Treatment of Highly Drug-Resistant Pulmonary Tuberculosis
Treatment of Highly Drug-Resistant Pulmonary Tuberculosis
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DOI：
10.1056/nejmoa1901814
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发表时间：
2020-03-05
影响因子：
158.5
通讯作者：
Spigelman, Melvin
中科院分区：
文献类型：
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作者：
Conradie, Francesca;Diacon, Andreas H.;Spigelman, Melvin
背景：高度耐药结核病患者的治疗选择有限，历史上预后较差。方法在一项开放标签的单组研究中，我们在南非的三个地点进行了随访，研究了三种口服药物——贝达喹啉、普雷托马尼和利奈唑胺的治疗方法，这三种药物对结核病具有杀菌活性，并且几乎没有预先存在的耐药性。我们对广泛耐药结核病患者和多药耐药结核病患者进行了为期26周的安全性和有效性评估，这些患者对治疗无反应或因副作用而停止了二线治疗方案。主要终点是不良结局的发生率，定义为治疗失败（细菌学或临床）或随访期间复发，持续到治疗结束后6个月。如果患者在6个月时临床疾病消退，阴性培养状态，并且尚未被分类为具有不良结果，则将患者分类为具有良好结果。其他疗效终点和安全性也进行了评估。结果共纳入109例患者，纳入疗效和安全性评价终点。在意向治疗分析中，治疗结束后6个月，11例患者（10%）出现不良结果，98例患者（90%；95%可信区间为83 ~ 95）出现良好结果。11个不良结局包括7例死亡（6例在治疗期间死亡，1例在随访期间死亡原因不明），1例在治疗期间撤回同意，2例在随访期间复发，1例失去随访。预期的利奈唑胺毒性作用，包括周围神经病变（发生在81%的患者中）和骨髓抑制（48%），虽然很常见，但是可控的，经常导致剂量减少或利奈唑胺治疗中断。结论：贝达喹啉、普雷托马奈和利奈唑胺联合治疗对高耐药结核病患者在治疗结束后6个月的预后有利；观察到一些相关的毒性作用。（由结核病联盟和其他机构资助；ClinicalTrials.gov号码，.）高度耐药结核病的治疗选择有限。在南非的这项研究中，一种新的药物pretomanid与贝达喹啉和利奈唑胺联合治疗广泛耐药和复杂的多药耐药肺结核，疗程为26周。尽管存在毒性作用，但90%的患者预后良好。
Background Patients with highly drug-resistant forms of tuberculosis have limited treatment options and historically have had poor outcomes.Methods In an open-label, single-group study in which follow-up is ongoing at three South African sites, we investigated treatment with three oral drugs - bedaquiline, pretomanid, and linezolid - that have bactericidal activity against tuberculosis and to which there is little preexisting resistance. We evaluated the safety and efficacy of the drug combination for 26 weeks in patients with extensively drug-resistant tuberculosis and patients with multidrug-resistant tuberculosis that was not responsive to treatment or for which a second-line regimen had been discontinued because of side effects. The primary end point was the incidence of an unfavorable outcome, defined as treatment failure (bacteriologic or clinical) or relapse during follow-up, which continued until 6 months after the end of treatment. Patients were classified as having a favorable outcome at 6 months if they had resolution of clinical disease, a negative culture status, and had not already been classified as having had an unfavorable outcome. Other efficacy end points and safety were also evaluated.Results A total of 109 patients were enrolled in the study and were included in the evaluation of efficacy and safety end points. At 6 months after the end of treatment in the intention-to-treat analysis, 11 patients (10%) had an unfavorable outcome and 98 patients (90%; 95% confidence interval, 83 to 95) had a favorable outcome. The 11 unfavorable outcomes were 7 deaths (6 during treatment and 1 from an unknown cause during follow-up), 1 withdrawal of consent during treatment, 2 relapses during follow-up, and 1 loss to follow-up. The expected linezolid toxic effects of peripheral neuropathy (occurring in 81% of patients) and myelosuppression (48%), although common, were manageable, often leading to dose reductions or interruptions in treatment with linezolid.Conclusions The combination of bedaquiline, pretomanid, and linezolid led to a favorable outcome at 6 months after the end of therapy in a high percentage of patients with highly drug-resistant forms of tuberculosis; some associated toxic effects were observed. (Funded by the TB Alliance and others; ClinicalTrials.gov number, .)Treatment options for highly drug-resistant tuberculosis are limited. In this study in South Africa, a new agent, pretomanid, was combined with bedaquiline and linezolid for a 26-week course to treat extensively drug-resistant and complicated multidrug-resistant pulmonary TB. Although there were toxic effects, 90% of patients had favorable outcomes.