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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 林淑文(Shu-Wen Lin) | |
dc.contributor.author | Chih-Ning Cheng | en |
dc.contributor.author | 鄭芷寧 | zh_TW |
dc.date.accessioned | 2021-06-17T01:46:47Z | - |
dc.date.available | 2022-09-08 | |
dc.date.copyright | 2017-09-08 | |
dc.date.issued | 2017 | |
dc.date.submitted | 2017-07-26 | |
dc.identifier.citation | 1. Livermore DM. Linezolid in vitro: mechanism and antibacterial spectrum. The Journal of antimicrobial chemotherapy 2003; 51 Suppl 2: ii9-16.
2. Perry CM, Jarvis B. Linezolid: a review of its use in the management of serious gram-positive infections. Drugs 2001; 61: 525-51. 3. Fung HB, Kirschenbaum HL, Ojofeitimi BO. Linezolid: an oxazolidinone antimicrobial agent. Clinical therapeutics 2001; 23: 356-91. 4. Zyvox (R) IV injection , oral tablets, suspension. [Package insert]. Pfizer Pharmaceuticals Inc, NY, USA ; July, 2015. 5. Slatter JG, Stalker DJ, Feenstra KL et al. Pharmacokinetics, metabolism, and excretion of linezolid following an oral dose of [(14)C]linezolid to healthy human subjects. Drug metabolism and disposition: the biological fate of chemicals 2001; 29: 1136-45. 6. Liu C, Bayer A, Cosgrove SE et al. Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children: executive summary. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2011; 52: 285-92. 7. Baddour LM, Wilson WR, Bayer AS et al. Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of Complications: A Scientific Statement for Healthcare Professionals From the American Heart Association. Circulation 2015; 132: 1435-86. 8. Griffith DE, Aksamit T, Brown-Elliott BA et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007; 175: 367-416. 9. Lee M, Lee J, Carroll MW et al. Linezolid for treatment of chronic extensively drug-resistant tuberculosis. The New England journal of medicine 2012; 367: 1508-18. 10. MacGowan AP. Pharmacokinetic and pharmacodynamic profile of linezolid in healthy volunteers and patients with Gram-positive infections. The Journal of antimicrobial chemotherapy 2003; 51 Suppl 2: ii17-25. 11. Bhalodi AA, Papasavas PK, Tishler DS et al. Pharmacokinetics of intravenous linezolid in moderately to morbidly obese adults. Antimicrobial agents and chemotherapy 2013; 57: 1144-9. 12. Rubinstein E, Isturiz R, Standiford HC et al. Worldwide assessment of linezolid's clinical safety and tolerability: comparator-controlled phase III studies. Antimicrobial agents and chemotherapy 2003; 47: 1824-31. 13. Gerson SL, Kaplan SL, Bruss JB et al. Hematologic effects of linezolid: summary of clinical experience. Antimicrobial agents and chemotherapy 2002; 46: 2723-6. 14. Attassi K, Hershberger E, Alam R et al. Thrombocytopenia associated with linezolid therapy. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2002; 34: 695-8. 15. Orrick JJ, Johns T, Janelle J et al. Thrombocytopenia secondary to linezolid administration: what is the risk? Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2002; 35: 348-9. 16. Bishop E, Melvani S, Howden BP et al. Good clinical outcomes but high rates of adverse reactions during linezolid therapy for serious infections: a proposed protocol for monitoring therapy in complex patients. Antimicrobial agents and chemotherapy 2006; 50: 1599-602. 