二线结核药物血药浓度与耐药结核疗效及药物性肝损伤相关研究进展
Research Progress on the Correlation between Serum Concentration of Second-Line Tuberculosis Drugs and Treatment Efficacy of Drug-Resistant Tuberculosis as Well as Drug-Induced Liver Injury
DOI: 10.12677/acm.2025.15113221, PDF,   
作者: 唐 雷*：吉首大学株洲临床学院，湖南 吉首；谭英征, 周 青, 龙云铸#：株洲市中心医院感染内科，湖南 株洲
关键词: 耐药结核病；二线抗结核药物；血药浓度；药物性肝损害；Drug-Resistant Tuberculosis； Second-Line Anti-Tuberculosis Drugs； Blood Drug Concentration； Drug-Induced Liver Injury
摘要: 全球范围内耐药结核病的负担依然沉重，2024年，世界卫生组织(WHO)提出了最新的耐药结核治疗方案。由于耐药结核患者存在个体差异，部分患者在按照WHO推荐剂量给药时，血药浓度无法达到目标治疗浓度，导致药物疗效不佳及各种不良反应发生，尤其是药物性肝损伤(DILI)。本文综述部分耐药结核二线药物，如：A组核心药物(莫西沙星或左氧氟沙星、贝达喹啉、利奈唑胺)血药浓度与疗效及药物性肝损伤之间的关系，并从药代动力学/药效动力学参数进行阐述，旨在为耐药结核患者的临床治疗提供参考。
Abstract: The global burden of drug-resistant tuberculosis remains significant. In 2024, the World Health Organization (WHO) proposed the latest treatment protocol for drug-resistant tuberculosis. Due to the individual differences among patients with drug-resistant tuberculosis, some patients cannot achieve the target therapeutic concentration of the drug in their blood when administered at the recommended dosage by WHO, resulting in poor drug efficacy and various adverse reactions, especially drug-induced liver injury (DILI). This article reviews some second-line drugs for drug-resistant tuberculosis, such as the core drugs of group A (moxifloxacin or levofloxacin, bedaquiline, linezolid), and discusses the relationship between the blood drug concentration and efficacy as well as drug-induced liver injury from the perspectives of pharmacokinetics/pharmacodynamics parameters. The aim is to provide a reference for the clinical treatment of patients with drug-resistant tuberculosis.
文章引用：唐雷, 谭英征, 周青, 龙云铸. 二线结核药物血药浓度与耐药结核疗效及药物性肝损伤相关研究进展[J]. 临床医学进展, 2025, 15(11): 1282-1290. https://doi.org/10.12677/acm.2025.15113221

参考文献

[1] Karanikas, M., Porpodis, K., Zarogoulidis, P., Mitrakas, A., Touzopoulos, P., Lyratzopoulos, N., et al. (2012) Tuberculosis in the Peritoneum: Not Too Rare after All. Case Reports in Gastroenterology, 6, 369-374. [Google Scholar] [CrossRef] [PubMed]
[2] WHO (2024) Key Updates to the Treatment of Drug-Resistant Tuberculosis: Rapid Communication, June.
[3] WHO (2024) Global Tuberculosis Report 2024. World Health Organization.
[4] WHO (2021) Meeting Report of the WHO Expert Consultation on the Definition of Extensively Drug-Resistant Tuberculosis, 27-29 October 2020. World Health Organization.
[5] WHO (2022) WHO Consolidated Guidelines on Tuberculosis. Module 4: Treatment-Drug-Resistant Tuberculosis Treatment, 2022 Update. World Health Organization.
[6] Lange, C., Aarnoutse, R., Chesov, D., van Crevel, R., Gillespie, S.H., Grobbel, H., et al. (2020) Perspective for Precision Medicine for Tuberculosis. Frontiers in Immunology, 11, Article ID: 566608. [Google Scholar] [CrossRef] [PubMed]
[7] 陆宇, 朱慧. 抗结核药治疗药物监测临床应用专家共识[J]. 中国防痨杂志, 2021, 43(9): 867-873.
