Linezolid for Treating Tuberculosis: A Delicate Balancing Act

There is an urgent need for better regimens to treat drug-resistant tuberculosis (DR-TB). Treatment for multi-drug resistant tuberculosis (MDR-TB, defined as resistance to both isoniazid and rifampicin) has a success rate of only 64% (Falzon et al., 2013), is prolonged for up to 24 months, and is poorly tolerated. Treatment success for extensively drug-resistant tuberculosis (XDR-TB, defined as MDR-TB with additional resistance to fluoroquinolones and an injectable) is only 40% (Falzon et al., 2013). The oxazolidinone antimicrobial linezolid, which is registered for use in Gram-positive bacterial infections, has potentially useful antimycobacterial activity. Two small randomised controlled trials (RCTs) of linezolid in patients with XDR-TB have shown improved rates of sputum culture conversion (Lee et al., 2012; Tang et al., 2015). However, linezolid is poorly tolerated inDR-TB. Ameta-analysis of linezolid use in MDRand XDR-TB showed that 35% of patients interrupted linezolid due to toxicity (Zhang et al., 2015). Linezolid causes reversible myelosuppression and neuropathy, both of which are mediated by a doseand time-dependent inhibition ofmitochondrial protein synthesis (De Vriese et al., 2006). Linezolid's cumulative dose-related toxicity is a particular problem for patients with DR-TB, who need prolonged therapy. In a paper published in this edition of EBioMedicine, Song and colleagues (Song et al., 2015) monitored serial mitochondrial function (cytochrome c oxidase:citrate synthase activity ratio), and correlated this with both adverse events and trough linezolid concentrations in participants from their trial of linezolid in XDR-TB (Lee et al., 2012). Themitochondrial function assay they developed appears to be a useful surrogate marker of mitochondrial toxicity. Their finding of a 2 μg/mL cutpoint for linezolid trough concentrations for toxicity is an important