Comparative effectiveness of three linezolid management strategies for peripheral neuropathy during multidrug- or rifampicin-resistant tuberculosis treatment

BackgroundPeripheral neuropathy frequently leads to linezolid dose reductions or interruptions during multidrug- or rifampicin-resistant tuberculosis treatment. The effect of these modifications to linezolid on treatment success is uncertain. MethodsWe conducted a target trial emulation using the endTB Observational Study among individuals who developed mild or moderate peripheral neuropathy while receiving linezolid 600 mg daily within 6 months of initiating an individualized regimen. We examined three linezolid management strategies: immediate change (suspension or dose reduction) during Weeks 1-7, deferred change during Weeks 8-26, and no change (i.e., continuing linezolid 600 mg daily) during Weeks 1-26. We used a clone-censor-weight approach to estimate the observational analog of the per-protocol effect on treatment success. ResultsAmong 303 eligible participants from 12 countries, peripheral neuropathy occurred a median (interquartile range) of 11 (4-18) weeks after treatment initiation. Weighted, standardized probabilities of treatment success were 85.8% (95% CI: 72.7%, 93.9%) for immediate change, 78.8% (95% CI: 66.1%, 87.1%) for deferred change, and 85.2% (95% CI: 80.5%, 89.1%) for no change. Compared with no change, treatment success ratios were 1.01 for immediate change (95% CI: 0.86, 1.11) and 0.93 for deferred change (95% CI: 0.78, 1.01) strategies. ConclusionsWe did not find evidence of a substantial negative impact of immediate modification to linezolid among people who developed mild or moderate peripheral neuropathy in the first six months of an individualized regimen. Our results support the clinical practice of cautiously adjusting linezolid when needed to manage non-severe peripheral neuropathy. Key pointsIn this target trial emulation, we found that immediate modifications to linezolid (dose reduction or suspension) in response to mild or moderate peripheral neuropathy during the first six months of MDR/RR-TB treatment did not substantially compromise MDR/RR-TB treatment success.