Expert consensus on all-oral short-course therapy for drug-resistant tuberculosis

doi:10.19982/j.issn.1000-6621.20250087

Abstract

Abstract:

The World Health Organization (WHO) Treatment Guidelines for Drug-Resistant Tuberculosis (2016 Update) recommend an entirely oral treatment regimen for drug-resistant tuberculosis (DR-TB). Previous studies have shown that compared to injection-containing or longer-course treatment regimens, short-course oral treatment regimens can achieve better medication safety, tolerability, and treatment adherence, while maintaining treatment success rates. In the WHO Consolidated Guidelines on Tuberculosis, Module 4: Treatment of Drug-Resistant Tuberculosis (2022 Update), a 6-month short-course treatment regimen for DR-TB (6BPaLM; where B: bedaquiline, Pa: pretomanid, L: linezolid, M: moxifloxacin) was proposed, marking the dawn of an era of entirely oral short-course treatment for DR-TB. In June 2024, the WHO issued a rapid communication on new treatment regimens for DR-TB, which are more aligned with the actual situation in China compared to previously recommended short-course oral regimens. To develop a fully oral DR-TB treatment regimen tailored to China’s context, the Chinese Antituberculosis Association took the lead in collaborating with Beijing Chest Hospital/Beijing Tuberculosis and Thoracic Tumor Research Institute affiliated to Capital Medical University and the Editorial Board of the Chinese Journal of Antituberculosis to organize experts in the field to draft the Expert consensus on all-oral short-course therapy for drug-resistant tuberculosis. Based on recent domestic and international research progress on entirely oral regimens for DR-TB, this consensus recommends a short-course, entirely oral treatment regimen suitable for China’s national conditions and identifies the appropriate patient populations. It also provides consensus opinions on precautions for using entirely oral treatment regimens and the management of adverse reactions. It is hoped that the publication of this consensus will provide technical guidance for the comprehensive application of short-course treatment regimens for DR-TB in China, thereby further improving the treatment success rates for DR-TB patients in the country.

Key words: Tuberculosis, Drug resistance, Antitubercular agents, Therapeutic uses, Consensus development conferences as topic

CLC Number:

Chinese Antituberculosis Association, Editorial Board of Chinese Journal of Antituberculosis, Beijing Chest Hospital Capital Medlical University/Beijing Tuberculosis and Thoracic Tumor Research Institute. Expert consensus on all-oral short-course therapy for drug-resistant tuberculosis[J]. Chinese Journal of Antituberculosis, 2025, 47(7): 830-839. doi: 10.19982/j.issn.1000-6621.20250087

