Amino acid replacements in the NADH binding site of InhA apparently result in INH resistance by preventing the inhibition of mycolic acid biosynthesis, which the bacterium uses in its cell wall. Mutations in the katG gene make the enzyme catalase peroxidase unable to convert INH to its biologically active form. Hence, INH is ineffective and the bacterium is resistant. The discovery of new molecular targets is essential to overcome drug-resistance problems.In some TB bacteria, the acquisition of these mutations can be explained by other mutations in the DNA recombination, recognition and repair machinery. Mutations in these genes allow the bacteria to have a higher overall mutation rate and to accumulate mutations that cause drug resistance more quickly. Extensively drug-resistant TB
MDR-TB can become resistant to the major second-line TB drug groups: fluoroquinolones (moxifloxacin, ofloxacin) and injectable aminoglycoside or polypeptide drugs (amikacin, capreomycin, kanamycin). When MDR-TB is resistant to at least one drug from each group, it is classified as extensively drug-resistant tuberculosis (XDR-TB).WHO has revised the definitions of pre-XDR-TB and XDR-TB in 2021 as following:Pre-XDR-TB: TB caused by Mycobacterium tuberculosis (M.tuberculosis) strains that fulfill the definition of MDR/RR-TB and which are also resistant to any fluoroquinolone. XDR-TB: TB caused by Mycobacterium tuberculosis (M. tuberculosis) strains that fulfill the definition of MDR/RR-TB and which are also resistant to any fluoroquinolone and at least one additional Group A drug.
As medical anthropologists like Erin Koch have shown, this form of implementation does not suit all cultural structures. They urge that the DOTS protocol be constantly reformed in the context of local practices, forms of knowledge and everyday life.Erin Koch has used Paul Farmers concept of "structural" violence as a perspective for understanding how "institutions, environment, poverty, and power reproduce, solidify, and naturalize the uneven distribution of disease and access to resources". She has also studied the effectiveness of the DOTS protocol in the widespread disease of tuberculosis in the Georgian prison system. Unlike the DOTS passive case finding used for the general Georgian public, the multiple-level surveillance in the prison system has proven more successful in reducing the spread of tuberculosis while increasing rates of cure.Koch critically notes that because the DOTS protocol aims to change the individuals behavior without addressing the need to change the institutional, political, and economic contexts, certain limitations arise, such as MDR tuberculosis. Treatment
Usually, multidrug-resistant tuberculosis can be cured with long treatments of second-line drugs, but these are more expensive than first-line drugs and have more adverse effects. The treatment and prognosis of MDR-TB are much more akin to those for cancer than to those for infection.