Linezolid toxicity in patients with drug-resistant tuberculosis: a prospective cohort study

• Type of Material: Article
• Authors: Sean Wasserman, University of Cape Town; James CM Brust, Albert Einstein College of Medicine; Mahmoud T Abdelwahab, University of Cape Town; Francesca Little, University of Cape Town; Paolo Denti, University of Cape Town; Lubbe Wiesner, University of Cape Town; Neel Gandhi, Emory University; Graeme Meintjes, University of Cape Town; Gary Maartens, University of Cape Town
• Language: English
• Date: 2022-03-31
• Publisher: OXFORD UNIV PRESS
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: [e-mail]
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1093/jac/dkac019
• Title of Journal or Parent Work: JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY
• Volume: 77
• Issue: 4
• Start Page: 1146
• End Page: 1154
• Grant/Funding Information: This work was supported by the Wellcome Trust through core funding from the Wellcome Centre for Infectious Diseases Research in Africa (203135/Z/16/Z). S.W. was supported by the European & Developing Countries Clinical Trials Partnership (grant number CDF1018) and National Institutes of Health (K43TW011421). G. Meintjes was supported by Wellcome (098316, 214321/Z/18/Z), and the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation (NRF) of South Africa (grant number 64787). J.C.M.B. was supported by the US National Institute of Allergy and Infectious Diseases, National Institutes of Health: R01AI114304 (to J.C.M.B.), R01AI145679 (to J.C.M.B.), K24AI155045 (to J.C.M.B.), Einstein-Rockefeller-CUNY CFAR P30AI124414, and the Einstein/Montefiore ICTR UL1TR001073. M.T.A. received training in research that was supported by the Fogarty International Center of the National Institutes of Health under Award Number D43 TW010559. N.R.G. was supported by the US National Institute of Allergy and Infectious Diseases, National Institutes of Health: K24AI114444 (to N.R.G.) and Emory TB Research Unit U19AI111211. For the purpose of Open Access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
• Keywords: MULTIDRUG-RESISTANT; THERAPY; Life Sciences & Biomedicine; Pharmacology & Pharmacy; LACTIC-ACIDOSIS; EFFICACY; Infectious Diseases; OUTCOMES; INHIBITION; Microbiology; SAFETY; REGIMENS; Science & Technology; TOLERABILITY; TB
• Research Categories: Health Sciences, Pharmacology; Health Sciences, Epidemiology

Abstract

Background: Linezolid is recommended for treating drug-resistant TB. Adverse events are a concern to prescribers but have not been systematically studied at the standard dose, and the relationship between linezolid exposure and clinical toxicity is not completely elucidated. Patients and methods: We conducted an observational cohort study to describe the incidence and determinants of linezolid toxicity, and to determine a drug exposure threshold for toxicity, among patients with rifampicin-resistant TB in South Africa. Linezolid exposures were estimated from a population pharmacokinetic model. Mixed-effects modelling was used to analyse toxicity outcomes. Results: One hundred and fifty-one participants, 63% HIV positive, were enrolled and followed for a median of 86 weeks. Linezolid was permanently discontinued for toxicity in 32 (21%) participants. Grade 3 or 4 linezolid-associated adverse events occurred in 21 (14%) participants. Mean haemoglobin concentrations increased with time on treatment (0.03 g/dL per week; 95% CI 0.02-0.03). Linezolid trough concentration, male sex and age (but not HIV positivity) were independently associated with a decrease in haemoglobin >2 g/dL. Trough linezolid concentration of 2.5 mg/L or higher resulted in optimal model performance to describe changing haemoglobin and treatment-emergent anaemia (adjusted OR 2.9; 95% CI 1.3-6.8). SNPs 2706A > G and 3010G > A in mitochondrial DNA were not associated with linezolid toxicity. Conclusions: Permanent discontinuation of linezolid was common, but linezolid-containing therapy was associated with average improvement in toxicity measures. HIV co-infection was not independently associated with linezolid toxicity. Linezolid trough concentration of 2.5 mg/L should be evaluated as a target for therapeutic drug monitoring.