Figures/Tables 3

References 41

[1]	World Health Organization. Rapid communication: novel regimens for drug-resistant tuberculosis treatment. Geneva: World Health Organization, 2024.
[2]	胡鑫洋, 高静韬. 世界卫生组织《2024年全球结核病报告》解读. 结核与肺部疾病杂志, 2024, 5(6):500-504. doi:10.19983/j.issn.2096-8493.2024164.
[3]	World Health Organization. Key Updates to the Treatment of Drug-Resistant Tuberculosis: Rapid Communication. Geneva: World Health Organization, 2024.
[4]	首都医科大学附属北京胸科医院/北京市结核病胸部肿瘤研究所, 中国防痨协会, 《中国防痨杂志》编辑委员会. 耐药肺结核全口服化学治疗方案中国专家共识(2021年版). 中国防痨杂志, 2021, 43(9): 859-866. doi:10.3969/j.issn.1000-6621.2021.09.002.
[5]	World Health Organization. Rapid communication: key changes to treatment of multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB). Geneva: World Health Organization, 2024.
[6]	World Health Organization. Global tuberculosis report 2024. Geneva: World Health Organization, 2024.
[7]	Vanino E, Granozzi B, Akkerman OW, et al. Update of drug-resistant tuberculosis treatment guidelines: A turning point. Int J Infect Dis, 2023, 130 Suppl 1: S12-S15. doi:10.1016/j.ijid.2023.03.013.
[8]	姚琳, 顾斌斌, 张建平. 抗结核药物所致药物不良反应的临床表现及其处置的研究进展. 抗感染药学, 2023, 20(12): 1229-1234. doi:10.13493/j.issn.1672-7878.2023.12-001.
[9]	吴波. 结核病患者治疗管理新技术的应用与进展. 中国防痨杂志, 2019, 41(10): 1136-1140. doi:10.3969/j.issn.1000-6621.2019.10.014.
[10]	Fregonese F, Ahuja SD, Akkerman OW, et al. Comparison of different treatments for isoniazid-resistant tuberculosis: an individual patient data meta-analysis. Lancet Respir Med, 2018, 6(4): 265-275. doi:10.1016/S2213-2600(18)30078-X. pmid: 29595509
[11]	Conradie F, Diacon AH, Ngubane N, et al. Treatment of highly drug-resistant pulmonary tuberculosis. N Engl J Med, 2020, 382(10): 893-902. doi:10.1056/NEJMoa1901814.
[12]	Conradie F, Bagdasaryan TR, Borisov S, et al. Bedaquiline-pretomanid-linezolid regimens for drug-resistant tuberculosis. N Engl J Med, 2022, 387(9): 810-823. doi:10.1056/NEJMoa2119430.
[13]	Das M, Dalal A, Laxmeshwar C, et al. One step forward: successful end-of-treatment outcomes of patients with drug-resistant tuberculosis who received concomitant bedaquiline and delamanid in Mumbai, India. Clin Infect Dis, 2021, 73(9): e3496-e3504. doi:10.1093/cid/ciaa1577.
[14]	World Health Organization. WHO consolidated guidelines on tuberculosis: module 4: treatment-drug-resistant tuberculosis treatment. Geneva: World Health Organization, 2022.
[15]	Guglielmetti L, Khan U, Velásquez GE, et al. Oral regimens for rifampin-resistant, fluoroquinolone-susceptible tuberculosis. N Engl J Med, 2025, 392(5): 468-482. doi:10.1056/NEJMoa2400327.
[16]	Padmapriyadarsini C, Vohra V, Bhatnagar A, et al. Bedaquiline, delamanid, linezolid and clofazimine for treatment of pre-extensively drug-resistant tuberculosis. Clin Infect Dis, 2022, 76(3): e938-e946. doi:10.1093/cid/ciac528.
[17]	Bouton TC, de Vos M, Ragan EJ, et al. Switching to bedaquiline for treatment of rifampicin-resistant tuberculosis in South Africa: A retrospective cohort analysis. PLoS One, 2019, 14(10): e0223308. doi:10.1371/journal.pone.0223308.
[18]	Tack I, Dumicho A, Ohler L, et al. Safety and effectiveness of an all-oral, bedaquiline-based, shorter treatment regimen for rifampicin-resistant tuberculosis in high human immunodeficiency virus (HIV) burden rural South Africa: a retrospective cohort analysis. Clin Infect Dis, 2021, 73(9): e3563-e3571. doi:10.1093/cid/ciaa1894.
[19]	Van Deun A, Maug AK, Salim MA, et al. Short, highly effective, and inexpensive standardized treatment of multidrug-resistant tuberculosis. Am J Respir Crit Care Med, 2010, 182(5): 684-692. doi:10.1164/rccm.201001-0077OC.
[20]	Guglielmetti L, Ardizzoni E, Atger M, et al. Evaluating newly approved drugs for multidrug-resistant tuberculosis (endTB): study protocol for an adaptive, multi-country randomized controlled trial. Trials, 2021, 22(1):651. doi:10.1186/s13063-021-05491-3. pmid: 34563240
[21]	Wang J, Nie W, Ma L, et al. Clinical utility of contezolid-containing regimens in 25 cases of linezolid-intolerable tuberculosis patients. Infect Drug Resist, 2023, 16: 6237-6245. doi:10.2147/IDR.S425743. pmid: 37745897
