PMID- 26870788
OWN - NLM
STAT- MEDLINE
DCOM- 20161104
LR  - 20181113
IS  - 2352-3964 (Electronic)
IS  - 2352-3964 (Linking)
VI  - 2
IP  - 11
DP  - 2015 Nov
TI  - Linezolid Trough Concentrations Correlate with Mitochondrial Toxicity-Related 
      Adverse Events in the Treatment of Chronic Extensively Drug-Resistant 
      Tuberculosis.
PG  - 1627-33
LID - 10.1016/j.ebiom.2015.09.051 [doi]
AB  - 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 rho = - 0.48; P = 0.005). Mitochondrial toxicity risk increased 
      with increasing linezolid trough concentrations, with all patients with mean 
      linezolid trough > 2 mug/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.
FAU - Song, Taeksun
AU  - Song T
AD  - International Tuberculosis Research Center, Changwon, Republic of Korea.
FAU - Lee, Myungsun
AU  - Lee M
AD  - International Tuberculosis Research Center, Changwon, Republic of Korea.
FAU - Jeon, Han-Seung
AU  - Jeon HS
AD  - International Tuberculosis Research Center, Changwon, Republic of Korea.
FAU - Park, Yumi
AU  - Park Y
AD  - International Tuberculosis Research Center, Changwon, Republic of Korea.
FAU - Dodd, Lori E
AU  - Dodd LE
AD  - Biostatistics Research Branch, National Institute of Allergy and Infectious 
      Diseases, National Institutes of Health, Bethesda, MD, USA.
FAU - Dartois, Veronique
AU  - Dartois V
AD  - Public Health Research Institute, New Jersey Medical School, Rutgers, Newark, NJ, 
      USA.
FAU - Follman, Dean
AU  - Follman D
AD  - Biostatistics Research Branch, National Institute of Allergy and Infectious 
      Diseases, National Institutes of Health, Bethesda, MD, USA.
FAU - Wang, Jing
AU  - Wang J
AD  - Clinical Research Directorate, Clinical Monitoring Research Program, Leidos 
      Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, 
      Frederick, MD, USA.
FAU - Cai, Ying
AU  - Cai Y
AD  - Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, 
      National Institute of Allergy and Infectious Diseases, National Institutes of 
      Health, Bethesda, MD, USA.
FAU - Goldfeder, Lisa C
AU  - Goldfeder LC
AD  - Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, 
      National Institute of Allergy and Infectious Diseases, National Institutes of 
      Health, Bethesda, MD, USA.
FAU - Olivier, Kenneth N
AU  - Olivier KN
AD  - Cardiovascular and Pulmonary Branch, Division of Intramural Research, National 
      Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, 
      USA.
FAU - Xie, Yingda
AU  - Xie Y
AD  - Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, 
      National Institute of Allergy and Infectious Diseases, National Institutes of 
      Health, Bethesda, MD, USA.
FAU - Via, Laura E
AU  - Via LE
AD  - 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.
FAU - Cho, Sang Nae
AU  - Cho SN
AD  - Department of Microbiology and Institute for Immunology and Immunological 
      Diseases, Yonsei University College of Medicine, Seoul, Republic of Korea.
FAU - Barry, Clifton E 3rd
AU  - Barry CE 3rd
AD  - 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.
FAU - Chen, Ray Y
AU  - Chen RY
AD  - Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, 
      National Institute of Allergy and Infectious Diseases, National Institutes of 
      Health, Bethesda, MD, USA.
LA  - eng
GR  - HHSN261200800001C/RC/CCR NIH HHS/United States
GR  - HHSN261200800001E/CA/NCI NIH HHS/United States
GR  - HHSN261200800001E/PHS HHS/United States
PT  - Clinical Trial
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20151009
PL  - Netherlands
TA  - EBioMedicine
JT  - EBioMedicine
JID - 101647039
RN  - 0 (Antitubercular Agents)
RN  - ISQ9I6J12J (Linezolid)
SB  - IM
CIN - EBioMedicine. 2015 Nov;2(11):1568-9. PMID: 26870767
MH  - Adult
MH  - Antitubercular Agents/*administration & dosage/*adverse effects/pharmacokinetics
MH  - Comorbidity
MH  - Drug Monitoring
MH  - Extensively Drug-Resistant Tuberculosis/diagnosis/*drug 
      therapy/immunology/*metabolism
MH  - Female
MH  - Genes, Mitochondrial
MH  - Genes, rRNA
MH  - Humans
MH  - Linezolid/*administration & dosage/*adverse effects/pharmacokinetics
MH  - Male
MH  - Middle Aged
MH  - Mitochondria/*drug effects/*metabolism
MH  - Polymorphism, Single Nucleotide
MH  - Risk Factors
PMC - PMC4740314
OTO - NOTNLM
OT  - Adverse events
OT  - Drug resistant
OT  - Linezolid
OT  - Mitochondrial toxicity
OT  - Therapeutic drug monitoring
OT  - Tuberculosis
EDAT- 2016/02/13 06:00
MHDA- 2016/11/05 06:00
PMCR- 2015/10/09
CRDT- 2016/02/13 06:00
PHST- 2015/09/04 00:00 [received]
PHST- 2015/09/28 00:00 [revised]
PHST- 2015/09/29 00:00 [accepted]
PHST- 2016/02/13 06:00 [entrez]
PHST- 2016/02/13 06:00 [pubmed]
PHST- 2016/11/05 06:00 [medline]
PHST- 2015/10/09 00:00 [pmc-release]
AID - S2352-3964(15)30166-3 [pii]
AID - 10.1016/j.ebiom.2015.09.051 [doi]
PST - epublish
SO  - EBioMedicine. 2015 Oct 9;2(11):1627-33. doi: 10.1016/j.ebiom.2015.09.051. 
      eCollection 2015 Nov.