BACKGROUND Treatment of drug-resistant tuberculosis with bedaquiline-pretomanid-linezolid regimen has demonstrated good treatment efficacy. Given linezolid's toxicity profile, prudence suggests reconsidering its dose and duration. We determined the effectiveness and safety of structured dose reduction of linezolid with bedaquiline and pretomanid in adults with pre-extensively drug-resistant (pre-XDR) or treatment-intolerant/nonresponsive multidrug-resistant (MDRTI/NR) pulmonary tuberculosis. METHOD Adults with pre-XDR or MDRTI/NR pulmonary tuberculosis were enrolled in a multicenter, parallel-group, randomized clinical trial in India. Patients were randomized to 26 weeks of bedaquiline, pretomanid, and daily linezolid, at 600 mg for 26 weeks (arm 1); 600 mg for 9 weeks followed by 300 mg for 17 weeks (arm 2); or 600 mg for 13 weeks followed by 300 mg for 13 weeks (arm 3). Study end points included sustained cure, bacteriological failure, toxicity, and death. RESULTS Of 403 patients enrolled, 255 (63%) were <30 years old, 273 (68%) had prior tuberculosis episodes, and 238 (59%) were malnourished. At the end of treatment, after excluding those with negative baseline cultures, cure was seen in 120 (93%), 117 (94%), and 115 (93%) in arms 1, 2, and 3 respectively. Myelosuppression seen in 85 patients each in arms 1 and 2 and 77 patients in arm 3, not significantly different. Peripheral neuropathy was noticed in 66 patients (30, 17, and 19 in arms 1, 2, and 3) at 10-26 weeks (P = .02). The linezolid dose was reduced because of toxicity in 13, 2, and 4 patients in arms 1, 2, and 3, respectively. CONCLUSIONS In adults with pre-XDR or MDRTI/NR pulmonary tuberculosis, structured linezolid dose reduction to 300 mg/d is as effective as the standard 600-mg dose but with fewer cases of peripheral neuropathy when given with bedaquiline and pretomanid. CLINICAL TRIALS REGISTRATION Clinical Trial Registry of India (CTRI/2021/03/032189).

中文翻译：

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不同剂量的利奈唑胺与贝达喹啉和普雷托马尼治疗耐药肺结核的有效性和安全性：开放标签、随机临床试验。


背景 用贝达喹啉-普雷托马尼-利奈唑胺方案治疗耐药结核病已显示出良好的治疗效果。鉴于利奈唑胺的毒性特征，谨慎建议重新考虑其剂量和持续时间。我们确定了利奈唑胺与贝达喹啉和普雷托马尼德结构性剂量减少对患有广泛耐药前 （pre-XDR） 或治疗不耐受/无反应的多重耐药 （MDRTI/NR） 肺结核成人的有效性和安全性。方法 在印度，患有 pre-XDR 或 MDRTI/NR 肺结核的成人患者被纳入一项多中心、平行组、随机临床试验。患者被随机分配到 26 周的贝达喹啉、pretomanid 和每日利奈唑胺组，剂量为 600 mg，持续 26 周（第 1 组）;600 毫克，持续 9 周，然后 300 毫克，持续 17 周（第 2 组）;或 600 毫克，持续 13 周，然后 300 毫克，持续 13 周（第 3 组）。研究终点包括持续治愈、细菌学失败、毒性和死亡。结果 在入组的 403 例患者中，255 例 （63%） 为 <30 岁，273 例 （68%） 既往有结核病发作史，238 例 （59%） 营养不良。在治疗结束时，排除基线培养阴性的患者后，第 1 组、第 2 组和第 3 组分别为 120 例 （93%） 、 117 例 （94%） 和 115 例 （93%） 治愈。第 1 组和第 2 组各有 85 名患者，第 3 组有 77 名患者出现骨髓抑制，差异无统计学意义。在 10-26 周时，66 例患者 （第 1 、 2 和 3 组有 30 例、 17 例和 19 例） 观察到周围神经病变 （P = .02）。利奈唑胺剂量因毒性而减少，分别在第 1 、 2 和 3 组中的 13 、 2 和 4 名患者中。 结论 在 pre-XDR 或 MDRTI/NR 肺结核成人患者中，结构性利奈唑胺剂量减少至 300 mg/d 与标准 600 mg 剂量一样有效，但与贝达喹啉和前托马尼一起给药时周围神经病变病例较少。临床试验注册印度临床试验注册中心 （CTRI/2021/03/032189）。