Therapeutic drug monitoring for linezolid in the treatment of rifampin-resistant tuberculosis: a pragmatic randomized controlled trial - PROJECT SUMMARY Drug-resistant tuberculosis (TB) is a major global epidemic and poses a particular threat to people living with HIV. With limited effective drugs available for treatment, multidrug-, and extensively drug-resistant TB carry a high mortality rate and threaten global TB and HIV control efforts. New and repurposed medications have recently been found to improve survival and cure rates. Linezolid— a drug initially developed for the treatment of Gram-positive infections—has considerable anti-TB activity and has been at the center of this treatment revolution. Since 2018, WHO has recommended that all rifampin- resistant (RR-TB) TB treatment regimens include linezolid. When given long-term, however, linezolid- associated toxicity—particularly myelosuppression and peripheral neuropathy—is very common, affecting 50- 80% of patients and often requiring a temporary or permanent discontinuation of therapy. Such interruptions put patients at risk of treatment failure and the emergence of additional resistance to linezolid or one of the other drugs in the regimen. As linezolid use continues to increase worldwide, such resistance could become widespread, squandering a valuable medication. Our group has previously shown that linezolid toxicities are associated with trough plasma concentration. Further, linezolid has a narrow therapeutic window and considerable inter-individual variability. We therefore hypothesize that identifying those with higher linezolid concentrations using therapeutic drug monitoring (TDM) may allow pre-emptive dose reductions that could avert drug toxicity and premature discontinuation. We propose a pragmatic, randomized clinical trial to determine the efficacy of TDM in preventing premature discontinuation of linezolid. We will enroll 280 participants with rifampin-resistant TB (RR-TB) at our research site in South Africa and will randomize them to receive TDM or standard of care (SOC). Participants in the TDM arm will have their linezolid dose reduced if their trough concentration is greater than 2.5 mg/L, while those in the SOC arm will have their linezolid adjusted or held only if they develop clinical adverse events. Participants will be followed for the 6-month duration of RR-TB therapy. In Aim 1, we will compare the rates of premature linezolid discontinuation between the two arms. All participants will receive identical screening for linezolid toxicity at each visit, and in Aim 2, we will compare the incidence of hematologic and neurologic toxicities between the two groups. In Aim 3, we will use population PK modeling to explore the complex relationship between linezolid pharmacokinetic parameters and the trajectory of toxicities over time. We will also determine whether those whose dose is lowered still meet exposure targets for drug efficacy. South Africa has among the highest global burden of drug-resistant TB and HIV and has led the world in the rollout of new RR-TB drugs and regimens. The aims of this study will answer fundamental questions about linezolid pharmacology that will directly inform its use in South Africa and worldwide.
