利奈唑胺血液系统不良反应发生率及危险因素分析:一项多中心队列研究

doi:10.19982/j.issn.1000-6621.20240539

中国防痨杂志 ›› 2025, Vol. 47 ›› Issue (6): 719-726.doi: 10.19982/j.issn.1000-6621.20240539

利奈唑胺血液系统不良反应发生率及危险因素分析:一项多中心队列研究

李雪莲¹, 朱庆东², 马怡静³, 吐送江·买托合提³, 米日古丽·买托合提³, 王庆枫¹, 马丽萍¹, 初乃惠¹, 聂文娟¹, 林艳荣²(), 李纬²(), 王敬¹()

¹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结核一科,北京 101149
²南宁市第四人民医院结核科,南宁 530000
³新疆维吾尔自治区和田地区传染病专科医院呼吸一科,和田 848000

收稿日期:2024-12-02 出版日期:2025-06-10 发布日期:2025-06-11
通信作者: 林艳荣,Email:linyanrong2009@126.com;李纬,Email:6511899@qq.com;王敬,Email:wj2004629@sina.cn
基金资助:
北京重大呼吸道传染病研究中心课题(BJRID2025-013);北京市卫健委研究型病房卓越临床研究计划(BRWEP2024W042160109);北京市医管中心扬帆3.0项目(ZLRK202331)

Analysis of incidence and risk factors for linezolid-related hematological side effects: a multicenter cohort study

Li Xuelian¹, Zhu Qingdong², Ma Yijing³, Tusongjiang Maituoheti³, Miriguli Maituoheti³, Wang Qingfeng¹, Ma Liping¹, Chu Naihui¹, Nie Wenjuan¹, Lin Yanrong²(), Li Wei²(), Wang Jing¹()

¹The First Department of Tuberculosis, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101149, China
²Department of Tuberculosis, Nanning Fourth People’s Hospital, Nanning 530000, China
³The First Department of Respiratory Medicine Diseases, Xinjiang Uygur Autonomous Region Hetian Infectious Disease Hospital, Hetian 848000, China

Received:2024-12-02 Online:2025-06-10 Published:2025-06-11
Contact: Lin Yanrong, Email: linyanrong2009@126.com;Li Wei, Email: 6511899@qq.com;Wang Jing, Email: wj2004629@sina.cn
Supported by:
Beijing Major Respiratory Infectious Disease Research Center(BJRID2025-013);Excellent Clinical Research Program for Research Wards of Beijing Municipal Health Commission(BRWEP2024W042160109);Beijing Medical Management Center Yangfan 3.0 Project(ZLRK202331)

摘要/Abstract

摘要：

目的: 研究含利奈唑胺方案治疗耐多药/利福平耐药肺结核患者时血液系统不良反应的发生情况,探讨可能的危险因素。方法: 研究纳入2023年5月至2024年5月就诊于我国三家不同地区医疗机构的耐多药/利福平耐药肺结核患者的研究队列,收集所有患者的人口学特征(年龄、性别、体质量等)、血液学检测结果(白细胞计数、血红蛋白、血小板计数等)、出现不良反应的时间及严重程度、抗结核治疗方案、治疗转归等信息。通过单因素分析和多因素logistic回归分析筛选高危因素。结果: 利奈唑胺相关血液系统不良反应的发生率为45.5%(122/268),男性多于女性[59.8%(73/122)和40.2%(49/122)],40~59岁年龄组所占比例最高,为35.3%(43/122)。发生利奈唑胺相关血液系统不良反应的患者出现不良反应的时间为1~29周,中位数(四分位数)为13(12,24)周。16例(13.1%,16/122)患者出现白细胞减少,其中1级7例,2级8例,3级1例。111例(91.0%,111/122)患者出现贫血,其中1级45例,2级54例,3级12例。6例(4.9%,6/122)患者出现血小板减少,其中1级4例,2级1例,3级1例。11例(9.0%,11/122)患者同时出现贫血和白细胞减少;6例(4.9%,6/122)患者同时出现贫血和血小板减少;1例(0.8%,1/122)患者同时出现白细胞减少、贫血和血小板减少。所有患者均未发生出血性疾病。多因素logistic回归分析结果显示,治疗前血清白蛋白水平<35g/L的耐多药/利福平耐药肺结核患者出现利奈唑胺相关血液系统不良反应是血清白蛋白水平≥35g/L者的20.136倍(95%CI:4.843~83.714)。结论: 利奈唑胺相关血液系统不良反应的发生率较高,多见于40~59岁中年人,男性多于女性,不良反应以贫血最为常见,治疗前血清白蛋白水平低者易发生利奈唑胺相关血液系统不良反应。

