贝达喹啉耐药及耐药诊断的研究进展

doi:10.19982/j.issn.1000-6621.20240391

摘要/Abstract

摘要：

贝达喹啉是一种二芳基喹啉化合物,是用于治疗利福平耐药结核病和耐多药结核病的新型抗结核药物。自从批准使用以来,贝达喹啉已显著提高了耐药结核病的治疗效果。然而,随着该药物的广泛使用,贝达喹啉耐药发生及耐药监测成为了一个备受关注的临床问题。笔者分析了贝达喹啉耐药分子机制、耐药表型及基因型的诊断方法,以期为贝达喹啉的临床使用及耐药监测管理提供参考。

关键词: 结核, 抗药性, 诊断

Abstract:

Bedaquiline, a diarylquinoline compound, is a novel anti-tuberculosis drug used for treatment of rifampicin-resistant and multi-drug resistant tuberculosis. Since its approval, bedaquiline has significantly improved anti-tuberculosis treatment outcomes. However, with its widespread usage, the emergence of bedaquiline resistance and its monitoring have become critical clinical concerns. This paper reviews molecular mechanisms of bedaquiline resistance, methods for identifying different resistance phenotypes and genotypes, aiming to provide insights for the clinical usage of bedaquiline and the monitoring and management of resistance.

Key words: Tuberculosis, Drug resistance, Diagnosis

中图分类号:

杨子仪, 陈素婷. 贝达喹啉耐药及耐药诊断的研究进展[J]. 中国防痨杂志, 2025, 47(3): 374-379. doi: 10.19982/j.issn.1000-6621.20240391

Yang Ziyi, Chen Suting. Research progress on bedaquiline resistance and drug resistance diagnosis[J]. Chinese Journal of Antituberculosis, 2025, 47(3): 374-379. doi: 10.19982/j.issn.1000-6621.20240391