17. Matsumoto K, Takeshita A, Ikawa K et al. Higher linezolid exposure and higher frequency of thrombocytopenia in patients with renal dysfunction. International journal of antimicrobial agents 2010; 36: 179-81. 18. Hiraki Y, Tsuji Y, Hiraike M et al. Correlation between serum linezolid concentration and the development of thrombocytopenia. Scandinavian journal of infectious diseases 2012; 44: 60-4. 19. Nukui Y, Hatakeyama S, Okamoto K et al. High plasma linezolid concentration and impaired renal function affect development of linezolid-induced thrombocytopenia. The Journal of antimicrobial chemotherapy 2013; 68: 2128-33. 20. Sasaki T, Takane H, Ogawa K et al. Population pharmacokinetic and pharmacodynamic analysis of linezolid and a hematologic side effect, thrombocytopenia, in Japanese patients. Antimicrobial agents and chemotherapy 2011; 55: 1867-73. 21. Lin YH, Wu VC, Tsai IJ et al. High frequency of linezolid-associated thrombocytopenia among patients with renal insufficiency. International journal of antimicrobial agents 2006; 28: 345-51. 22. Wu VC, Wang YT, Wang CY et al. High frequency of linezolid-associated thrombocytopenia and anemia among patients with end-stage renal disease. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2006; 42: 66-72. 23. Narita M, Tsuji BT, Yu VL. Linezolid-associated peripheral and optic neuropathy, lactic acidosis, and serotonin syndrome. Pharmacotherapy 2007; 27: 1189-97. 24. Im JH, Baek JH, Kwon HY et al. Incidence and risk factors of linezolid-induced lactic acidosis. International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases 2015; 31: 47-52. 25. Palenzuela L, Hahn NM, Nelson RP, Jr. et al. Does linezolid cause lactic acidosis by inhibiting mitochondrial protein synthesis? Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2005; 40: e113-6. 26. Carson J, Cerda J, Chae JH et al. Severe lactic acidosis associated with linezolid use in a patient with the mitochondrial DNA A2706G polymorphism. Pharmacotherapy 2007; 27: 771-4. 27. Del Pozo JL, Fernandez-Ros N, Saez E et al. Linezolid-induced lactic acidosis in two liver transplant patients with the mitochondrial DNA A2706G polymorphism. Antimicrobial agents and chemotherapy 2014; 58: 4227-9. 28. Pea F, Furlanut M, Cojutti P et al. Therapeutic drug monitoring of linezolid: a retrospective monocentric analysis. Antimicrobial agents and chemotherapy 2010; 54: 4605-10. 29. Bolhuis MS, van Altena R, van Soolingen D et al. Clarithromycin increases linezolid exposure in multidrug-resistant tuberculosis patients. The European respiratory journal 2013; 42: 1614-21. 30. Pea F, Cadeo B, Cojutti PG et al. Linezolid underexposure in a hypothyroid patient on levothyroxine replacement therapy: a case report. Ther Drug Monit 2014; 36: 687-9. 31. Stalker DJ, Jungbluth GL, Hopkins NK et al. Pharmacokinetics and tolerance of single- and multiple-dose oral or intravenous linezolid, an oxazolidinone antibiotic, in healthy volunteers. The Journal of antimicrobial chemotherapy 2003; 51: 1239-46. 32. Rosenbaum SE. Basic Pharmacokinetics and Pharmacodynamics: An Integrated Textbook and Computer Simulations: Wiley, 2012. 33. Plock N, Buerger C, Joukhadar C et al. Does linezolid inhibit its own metabolism? Population pharmacokinetics as a tool to explain the observed nonlinearity in both healthy volunteers and septic patients. Drug metabolism and disposition: the biological fate of chemicals 2007; 35: 1816-23. 