关键词: 利奈唑胺, 结核, 抗药性, 毒性作用, 因素分析, 统计学, 多中心研究

Abstract:

Objective: To investigate the incidence of hematological side effect (HSE) in patients with drug-resistant tuberculosis treated with a linezolid-containing regimen and to explore the risk factors. Methods: This study included drug-resistant tuberculosis patients who visited three medical institutions centers in three different regions of China from May 2023 to May 2024. Demographic characteristics (age, sex, weight, etc.), hematological test results (white blood cell count, hemoglobin, platelet count, etc.), the time and severity of adverse reactions, anti-tuberculosis treatment regimens, treatment outcomes and other information of all patients were collected. Univariate analysis and multivariate logistic regression analysis were used to screen high-risk factors. Results: The incidence of linezolid-related HSE was 45.5% (122/268), with a higher rate in males than in females (59.8%, 73/122 vs. 40.2%, 49/122) and the greatest proportion in the 40-59 age group accounted for 35.3% (43/122). Time of onset of linezolid-related HSE was between 1 to 29 weeks, with a median of 13 (12,24) weeks. Sixteen patients (13.1%, 16/122) developed leukopenia, with 7 cases at grade 1, 8 cases at grade 2, and 1 case at grade 3. One hundred and eleven patients (91.0%, 111/122) developed anemia, with 45 cases at grade 1, 54 cases at grade 2, and 12 cases at grade 3. Six patients (4.9%, 6/122) experienced thrombocytopenia, with 4 cases at grade1, 1 case at grade 2, and 1 case at grade 3. Eleven patients (9.0%, 11/12) experienced both anemia and leukopenia; 6 patients (4.9%, 6/122) had both anemia and thrombocytopenia; 1 patient (0.8%, 1/122) had leukopenia, anemia, and thrombocytopenia simultaneously. No bleeding disorders occurred in any of patients. Logistic regression analysis showed that the risk of linezolid-related HSE was 20.136 (95%CI: 4.843-83.714) times higher in patients in pre-treatment hypoalbuminemia (<35 g/L) than in those with albumin levels ≥35 g/L. Conclusion: The incidence of linezolid-related HSE was high, which was more common in 40-59 age group, more in males than in females, and anemia was the most common. HSE was mostly mild to moderate, and hematological parameters could return to normal after treatment. Patients with low serum albumin levels before treatment were prone to linezolid-related HSE.

Key words: Linezolid, Tuberculosis, Drug resistance, Toxic actions, Factor analysis, statistical, Multicenter study

中图分类号:

李雪莲, 朱庆东, 马怡静, 吐送江·买托合提, 米日古丽·买托合提, 王庆枫, 马丽萍, 初乃惠, 聂文娟, 林艳荣, 李纬, 王敬. 利奈唑胺血液系统不良反应发生率及危险因素分析:一项多中心队列研究[J]. 中国防痨杂志, 2025, 47(6): 719-726. doi: 10.19982/j.issn.1000-6621.20240539

Li Xuelian, Zhu Qingdong, Ma Yijing, Tusongjiang Maituoheti, Miriguli Maituoheti, Wang Qingfeng, Ma Liping, Chu Naihui, Nie Wenjuan, Lin Yanrong, Li Wei, Wang Jing. Analysis of incidence and risk factors for linezolid-related hematological side effects: a multicenter cohort study[J]. Chinese Journal of Antituberculosis, 2025, 47(6): 719-726. doi: 10.19982/j.issn.1000-6621.20240539

