Mitochondrial toxicity of linezolid in blood cells and skin nerve fibers: influence of mitochondrial genetics [PublishAheadOfPrint]

Background: The antibiotic linezolid is a ribosomal inhibitor with excellent efficacy. Despite reduction in the administration period to 28 days, side effects usually of hematologic or neuropathic origin are still reported due to secondary inhibition of mitochondrial protein synthesis. Susceptibility to linezolid toxicity remains unknown.

Objective: To understand clinical heterogenicity in response to identical linezolid exposition through the exhaustive examination of the molecular basis of tissue-dependent mitotoxicity, derived cell dysfunction and mitochondrial genetic association to adverse effects of linezolid under the recommended period of administration.

Methods: Peripheral blood mononuclear cells (PBMC) and skin nerve fibers from 19 and 6 patients, respectively, were evaluated before and after 28-day linezolid treatment to assess mitochondrial and cell toxic consequences. Mitochondrial DNA haplotypes and SNPs in ribosomal sequences where linezolid binds to mitochondrial ribosome were additionally analyzed to investigate genetic contribution.

Results: Linezolid reduced mitochondrial protein levels, complex IV activity and mitochondrial mass in PBMC and trended to increase apoptosis. In skin tissue, mitochondrial amount increased within nerve fiber accompanied by subclinical axonal swelling. Mitochondrial U haplogroup, mutations in 12SrRNA and polymorphisms m.2706A>G, m.3197T>C and m.3010G>A in 16SrRNA trended to be associated to increased mitochondrial and clinical adverse effects.

Conclusions: Even with a shorter administration, adverse effects of linezolid are reported by 63% of patients. Linezolid exerts correlated tissue-dependent mitotoxicity responsible for downstream cellular consequences (blood cell death and nerve fiber swelling) leading to adverse hematologic and peripheral nervous side effects. Multicentric studies should confirm genetic susceptibility in bigger cohorts.

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