参考文献 49

[1]	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.
[2]	Lin Y, Harries AD, Kumar AM, et al. Management of diabetes-tuberculosis: a guide to the essential practice. France: International Union Against Tuberculosis and Lung Disease, 2019.
[3]	Nguyen TVA, Anthony RM, Bañuls AL, et al. Bedaquiline Resistance: Its Emergence, Mechanism, and Prevention. Clin Infect Dis, 2018, 66(10):1625-1630. doi:10.1093/cid/cix992. pmid: 29126225
[4]	Zuur MA, Bolhuis MS, Anthony R, et al. Current status and opportunities for therapeutic drug monitoring in the treatment of tuberculosis. Expert Opin Drug Metab Toxicol, 2016, 12(5):509-521. doi:10.1517/17425255.2016.1162785.
[5]	World Health Organization. Global tuberculosis report 2023. World Health Organization, 2023.
[6]	World Health Organization. WHO consolidated guidelines on tuberculosis. Module 4, Treatment: drug-resistant tuberculosis treatment. Geneva: World Health Organization, 2020.
[7]	Chahine EB, Karaoui LR, Mansour H. Bedaquiline: A Novel Diarylquinoline for Multidrug-Resistant Tuberculosis. Ann Pharmacother, 2014, 48(1):107-115. doi:10.1177/1060028013504087. pmid: 24259600
[8]	Worley MV, Estrada SJ. Bedaquiline: A Novel Antitubercular Agent for the Treatment of Multidrug-Resistant Tuberculosis. Pharmacotherapy, 2014, 34(11):1187-11197. doi:10.1002/phar.1482.
[9]	Shaw ES, Stoker NG, Potter JL, et al. Bedaquiline: what might the future hold?. Lancet Microbe, 2024, 5(12):100909. doi:10.1016/S2666-5247(24)00149-6.
[10]	张玉霞, 熊瑜, 常婷婷, 等. 含贝达喹啉方案治疗耐药肺结核的不良反应分析. 中国防痨杂志, 2022, 44(3): 239-245. doi:10.19982/j.issn.1000-6621.20210702.
[11]	Veziris N, Bernard C, Guglielmetti L, et al. Rapid emergence of Mycobacterium tuberculosis bedaquiline resistance: lessons to avoid repeating past errors. Eur Respir J, 2017, 49(3):1601719. doi:10.1183/13993003.01719-2016.
[12]	Ismail NA, Omar SV, Joseph L, et al. Defining Bedaquiline Susceptibility, Resistance, Cross-Resistance and Associated Genetic Determinants: A Retrospective Cohort Study. EBioMedicine, 2018, 28: 136-142. doi:10.1016/j.ebiom.2018.01.005. pmid: 29337135
[13]	Olayanju O, Limberis J, Esmail A, et al. Long-term bedaquiline-related treatment outcomes in patients with extensively drug-resistant tuberculosis from South Africa. Eur Respir J, 2018, 51(5):1800544. doi:10.1183/13993003.00544-2018.
[14]	Pai H, Ndjeka N, Mbuagbaw L, et al. Bedaquiline safety, efficacy, utilization and emergence of resistance following treatment of multidrug-resistant tuberculosis patients in South Africa: a retrospective cohort analysis. BMC Infect Dis, 2022, 22(1):870. doi:10.1186/s12879-022-07861-x. pmid: 36414938
[15]	Barilar I, Fernando T, Utpatel C, et al. Emergence of bedaqui-line-resistant tuberculosis and of multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis strains with rpoB Ile491Phe mutation not detected by Xpert MTB/RIF in Mozambique: a retrospective observational study. Lancet Infect Dis, 2024, 24(3):297-307. doi:10.1016/S1473-3099(23)00498-X.
[16]	Derendinger B, Dippenaar A, De Vos M, et al. Bedaquiline resistance in patients with drug-resistant tuberculosis in Cape Town, South Africa: a retrospective longitudinal cohort study. Lancet Microbe, 2023, 4(12):e972-e982. doi:10.1016/S2666-5247(23)00172-6. pmid: 37931638
[17]	Chesov E, Chesov D, Maurer FP, et al. Emergence of beda-quiline resistance in a high tuberculosis burden country. Eur Respir J, 2022, 59(3):2100621. doi:10.1183/13993003.00621-2021.
[18]	Liu Y, Gao M, Du J, et al. Reduced Susceptibility of Mycobacterium tuberculosis to Bedaquiline During Antituberculosis Treatment and Its Correlation With Clinical Outcomes in China. Clin Infect Dis, 2021, 73(9):e3391-e3397. doi:10.1093/cid/ciaa1002.
[19]	张书, 雷卉, 王为娜, 等. 2020—2021年凉山州4个彝族聚居县297株结核分枝杆菌耐药及菌株谱系分析. 预防医学情报杂志, 2024, 12: 1-9. doi:10.19971/j.cnki.1006-4028.230601.
[20]	田娜, 董巧琰, 初乃惠. 抗结核药物贝达喹啉与氯法齐明交叉耐药机制及其与治疗结局相关性. 中国临床医生杂志, 2024, 52(3): 283-285. doi:10.3969/j.issn.2095-8552.2024.03.008.
[21]	Cook GM, Hards K, Vilchèze C, et al. Energetics of Respiration and Oxidative Phosphorylation in Mycobacteria. Microbiol Spectr, 2014, 2(3):10.1128/microbiolspec.MGM2-0015-2013. doi:10.1128/microbiolspec.MGM2-0015-2013.
[22]	Jones D. Tuberculosis success. Nat Rev Drug Discov, 2013, 12(3):175-176. doi:10.1038/nrd3957. pmid: 23449293
[23]	Koul A, Dendouga N, Vergauwen K, et al. Diarylquinolines target subunitc of mycobacterial ATP synthase. Nat Chem Biol, 2007, 3(6):323-324. doi:10.1038/nchembio884.
[24]	Andries K, Verhasselt P, Guillemont J, et al. A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis. Science, 2005, 307(5707): 223-227. doi:10.1126/science.1106753. pmid: 15591164
[25]	Petrella S, Cambau E, Chauffour A, et al. Genetic Basis for Natural and Acquired Resistance to the Diarylquinoline R207910 in Mycobacteria. Antimicrob Agents Chemother, 2006, 50(8):2853-2856. doi:10.1128/AAC.00244-06. pmid: 16870785
[26]	向煜, 杨淑柳, 武娅宁, 等. 基于新疆维吾尔自治区南疆地区169株结核分枝杆菌探讨基因缺失对贝达喹啉的耐药机制. 疾病监测, 2024, 39(5): 639-646. doi:10.3784/jbjc.202311200629.
