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.