The novel regimen of bedaquiline, pretomanid, and linezolid (BPaL) is highly effective against drug-resistant tuberculosis, but linezolid toxicities are frequent. We hypothesized that, for a similar total weekly cumulative dose, thrice-weekly administration of linezolid would preserve efficacy while reducing toxicity compared with daily dosing, in the context of the BPaL regimen. Using C3HeB/FeJ and BALB/c mouse models of tuberculosis disease, thrice-weekly linezolid dosing was compared with daily dosing, with intermittent dosing introduced (i) from treatment initiation or (ii) after an initial period of daily dosing. In all animals, BPa was dosed daily throughout treatment. Blood counts were used to assess hematologic toxicity. After unexpected findings of apparent antagonism, we conducted additional experiments to investigate strain-to-strain differences in the contribution of linezolid to regimen efficacy by comparing each 1- and 2-drug component to the BPaL regimen in BALB/c mice infected with Mycobacterium tuberculosis H37Rv or HN878. Giving linezolid daily for 1 to 2 months achieved the greatest efficacy but, after that, results were similar if the drug was stopped, dosed thrice-weekly, or continued daily. Erythrocyte counts were lower with daily than thrice-weekly dosing. Linezolid had additive effects with BPa against M. tuberculosis H37Rv but antagonistic effects with BPa against M. tuberculosis HN878. However, the overall efficacy of BPaL was high and similar against both strains. Dosing linezolid daily for the first 2 months and then less frequently thereafter may optimize its therapeutic margin. Linezolid’s contribution to BPaL regimens may depend on the M. tuberculosis strain.

中文翻译：

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在小鼠结核病模型中，间歇性利奈唑胺剂量与贝达喹啉和类前驱体合用可保持疗效并降低毒性。

苯达喹啉，类前驱体和利奈唑胺（BPaL）的新方案对耐药性结核病非常有效，但利奈唑胺的毒性却很常见。我们假设，在BPaL方案的情况下，对于相似的每周总累积剂量，与每日给药相比，每周三次利奈唑胺给药可保持疗效，同时降低毒性。使用结核病的C3HeB / FeJ和BALB / c小鼠模型，将每周三次利奈唑胺剂量与每日剂量进行比较，并在（i）开始治疗后或（ii）在每日剂量的初始阶段后引入间歇剂量。在所有动物中，在整个治疗过程中每天都要服用BPa。血液计数用于评估血液学毒性。在意外发现明显的拮抗作用后，结核分枝杆菌H37Rv或HN878。每天给予利奈唑胺1至2个月疗效最佳，此后，如果停用，每周三次或每天持续服用该药物，效果相似。每天的红细胞计数低于每周三次的剂量。利奈唑胺与BPa对抗结核分枝杆菌H37Rv具有累加作用，但与BPa对抗结核分枝杆菌HN878具有拮抗作用。但是，BPaL的整体功效很高，并且对两种菌株都相似。在头两个月内每天服用利奈唑胺，此后减少服用频率可能会优化其治疗范围。利奈唑胺对BPaL方案的贡献可能取决于结核分枝杆菌菌株。