Linezolid toxicity in patients with drug-resistant tuberculosis: a prospective cohort study. Wasserman, S., Brust, J. C M, Abdelwahab, M. T, Little, F., Denti, P., Wiesner, L., Gandhi, N. R, Meintjes, G., & Maartens, G. Journal of Antimicrobial Chemotherapy, 77(4):1146–1154, Oxford University Press (OUP), 2022.
Linezolid toxicity in patients with drug-resistant tuberculosis: a prospective cohort study [link]Paper  doi  abstract   bibtex   
Background: Linezolid is recommended for treating drug-resistant TB. Adverse events are a concern to prescri-bers 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 rifam-picin-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 line-zolid concentration of 2.5 mg/L or higher resulted in optimal model performance to describe changing haemo-globin 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.
@article{Wasserman2022,
abstract = {Background: Linezolid is recommended for treating drug-resistant TB. Adverse events are a concern to prescri-bers 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 rifam-picin-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 line-zolid concentration of 2.5 mg/L or higher resulted in optimal model performance to describe changing haemo-globin 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.},
author = {Wasserman, Sean and Brust, James C M and Abdelwahab, Mahmoud T and Little, Francesca and Denti, Paolo and Wiesner, Lubbe and Gandhi, Neel R and Meintjes, Graeme and Maartens, Gary},
doi = {10.1093/JAC/DKAC019},
issn = {0305-7453},
journal = {Journal of Antimicrobial Chemotherapy},
keywords = {OA,anemia,hemoglobin,linezolid,original,toxic effect,trough concentration},
mendeley-tags = {OA,original},
number = {4},
pages = {1146--1154},
pmid = {35134182},
publisher = {Oxford University Press (OUP)},
title = {{Linezolid toxicity in patients with drug-resistant tuberculosis: a prospective cohort study}},
url = {https://academic.oup.com/jac/advance-article/doi/10.1093/jac/dkac019/6520540},
volume = {77},
year = {2022}
}

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