The ahpC c-54t compensatory mutation is not always a valid surrogate for isoniazid resistance in Mycobacterium tuberculosis.

Thirteen commercial genotypic antimicrobial susceptibility assays interrogate mutations upstream of ahpC to infer isoniazid resistance for Mycobacterium tuberculosis. We demonstrate that relying on one of these compensatory mutations (i.e., ahpC c-54t)-rather than causative resistance mutations in katG that ahpC compensates for-can result in systematic false-resistant results for isoniazid with the Cepheid Xpert MTB/XDR and suboptimal treatment. The WHO mutation catalog should be refined to address this scenario.