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

Abstract

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.

Keywords: Adverse events; Drug resistant; Linezolid; Mitochondrial toxicity; Therapeutic drug monitoring; Tuberculosis.

Fig. 1

Boxplot of subject-level mean mitochondrial function by linezolid dose. Mean mitochondrial function values for patients receiving linezolid 300 mg daily and 600 mg daily were significantly lower than for the same patients at baseline (pre-linezolid). Mean mitochondrial function for patients on linezolid 600 mg daily was also significantly lower than for patients on 300 mg daily. Note that the bars of the boxplots summarize the median and interquartile values of the subject's mean values.

Fig. 2

A: Mean linezolid trough concentration by linezolid dose. Mean linezolid trough concentration was significantly higher for patients on 600 mg daily compared to 300 mg daily. Note that the bars of the boxplots summarize the median and interquartile values of the subject's mean values. B: Mean mitochondrial function level by mean linezolid trough concentration. There is a significant inverse correlation such that higher mean linezolid trough concentrations correlate with lower mean mitochondrial function levels. Note that the bars of the boxplot summarize the median and interquartile values of the subject's mean values.

Fig. 3

Time to adverse event from linezolid start (3A) or second randomization (3B) by mean linezolid trough concentration. All patients with a mean linezolid trough concentration > 2 μg/ml, regardless of dose, developed a mitochondrial toxicity-related adverse event. 6 = patient on 600 mg dose. 3 = patient on 300 mg dose. Note: Five patients who reduced their linezolid dose from 600 mg to 300 mg due to adverse events before the second randomization are not included.