Safety and Tolerability of a Short Course of Linezolid for the Treatment of Predominantly Moderate to Severe Tuberculous Meningitis in Adults with HIV

Abstract

Background Tuberculous meningitis (TBM)-related deaths occur early, often within weeks after initiation of treatment. Enhanced treatment early in the disease course with agents that effectively penetrate the central nervous system may improve outcomes in TBM. Methods We conducted a phase 2, open-label, randomized trial in Masaka, Uganda to assess the safety and tolerability of linezolid 1200 mg versus no linezolid with high (35 mg/kg/day) or standard-dose (10 mg/kg/day) rifampin for 4 weeks in participants with definite or suspected TBM. The primary endpoint was any >grade 3 adverse event during the interventional period. Secondary endpoints included overall survival and functional independence adjusted for TBM disease grade. Results We randomized 40 participants (98% with HIV). One-fourth had microbiologically-confirmed TBM. Nearly 75% had moderate to severe disease (Medical Research Council grades II and III). No significant difference in >grade 3 adverse event-free survival was observed across the 4 treatment arms (p=0.18), or by linezolid (p=0.97) or rifampin (p=0.46) group. More favorable overall survival (OR 0.28 for death at 12 weeks, p=0.10; OR 0.43 at 24 weeks, p=0.24) and functional outcome [OR 2.22 for lower modified Rankin Scale score (i.e., less disability) at 12 weeks, p=0.18; OR 2.00 at 24 weeks, p=0.24) were observed in the linezolid group. Conclusions The addition of a short course of linezolid to treat predominantly moderate to severe TBM in adults with HIV did not introduce excess toxicity. Our findings add to growing evidence that linezolid is a safe and acceptable treatment for TBM that merits further investigation in larger multi-site trials.