[8] Fitzsimons, D.W. (2013) World Health Organization. Acta Médica Portuguesa, 26, 186-187.
[9] Andries, K., Verhasselt, P., Guillemont, J., Göhlmann, H.W.H., Neefs, J., Winkler, H., et al. (2005) A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis. Science, 307, 223-227. [Google Scholar] [CrossRef] [PubMed]
[10] 谢莉, 朱慧, 高静韬, 等. 贝达喹啉血药浓度在耐药肺结核治疗中的变化及其与QTc间期延长的相关性[J]. 中国防痨杂志, 2022, 44(3): 219-226.
[11] 中华医学会结核病学分会. 抗结核新药贝达喹啉临床应用专家共识(2020年更新版) [J]. 中华结核和呼吸杂志, 2021, 44(2): 81-87.
[12] Mallikaarjun, S., Chapagain, M.L., Sasaki, T., Hariguchi, N., Deshpande, D., Srivastava, S., et al. (2020) Cumulative Fraction of Response for Once-and Twice-Daily Delamanid in Patients with Pulmonary Multidrug-Resistant Tuberculosis. Antimicrobial Agents and Chemotherapy, 65, e01207-20. [Google Scholar] [CrossRef] [PubMed]
[13] Koul, A., Vranckx, L., Dhar, N., Göhlmann, H.W.H., Özdemir, E., Neefs, J., et al. (2014) Delayed Bactericidal Response of Mycobacterium Tuberculosis to Bedaquiline Involves Remodelling of Bacterial Metabolism. Nature Communications, 5, Article No. 3369. [Google Scholar] [CrossRef] [PubMed]
[14] 王乐乐, 岳午阳, 李同心, 等. 耐多药和利福平耐药肺结核患者体内贝达喹啉血药浓度及其与近期疗效和安全性的相关性[J]. 中华结核和呼吸杂志, 2023, 46(3): 228-236.
[15] 朱慧, 刘忠泉, 谢莉, 等. 应用高效液相色谱-质谱/质谱联用技术检测贝达喹啉血药浓度[J]. 结核病与胸部肿瘤, 2019(1): 1-6.
[16] Sturkenboom, M.G.G., Märtson, A., Svensson, E.M., Sloan, D.J., Dooley, K.E., van den Elsen, S.H.J., et al. (2021) Population Pharmacokinetics and Bayesian Dose Adjustment to Advance TDM of Anti-TB Drugs. Clinical Pharmacokinetics, 60, 685-710. [Google Scholar] [CrossRef] [PubMed]
[17] Hashemian, S.M., Farhadi, T. and Ganjparvar, M. (2018) Linezolid: A Review of Its Properties, Function, and Use in Critical Care. Drug Design, Development and Therapy, 12, 1759-1767. [Google Scholar] [CrossRef] [PubMed]
[18] 中华医学会结核病学分会. 利奈唑胺抗结核治疗专家共识(2022年版) [J]. 中华结核和呼吸杂志, 2022, 45(10): 988-995.
[19] Srivastava, S., Magombedze, G., Koeuth, T., Sherman, C., Pasipanodya, J.G., Raj, P., et al. (2017) Linezolid Dose That Maximizes Sterilizing Effect While Minimizing Toxicity and Resistance Emergence for Tuberculosis. Antimicrobial Agents and Chemotherapy, 61, e00751-17. [Google Scholar] [CrossRef] [PubMed]
[20] de Miranda Silva, C., Hajihosseini, A., Myrick, J., Nole, J., Louie, A., Schmidt, S., et al. (2018) Effect of Linezolid Plus Bedaquiline against Mycobacterium Tuberculosis in Log Phase, Acid Phase, and Nonreplicating-Persister Phase in an in Vitro Assay. Antimicrobial Agents and Chemotherapy, 62. [Google Scholar] [CrossRef] [PubMed]
[21] WHO Guidelines Approved by the Guidelines Review Committee (2019) WHO Consolidated Guidelines on Drug-Resistant Tuberculosis Treatment. World Health Organization.
