利奈唑胺血清药物浓度监测在耐药结核病患者中的应用

doi:10.19871/j.cnki.xfcrbzz.2023.05.014

摘要/Abstract

摘要： 利奈唑胺是一种新型的噁唑烷酮类抗生素,是治疗耐药结核病的关键药物,该药治疗窗口狭窄,虽然疗效明显,但是临床应用不良反应的发生率高,如何安全有效地应用该药治疗耐药结核病一直困扰临床医生。治疗药物监测（therapeutic drug monitoring,TDM）通过监测患者血液中的药物浓度,可为药物剂量调整提供依据,使药物达到有效治疗浓度的同时最大程度地降低不良反应发生。目前国内外均有报道利用TDM研究利奈唑胺在耐药结核病患者中的最佳使用剂量和疗程,探讨利奈唑胺的谷浓度、峰浓度与不良反应发生率之间的关系,特别是对老年人、儿童、肝肾功能不全的患者临床安全使用利奈唑胺个体化治疗进行系列的探索研究。本文对利奈唑胺不良反应的发生机制、利奈唑胺的使用剂量及安全性、利奈唑胺药物浓度的影响因素、TDM的方式和应用等进行综述,为更加安全有效地应用利奈唑胺治疗耐药结核病提供参考。

关键词: 利奈唑胺, 不良反应, 治疗药物监测, 耐药结核

Abstract: Linezolid is a novel oxazolidinone antibiotics and a key drug for treatment of drug-resistant tuberculosis. With narrow therapeutic window, linezolid is characterized with great efficacy, and high incidence of adverse reaction. How to tailor optimal dosage for every patient to balance efficacy and safety is still a problem for clinician. Therapeutic drug monitoring (TDM) remains a standard clinical technique for using plasma drug concentrations to make informed dosing decisions. Many studies worldwide have demonstrated the possible optimal dosage of linezolid in drug-resistant TB patients, explored the relationship between the trough concentration, peak concentration and the incidence of adverse reactions of linezolid by TDM, particularly for fragile patients, like the aged, children and patients with injured liver and kidney function. We hereby review the mechanism of linezolid, the relationship between dosage and safety of linezolid, risk factors affecting the concentration of linezolid, evidence and available methods of TDM of linezolid, so as to provide a reference for clinician to do TDM of linezolid during the treatment of drug-resistant tuberculosis.

Key words: Linezolid, Adverse effects, Therapeutic drug monitoring, Drug-resistant tuberculosis

中图分类号:

R52
R917

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.

Hu Qiumeng, Zhang Peize. Application of linezolid serum concentration monitoring in patients with drug-resistant tu-berculosis[J]. Electronic Journal of Emerging Infectious Diseases, 2023, 8(5): 75-79.