[27]	Milano A, Pasca MR, Provvedi R, et al. Azole resistance in Mycobacterium tuberculosis is mediated by the MmpS5-MmpL 5 efflux system. Tuberculosis, 2009, 89(1): 84-90. doi:10.1016/j.tube.2008.08.003. pmid: 18851927
[28]	Kadura S, King N, Nakhoul M, et al. Systematic review of mutations associated with resistance to the new and repurposed Mycobacterium tuberculosis drugs bedaquiline, clofazimine, linezolid, delamanid and pretomanid. J Antimicrob Chemother, 2020, 75(8):2031-2043. doi:10.1093/jac/dkaa136. pmid: 32361756
[29]	Almeida D, Ioerger T, Tyagi S, et al. Mutations in pepQ Confer Low-Level Resistance to Bedaquiline and Clofazimine in Mycobacterium tuberculosis. Antimicrob Agents Chemother, 2016, 60(8):4590-4599. doi:10.1128/AAC.00753-16. pmid: 27185800
[30]	Zhang S, Chen J, Cui P, et al. Identification of novel mutations associated with clofazimine resistance in Mycobacterium tuberculosis: Table 1. J Antimicrob Chemother, 2015, 70(9):2507-2510. doi:10.1093/jac/dkv150. pmid: 26045528
[31]	Perumal R, Bionghi N, Nimmo C, et al. Baseline and treatment-emergent bedaquiline resistance in drug-resistant tuberculosis: a systematic review and meta-analysis. Eur Respir J, 2023, 62(6):2300639. doi:10.1183/13993003.00639-2023.
[32]	Köser CU, Miotto P, Ismail N, et al. A composite reference standard is needed for bedaquiline antimicrobial susceptibility testing for Mycobacterium tuberculosis complex. Eur Respir J, 2024, 64(1):2400391. doi:10.1183/13993003.00391-2024.
[33]	宋媛媛, 夏辉, 赵雁林. 结核分枝杆菌表型药物敏感性试验临界浓度设定发展历程. 中国防痨杂志, 2023, 45(7): 631-638. doi:10.19982/j.issn.1000-6621.20230153.
[34]	World Health Organization. WHO consolidated guidelines on tuberculosis. Module 3. Diagnosis: rapid diagnostics for tuberculosis detection. Third edition. Geneva: World Health Organization, 2024.
[35]	Witney AA, Cosgrove CA, Arnold A, et al. Clinical use of whole genome sequencing for Mycobacterium tuberculosis. BMC Medicine, 2016, 14(1): 46. doi:10.1186/s12916-016-0598-2.
[36]	Nimmo C, Bionghi N, Cummings MJ, et al. Opportunities and limitations of genomics for diagnosing bedaquiline-resistant tuberculosis: a systematic review and individual isolate meta-analysis. Lancet Microbe, 2024, 5(2): e164-e172. doi:10.1016/S2666-5247(23)00317-8. pmid: 38215766
[37]	Updated Guidelines for the Use of Nucleic Acid Amplification Tests in the Diagnosis of Tuberculosis. JAMA, 2009, 301(10): 1014. doi:10.1001/jama.2009.148.
[38]	Anagoni S, Mudhigeti N, Alladi M, et al. Effect of delay in processing and storage temperature on diagnosis of SARS-CoV-2 by RTPCR testing. Indian J Med Microbiol, 2022, 40(3):427-432. doi:10.1016/j.ijmmb.2022.03.005. pmid: 35393127
[39]	Jin W, Wang J, Yang X. Analysis of three cases with false positive PCR results of non tuberculosis mycobacterium. Respir Med Case Rep, 2023, 47:101973. doi:10.1016/j.rmcr.2023.101973.
[40]	Lin CR, Wang HY, Lin TW, et al. Development of a two-step nucleic acid amplification test for accurate diagnosis of the Mycobacterium tuberculosis complex. Sci Rep, 2021, 11(1):5750. doi:10.1038/s41598-021-85160-2.
[41]	Long S. In pursuit of sensitivity: Lessons learned from viral nucleic acid detection and quantification on the Raindance ddPCR platform. Methods, 2022, 201: 82-95. doi:10.1016/j.ymeth.2021.04.008.
[42]	MacLean E, Kohli M, Weber SF, et al. Advances in Molecular Diagnosis of Tuberculosis. J Clin Microbiol, 2020, 58(10):e01582-19. doi:10.1128/JCM.01582-19.
[43]	Pradhan S, Gautam K, Pant V. Variation in Laboratory Reports: Causes other than Laboratory Error. JNMA J Nepal Med Assoc, 2022, 60(246):222-224. doi:10.31729/jnma.6022. pmid: 35210649
[44]	Reinicke M, Braun SD, Diezel C, et al. From Shadows to Spotlight: Enhancing Bacterial DNA Detection in Blood Samples through Cutting-Edge Molecular Pre-Amplification. Antibiotics, 2024, 13(2): 161. doi:10.3390/antibiotics13020161.
[45]	World Health Organization. Catalogue of Mutations in Mycobacterium Tuberculosis Complex and Their Association with Drug Resistance Second Edition. Geneva: World Health Organization, 2023.
[46]	Del Giovane S, Bagheri N, Di Pede AC, et al. Challenges and perspectives of CRISPR-based technology for diagnostic applications. TrAC Trends in Analytical Chemistry, 2024, 172: 117594. doi:10.1016/j.trac.2024.117594.
[47]	Yuan X, Sui G, Zhang D, et al. Recent developments and trends of automatic nucleic acid detection systems. J Biosaf Biosecur, 2022, 4(1):54-58. doi:10.1016/j.jobb.2022.02.001.
[48]	Colman RE, Mace A, Seifert M, et al. Whole-genome and targeted sequencing of drug-resistant Mycobacterium tuberculosis on the iSeq100 and MiSeq: A performance, ease-of-use, and cost evaluation. PLoS Med, 2019, 16(4):e1002794. doi:10.1371/journal.pmed.1002794.
[49]	Murphy SG, Smith C, Lapierre P, et al. Direct detection of drug-resistant Mycobacterium tuberculosis using targeted next generation sequencing. Front Public Health, 2023, 11:1206056. doi:10.3389/fpubh.2023.1206056.