[22] WHO Guidelines Approved by the Guidelines Review Committee (2022) WHO Consolidated Guidelines on Tuberculosis: Module 4: Treatment-Drug-Susceptible Tuberculosis Treatment. World Health Organization.
[23] Bolhuis, M.S., Akkerman, O.W., Sturkenboom, M.G.G., Ghimire, S., Srivastava, S., Gumbo, T., et al. (2018) Linezolid-based Regimens for Multidrug-Resistant Tuberculosis (TB): A Systematic Review to Establish or Revise the Current Recommended Dose for TB Treatment. Clinical Infectious Diseases, 67, S327-S335. [Google Scholar] [CrossRef] [PubMed]
[24] Kim, H.Y., Srivastava, S., AK, H.K., Marais, B.J. and Alffenaar, J. (2020) Optimal Dose or Optimal Exposure? Consideration for Linezolid in Tuberculosis Treatment. Antimicrobial Agents and Chemotherapy, 64. [Google Scholar] [CrossRef] [PubMed]
[25] Diacon, A.H., De Jager, V.R., Dawson, R., Narunsky, K., Vanker, N., Burger, D.A., et al. (2020) Fourteen-Day Bactericidal Activity, Safety, and Pharmacokinetics of Linezolid in Adults with Drug-Sensitive Pulmonary Tuberculosis. Antimicrobial Agents and Chemotherapy, 64, e02012-19. [Google Scholar] [CrossRef] [PubMed]
[26] Nahid, P., Mase, S.R., Migliori, G.B., Sotgiu, G., Bothamley, G.H., Brozek, J.L., et al. (2019) Treatment of Drug-Resistant Tuberculosis. an Official ATS/CDC/ERS/IDSA Clinical Practice Guideline. American Journal of Respiratory and Critical Care Medicine, 200, e93-e142. [Google Scholar] [CrossRef] [PubMed]
[27] Wasserman, S., Denti, P., Brust, J.C.M., Abdelwahab, M., Hlungulu, S., Wiesner, L., et al. (2019) Linezolid Pharmacokinetics in South African Patients with Drug-Resistant Tuberculosis and a High Prevalence of HIV Coinfection. Antimicrobial Agents and Chemotherapy, 63, e02164-18. [Google Scholar] [CrossRef] [PubMed]
[28] Wasserman, S., Meintjes, G. and Maartens, G. (2016) Linezolid in the Treatment of Drug-Resistant Tuberculosis: The Challenge of Its Narrow Therapeutic Index. Expert Review of Anti-Infective Therapy, 14, 901-915. [Google Scholar] [CrossRef] [PubMed]
[29] Rajendran, A. and Palaniyandi, K. (2022) Mutations Associated with Pyrazinamide Resistance in Mycobacterium Tuberculosis: A Review and Update. Current Microbiology, 79, Article No. 348. [Google Scholar] [CrossRef] [PubMed]
[30] Deshpande, D., Pasipanodya, J.G., Mpagama, S.G., Bendet, P., Srivastava, S., Koeuth, T., et al. (2018) Levofloxacin Pharmacokinetics/Pharmacodynamics, Dosing, Susceptibility Breakpoints, and Artificial Intelligence in the Treatment of Multidrug-Resistant Tuberculosis. Clinical Infectious Diseases, 67, S293-S302. [Google Scholar] [CrossRef] [PubMed]
[31] Sidamo, T., Rao, P.S., Aklillu, E., Shibeshi, W., Park, Y., Cho, Y., et al. (2022) Population Pharmacokinetics of Levofloxacin and Moxifloxacin, and the Probability of Target Attainment in Ethiopian Patients with Multidrug-Resistant Tuberculosis. Infection and Drug Resistance, 15, 6839-6852. [Google Scholar] [CrossRef] [PubMed]
[32] 滕田璐, 黄海荣, 初乃惠. 高剂量异烟肼治疗结核病的研究进展[J]. 中华结核和呼吸杂志, 2021, 44(4): 383-386.
