The most common mechanism of isoniazid resistance is the mycobacteria's formation of mutations in cata-lase-peroxidase KatG, the enzyme that is responsible for activation of isoniazid. Another resistance mechanism is through a missense mutation related to the inhA gene involved in mycolic acid biosynthesis.
An active tuberculosis cavity may contain as many as 107 to 1010 microorganisms. The frequency of isoni-azid-resistant mutants in a susceptible mycobacterial population is about 1 bacillus in 106, and this organism is readily selected out if isoniazid is given as the sole agent. If a second drug having a similar drug resistance (1in 106) is combined with isoniazid, the odds that a bacillus is resistant to both drugs become 1 in 1012. Therefore, it is vital to combine at least two antitubercular agents to which the organism is susceptible.
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