图/表 6

表1

表2

表3

表4

表5

表6

参考文献 25

[1]	Sotgiu G, Centis R, D’Ambrosio L, et al. Efficacy, safety and tolerability of linezolid containing regimens in treating MDR-TB and XDR-TB: systematic review and meta-analysis. Eur Respir J, 2012, 40(6):1430-1442. doi:10.1183/09031936.00022912. pmid: 22496332
[2]	World Health Organization. WHO consolidated guidelines on drug-resistant tuberculosis treatment. Geneva: World Health Organization, 2019.
[3]	Dong H, Wang X, Dong Y, et al. Clinical pharmacokinetic/pharmacodynamic profile of linezolid in severely ill intensive care unit patients. Int J Antimicrob Agents, 2011, 38(4):296-300. doi:10.1016/j.ijantimicag.2011.05.007.
[4]	Caminero JA, Sotgiu G, Zumla A, et al. Best drug treatment for multidrug-resistant and extensively drug-resistant tuberculosis. Lancet Infect Dis, 2010, 10(9):621-629. doi:10.1016/S1473-3099(10)70139-0. pmid: 20797644
[5]	Bolhuis MS, van Altena R, Uges DR, et al. Clarithromycin significantly increases linezolid serum concentrations. Antimicrob Agents Chemother, 2010, 54(12):5418-5419. doi:10.1128/AAC.00757-10. pmid: 20837753
[6]	王颖, 蔡春葵, 许岩, 等. 利奈唑胺治疗广泛耐药肺结核疗效分析. 结核与肺部疾病杂志, 2020, 1(2):136-139. doi:10.3969/j.issn.2096-8493.2020.02.009.
[7]	Liu X, Aoki M, Osa S, et al. Safety of linezolid in patients with decreased renal function and trough monitoring: a systematic review and meta-analysis. BMC Pharmacol Toxicol, 2022, 23(1): 9. doi:10.1186/s40360-022-00628-9.
[8]	Maray I, Rodríguez-Ferreras A, Álvarez-Asteinza C, et al. Linezolid induced thrombocytopenia in critically ill patients: Risk factors and development of a machine learning-based prediction model. J Infect Chemother, 2022, 28(9):1249-1254. doi:10.1016/j.jiac.2022.05.004.
[9]	Qin Y, Chen Z, Gao S, et al. Development and validation of a risk prediction model for linezolid-induced thrombocytopenia in elderly patients. Eur J Hosp Pharm, 2024, 31(2):94-100. doi:10.1136/ejhpharm-2022-003258.
[10]	Han X, Wang J, Zan X, et al. Risk factors for linezolid-induced thrombocytopenia in adult inpatients. Int J Clin Pharm, 2022, 44(2):330-338. doi:10.1007/s11096-021-01342-y.
[11]	Tsuji Y, Hiraki Y, Matsumoto K, et al. Thrombocytopenia and anemia caused by a persistent high linezolid concentration in patients with renal dysfunction. J Infect Chemother, 2011, 17(1):70-75. doi:10.1007/s10156-010-0080-6. pmid: 20582446
[12]	Pratama NYI, Zulkarnain BS, Soedarsono, et al. Hematological side effect analysis of linezolid in MDR-TB patients with individual therapy. J Basic Clin Physiol Pharmacol, 2021, 32(4):777-781. doi:10.1515/jbcpp-2020-0468. pmid: 34214355
[13]	World Health Organization. WHO consolidated guidelines on tuberculosis: Module 4: treatment-drug-resistant tuberculosis treatment, 2022 update. Geneva: World Health Organization, 2022.
[14]	Millard J, Pertinez H, Bonnett L, et al. Linezolid pharmacokinetics in MDR-TB: a systematic review, meta-analysis and Monte Carlo simulation. J Antimicrob Chemother, 2018, 73(7):1755-1762. doi:10.1093/jac/dky096. pmid: 29584861
[15]	Shiromwar SS, Khan AH, Chidrawar V. A systematic review on extensively drug-resistant tuberculosis from 2009 to 2020: special emphases on treatment outcomes. Rev Esp Quimioter, 2023, 36(1):30-44. doi:10.37201/req/029.2022.
[16]	World Health Organization. Global tuberculosis report 2023:executive summary. Geneva: World Health Organization, 2023.
[17]	Wang TL, Guo DH, Bai Y, et al. Thrombocytopenia in Patients Receiving Prolonged Linezolid May be Caused by Oxidative Stress. Clin Drug Investig, 2016, 36(1):67-75. doi:10.1007/s40261-015-0352-0.
[18]	Pea F, Viale P, Cojutti P, et al. Therapeutic drug monitoring may improve safety outcomes of long-term treatment with linezolid in adult patients. J Antimicrob Chemother, 2012, 67(8):2034-2042. doi:10.1093/jac/dks153. pmid: 22553142
[19]	Zhang D, Xu Y, Wang X, et al. Risk factors for thrombocytopenia in patients receiving linezolid therapy: a systematic review and meta-analysis. Eur J Clin Pharmacol, 2023, 79(10):1303-1314. doi:10.1007/s00228-023-03542-z. pmid: 37578552
[20]	Shi Y, Wu HL, Wu YH, et al. Safety and clinical efficacy of linezolid in children: a systematic review and meta-analysis. World J Pediatr, 2023, 19(2):129-138. doi:10.1007/s12519-022-00650-1.
[21]	Polasa K, Murthy KJ, Krishnaswamy K. Rifampicin kinetics in undernutrition. Br J Clin Pharmacol, 1984, 17(4): 481-484. doi:10.1111/j.1365-2125.1984.tb02377.x.
[22]	Fage D, Aalhoul F, Cotton F. Protein binding investigation of first-line and second-line antituberculosis drugs. Int J Antimicrob Agents, 2023, 62(6): 106999. doi:10.1016/j.ijantimicag.2023.106999.
[23]	Morata L, De la Calle C, Gómez-Cerquera JM, et al. Risk factors associated with high linezolid trough plasma concentrations. Expert Opin Pharmacother, 2016, 17(9):1183-1187. doi:10.1080/14656566.2016.1182154. pmid: 27156708
[24]	Zhang P, Li W, Liu M, et al. Linezolid-Associated Neuropathy in Patients with MDR/XDR Tuberculosis in Shenzhen, China. Infect Drug Resist, 2022, 15:2617-2624. doi:10.2147/IDR.S365371. pmid: 35634579
[25]	王红红, 郭少晨, 周文强, 等. 耐药结核病患者利奈唑胺血药浓度对血液系统毒性发生的影响. 中国防痨杂志, 2023, 45(2):165-171. doi:10.19982/j.issn.1000-6621.20220301.

