br Author Contributions br Acknowledgements funding We thank

Author Contributions
Acknowledgements/funding We thank the volunteers for their participation in this study, Dr. Matthew Neville and Sr Jane Cheeseman for the assistance in enrolling participants and Dr. Seiko Makino for the technical assistance in isolation of monocytes. We thank Dr. Robert Petryszak for generating the gene lists for diseases curated in the ExpressionAtlas. We thank the volunteers from the Oxford Biobank(www.oxfordbiobank.org.uk), a NIHR Oxford Biomedical Research Centre, for their participation. The Oxford Biobank is also part of the NIHR National Bioresource which supported the recalling process of the volunteers. This work was supported by the Wellcome Trust (grants 074318, 088891 and 090532/Z/09/Z [core facilities Wellcome Trust Centre for Human Genetics including High-Throughput Genomics Group]), the European Research Council under the European Union\'s Seventh Framework Programme (FP7/2007–2013)/ERC Grant agreement no. 281824 (J.C.K.) and the NIHR Oxford Biomedical Research Centre. VN is supported by the Rhodes Trust, HMcS is a Wellcome Trust Senior Clinical Research Fellow, BPF is a Wellcome Trust MB/PHD fellow and AVSH a Wellcome Trust Senior Investigator. The funders had no role in the study design, data collection, data analysis, interpretation, and writing of the report.
1. Introduction Linezolid is a protein synthesis inhibitor approved by the U.S. Food and Drug Administration for the treatment of vancomycin-resistant Enterococcus faecium infections, nosocomial pneumonias, and skin and skin structure infections. Linezolid binds to the 50S subunit of the bacterial ribosome, competing with recognition of the incoming aminoacyl-tRNA molecule that would normally bind to this site (Ippolito et al., 2008). Mammalian mitochondrial ribosomes, unlike cytosolic ribosomes, are thought to have been symbiotically acquired from free-living prokaryotes (Sagan, 1967). Although mammalian mitochondrial ribosomes have evolved substantially from their prokaryotic progenitors (Greber et al., 2014, 2015), in the region of the central loop of Domain V containing the cleft where linezolid (and the amino muscarinic agonist side chains of charged tRNAs) binds, the rRNA is very conserved. Further experimental evidence that linezolid binds to this region of the mammalian ribosome has been obtained (Leach et al., 2007). The use of linezolid for longer than 2–3weeks is therefore limited by adverse events such as bone marrow suppression, lactic acidosis, and peripheral and optic neuropathy that have been associated with the inhibition of mitochondrial protein synthesis (De Vriese et al., 2006; McKee et al., 2006; Soriano et al., 2005). Linezolid has been used off-label in the treatment of drug-resistant tuberculosis, with growing evidence for its efficacy but with use limited by these adverse events (Lee et al., 2012, 2015; Tang et al., 2015; Sotgiu et al., 2012; Koh et al., 2012). In this analysis, we describe in more detail the adverse events associated with mitochondrial toxicity that occurred in the trial conducted by our group (Lee et al., 2012, 2015) and quantify the extent of mitochondrial toxicity in association with linezolid dose and trough concentrations.
2. Methods
3. Results The baseline characteristics of the 38 participants who received linezolid are listed in Table 1, according to the presence or absence of a mitochondrial toxicity-associated adverse event. Overall, 23/38 (60·5%) developed an adverse event and 15/38 (39·5%) did not. Patients who developed an adverse event had similar baseline characteristics to those who did not except that more were older (P=0·01) and fewer had received BCG vaccination (P=0·03). Patients failing their best background regimen for the previous six months were randomized to add linezolid 600mg daily immediately or after a delay of two months while maintaining their existing (failing) treatment regimen. Median time from linezolid start to first adverse event was 237days. At sputum smear conversion or receipt of 4months of linezolid, patients were randomized a second time either to remain on linezolid 600mg daily or to reduce to 300mg daily. Median time to first adverse event after the second randomization was 92days for patients on 600mg and beyond the observation period (>2years) for those on 300mg. Those continuing on 600mg had a significantly higher risk of adverse events than those who reduced to 300mg (hazard ratio 3·10, 95% confidence interval 1·23–7·86).