Laboratory Diagnosis of Drug-resistant Tuberculosis: Reading between the Lines

Abstract

Drug-resistant tuberculosis (DR-TB) remains a major diagnostic and therapeutic challenge despite advances in molecular and phenotypic testing methods. Interpretation of discordant phenotypic and genotypic drug susceptibility testing (DST) results is particularly difficult in cases with heteroresistant Mycobacterium tuberculosis (MTB) populations. We describe a 76-year-old male with chronic obstructive pulmonary disease, asthma, and diabetes mellitus who presented with fever, productive cough, breathlessness, weight loss, and left lower-lobe pulmonary nodules. Bronchoalveolar lavage Xpert MTB/RIF Ultra detected MTB with indeterminate rifampicin resistance due to trace bacillary load. Initial mycobacterial growth indicator tube (MGIT) culture DST demonstrated susceptibility to all first-line drugs; however, the isoniazid (INH) tube showed a growth unit (GU) of 86, suggestive of a low-level nonwild-type subpopulation. Reflex molecular testing performed on the INH tube isolate using Xpert MTB/XDR identified a katG codon 315 mutation associated with high-level INH resistance. Repeat Xpert MTB/RIF Ultra performed on the same isolate subsequently detected rifampicin resistance with multiple rpoB mutant melting temperature signatures suggestive of rifampicin heteroresistance. Repeat restricted MGIT DST confirmed INH resistance and demonstrated low-level rifampicin-resistant subpopulation growth despite phenotypic rifampicin susceptibility. This case highlights the diagnostic importance of careful interpretation of MGIT GUs and integration of molecular and phenotypic DST results for the detection of MTB heteroresistance. Detection of clinically significant resistant subpopulations below the conventional 1% threshold may have important therapeutic implications and can potentially influence treatment outcomes in DR-TB.