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The majority of  Mycobacterium tuberculosis  isolates resistant to isoniazid harbour a mutation in  katG . Since these mutations cause a wide range of minimum inhibitory concentrations (MICs), largely below the serum level reached with higher dosing (15 mg/L upon 15–20 mg/kg), the drug might still remain partly active in presence of a  katG  mutation. We therefore investigated which genetic mutations predict the level of phenotypic isoniazid resistance in clinical  M. tuberculosis  isolates. To this end, the association between known and unknown isoniazid resistance-conferring mutations in whole genome sequences, and the isoniazid MICs of 176 isolates was examined. We found mostly moderate-level resistance characterized by a mode of 6.4 mg/L for the very common  katG  Ser315Thr mutation, and always very high MICs (≥19.2 mg/L) for the combination of  katG  Ser315Thr and  inhA  c-15t. Contrary to common belief, isolates harbouring  inhA  c-15t alone, partly also showed moderate-level resistance, particularly when combined with  inhA  Ser94Ala. No overt association between low-confidence or unknown mutations, except in  katG , and isoniazid resistance (level) was found. Except for the rare  katG  deletion, line probe assay is thus not sufficiently accurate to predict the level of isoniazid resistance for a single mutation in  katG  or  inhA .

Isoniazid resistance levels of Mycobacterium tuberculosis can largely be predicted by high-confidence resistance-conferring mutations