参考文献

[1] WORLD HEALTH ORGANIZATION. WHO consolidated guidelines on tuberculosis. Module 4: treatment-drug-resistant tuberculosis treatment[EB/OL]. [2022-12-15].https://www.who.int/publications/i/item/9789240063129,2022 update.
[2] WORLD HEALTH ORGANIZATION.Drug-resistant tuberculosis remains A public health crisis[EB/OL]. [2022-12-26].https://www.who.int/multi-media/details/global-tuberculosis-report-2022-infographic-3,26 October 2022.
[3] LEE M, LEE J, CARROLL MW, et al.Linezolid for treatment of chronic extensively drug-resistant tuberculosis[J]. N Engl J Med, 2012, 367(16):1508-1518.
[4] AHMAD N, AHUJA SD, AKKERMAN OW, et al.Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an individual patient data meta-analysis[J]. Lancet, 2018, 392(10150):821-834.
[5] LAN Z, AHMAD N, BAGHAEI P, et al.Drug-associated adverse events in the treatment of multidrug-resistant tuberculosis: an individual patient data meta-analysis[J]. Lancet Respir Med, 2020, 8(4):383-394.
[6] BOLHUIS MS, AKKERMAN OW, STURKENBOOM M, et al.Linezolid-based Regimens for Multidrug-resistant Tuberculosis (TB): A Systematic Review to Establish or Revise the Current Recommended Dose for TB Treatment[J]. Clin Infect Dis, 2018, 67(suppl_3): S327-S335.
[7] VAN DEN ELSEN S, AKKERMAN OW, JONGEDIJK EM, et al. Therapeutic drug monitoring using saliva as matrix: an opportunity for linezolid, but challenge for moxifloxacin[J]. Eur Respir J, 2020, 55(5):1901903.
[8] ATES HC, ROBERTS JA, LIPMAN J, et al.On-Site Therapeutic Drug Monitoring[J]. Trends Biotechnol, 2020, 38(11):1262-1277.
[9] HASHEMIAN S, FARHADI T, GANJPARVAR M.Linezolid: a review of its properties, function, and use in critical care[J]. Drug Des Devel Ther, 2018, 12:1759-1767.
[10] RUBINSTEIN E, ISTURIZ R, STANDIFORD HC, et al.Worldwide assessment of linezolid's clinical safety and tolerability: comparator-controlled phase III studies[J]. Antimicrob Agents Chemother,2003,47(6):1824-1831.
[11] MCKEE EE, FERGUSON M, BENTLEY AT, et al.Inhibition of mammalian mitochondrial protein synthesis by oxazolidinones[J]. Antimicrob Agents Chemother,2006,50(6):2042-2049.
[12] APODACA AA, RAKITA RM.Linezolid-induced lactic acidosis[J]. N Engl J Med, 2003, 348(1):86-87.
[13] ATTASSI K, HERSHBERGER E, ALAM R, et al.Thrombocytopenia associated with linezolid therapy[J]. Clin Infect Dis, 2002, 34(5):695-698.
[14] ZHOU CC, SWANEY SM, SHINABARGER DL, et al.1H nuclear magnetic resonance study of oxazolidinone binding to bacterial ribosomes[J]. Antimicrob Agents Chemother, 2002, 46(3):625-629.
[15] BRESSLER AM, ZIMMER SM, GILMORE JL, et al.Peripheral neuropathy associated with prolonged use of linezolid[J]. Lancet Infect Dis, 2004, 4(8):528-531.
[16] SPELLBERG B, YOO T, BAYER AS.Reversal of linezolid-associated cytopenias, but not peripheral neuropathy, by administration of vitamin B6[J]. J Antimicrob Chemother, 2004, 54(4):832-835.
[17] BERNSTEIN WB, TROTTA RF, RECTOR JT, et al.Mechanisms for linezolid-induced anemia and thrombocytopenia[J]. Ann Pharmacother, 2003, 37(4):517-520.
[18] BERGERON L, BOULÉ M, PERREAULT S.Serotonin toxicity associated with concomitant use of linezolid[J]. Ann Pharmacother, 2005, 39(5):956-961.
[19] DAS PK, WARKENTIN DI, HEWKO R, et al.Serotonin syndrome after concomitant treatment with linezolid and meperidine[J]. Clin Infect Dis, 2008, 46(2):264-265.
[20] 季乐财,余卫业,谭卫国,等. 利奈唑胺治疗重症耐多药肺结核临床观察及不良反应分析[J/CD]. 新发传染病电子杂志, 2019, 4(4):217-219.
[21] LIFAN Z, SAINAN B, FENG S, et al.Linezolid for the treatment of extensively drug-resistant tuberculosis: a systematic review and meta-analysis[J]. Int J Tuberc Lung Dis, 2019, 23(12):1293-1307.
[22] RAO GG, KONICKI R, CATTANEO D, et al.Therapeutic Drug Monitoring Can Improve Linezolid Dosing Regimens in Current Clinical Practice: A Review of Linezolid Pharmacokinetics and Pharmacodynamics[J]. Ther Drug Monit, 2020, 42(1):83-92.
[23] SAZDANOVIC P, JANKOVIC SM, KOSTIC M, et al.Pharmacokinetics of linezolid in critically ill patients[J]. Expert Opin Drug Metab Toxicol, 2016, 12(6):595-600.
[24] PADMAPRIYADARSINI C, SOLANKI R, JEYAKUMAR SM, et al.Linezolid Pharmacokinetics and Its Association with Adverse Drug Reactions in Patients with Drug-Resistant Pulmonary Tuberculosis[J]. Antibiotics (Basel), 2023, 12(4):714.
