1. Antimicrob Agents Chemother. 2018 Feb 23;62(3). pii: e01599-17. doi:
10.1128/AAC.01599-17. Print 2018 Mar.

Mitochondrial Alterations (Inhibition of Mitochondrial Protein Expression,
Oxidative Metabolism, and Ultrastructure) Induced by Linezolid and Tedizolid at
Clinically Relevant Concentrations in Cultured Human HL-60 Promyelocytes and
THP-1 Monocytes.

Milosevic TV(1), Payen VL(2), Sonveaux P(2), Muccioli GG(3), Tulkens PM(1), Van
Bambeke F(4).

Author information: 
(1)Pharmacologie Cellulaire et Moléculaire, Louvain Drug Research Institute,
Université catholique de Louvain, Brussels, Belgium.
(2)Pole of Pharmacology, Institute of Experimental and Clinical Research,
Université catholique de Louvain, Brussels, Belgium.
(3)Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug 
Research Institute, Université catholique de Louvain, Brussels, Belgium.
(4)Pharmacologie Cellulaire et Moléculaire, Louvain Drug Research Institute,
Université catholique de Louvain, Brussels, Belgium
francoise.vanbambeke@uclouvain.be.

Linezolid, the first clinically available oxazolidinone antibiotic, causes
potentially severe toxicities (myelosuppression, lactic acidosis, and
neuropathies) ascribed to impairment of mitochondrial protein synthesis and
consecutive mitochondrial dysfunction. Tedizolid, a newly approved oxazolidinone,
shows an enhanced activity compared to linezolid but is also a more potent
inhibitor of mitochondrial protein synthesis. We compared linezolid and tedizolid
for (i) inhibition of the expression of subunit I of cytochrome c-oxidase (CYTox 
I; Western blot analysis), (ii) cytochrome c-oxidase activity (biochemical
assay), (iii) mitochondrial oxidative metabolism (Seahorse technology), and (iv) 
alteration of mitochondrial ultrastructure (electron microscopy) using HL-60
promyelocytes and THP-1 monocytes exposed to microbiologically (multiples of
modal MIC against Staphylococcus aureus) and therapeutically (Cmin - Cmax)
pertinent concentrations. Both drugs caused a rapid and complete (48 to 72 h)
inhibition of CYTox I expression, cytochrome c-oxidase activity, and spare
respiratory capacity, with conspicuous swelling of the mitochondrial matrix and
loss of their cristae. Globally, tedizolid was a more potent inhibitor than
linezolid. For both drugs, all effects were quickly (48 to 72 h) and fully
reversible upon drug withdrawal. Using an alternation of exposure to and
withdrawal from drug mimicking their approved schedule of administration (twice
daily and once daily [qD] for linezolid and tedizolid, respectively), only
partial inhibition of CYTox I expression was noted for up to 96 h. Thus, rapid
reversal of toxic effects upon discontinuous administration may mitigate
oxazolidinone toxicity. Since tedizolid is given qD, this may help to explain its
reported lower preclinical and clinical toxicity.

Copyright © 2018 American Society for Microbiology.

DOI: 10.1128/AAC.01599-17 
PMCID: PMC5826137 [Available on 2018-08-23]
PMID: 29263063