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

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Title: Linezolid Trough Concentrations Correlate with Mitochondrial Toxicity-Related Adverse Events in the Treatment of Chronic Extensively Drug-Resistant Tuberculosis
Authors: Ray Y. Chen, Lisa C. Goldfeder, Clifton E. Barry, Véronique Dartois, Dean Follman, Yingda Xie, Myungsun Lee, Kenneth N. Olivier, Ying Cai, Taeksun Song, Lori E. Dodd, Sang Nae Cho, Han Seung Jeon, Laura E. Via, Jing Wang, Yumi Park
Contributors: College of Medicine, Dept. of Microbiology, 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, Sang Nae Cho, Clifton E. Barry III, Ray Y. Chen, Cho, Sang Nae
Source: EBioMedicine
EBioMedicine, Vol 2, Iss 11, Pp 1627-1633 (2015)
Publisher Information: Elsevier BV, 2015.
Publication Year: 2015
Subject Terms: Adult, Male, 0301 basic medicine, Medicine (General), Extensively Drug-Resistant Tuberculosis, Antitubercular Agents, Comorbidity, Linezolid/administration & dosage, Therapeutic drug monitoring, Linezolid/pharmacokinetics, Drug resistant, Polymorphism, Single Nucleotide, 03 medical and health sciences, R5-920, Risk Factors, Extensively Drug-Resistant Tuberculosis/diagnosis, Tuberculosis, Humans, rRNA, Polymorphism, 0303 health sciences, Mitochondrial toxicity, Antitubercular Agents/pharmacokinetics, Linezolid, Genes, rRNA, Antitubercular Agents/adverse effects, Single Nucleotide, Linezolid/adverse effects, Middle Aged, Mitochondrial, Mitochondria/metabolism, Mitochondria, 3. Good health, Extensively Drug-Resistant Tuberculosis/immunology, Genes, Mitochondrial, Genes, Adverse events, Extensively Drug-Resistant Tuberculosis/drug therapy, Extensively Drug-Resistant Tuberculosis/metabolism, Medicine, Female, Antitubercular Agents/administration & dosage, Drug Monitoring, Mitochondria/drug effects, Research Article
Description: 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.
Document Type: Article
Other literature type
Language: English
ISSN: 2352-3964
DOI: 10.1016/j.ebiom.2015.09.051
Access URL: http://www.ebiomedicine.com/article/S2352396415301663/pdf
https://pubmed.ncbi.nlm.nih.gov/26870788
https://doaj.org/article/7beaa75555b04827aa0e2b13b0e0cec4
https://doaj.org/article/7beaa75555b04827aa0e2b13b0e0cec4
https://www.sciencedirect.com/science/article/abs/pii/S2352396415301663
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4740314/
http://europepmc.org/articles/PMC4740314
https://yonsei.pure.elsevier.com/en/publications/linezolid-trough-concentrations-correlate-with-mitochondrial-toxi
https://core.ac.uk/display/91864933
Rights: CC BY NC ND
Accession Number: edsair.doi.dedup.....08685b7fa3502d43eb3530775a81c5a0
Database: OpenAIRE
Description
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.
ISSN:23523964
DOI:10.1016/j.ebiom.2015.09.051