[33] Aithal, G.P., Watkins, P.B., Andrade, R.J., Larrey, D., Molokhia, M., Takikawa, H., et al. (2011) Case Definition and Phenotype Standardization in Drug-Induced Liver Injury. Clinical Pharmacology & Therapeutics, 89, 806-815. [Google Scholar] [CrossRef] [PubMed]
[34] Naidoo, K., Hassan-Moosa, R., Mlotshwa, P., Yende-Zuma, N., Govender, D., Padayatchi, N., et al. (2020) High Rates of Drug-Induced Liver Injury in People Living with HIV Coinfected with Tuberculosis (TB) Irrespective of Antiretroviral Therapy Timing during Antituberculosis Treatment: Results from the Starting Antiretroviral Therapy at Three Points in TB Trial. Clinical Infectious Diseases, 70, 2675-2682. [Google Scholar] [CrossRef] [PubMed]
[35] Lomtadze, N., Kupreishvili, L., Salakaia, A., Vashakidze, S., Sharvadze, L., Kempker, R.R., et al. (2013) Hepatitis C Virus Co-Infection Increases the Risk of Anti-Tuberculosis Drug-Induced Hepatotoxicity among Patients with Pulmonary Tuberculosis. PLOS ONE, 8, e83892. [Google Scholar] [CrossRef] [PubMed]
[36] Li, M., Wang, Y., Lv, T.T., Liu, J.M., Kong, Y.Y., Jia, J.D., et al. (2023) Mapping the Incidence of Drug‐Induced Liver Injury: A Systematic Review and Meta‐Analysis. Journal of Digestive Diseases, 24, 332-339. [Google Scholar] [CrossRef] [PubMed]
[37] Jiang, F., Yan, H., Liang, L., Du, J., Jin, S., Yang, S., et al. (2021) Incidence and Risk Factors of Anti‐Tuberculosis Drug Induced Liver Injury (DILI): Large Cohort Study Involving 4652 Chinese Adult Tuberculosis Patients. Liver International, 41, 1565-1575. [Google Scholar] [CrossRef] [PubMed]
[38] Cusack, R.P., Chawke, L., O’brien, D.J., et al. (2017) Predictors of Hepatotoxicity among Patients Treated with Ant tuberculous Medication. QJM, 110, 219-225.
[39] Liu, Y., Guo, Y., Xu, H., Feng, H. and Chen, D. (2021) Impact of Non-Alcoholic Simple Fatty Liver Disease on Antituberculosis Drug-Induced Liver Injury. Infection and Drug Resistance, 14, 3667-3671. [Google Scholar] [CrossRef] [PubMed]
[40] Wang, J., Xiong, K., Xu, L., Zhang, C., Zhao, S., Liu, Y., et al. (2021) Dietary Intake of Vegetables and Cooking Oil Was Associated with Drug-Induced Liver Injury during Tuberculosis Treatment: A Preliminary Cohort Study. Frontiers in Nutrition, 8, Article ID: 652311. [Google Scholar] [CrossRef] [PubMed]
[41] Chen, L., Bao, D., Gu, L., Gu, Y., Zhou, L., Gao, Z., et al. (2018) Co-Infection with Hepatitis B Virus among Tuberculosis Patients Is Associated with Poor Outcomes during Anti-Tuberculosis Treatment. BMC Infectious Diseases, 18, Article No. 295. [Google Scholar] [CrossRef] [PubMed]