因素		HSE组(122例)		NHSE组(146例)		χ²值		P值
年龄组(岁)						0.081		0.775
14~39		42(34.4)		60(41.1)
40~59		43(35.3)		50(34.2)
60~79		36(29.5)		35(24.0)
80~83		1(0.8)		1(0.7)
性别						2.177		0.140
男性		73(59.8)		100(68.5)
女性		49(40.2)		46(31.5)
体质量指数						8.807		0.003
≥18.5		76(62.3)		115(78.8)
<18.5		46(37.7)		31(21.2)
耐药情况						0.024		0.877
耐多药		49(40.2)		60(41.1)
利福平耐药		73(59.8)		86(58.9)
治疗前血液检测结果
白细胞(×10⁹/L)						2.411		0.120
≥3.5		120(98.4)		146(100.0)
<3.5		2(1.6)		0(0.0)
血小板(×10⁹/L)						1.201		0.273
≥100		121(99.2)		146(100.0)
<100		1(0.8)		0(0.0)
血红蛋白(g/L)						4.793		0.029
≥120		99(81.1)		132(90.4)
<120		23(18.9)		14(9.6)
血清白蛋白(g/L)						22.548		0.000
≥35		78(63.9)		129(88.4)
<35		44(36.1)		17(11.6)
血肌酐(μmol/L)						4.682		0.030
≥110		6(4.9)		1(0.7)
<110		116(95.1)		145(99.3)
民族						4.514		0.211
汉族		80(65.6)		87(59.6)
壮族		18(14.8)		15(10.3)
维吾尔族		21(17.2)		40(27.4)
其他民族		3(2.4)		4(2.7)
合并用药情况
使用贝达喹啉						0.982		0.322
是		47(38.5)		65(44.5)
否		75(61.5)		81(55.5)
使用氟喹诺酮类药物						0.000		0.985
是		101(82.8)		121(82.9)
否		21(17.2)		25(17.1)
使用氯法齐明						0.329		0.566
是		71(58.2)		90(61.6)
否		51(41.8)		56(38.4)
使用环丝氨酸						0.088		0.766
是		102(83.6)		124(84.9)
否		20(16.4)		22(15.1)
使用吡嗪酰胺						3.595		0.058
是		51(41.8)		78(53.4)
否		71(58.2)		68(46.6)
使用乙胺丁醇					0.081		0.775
是	34(27.9)		43(29.5)
否	88(72.1)		103(70.5)
使用阿米卡星					0.883		0.347
是	19(15.6)		17(11.6)
否	103(84.4)		129(88.4)
使用丙硫异烟胺					0.004		0.951
是	33(27.0)		39(26.7)
否	89(73.0)		107(73.3)

