贝达喹啉- Pretomanid -利奈唑胺方案治疗耐药结核

SCI

12 September 2022

Bedaquiline–Pretomanid–Linezolid Regimens for Drug-Resistant Tuberculosis

(The New England Journal of Medicine, IF: 176.08)

F. Conradie, T.R. Bagdasaryan, S. Borisov, P. Howell, L. Mikiashvili, N. Ngubane, A. Samoilova, S. Skornykova, E. Tudor, E. Variava, P. Yablonskiy, D. Everitt, G.H. Wills, E. Sun, M. Olugbosi, E. Egizi, M. Li, A. Holsta, J. Timm, A. Bateson, A.M. Crook, S.M. Fabiane, R. Hunt, T.D. McHugh, C.D. Tweed, S. Foraida, C.M. Mendel, and M. Spigelman, for the ZeNix Trial Team

CORRESPONDENCE TO: c.tweed@ucl.ac.uk

BACKGROUND 背景

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.

据报道，贝达喹啉- pretomanid -利奈唑胺方案对高度耐药结核有90%的疗效，但每天应用1200毫克利奈唑啉的不良事件发生率很高。目前尚不清楚利奈唑胺的适当剂量和该药物治疗的持续时间以尽量减少毒性作用，同时维持对高度耐药结核的疗效。

METHODS 方法

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.

我们招募了广泛耐药（XDR）结核（即对利福平、氟喹诺酮和氨基糖苷类药物耐药）、既往XDR结核（即，对利福平和氟喹诺酮类或氨基糖苷类抗生素耐药）的参与者，或对治疗无效或因副作用而中断二线方案的利福平耐药结核。我们随机分配参与者接受贝达喹啉治疗26周（8周每天200mg，然后18周每天100mg）、pretomanid（26周每天200 mg）和利奈唑胺（26周或9周每天1200 mg或26周或九周每天600 mg）。改良意向治疗人群的主要终点是不良结局的发生率，定义为治疗失败或疾病复发（临床或细菌学）。我们还同时评估了安全性。

RESULTS 结果

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.

共纳入181名参与者，其中88%患有广泛耐药或既往广泛耐药结核病。在接受贝达喹啉- pretomanid -利奈唑胺联合利奈唑啉（剂量为1200 mg，持续26周或9周或600 mg，持续6周或9周）的参与者中，分别有93%、89%、91%和84%的患者有良好的结果；周围神经病变发生率分别为38%、24%、24%和13%；骨髓抑制发生率分别为22%、15%、2%和7%；利奈唑胺的剂量分别为51%、30%、13%和13%。4名接受26周1200 mg利奈唑胺治疗的参与者（9%）出现视神经病变；所有案例均已完成。在78周的随访中，7个不良微生物学结果中的6个发生在分配到9周利奈唑胺组的参与者中。

CONCLUSION 结论

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.)

在所有四个贝达喹啉- pretomanid -利奈唑胺治疗组中，共有84%至93%的参与者有良好的结果。总体风险效益比有利于接受600 mg利奈唑胺三药方案治疗26周的组，不良事件发生率较低，利奈唑啉剂量修改较少。（由结核病联盟等资助；ZeNix ClinicalTrials.gov编号：NCT03086486）

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