medRxiv : the preprint server for health sciences · 2026
Comparison of three linezolid management strategies for peripheral neuropathy in multidrug- or rifampicin-resistant tuberculosis treatment: a target trial emulation.
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Romo Matthew, LaHood Allison, Mitnick Carole D, Rich Michael L, Trevisi Letizia, Skrahina Alena, Oyewusi Lawrence, Bastard Mathieu, Khan Palwasha Y, Huerga Helena, Khan Uzma, Flores Edwin Herrera, Atshemyan Hakob, Hewison Catherine, Rashitov Mahmud, Samieva Nazgul, Gómez-Restrepo Camilo, Krisnanda Aga, Kotrikadze Tinatin, Siraj Faisal, Khan Abdul Wali, Ndjeka Norbert, Adenov Malik, Seung Kwonjune J, Kumsa Andargachew, Franke Molly F
Аннотация
BACKGROUND: Peripheral neuropathy frequently leads to linezolid dose reductions or interruptions during multidrug- or rifampicin-resistant tuberculosis (MDR/RR-TB) treatment. The implications of these modifications on treatment success are uncertain.
METHODS: We conducted a target trial emulation using the endTB Observational Study among individuals who developed non-severe peripheral neuropathy while receiving linezolid 600 mg daily within 6 months of initiating an individualized MDR/RR-TB regimen. We examined three linezolid management strategies: immediate change (i.e., dose reduction, temporary interruption, discontinuation) within Weeks 1-7 after peripheral neuropathy onset, deferred change within Weeks 8-26, and no change (i.e., continuing linezolid 600 mg daily) during Weeks 1-26. To emulate the per-protocol analysis of a trial, we used an approach involving cloning and censoring participant data, and applying inverse probability of censoring weights.
RESULTS: Among 303 eligible participants from 12 countries, peripheral neuropathy occurred a median of 11 weeks (interquartile range: 4-18) after treatment initiation. Weighted, standardized probabilities of treatment success were 84.7% (95% CI: 69.2%, 92.9%) for immediate change, 78.9% (95% CI: 65.9%, 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 0.99 (95% CI: 0.83, 1.11) for immediate change and 0.93 (95% CI: 0.78, 1.01) for deferred change.
CONCLUSIONS: We did not find evidence of a substantial negative impact of immediate modification to linezolid on MDR/RR-TB treatment success. Our results support the clinical practice of cautiously adjusting linezolid when needed to manage non-severe peripheral neuropathy.
METHODS: We conducted a target trial emulation using the endTB Observational Study among individuals who developed non-severe peripheral neuropathy while receiving linezolid 600 mg daily within 6 months of initiating an individualized MDR/RR-TB regimen. We examined three linezolid management strategies: immediate change (i.e., dose reduction, temporary interruption, discontinuation) within Weeks 1-7 after peripheral neuropathy onset, deferred change within Weeks 8-26, and no change (i.e., continuing linezolid 600 mg daily) during Weeks 1-26. To emulate the per-protocol analysis of a trial, we used an approach involving cloning and censoring participant data, and applying inverse probability of censoring weights.
RESULTS: Among 303 eligible participants from 12 countries, peripheral neuropathy occurred a median of 11 weeks (interquartile range: 4-18) after treatment initiation. Weighted, standardized probabilities of treatment success were 84.7% (95% CI: 69.2%, 92.9%) for immediate change, 78.9% (95% CI: 65.9%, 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 0.99 (95% CI: 0.83, 1.11) for immediate change and 0.93 (95% CI: 0.78, 1.01) for deferred change.
CONCLUSIONS: We did not find evidence of a substantial negative impact of immediate modification to linezolid on MDR/RR-TB treatment success. Our results support the clinical practice of cautiously adjusting linezolid when needed to manage non-severe peripheral neuropathy.