Interventions for Tuberculosis Control and Elimination 2002

found in caseous foci did not exceed 10 2 to 10 4 bacilli. 466 It has been
experimentally demonstrated that it is selection of these mutants rather than
adaptation to the medication. 467 In a cavitary lesion containing 10 8 organisms,
there will be around 10 2 isoniazid resistant mutants (i.e., one in a
million) with the opportunity to replicate and become the dominant strain
while the susceptible organisms are being killed off (figure 36). 468,469
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56
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Figure 36. Diagrammatic presentation of the emergence of resistance to isoniazid
during isoniazid monotherapy. Reproduced from 469 by the permission of the
publisher Churchill Livingstone and the author.
Monotherapy during sterilization of special populations
Not all drugs work equally well on all bacillary sub-populations. These
sub-populations are exemplified in figure 37. 456 None of the drugs works
on the “dormant” or “latent” 470 sub-population. Other specific sub-populations
are the target of some drugs, such as pyrazinamide, which is active
only in an acid environment. If, for instance, a patient with an initially
isoniazid-resistant strain receives isoniazid, pyrazinamide, and ethambutol,
the sub-population hypothesis would suggest that the patient’s large bulk
of rapidly metabolizing organisms is treated with ethambutol monotherapy.
As there will be effective monotherapy in these special populations, resistant
mutants should have a survival benefit. 464