From Molecular Surveillance to Governance Intelligence: Insights from Routine Drug-Resistance Mutation Proxies in Rural Eastern Cape

Background/Objectives: Drug-resistant tuberculosis (TB) remains a major challenge in high-burden settings, where timely identification of emerging resistance and effective governance responses are critical. While routine molecular diagnostics generate large volumes of resistance-associated mutation data, these outputs are typically used for individual patient management and remain underutilized for population-level surveillance and for the application of clinical governance approaches for improved TB care. Methods: We conducted a retrospective cross-sectional analysis of 1,386 molecular diagnostic records for Mycobacterium tuberculosis, collected between March 2021 and December 2024, from 30 health facilities in the K.S.D Local Municipality of O.R. Tambo District. Resistance-associated mutation proxies were identified for loci associated with isoniazid (katG, inhA), fluoroquinolone (gyrA), and second-line injectable agents (amikacin, kanamycin, and capreomycin) through mutations in the rrs locus. Mutation proxy prevalence was examined overall, by age group, over time, and across facilities. Persistence of resistance detection was assessed using consecutive-month analyses to characterize temporal continuity at the facility level. Results: At least one resistance-associated mutation proxy was detected in 72.7% of tests. Isoniazid-associated mutation proxies predominated, with katG detected in 52.2% and inhA in 20.2% of records, while fluoroquinolone- and injectable-associated proxies were less frequent. Resistance-associated mutation proxies were observed across all adult age groups, with the highest burden and greatest resistance diversity among individuals aged 25–44 years. Substantial temporal variation was evident, including declining annual prevalence for most mutation proxies between 2022 and 2024, alongside increasing inhA prevalence. Marked facility-level heterogeneity was observed, with high-volume referral sites contributing the largest absolute burden of resistant cases. Prolonged persistence of mutation detection, including uninterrupted runs of up to 15 months, was identified at selected facilities. Conclusions: Routine molecular diagnostic data revealed a substantial and heterogeneous burden of drug-resistant Mycobacterium tuberculosis in K.S.D. Local Municipality, characterized by age-specific patterns, temporal shifts, and sustained facility-level persistence. Beyond descriptive epidemiology, routinely generated mutation proxy data can serve as early-warning indicators of clinical governance stress, signaling emerging pressures on TB care systems when resistance patterns persist or worsen. Interpreting these trends can support more anticipatory clinical governance, strengthen resistance surveillance, and guide prioritized interventions in high-burden, resource-constrained settings.