This study is a two-arm, pragmatic, open-label, randomized clinical trial to determine the efficacy of Therapeutic Drug Monitoring (TDM) in preventing premature discontinuation of Linezolid (LZD) in participants with Rifampicin-resistant tuberculosis (RR-TB). Following the initiation of treatment, participants will be monitored throughout the approximate 6-month duration of RR-TB therapy.

Drug-resistant tuberculosis (TB) is a major global epidemic and poses a particular threat to HIV-infected individuals. 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 multi DR/rifampicin-resistant (MDR) and extensively drug-resistant tuberculosis (XDR) tuberculosis 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. Previously conducted research has shown that linezolid toxicities are associated with trough plasma concentration and that the drug has considerable inter-individual variability. The investigator team, therefore, hypothesize that therapeutic drug monitoring (TDM) could identify those with higher linezolid concentrations and permit pre-emptive dose reductions that could avert drug toxicity and premature discontinuation.

This study will take place at the Nkqubela TB Specialist Hospital in East London, South Africa. TB diagnosis and initial treatment regimen will be determined by the hospital clinical team, per local guidelines. Following enrollment, participants will be randomized after enrollment to either undergo a therapeutic drug monitoring (TDM) strategy for LZD, or standard of care (SOC). Participants in both arms will have a trough plasma linezolid concentration drawn approximately one week after enrollment (within one month of TB treatment initiation). The PK specimens collected from TDM arm participants will be analyzed by University of Cape Town lab staff. The PK specimens collected from SOC participants will be stored for future analysis.

Standard treatment for RR-TB in South Africa includes 6 months of therapy, including linezolid 600 mg daily for duration of treatment. Those in the TDM arm whose concentration is above a set threshold (2.5 mg/L) will have their LZD dose reduced to 300mg daily, while those in the SOC arm will receive routine monitoring alone. All participants will be screened monthly for hematologic and neurologic toxicity. Hospital and clinic providers will manage all treatment other than the TDM-guided linezolid dose reduction. If participants in either the SOC or TDM arm experience linezolid toxicity, hospital and clinic providers may choose to temporarily or permanently discontinue linezolid, regardless of any prior TDM-guided dose reduction, in accordance with South African national guidelines.

Aim 1 (Primary Outcome Measure of this study) and Aim 2 (the first Secondary Outcome Measure) are described in the Outcome Measures section. For Aim 3, population PK modeling will be used to explore the complex relationship between linezolid pharmacokinetic parameters and the trajectory of toxicities over time. It will also be determined as to 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 LZD pharmacology that will directly inform its use in South Africa and worldwide.

Inclusion Criteria:

• Adult male or female patient > 18 years of age

• Microbiological confirmation of rifampicin-resistant tuberculosis (e.g., phenotypic or genotypic drug susceptibility testing, GeneXpert MTB/RIF™). Participants may have resistance to additional medications as well - i.e., MDR and XDR TB - but must have resistance to at least rifampin

• Initiated on a rifampicin-resistant tuberculosis (RR-TB) treatment regimen containing linezolid, no more than 14 days prior to randomization

• HIV status is known and confirmed

  • Both HIV-positive and HIV-negative individuals are eligible
  • If an individual reports unknown HIV status, they must consent to HIV testing at time of enrollment to confirm status. If they decline to be tested, they are not eligible for the study

Exclusion Criteria:

• Severe medical condition with expected death in the next 7 days
• Pregnant at time of screening
• Initial linezolid dose < 600mg daily
• Severe form of extrapulmonary TB (i.e., meningitis, pericarditis, or osteomyelitis)
• Unlikely to follow-up at Nkqubela Hospital based on location of residence

The study will generate a range of data types from structured participant interviews to linezolid trough plasma concentrations. The investigators aim to widely share the knowledge generated by this proposal to advance knowledge in the field of TB research and avoid duplication of relevant work. Participant-level clinical and laboratory data will be preserved through deposition of the data in a controlled access public repository.

Scientific data included in published manuscripts will be available at the time of publication or the end of the award, whichever comes first; all other generated scientific data will be shared no later than the end of the award. Data will be made available for an indefinite period or until Emory University requests that it be withdrawn.

All de-identified study data not designated as restricted use will be made available to the research community upon request and approval by study MPIs. Code used to perform statistical analysis will be deposited in a publicly available repository or may be requested from the investigators to ensure others can seek to reproduce the results, if desired. Public use and restricted access study data and associated documentation will be made available to the research community free of charge through the Emory Dataverse, an open data repository intended for the preservation, discoverability and accessibility of data produced by the Emory University research community, or other appropriate data repository.