The safety and tolerability of linezolid in novel short-course regimens containing bedaquiline, pretomanid and linezolid to treat rifampicin-resistant tuberculosis: an individual patient data meta-analysis.

BACKGROUND: Effectiveness, safety, tolerability and adherence are critical considerations in shifting to shorter tuberculosis (TB) regimens. Novel six-month oral regimens that include bedaquiline (B), pretomanid (Pa), linezolid (L) with or without a fourth drug, have been shown to be as or more effective than the established longer regimens for the treatment of multi-drug resistant tuberculosis/rifampicin resistant (MDR/RR-TB). We aimed to evaluate the safety and tolerability of linezolid in BPaL-containing regimens for the treatment of MDR/RR-TB among recently-completed clinical trials. METHODS: A review and meta-analysis was undertaken including published and unpublished data from clinical trials, conducted between 2010 and 2021, that evaluated regimens containing BPaL for the treatment of MDR/RR-TB. Individual patient data were obtained. For each BPaL-containing regimen, we evaluated the frequency and severity of treatment related adverse events. The risk difference of adverse events for each regimen was calculated, in comparison to patients assigned to receiving the lowest cumulative exposure of linezolid. RESULTS: Data from three clinical trials investigating eight unique BPaL-containing regimens were included, comprising a total of 591 participants. Adverse events were more frequent in groups randomized to a higher cumulative linezolid dose. Among patients who were randomized to a daily dose of 1200mg of linezolid, 68/195 (35%) experienced a Grade 3-4 adverse event vs 89/396 (22%) of patients receiving BPaL-containing regimens containing 600mg of linezolid. CONCLUSIONS: Regimens containing BPaL were relatively well-tolerated when they included a daily linezolid dose of 600mg. These novel regimens promise to improve the tolerability of treatment for MDR/RR-TB