Screening for heterogeneous drug resistance in tuberculosis and its impact on clinical prognosis: A comprehensive review

Tuberculosis (TB) remains a leading global health threat, with the rise of drug-resistant (DR-TB) strains posing a significant impediment to disease control. An increasingly recognized and complex challenge is heteroresistance, the coexistence of drug-susceptible and drug-resistant <i>Mycobacterium tuberculosis</i> subpopulations within a single host. This phenomenon acts as a crucial intermediate in the evolution toward fixed resistance and has been strongly associated with poor clinical prognoses, including treatment failure and the amplification of resistance. This review synthesizes the current state of knowledge regarding the screening methodologies for and the adverse outcomes associated with TB heteroresistance. The diagnostic gap creates a substantial risk of misclassifying patients and prescribing functionally inadequate therapeutic regimens. Further, the presence of heteroresistance significantly correlates with diminished treatment efficacy and an increased likelihood of unfavorable outcomes. Importantly, the precise clinical significance of low-frequency resistant variants remains a critical area of investigation, with an urgent need to establish evidence-based thresholds to guide therapy. Future research must focus on defining clinically relevant heteroresistance thresholds, standardizing advanced diagnostic platforms, and further elucidating the biological mechanisms that govern the emergence and persistence of these heteroresistance bacterial populations to ultimately improve patient outcomes and curb the spread of drug-resistant tuberculosis.