Interventions for Tuberculosis Control and Elimination 2002

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Activity, mechanism of action and resistance. Ethambutol is only active
against mycobacteria. 340 Ethambutol is bactericidal on both extracellular
and intracellular tubercle bacilli. 341 The MIC of ethambutol for
M. tuberculosis is about 0.95 to 7.5 mg/L in broth and 1.9 to 7.5 mg/L
on agar. 21,23
Ethambutol specifically inhibits biosynthesis of the mycobacterial cell
wall. 46 It acts on the biosynthesis of arabinogalactan, the major polysaccharide
of the mycobacterial cell wall. 342 It inhibits the polymerization of
cell wall arabinogalactan and of lipoarabinomannan. 343,344 It indirectly
inhibits mycolic acid synthesis (by limiting the availability of arabinan for
the mycolic acids to attach to) 345 and triggers a cascade of changes in the
lipid metabolism of mycobacteria, leading to the disaggregation of bacteria
clumps into smaller clusters. 346 It appears to be able to break down
the “exclusion barrier” located in the M. avium cell wall and thus significantly
enables the activity of other drugs, both intracellularly and extracellularly.
347,348
The maximum proportion of ethambutol-resistant mutants able to grow
during ethambutol monotherapy of an isoniazid-susceptible strain is estimated
to be approximately 1 in 10 8 . 53
Pharmacokinetics. The absorption of ethambutol is rapid. Following a
dosage of 25 mg/kg body weight, a peak serum concentration of 4 to 5 mg/L
is achieved approximately two to four hours after administration (figure
21). 349,350 The drug is not extensively metabolized. Roughly 80% of
ethambutol is eliminated by glomerular filtration and tubular secretion. 349-351
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Figure 20. Chemical structure of ethambutol, reported by Thomas and collaborators
in 1961. 337