因素	赋值
体质量指数	≥18.5=1,<18.5=0
血清白蛋白	≥35g/L=1,<35g/L=0
血肌酐	≥110μmol/L=1,<110μmol/L=0
血红蛋白	≥120g/L=1,<120g/L=0

变量	β值	$s_{\bar{x}} $值	Wald χ²值	P值	OR值	95%CI值
体质量指数(≥18.5)	0.045	0.892	0.003	0.960	1.046	0.182~6.010
血清白蛋白(≥35g/L)	3.003	0.727	17.057	0.000	20.136	4.843~83.714
血肌酐(≥110μmol/L)	12.309	3090.570	0.000	0.997	221636.451	0.000~63.290
血红蛋白(≥120g/L)	33.520	4355.937	0.000	0.994	3.610×10¹⁴	0.000~96.000
常量	―32.804	4355.937	0.000	0.994	0.000	―

利奈唑胺血液系统不良反应发生率及危险因素分析:一项多中心队列研究

Analysis of incidence and risk factors for linezolid-related hematological side effects: a multicenter cohort study

RichHTML

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

图/表 6

参考文献 25

相关文章 15

编辑推荐

Metrics

本文评价

友情链接

年龄组(岁)	男性(例)	女性(例)	合计(例)	构成比(%)
14~39	18	24	42	34.4
40~59	34	9	43	35.3
60~79	20	16	36	29.5
80~83	1	0	1	0.8
合计	73	49	122	100.0

分类	例数	发生率 (%)	发生时间 [周,M(Q₁,Q₃)]	分类	例数	发生率 (%)	发生时间 [周,M(Q₁,Q₃)]
贫血	111	91.0	13(12,24)	血小板减少	6	4.9	12(2,24)
1级	45	40.5^a		1级	4	4/6^a
2级	54	48.6^a		2级	1	1/6^a
3级	12	10.9^a		3级	1	1/6^a
白细胞减少	16	13.1	24(13,28)	贫血+白细胞减少	11	9.0
1级	7	43.8^a		贫血+血小板减少	6	4.9
2级	8	50.0^a		贫血+白细胞减少+血小板减少	1	0.8
3级	1	6.2^a

机构	白细胞减少		贫血		血小板减少		合计
机构	例数	例次	例数	例次	例数	例次	例数	例次
首都医科大学附属北京胸科医院	10	10	29	29	1	1	30	40
南宁市第四人民医院	0	0	65	65	5	5	70	70
新疆维吾尔自治区和田地区传染病专科医院	6	6	17	17	0	0	22	23
合计	16	16	111	111	6	6	122	133