[22]	Jiang G, Liu R, Xue Y, et al. Contezolid Harbored Equivalent Efficacy to Linezolid in Tuberculosis Treatment in a Prospective and Randomized Early Bactericidal Activity Study. Infect Drug Resist, 2025, 18: 261-268. doi:10.2147/IDR.S499816. pmid: 39830036
[23]	Tingting C, Yuxia Z, Yanming S, et al. P-1070. Safety and Efficacy of Replacement with Contezolid-Containing Regimens in Patients with Multidrug-Resistant/Rifampicin-Resistant Tuberculosis Who are Intolerant to Linezolid-Containing Regimens: A Retrospective Case Analysis. Open Forum Infect Dis, 2025 (Suppl_1): Supplement_1. doi:10.1093/ofid/ofae631.1258.
[24]	中国防痨协会, 《中国防痨杂志》编辑委员会, 首都医科大学附属北京胸科医院/北京市结核病胸部肿瘤研究所, 等. 康替唑胺治疗结核病专家共识. 中国防痨杂志, 2025, 47(2): 123-129. doi:10.19982/j.issn.1000-6621.20240480.
[25]	薛玉, 张静, 聂文娟. 含贝达喹啉方案治疗老年耐药肺结核患者的有效性及安全性. 中国防痨杂志, 2022, 44(6): 582-586. doi:10.19982/j.issn.1000-6621.20220019.
[26]	Li Y, Chen L, Tang X, et al. Safety analysis of fluoroquinolone drugs in elderly patients over 65 based on FAERS. Expert Opin Drug Saf, 2024, 23(3): 1-13. doi:10.1080/14740338.2024.2392862.
[27]	Padmapriyadarsini C, Oswal VS, Jain CD, et al. Effectiveness and safety of varying doses of linezolid with bedaquiline and pretomanid in treatment of drug-resistant pulmonary tuberculosis: Open-label, randomized clinical trial. Clin Infect Dis, 2024, 79(6): 1375-1385. doi:10.1093/cid/ciae388. pmid: 39194339
[28]	Wang X, Mallikaarjun S, Gibiansky E. Population pharmacokinetic analysis of delamanid in patients with pulmonary multidrug-resistant tuberculosis. Antimicrob Agents Chemother, 2020, 65(1): e01202-20. doi:10.1128/AAC.01202-20.
[29]	Liu Y, Tan Y, Wei G, et al. Safety and pharmacokinetic profile of pretomanid in healthy Chinese adults: Results of a phase I single dose escalation study. Pulm Pharmacol Ther, 2022, 73-74: 102132. doi:10.1016/j.pupt.2022.102132.
[30]	Ryan NJ, Lo JH. Delamanid: first global approval. Drugs, 2014, 74(9): 1041-1045. doi:10.1007/s40265-014-0241-5. pmid: 24923253
[31]	Cao L, Greenblatt DJ, Kwara A. Inhibitory effects of selected antituberculosis drugs on common human hepatic cytochrome P450 and UDP-glucuronosyltransferase enzymes. Drug Metab Dispos, 2017, 45(9): 1035-1043. doi:10.1124/dmd.117.076034. pmid: 28663285
[32]	Pandie M, Wiesner L, McIlleron H, et al. Drug-drug interactions between bedaquiline and the antiretrovirals lopinavir/ritonavir and nevirapine in HIV-infected patients with drug-resistant TB. J Antimicrob Chemother, 2016, 71(4): 1037-1040. doi:10.1093/jac/dkv447. pmid: 26747099
[33]	Shimokawa Y, Sasahara K, Yoda N, et al. Delamanid does not inhibit or induce cytochrome P 450 enzymes in vitro. Biol Pharm Bull, 2014, 37(11): 1727-1735. doi:10.1248/bpb.b14-00311.
[34]	Mallikaarjun S, Wells C, Petersen C, et al. Delamanid coadministered with antiretroviral drugs or antituberculosis drugs shows no clinically relevant drug-drug interactions in healthy subjects. Antimicrob Agents Chemother, 2016, 60(10): 5976-5985. doi:10.1128/AAC.00509-16. pmid: 27458223
[35]	中国防痨协会, 《中国防痨杂志》编辑委员会, 首都医科大学附属北京胸科医院. 抗结核药物所致QTc间期延长临床监测和管理专家共识. 中国防痨杂志, 2024, 46(1): 8-17. doi:10.19982/j.issn.1000-6621.20230271.
[36]	中华医学会结核病学分会. 抗结核药物性肝损伤诊治指南(2019年版). 中华结核和呼吸杂志, 2019, 42(5): 343-356. doi:10.3760/cma.j.issn.1001-0939.2019.05.007.
[37]	《中国防痨杂志》编委会, 中国医疗保健国际交流促进会结核病防治分会全国耐药结核病协作组. 耐药结核病化疗过程中药品不良反应处理的专家共识. 中国防痨杂志, 2019, 41(6): 591-603. doi:10.3969/j.issn.1000-6621.2019.06.003.
[38]	文新民, 杨坤云, 易恒仲, 等. 138例耐多药肺结核患者使用环丝氨酸后的不良反应分析. 结核病与肺部健康杂志, 2018, 7(3): 194-197. doi:10.3969/j.issn.2095-3755.2018.03.010.
[39]	Martiniano SL, Wagner BD, Levin A, et al. Safety and effectiveness of clofazimine for primary and refractory nontuberculous mycobacterial infection. Chest, 2017, 152(4): 800-809. doi:10.1016/j.chest.2017.04.175. pmid: 28483608
[40]	王怀冲, 徐颖颖, 张相彩, 等. 联合氯法齐明方案治疗耐多药肺结核的临床研究. 中国临床药理学与治疗学, 2012, 17(11): 1268-1271.
[41]	肖桂荣, 吴逢波, 龙霞, 等. 抗结核药物不良反应管理的国内外指南综述分析. 药物流行病学杂志, 2014, 23(7): 444-449.