[25] ZHOU W, NIE W, WANG Q, et al.Linezolid Pharmacokinetics/Pharmacodynamics-Based Optimal Dosing for Multidrug-Resistant Tuberculosis[J]. Int J Antimicrob Agents, 2022, 59(6):106589.
[26] CONRADIE F, DIACON AH, NGUBANE N, et al.Treatment of Highly Drug-Resistant Pulmonary Tuberculosis[J]. N Engl J Med, 2020, 382(10):893-902.
[27] CONRADIE F, BAGDASARYAN TR, BORISOV S, et al.Bedaquiline-Pretomanid-Linezolid Regimens for Drug-Resistant Tuberculosis[J]. N Engl J Med, 2022, 387(9):810-823.
[28] 李娟,张峻,王晶晶,等. 利奈唑胺血药浓度监测结果及影响因素分析[J]. 中国药师, 2022, 25(8):1406-1409.
[29] WASSERMAN S, DENTI P, BRUST J, et al.Linezolid Pharmacokinetics in South African Patients with Drug-Resistant Tuberculosis and a High Prevalence of HIV Coinfection[J]. Antimicrob Agents Chemother, 2019, 63(3): e2118-e2164.
[30] BOLHUIS MS, van ALTENA R, van SOOLINGEN D, et al. Clarithromycin increases linezolid exposure in multidrug-resistant tuberculosis patients[J]. Eur Respir J, 2013, 42(6):1614-1621.
[31] GANDELMAN K, ZHU T, FAHMI OA, et al.Unexpected effect of rifampin on the pharmacokinetics of linezolid: in silico and in vitro approaches to explain its mechanism[J]. J Clin Pharmacol, 2011, 51(2):229-236.
[32] TOBIN CM, SUNDERLAND J, WHITE LO, et al.A simple, isocratic high-performance liquid chromatography assay for linezolid in human serum[J]. J Antimicrob Chemother, 2001, 48(5):605-608.
[33] 张秀华,胡卢丰,王志强. 高效液相色谱法测定人血浆中利奈唑胺的血药浓度[J]. 中国药学杂志,2010,45(18):1417-1420.
[34] EL-NAJJAR N, HÖSL J, HOLZMANN T, et al. UPLC-MS/MS method for therapeutic drug monitoring of 10 antibiotics used in intensive care units[J]. Drug Test Anal, 2018, 10(3):584-591.
[35] FERRARI D, RIPA M, PREMASCHI S, et al.LC-MS/MS method for simultaneous determination of linezolid, meropenem, piperacillin and teicoplanin in human plasma samples[J]. J Pharm Biomed Anal, 2019, 169:11-18.
[36] LU W, PAN M, KE H, et al.An LC-MS/MS method for the simultaneous determination of 18 antibacterial drugs in human plasma and its application in therapeutic drug monitoring[J]. Front Pharmacol, 2022, 13:1044234.
[37] VU DH, BOLHUIS MS, KOSTER RA, et al.Dried blood spot analysis for therapeutic drug monitoring of linezolid in patients with multidrug-resistant tuberculosis[J]. Antimicrob Agents Chemother, 2012, 56(11):5758-5763.
[38] XIAOYONG X, JINGLIN W, GUANGFEI W, et al.Applicability of vancomycin, meropenem, and linezolid in capillary microsamples vs. dried blood spots: A pilot study for microsampling in critically ill children[J]. Front Pediatr, 2022, 10:1055200.
[39] BOLHUIS MS, van ALTENA R, van HATEREN K, et al. Clinical validation of the analysis of linezolid and clarithromycin in oral fluid of patients with multidrug-resistant tuberculosis[J]. Antimicrob Agents Chemother, 2013, 57(8):3676-3680.
[40] INOUE Y, SATO Y, KASHIWAGI H, et al.Monitoring Salivary Concentrations of Tedizolid and Linezolid Using Rats[J]. Eur J Drug Metab Pharmacokinet, 2023, 48(4):387-395.
[41] ZHU H, GUO SC, LIU ZQ, et al.Therapeutic drug monitoring of cycloserine and linezolid during anti-tuberculosis treatment in Beijing, China[J]. Int J Tuberc Lung Dis, 2018, 22(8):931-936.
[42] BOLHUIS MS, VAN DER WERF TS, KERSTJENS H, et al. Treatment of multidrug-resistant tuberculosis using therapeutic drug monitoring: first experiences with sub-300 mg linezolid dosages using in-house made capsules[J]. Eur Respir J, 2019, 54(6):1900580.
[43] TIETJEN AK, KROEMER N, CATTANEO D, et al.Population pharmacokinetics and target attainment analysis of linezolid in multidrug-resistant tuberculosis patients[J]. Br J Clin Pharmacol, 2022, 88(4):1835-1844.
[44] SONG T, LEE M, JEON HS, et al.Linezolid Trough Concentrations Correlate with Mitochondrial Toxicity-Related Adverse Events in the Treatment of Chronic Extensively Drug-Resistant Tuberculosis[J]. EBio Medicine, 2015, 2(11):1627-1633.
[45] ZHANG P, LI W, LIU M, et al.Linezolid-Associated Neuropathy in Patients with MDR/XDR Tuberculosis in Shenzhen, China[J]. Infect Drug Resist, 2022, 15:2617-2624.
[46] 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[J]. 中国防痨杂志, 2023, 45(2):165-171.