不同剂量利奈唑胺联合贝达喹啉和普瑞玛尼治疗耐多药肺结核的有效性和安全性：开放标签随机临床试验
Effectiveness and Safety of Varying Doses of Linezolid With Bedaquiline and Pretomanid in Treatment of Drug-Resistant Pulmonary Tuberculosis: Open-Label, Randomized Clinical Trial.
作者信息
Padmapriyadarsini Chandrasekaran, Oswal Vikas S, Jain Chetankumar D, Mariappan Muthu Vijayalakshmi, Singla Neeta, Kumar Santosh, Daniel Bella Devaleenal, Dave Jigna D, Vadgama Parul, Ramraj Balaji, Kant Surya, Bhatnagar Anuj K, Shanmugam Sivakumar, Paul Dhamodharan, Bharathi Jeyadeepa, Palav Manasi, Shah Neha V, Santhanakrishnan Rameshkumar, Dewan Ravindra K, Shekh Nadim, Rathinam Prabhakaran, Sisara Arvind B, Mankar Shubhangi Dhakulkar, Bajpai Jyoti, Mittal Upasana, Chauhan Sandeep, Kumar Ravinder, Parmar Mallik, Mattoo Sanjay K, Jaju Jyoti
机构信息
Department of Clinical Research, ICMR-National Institute for Research in Tuberculosis, Chennai, India.
DRTB Site, Pandit Malviya Shatabdi Centenary Hospital, Mumbai, India.
出版信息
Clin Infect Dis. 2024 Dec 17;79(6):1375-1385. doi: 10.1093/cid/ciae388.
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).
背景
使用贝达喹啉-普瑞玛尼-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，谨慎起见建议重新考虑其剂量和疗程。我们确定了在患有广泛耐药前（pre-XDR）或不耐受治疗/无反应的耐多药（MDRTI/NR）肺结核的成人患者中，与贝达喹啉和普瑞玛尼联合使用时，利奈唑胺结构化减量的有效性和安全性。
方法
患有pre-XDR或MDRTI/NR肺结核的成人患者参加了印度的一项多中心、平行组、随机临床试验。患者被随机分为接受26周的贝达喹啉、普瑞玛尼和每日一次利奈唑胺治疗，其中600mg治疗26周（组1）；600mg治疗9周，随后300mg治疗17周（组2）；或600mg治疗13周，随后300mg治疗13周（组3）。研究终点包括持续治愈、细菌学失败、毒性和死亡。
结果
在纳入的403例患者中，255例（63%）年龄<30岁，273例（68%）既往有结核病史，238例（59%）营养不良。治疗结束时，排除基线培养阴性的患者后，组1、组2和组3分别有120例（93%）、117例（94%）和115例（93%）治愈。组1和组2各有85例患者出现骨髓抑制，组3有77例患者出现骨髓抑制，差异无统计学意义。在10 - 26周时，66例患者（组1、组2和组3分别为30例、17例和19例）出现周围神经病变（P = 0.02）。组1、组2和组3分别有13例、2例和4例患者因毒性反应而减少利奈唑胺剂量。
结论
在患有pre-XDR或MDRTI/NR肺结核的成人患者中，将利奈唑胺结构化减量至300mg/d与标准的600mg剂量同样有效，但与贝达喹啉和普瑞玛尼联合使用时周围神经病变的病例较少。
临床试验注册
印度临床试验注册中心（CTRI/2021/03/032189）
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