Project: Optimising linezolid use for drug-resistant tuberculosis in South Africa: the effects of linezolid exposure on toxicity, treatment response, and linezolid resistance

Acronym	Linezolid for DR-TB in South Africa (Reference Number: TMA 2015 CDF - 1018)
Duration	01/05/2017 - 30/04/2020
Project Topic	New evidence-based treatment options are urgently needed to improve outcomes of drug-resistant tuberculosis (DR-TB). Linezolid improves culture conversion and cure rates in complicated multidrug-resistant (MDR) and extensively drug-resistant (XDR)-TB, and has the potential to allow for injection-free regimens for multidrugresistant (MDR)-TB. Because of its impressive impact on outcomes, linezolid is likely to become a key component of treatment regimens for DR-TB in sub-Saharan Africa. However, it has never been systematically studied in this population and there are critical knowledge gaps that need to be addressed prior to the expanded use of this important agent. First, the mitochondrial toxicity associated with long term use of linezolid leads to treatment-limiting adverse events in over a third of patients, and it is unclear whether attempts to reduce this by reducing dosage may compromise efficacy and facilitate the emergence of linezolid resistance. Second, the risk of toxicity may potentially be different in patients from sub-Saharan Africa because of high rates of HIV co-infection, different population pharmacokinetics, and unique polymorphisms in mitochondrial DNA (mtDNA). Published reports of linezolid use for DR-TB include outcomes data for only 239 patients worldwide; fewer than 10% of these were HIV-infected and only 55 cases have been reported from Africa. To address these uncertainties and to support the scale up of safer and more effective DR-TB regimens, we propose a large prospective pharmacokinetic/pharmacodynamic (PK/PD) study aimed at defining the optimal use of linezolid in South African patients with DR-TB. The specific objectives of the project are to (1) develop a population PK model of linezolid in South African patients with DR-TB; (2) determine the effects of linezolid exposure on toxicity, treatment response, and linezolid resistance; and (3) define the relationships between linezolid PK parameters, functional mitochondrial activity, and clinical toxicity, and explore the association of polymorphisms in mtDNA with the risk of linezolid toxicity in this population. Our findings will impact on international practice by informing guidelines for linezolid use, ultimately translating into improved outcomes for patients with DR-TB. This project will also enable an emerging African research fellow to acquire the requisite skills to lead future clinical and translational studies in the fields of HIV and TB.
Network	EDCTP2
Call	Training and Mobility Awards: Career Development Fellowships

Project partner

Number	Name	Role	Country
1	University of Cape Town	Coordinator	South Africa