Linezolid Trough Concentrations Correlate with Mitochondrial Toxicity-Related Adverse Events in the Treatment of Chronic Extensively Drug-Resistant Tuberculosis

• Linezolid is increasingly being used to treat drug-resistant tuberculosis.
• Long-term use of linezolid is limited by mitochondrial toxicity-associated adverse events.
• We examined linezolid trough concentrations in chronic XDR-TB patients on linezolid.
• Mitochondrial toxicity risk increased with increasing linezolid trough concentrations.
• Therapeutic drug monitoring may help avoid mitochondrial toxicities in long-term linezolid treatment.Linezolid is increasingly being used to treat drug resistant tuberculosis, with the beneficial effect of linezolid tempered by the mitochondrial toxicity-associated adverse events seen with long-term use. Within a prospective, randomized controlled trial of linezolid for the treatment of chronic, extensively drug-resistant tuberculosis, we found that the risk of mitochondrial toxicity increased with increasing linezolid trough concentrations, with all patients with a mean trough > 2 μg/ml developing an adverse event related to mitochondrial toxicity. If our results are confirmed by other studies, therapeutic drug monitoring may become an important component of long-term linezolid treatment to prevent mitochondrial toxicity-related adverse events.

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 ρ = − 0.48; P = 0.005). Mitochondrial toxicity risk increased with increasing linezolid trough concentrations, with all patients with mean linezolid trough > 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.