Linezolid Trough Concentrations Correlate with Mitochondrial Toxicity-Related Adverse Events in the Treatment of Chronic Extensively Drug-Resistant Tuberculosis

• Published in: EBioMedicine Vol. 2; no. 11; pp. 1627 - 1633
• Main Authors: Song, Taeksun, Lee, Myungsun, Jeon, Han-Seung, Park, Yumi, Dodd, Lori E., Dartois, Véronique, Follman, Dean, Wang, Jing, Cai, Ying, Goldfeder, Lisa C., Olivier, Kenneth N., Xie, Yingda, Via, Laura E., Cho, Sang Nae, Barry, Clifton E., Chen, Ray Y.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-11-2015; Elsevier
• Subjects: Adult; Adverse events; Antitubercular Agents - administration & dosage; Antitubercular Agents - adverse effects; Antitubercular Agents - pharmacokinetics; Comorbidity; Drug Monitoring; Drug resistant; Extensively Drug-Resistant Tuberculosis - diagnosis; Extensively Drug-Resistant Tuberculosis - drug therapy; Extensively Drug-Resistant Tuberculosis - immunology; Extensively Drug-Resistant Tuberculosis - metabolism; Female; Genes, Mitochondrial; Genes, rRNA; Humans; Linezolid; Linezolid - administration & dosage; Linezolid - adverse effects; Linezolid - pharmacokinetics; Male; Middle Aged; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondrial toxicity; Polymorphism, Single Nucleotide; Risk Factors; Therapeutic drug monitoring; Tuberculosis; Linezolid; Therapeutic drug monitoring; Tuberculosis; Adverse events; Drug resistant; Mitochondrial toxicity
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2015.09.051

Long-term linezolid use is limited by mitochondrial toxicity-associated adverse events (AEs). Within a prospective, randomized controlled trial of linezolid to treat chronic extensively drug-resistant tuberculosis, we serially monitored the translational competence of mitochondria isolated from peripheral blood of participants by determining the cytochrome c oxidase/citrate synthase activity ratio. We compared this ratio with AEs associated with mitochondrial dysfunction. Linezolid trough concentrations were determined for 38 participants at both 600mg and 300mg doses. Those on 600mg had a significantly higher risk of AE than those on 300mg (HR 3·10, 95% CI 1·23–7·86). Mean mitochondrial function levels were significantly higher in patients before starting linezolid compared to their concentrations on 300mg (P=0·004) or 600mg (P<0·0001). Increasing mean linezolid trough concentrations were associated with lower mitochondrial function levels (Spearman's ρ=−0.48; P=0.005). Mitochondrial toxicity risk increased with increasing linezolid trough concentrations, with all patients with mean linezolid trough >2μg/ml developing an AE related to mitochondrial toxicity, whether on 300mg or 600mg. Therapeutic drug monitoring may be useful to prevent the development of mitochondrial toxicity associated with long-term linezolid use.
•Linezolid is increasingly being used to treat drug-resistant tuberculosis.•Long-term use of linezolid is limited by mitochondrial toxicity-associated adverse events.•We examined linezolid trough concentrations in chronic XDR-TB patients on linezolid.•Mitochondrial toxicity risk increased with increasing linezolid trough concentrations.•Therapeutic drug monitoring may help avoid mitochondrial toxicities in long-term linezolid treatment.
Linezolid is increasingly being used to treat drug resistant tuberculosis, with the beneficial effect of linezolid tempered by the mitochondrial toxicity-associated adverse events seen with long-term use. Within a prospective, randomized controlled trial of linezolid for the treatment of chronic, extensively drug-resistant tuberculosis, we found that the risk of mitochondrial toxicity increased with increasing linezolid trough concentrations, with all patients with a mean trough >2μg/ml developing an adverse event related to mitochondrial toxicity. If our results are confirmed by other studies, therapeutic drug monitoring may become an important component of long-term linezolid treatment to prevent mitochondrial toxicity-related adverse events.