterial
diseases. The MICs for M. tuberculosis in Middlebrook
broth are 0.25-3.0 mg/L for all three aminoglycosides
(Heifets, 1991). For M. avium streptomycin and
amikacin, MICs are 1-8 mg/L; those of kanamycin are
3-12 mg/L. M. kansasii is frequently susceptible to
these agents, but other nontuberculous mycobacteria
are only occasionally susceptible. The pharmacological
properties and therapeutic uses of aminoglycosides
are discussed in full in Chapter 54.
Bacterial Resistance. Primary resistance to streptomycin is found in
2-3% of M. tuberculosis clinical isolates. Streptomycin and the two
other aminoglycosides inhibit protein synthesis by binding to the
30S ribosomal subunit and causing misreading of the genetic code
during translation. The 30s ribosomal unit is made of the 16S mRNA
(encoded by rpsL), which binds to the ribosomal protein S12
(encoded by rrs) to optimize tRNA binding and mRNA decoding.
Mutations in rpsL and rrs are associated with high-level aminoglycoside
resistance in mycobacteria. However, mutations in these
genes are only encountered in half of clinical isolates with aminoglycoside
resistance. GidB is an rRNA methyltransferase for 16S rRNA,
and mutations in gidB gene are associated with low-level streptomycin
resistance (Okamoto et al., 2007). The gidB mutations lead to
high-level streptomycin resistant mutants at a rate 2000 times that in
wild type. Mutations in gidB are encountered in 33% of streptomycin-resistant
clinical isolates of M. tuberculosis. Finally, efflux
pump–mediated resistance was recently demonstrated in clinical isolates
with low-level streptomycin-resistant M. tuberculosis and interacted
with chromosomal mutations in gidB (Spies et al., 2008). Thus
resistance to aminoglycosides involves several genetic loci, as well
as efflux pumps.
Therapeutic Uses. Therapeutic uses of aminoglycosides in treatment
of mycobacterial infections are discussed later.
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CHAPTER 56
CHEMOTHERAPY OF TUBERCULOSIS, MYCOBACTERIUM AVIUM COMPLEX DISEASE, AND LEPROSY