TB patients undergoing treatment can be exposed
to such concentrations of anti-TB drugs either as a result of
inadequate dosing (e.g., low patient compliance or poor drug
quality) or gradients of drug concentration created in the body by
the differential penetration of drugs into tissues and lesions.24,99
The identification of patients infected with these ‘pre-resistant’
M.tb mutants may suggest the use of increased antibiotic dosages
or an alteration of treatment strategies before the establishment of
full-scale drug resistance.23 However, low-level mutants (such as
those recently described for ethambutol and streptomycin) cannot
be detected by standard culture-based susceptibility testing.
Current methods rely on breakpoint concentrations to qualitatively
define resistance and are, therefore, insensitive to changes in
drug susceptibility below those thresholds. Further studies are
needed to clarify the relationship between the presence of these
low-level mutations, the emergence of clinical resistance, and
patient outcomes to inform potential changes in current diagnostic
tests (e.g., broaden molecular tests for drug resistance to include
screening for such mutations). Given the putative pivotal role of
low-level mutations in the spread of resistance, surveillance
systems based on resistance produced by high-level mutations