Wild-type MIC distribution and evaluation of epidemiological cut-offs of second-line TB-drugs in susceptible and MDR-TB clinical isolates from Chennai, India

Deviations from the World Health Organization-recommended epidemiological cut-off values were observed, with lower thresholds for delamanid and levofloxacin and higher concentrations for clofazimine and bedaquiline. These shifts indicate region-specific susceptibility patterns in <i>Mycobacterium tuberculosis</i> that have direct implications for the effective treatment of multidrug-resistant tuberculosis. Inaccurate cut-off values may lead to misclassification of resistance, inappropriate regimen selection, and exposure to suboptimal drug concentrations, thereby compromising treatment efficacy and amplifying the risk of acquired resistance. Concordantly, pharmacodynamic analyses revealed sub-therapeutic exposure ranges for several newer and repurposed anti-TB drugs, underscoring the potential for treatment failure even in strains classified as susceptible. Collectively, these findings highlight the urgent need for regionally calibrated epidemiological cut-off values to optimize drug dosing, improve MDR-TB treatment outcomes, and strengthen resistance surveillance frameworks.