推荐强度	具体描述
强推荐(1级)	明确显示干预措施利大于弊
弱推荐(2级)	利弊不确定或无论质量高低的证据均显示利弊相当

证据级别	定义
高质量(A)	非常确信估计的效应值接近真实的效应值:进一步研究也不可能改变该估计效应值的可信度
中等质量(B)	对估计的效应值确信程度中等:估计值有可能接近真实值,但仍存在二者不相同的可能性,进一步研究有可能改变该估计效应值的可信度
低质量(C)	对估计的效应值的确信度有限:估计值与真实值可能大不相同。进一步研究极有可能改变该估计效应值的可信度
极低质量(D)	对估计的效应值几乎没有信心:估计值与真实值很可能完全不同。对效应值任何估计都很不确定

治疗方案	BDLLfx(C)	BLMZ	BLLfxCZ	BDLLfxZ
方案组成	贝达喹啉、德拉马尼、利奈唑胺、左氧氟沙星(氯法齐明)	贝达喹啉、利奈唑胺、莫西沙星、吡嗪酰胺	贝达喹啉、利奈唑胺、左氧氟沙星、氯法齐明、吡嗪酰胺	贝达喹啉、德拉马尼、利奈唑胺、左氧氟沙星、吡嗪酰胺
疗程	6个月	9个月
氟喹诺酮类耐药情况	氟喹诺酮类药物耐药或未知	氟喹诺酮类药物敏感
适用人群及条件	1.确诊为利福平耐药结核病的儿童和成年患者,无论其是否对异烟肼和(或)氟喹诺酮类药物耐药; 2.既往未暴露于方案中的药物(使用少于1个月)或既往使用时间超过1个月,但排除了所使用药物耐药可能,仍可以使用本方案	1.所有年龄段人群,包括成人、青少年、儿童和孕妇; 2.氟喹诺酮类药物敏感且无二线抗结核药物暴露史的耐多药/利福平耐药结核病患者; 3.既往未暴露于方案中的药物(使用少于1个月),或既往使用时间超过1个月,但排除了所使用药物耐药可能,仍可以使用本方案
备注	对于治疗第4个月后痰培养仍阳性的治疗效果不佳的患者,疗程可延长至9个月	1.推荐顺序为BLMZ>BLLfxCZ>BDLLfxZ 2.无法服用利奈唑胺或贝达喹啉,推荐DMCZ