Bedaquiline-Pretomanid-Linezolid Regimens for Drug-Resistant Tuberculosis.
Bedaquiline-Pretomanid-Linezolid Regimens for Drug-Resistant Tuberculosis.
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贝达喹啉-Pretomanid-利奈唑胺治疗耐药结核病的方案。
DOI：
10.1056/nejmoa2119430
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发表时间：
2022-09-01
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据报道，贝达喹啉-pretomanid-利奈唑胺方案对高度耐药结核病的疗效为90%，但每日1200 mg利奈唑胺的不良事件发生率较高。目前尚不清楚利奈唑胺的适当剂量和治疗持续时间，以最大限度地减少毒性作用，同时保持对高度耐药结核病的疗效。我们招募了广泛耐药（XDR）结核病（即，对利福平、氟喹诺酮和氨基糖苷类具有抗性），前XDR结核病（即，对利福平和氟喹诺酮或氨基糖苷类耐药），或对治疗无反应或因副作用而停止二线治疗的利福平耐药结核病。我们随机分配参与者接受贝达喹啉26周（每天200 mg，持续8周，然后每天100 mg，持续18周），pretomanid（每天200 mg，持续26周），以及每天1200 mg剂量的利奈唑胺26周或9周或600 mg剂量的26周或9周。改良意向治疗人群的主要终点是不良结局的发生率，定义为治疗结束后26周时治疗失败或疾病复发（临床或细菌学）。还评价了安全性。共有181名参与者入组，其中88%患有XDR或XDR前结核病。在接受贝达喹啉-pretomanid-利奈唑胺联合利奈唑胺1200 mg治疗26周或9周或600 mg治疗26周或9周的受试者中，分别有93%、89%、91%和84%的受试者结局良好;分别有38%、24%、24%和13%的受试者发生周围神经病变;骨髓抑制发生率分别为22%、15%、2%和7%;并调整了利奈唑胺剂量（即，中断、减少或中止）分别为51%、30%、13%和13%。4例（9%）接受利奈唑胺1200 mg治疗26周的受试者发生视神经病变;所有病例均消退。在78周的随访中，7个不利的微生物学结局中有6个发生在分配到9周利奈唑胺组的参与者中。在所有4个贝达喹啉-pretomanid-利奈唑胺治疗组中，共有84 - 93%的受试者结局良好。总体风险-获益比有利于接受利奈唑胺600 mg剂量26周三药方案的组，报告的不良事件发生率较低，利奈唑胺剂量调整较少。（由结核病联盟和其他组织资助; ZeNix ClinicalTrials.gov编号，NCT 03086486。
The bedaquiline–pretomanid–linezolid regimen has been reported to have 90% efficacy against highly drug-resistant tuberculosis, but the incidence of adverse events with 1200 mg of linezolid daily has been high. The appropriate dose of linezolid and duration of treatment with this agent to minimize toxic effects while maintaining efficacy against highly drug-resistant tuberculosis are unclear. We enrolled participants with extensively drug-resistant (XDR) tuberculosis (i.e., resistant to rifampin, a fluoroquinolone, and an aminoglycoside), pre-XDR tuberculosis (i.e., resistant to rifampin and to either a fluoroquinolone or an aminoglycoside), or rifampin-resistant tuberculosis that was not responsive to treatment or for which a second-line regimen had been discontinued because of side effects. We randomly assigned the participants to receive bedaquiline for 26 weeks (200 mg daily for 8 weeks, then 100 mg daily for 18 weeks), pretomanid (200 mg daily for 26 weeks), and daily linezolid at a dose of 1200 mg for 26 weeks or 9 weeks or 600 mg for 26 weeks or 9 weeks. The primary end point in the modified intention-to-treat population was the incidence of an unfavorable outcome, defined as treatment failure or disease relapse (clinical or bacteriologic) at 26 weeks after completion of treatment. Safety was also evaluated. A total of 181 participants were enrolled, 88% of whom had XDR or pre-XDR tuberculosis. Among participants who received bedaquiline–pretomanid–linezolid with linezolid at a dose of 1200 mg for 26 weeks or 9 weeks or 600 mg for 26 weeks or 9 weeks, 93%, 89%, 91%, and 84%, respectively, had a favorable outcome; peripheral neuropathy occurred in 38%, 24%, 24%, and 13%, respectively; myelosuppression occurred in 22%, 15%, 2%, and 7%, respectively; and the linezolid dose was modified (i.e., interrupted, reduced, or discontinued) in 51%, 30%, 13%, and 13%, respectively. Optic neuropathy developed in 4 participants (9%) who had received linezolid at a dose of 1200 mg for 26 weeks; all the cases resolved. Six of the seven unfavorable microbiologic outcomes through 78 weeks of follow-up occurred in participants assigned to the 9-week linezolid groups. A total of 84 to 93% of the participants across all four bedaquiline–pretomanid–linezolid treatment groups had a favorable outcome. The overall risk–benefit ratio favored the group that received the three-drug regimen with linezolid at a dose of 600 mg for 26 weeks, with a lower incidence of adverse events reported and fewer linezolid dose modifications. (Funded by the TB Alliance and others; ZeNix ClinicalTrials.gov number, NCT03086486.)