title: Linezolid Trough Concentrations Correlate with Mitochondrial Toxicity-Related Adverse Events in the Treatment of Chronic Extensively Drug-Resistant Tuberculosis.
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.
authors: International Tuberculosis Research Center, Changwon, Republic of Korea.
authors: Taeksun
authors: T
authors: Song
authors: International Tuberculosis Research Center, Changwon, Republic of Korea.
authors: Myungsun
authors: M
authors: Lee
authors: International Tuberculosis Research Center, Changwon, Republic of Korea.
authors: Han-Seung
authors: HS
authors: Jeon
authors: International Tuberculosis Research Center, Changwon, Republic of Korea.
authors: Yumi
authors: Y
authors: Park
authors: Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors: Lori E
authors: LE
authors: Dodd
authors: Public Health Research Institute, New Jersey Medical School, Rutgers, Newark, NJ, USA.
authors: Véronique
authors: V
authors: Dartois
authors: Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors: Dean
authors: D
authors: Follman
authors: Clinical Research Directorate, Clinical Monitoring Research Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
authors: Jing
authors: J
authors: Wang
authors: Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors: Ying
authors: Y
authors: Cai
authors: Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors: Lisa C
authors: LC
authors: Goldfeder
authors: Cardiovascular and Pulmonary Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors: Kenneth N
authors: KN
authors: Olivier
authors: Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors: Yingda
authors: Y
authors: Xie
authors: Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA; Department of Clinical Laboratory Sciences, Faculty of Health Sciences, University of Cape Town, Rondebosch, Cape Town, 7701, Republic of South Africa.
authors: Laura E
authors: LE
authors: Via
authors: Department of Microbiology and Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors: Sang Nae
authors: SN
authors: Cho
authors: Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA; Department of Clinical Laboratory Sciences, Faculty of Health Sciences, University of Cape Town, Rondebosch, Cape Town, 7701, Republic of South Africa.
authors: Clifton E
authors: CE
authors: Barry
authors: Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors: Ray Y
authors: RY
authors: Chen
mesh_terms: D000328:Adult; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D015897:Comorbidity; D016903:Drug Monitoring; D054908:Extensively Drug-Resistant Tuberculosis / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism*; D005260:Female; D050259:Genes, Mitochondrial; D020459:Genes, rRNA; D006801:Humans; D000069349:Linezolid / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: D000995:Antitubercular Agents; D000069349:Linezolid
keywords: Adverse events; Drug resistant; Linezolid; Mitochondrial toxicity; Therapeutic drug monitoring; Tuberculosis