[1]	姚秀钰, 杜莹, 陈斯婕, 耿红, 高磊. 传染性肺结核患者居家隔离治疗管理期间常见的护理问题与对策[J]. 中国防痨杂志, 2025, 47(6): 681-686.
[2]	欧喜超, 滕冲, 宋媛媛, 郑扬, 陈磊, 朱俊, 王建国, 潘兆宝, 康海涛, 王彦, 么鸿雁, 黄飞. 新型PCR荧光探针技术用于结核病患者早期诊断的多中心应用评价研究[J]. 中国防痨杂志, 2025, 47(6): 687-693.
[3]	谢忠尧, 张慕丽, 曹廷明, 曹洋, 孙照刚. 基于特异性配体蛋白SMAD2检测法用于活动性结核病的诊断价值研究[J]. 中国防痨杂志, 2025, 47(6): 694-700.
[4]	赵琰枫, 屠霞, 王嫩寒, 陈双双, 田丽丽, 樊瑞芳, 于兰, 李洁, 李传友, 代小伟. 三种检测方法在肺结核患者病原学阳性检出中的贡献分析[J]. 中国防痨杂志, 2025, 47(6): 701-707.
[5]	彭华, 崔俊伟, 尚秋白, 李四清, 彭瑞琴. 跨理论模型联合健康信念模型护理干预在肺结核合并慢性阻塞性肺疾病患者中的应用效果[J]. 中国防痨杂志, 2025, 47(6): 727-731.
[6]	王涵飞, 李锦浩, 文雅欣, 徐彩红. 2021年我国利福平耐药肺结核患者诊疗延迟及影响因素分析[J]. 中国防痨杂志, 2025, 47(6): 738-745.
[7]	师晓晶, 郭建花, 王鑫, 赵清冉, 王雨涵. 石家庄市结核分枝杆菌潜伏感染者预防性治疗接受度及影响因素研究[J]. 中国防痨杂志, 2025, 47(6): 746-752.
[8]	张曼晖, 张梦迪, 卢征, 李俊琦, 郑文静, 王鑫, 黄飞, 刘剑君, 么鸿雁, 王琦琦. 2005—2020年中国老年人群肺结核疾病负担趋势分析[J]. 中国防痨杂志, 2025, 47(6): 753-759.
[9]	李玉红, 梅金周, 李雪, 张慧, 刘小秋, 赵雁林. 2018—2022年全国跨省流动肺结核患者流行特征分析[J]. 中国防痨杂志, 2025, 47(6): 760-768.
[10]	石洁, 常文静, 郑丹薇, 苏茹月, 马晓光, 朱岩昆, 王少华, 孙建伟, 孙定勇. 基于GEO数据库筛选结核病关键基因及信号通路的研究[J]. 中国防痨杂志, 2025, 47(6): 769-778.
[11]	魏潇芮, 于泽洋, 杨琨, 周柯, 黄芳, 刘昊, 白露, 刘家云. 结核分枝杆菌感染者外周血单个核细胞中肝激酶B1的表达及其与γ-干扰素的相关性[J]. 中国防痨杂志, 2025, 47(6): 779-784.
[12]	李维, 周志超, 郑洁. 1995—2023年中国耐多药结核病研究的态势和热点分析[J]. 中国防痨杂志, 2025, 47(6): 785-791.
[13]	齐琦, 王子豪, 叶琳琳, 彭文贝, 周琼. 免疫检查点抑制剂与结核病[J]. 中国防痨杂志, 2025, 47(6): 792-797.
[14]	黄伟强, 袁楚楚, 张欢, 王丽丽, 钟小锋, 陈星星, 胡明. 45例有创机械通气重症结核病患者静脉使用抗结核药物血药浓度分析[J]. 中国防痨杂志, 2025, 47(6): 798-807.
[15]	田秀丽, 李青, 舒新云, 兰远波, 宗兆婧. 含贝达喹啉抗结核方案治疗准广泛耐药肠结核一例[J]. 中国防痨杂志, 2025, 47(6): 808-810.