Linezolid toxicity in patients with drug-resistant tuberculosis: a prospective cohort study. (2nd February 2022)

• Record Type: Journal Article
• Authors: Wasserman, Sean; Brust, James C. M.; Abdelwahab, Mahmoud T.; Little, Francesca; Denti, Paolo; Wiesner, Lubbe; Gandhi, Neel R.; Meintjes, Graeme; Maartens, Gary
• Is Part Of: Journal of antimicrobial chemotherapy. Volume 77:Number 4(2022)
• Page Start: 1146
• Page End: 1154
• Publication Date: 2022-02-02
• Subjects: Anti-infective agents -- Periodicals; Chemotherapy -- Periodicals; 615.58
• DOI: 10.1093/jac/dkac019
• Languages: English
• ISSNs: 0305-7453

Abstract

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.