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,
Sang Nae Cho,
Clifton E. Barry III,
Ray Y. Chen
Affiliations
Taeksun Song
International Tuberculosis Research Center, Changwon, Republic of Korea
Myungsun Lee
International Tuberculosis Research Center, Changwon, Republic of Korea
Han-Seung Jeon
International Tuberculosis Research Center, Changwon, Republic of Korea
Yumi Park
International Tuberculosis Research Center, Changwon, Republic of Korea
Lori E. Dodd
Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
Véronique Dartois
Public Health Research Institute, New Jersey Medical School, Rutgers, Newark, NJ, USA
Dean Follman
Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
Jing Wang
Clinical Research Directorate, Clinical Monitoring Research Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA
Ying Cai
Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
Lisa C. Goldfeder
Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
Kenneth N. Olivier
Cardiovascular and Pulmonary Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
Yingda Xie
Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
Laura E. Via
Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
Sang Nae Cho
Department of Microbiology and Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, Republic of Korea
Clifton E. Barry III
Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
Ray Y. Chen
Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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 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.
