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

Taeksun Song, Myungsun Lee, Han Seung Jeon, Yumi Park, Lori E. Dodd, Véronique Dartois, Dean Follman, Jing Wang, Ying Cai, Lisa C. Goldfeder, Kenneth N. Olivier, Yingda Xie, Laura E. Via, Sangnae Cho, Clifton E. Barry, Ray Y. Chen

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

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 600 mg and 300 mg doses. Those on 600 mg had a significantly higher risk of AE than those on 300 mg (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 300 mg (P = 0·004) or 600 mg (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 > 2 μg/ml developing an AE related to mitochondrial toxicity, whether on 300 mg or 600 mg. Therapeutic drug monitoring may be useful to prevent the development of mitochondrial toxicity associated with long-term linezolid use.

Original languageEnglish
Pages (from-to)1627-1633
Number of pages7
JournalEBioMedicine
Volume2
Issue number11
DOIs
Publication statusPublished - 2015 Nov 1

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Linezolid
Extensively Drug-Resistant Tuberculosis
Toxicity
Pharmaceutical Preparations
Therapeutics
Citrate (si)-Synthase
Mitochondria
Drug Monitoring
Electron Transport Complex IV
Mental Competency
Blood
Randomized Controlled Trials

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

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, Sangnae ; Barry, Clifton E. ; Chen, Ray Y. / Linezolid Trough Concentrations Correlate with Mitochondrial Toxicity-Related Adverse Events in the Treatment of Chronic Extensively Drug-Resistant Tuberculosis. In: EBioMedicine. 2015 ; Vol. 2, No. 11. pp. 1627-1633.
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abstract = "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 600 mg and 300 mg doses. Those on 600 mg had a significantly higher risk of AE than those on 300 mg (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 300 mg (P = 0·004) or 600 mg (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 > 2 μg/ml developing an AE related to mitochondrial toxicity, whether on 300 mg or 600 mg. Therapeutic drug monitoring may be useful to prevent the development of mitochondrial toxicity associated with long-term linezolid use.",
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Song, T, Lee, M, Jeon, HS, Park, Y, Dodd, LE, Dartois, V, Follman, D, Wang, J, Cai, Y, Goldfeder, LC, Olivier, KN, Xie, Y, Via, LE, Cho, S, Barry, CE & Chen, RY 2015, 'Linezolid Trough Concentrations Correlate with Mitochondrial Toxicity-Related Adverse Events in the Treatment of Chronic Extensively Drug-Resistant Tuberculosis', EBioMedicine, vol. 2, no. 11, pp. 1627-1633. https://doi.org/10.1016/j.ebiom.2015.09.051

Linezolid Trough Concentrations Correlate with Mitochondrial Toxicity-Related Adverse Events in the Treatment of Chronic Extensively Drug-Resistant Tuberculosis. / 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, Sangnae; Barry, Clifton E.; Chen, Ray Y.

In: EBioMedicine, Vol. 2, No. 11, 01.11.2015, p. 1627-1633.

Research output: Contribution to journalArticle

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AU - Song, Taeksun

AU - Lee, Myungsun

AU - Jeon, Han Seung

AU - Park, Yumi

AU - Dodd, Lori E.

AU - Dartois, Véronique

AU - Follman, Dean

AU - Wang, Jing

AU - Cai, Ying

AU - Goldfeder, Lisa C.

AU - Olivier, Kenneth N.

AU - Xie, Yingda

AU - Via, Laura E.

AU - Cho, Sangnae

AU - Barry, Clifton E.

AU - Chen, Ray Y.

PY - 2015/11/1

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N2 - 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 600 mg and 300 mg doses. Those on 600 mg had a significantly higher risk of AE than those on 300 mg (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 300 mg (P = 0·004) or 600 mg (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 > 2 μg/ml developing an AE related to mitochondrial toxicity, whether on 300 mg or 600 mg. Therapeutic drug monitoring may be useful to prevent the development of mitochondrial toxicity associated with long-term linezolid use.

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