[42] Abbara, A., Chitty, S., Roe, J.K., Ghani, R., Collin, S.M., Ritchie, A., et al. (2017) Drug-Induced Liver Injury from Antituberculous Treatment: A Retrospective Study from a Large TB Centre in the UK. BMC Infectious Diseases, 17, Article No. 231. [Google Scholar] [CrossRef] [PubMed]
[43] Araújo-Mariz, C., Lopes, E.P., Acioli-Santos, B., Maruza, M., Montarroyos, U.R., Ximenes, R.A.D.A., et al. (2016) Hepatotoxicity during Treatment for Tuberculosis in People Living with HIV/AIDS. PLOS ONE, 11, e0157725. [Google Scholar] [CrossRef] [PubMed]
[44] Li, F., Wang, P., Liu, K., Tarrago, M.G., Lu, J., Chini, E.N., et al. (2016) A High Dose of Isoniazid Disturbs Endobiotic Homeostasis in Mouse Liver. Drug Metabolism and Disposition, 44, 1742-1751. [Google Scholar] [CrossRef] [PubMed]
[45] Prieto, L.M., Santiago, B., del Rosal, T., Carazo, B., Jiménez, A.B., Pérez-Gorricho, B., et al. (2019) Linezolid-Containing Treatment Regimens for Tuberculosis in Children. Pediatric Infectious Disease Journal, 38, 263-267. [Google Scholar] [CrossRef] [PubMed]
[46] 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) [J]. 中华结核和呼吸杂志, 2019, 42(5): 343-356.
[47] Fontana, R.J., Liou, I., Reuben, A., Suzuki, A., Fiel, M.I., Lee, W., et al. (2023) AASLD Practice Guidance on Drug, Herbal, and Dietary Supplement-Induced Liver Injury. Hepatology, 77, 1036-1065. [Google Scholar] [CrossRef] [PubMed]
[48] Andrade, R.J., Aithal, G.P., Björnsson, E.S., Kaplowitz, N., Kullak-Ublick, G.A., Larrey, D., et al. (2019) EASL Clinical Practice Guidelines: Drug-Induced Liver Injury. Journal of Hepatology, 70, 1222-1261. [Google Scholar] [CrossRef] [PubMed]
[49] Worley, M.V. and Estrada, S.J. (2014) Bedaquiline: A Novel Antitubercular Agent for the Treatment of Multidrug‐resistant Tuberculosis. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 34, 1187-1197. [Google Scholar] [CrossRef] [PubMed]
[50] Kakkar, A.K. and Dahiya, N. (2014) Bedaquiline for the Treatment of Resistant Tuberculosis: Promises and Pitfalls. Tuberculosis, 94, 357-362. [Google Scholar] [CrossRef] [PubMed]
[51] 施春晶, 刘幸, 李龙芬, 等. 贝达喹啉, 德拉马尼和普托马尼治疗耐多药结核病对肝功能影响的研究进展[J]. 中国防痨杂志, 2024, 46(12): 1560-1565.
[52] Kim, J.H., Lee, H., Oh, I., Jeong, H.E., Bea, S., Jang, S.H., et al. (2023) Comparative Safety of Bedaquiline and Delamanid in Patients with Multidrug Resistant Tuberculosis: A Nationwide Retrospective Cohort Study. Journal of Microbiology, Immunology and Infection, 56, 842-852. [Google Scholar] [CrossRef] [PubMed]
[53] 胡秋萌, 张培泽. 利奈唑胺血清药物浓度监测在耐药结核病患者中的应用[J]. 新发传染病电子杂志, 2023, 8(5): 75-79.
[54] Zhao, H., Wang, Y., Zhang, T., Wang, Q. and Xie, W. (2020) Drug-Induced Liver Injury from Anti-Tuberculosis Treatment: A Retrospective Cohort Study. Medical Science Monitor, 26, e920350. [Google Scholar] [CrossRef] [PubMed]

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