34. Keel RA, Schaeftlein A, Kloft C et al. Pharmacokinetics of intravenous and oral linezolid in adults with cystic fibrosis. Antimicrobial agents and chemotherapy 2011; 55: 3393-8. 35. Cattaneo D, Orlando G, Cozzi V et al. Linezolid plasma concentrations and occurrence of drug-related haematological toxicity in patients with gram-positive infections. International journal of antimicrobial agents 2013; 41: 586-9. 36. Pea F, Viale P, Cojutti P et al. Therapeutic drug monitoring may improve safety outcomes of long-term treatment with linezolid in adult patients. The Journal of antimicrobial chemotherapy 2012; 67: 2034-42. 37. Matsumoto K, Shigemi A, Takeshita A et al. Analysis of thrombocytopenic effects and population pharmacokinetics of linezolid: a dosage strategy according to the trough concentration target and renal function in adult patients. International journal of antimicrobial agents 2014; 44: 242-7. 38. Rayner CR, Forrest A, Meagher AK et al. Clinical pharmacodynamics of linezolid in seriously ill patients treated in a compassionate use programme. Clinical pharmacokinetics 2003; 42: 1411-23. 39. Dong H, Xie J, Wang T et al. Pharmacokinetic/pharmacodynamic evaluation of linezolid for the treatment of staphylococcal infections in critically ill patients. International journal of antimicrobial agents 2016; 48: 259-64. 40. Niwa T, Watanabe T, Suzuki A et al. Reduction of linezolid-associated thrombocytopenia by the dose adjustment based on the risk factors such as basal platelet count and body weight. Diagnostic microbiology and infectious disease 2014; 79: 93-7. 41. Pea F, Cojutti P, Dose L et al. A 1 year retrospective audit of quality indicators of clinical pharmacological advice for personalized linezolid dosing: one stone for two birds? British journal of clinical pharmacology 2016; 81: 341-8. 42. DeRyke, Alexander D. Optimizing Vancomycin Dosing Through Pharmacodynamic Assessment Targeting Area Under the Concentration-Time Curve/Minimum Inhibitory Concentration. Hospital Pharmacy 2009; 44: 751-65. 43. Tobin CM, Sunderland J, White LO et al. A simple, isocratic high-performance liquid chromatography assay for linezolid in human serum. Journal of Antimicrobial Chemotherapy 2001; 48: 605-8. 44. la Marca G, Villanelli F, Malvagia S et al. Rapid and sensitive LC-MS/MS method for the analysis of antibiotic linezolid on dried blood spot. Journal of pharmaceutical and biomedical analysis 2012; 67-68: 86-91. 45. Naranjo CA, Busto U, Sellers EM et al. A method for estimating the probability of adverse drug reactions. Clinical pharmacology and therapeutics 1981; 30: 239-45. 46. Bioanalytical Method Validation (2013) U.S. Department of Health and Human Services Food and Drug Administration, CDER,CVM, 2013. 47. Zyvox (R). Clinical pharmacology and biopharmaceutics reviews. U.S. Food and Drug Administration. 2002. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/67734 | - |
dc.description.abstract | 背景
Linezolid 目前是治療革蘭氏陽性球菌及分枝桿菌感染的後線抗生素,嚴重的不良反應包括骨髓抑制、乳酸性酸中毒、周邊神經病變等。過去文獻提到linezolid 較高的血中濃度可能跟血小板低下有關,然而只有少數研究探討臨床療效及其他不良反應跟血中濃度的關係。同時劑量調整方式目前尚未有一致的共識;因此有進一步研究之必要性。 研究目的 此研究主要目的為分析linezolid 血中濃度的分布情形及劑量的關係、血中濃度與副作用及臨床療效之間的關係,以及尋找血中濃度的最佳切點。 研究方法 本研究為一前瞻性觀察性研究,於2016 年12 月1 日至2017 年5 月15 日間在國立臺灣大學醫學院附設醫院收案。收案對象為接受linezolid 治療且有進行療劑監測之成年病人,並使用高效能液相層析儀測量linezolid 的峰(Cpeak)、谷(Ctrough)濃度,再利用該濃度計算出最低(Cmin)、最高血中濃度(Cmax)以及24 小時曲線下面積(area-under-the-curve, AUC)。病人所有的資料都經由回顧電子病歷來記錄,同時會追蹤安全性及臨床療效直到療程結束後7 天,並記錄療程結束後30 天內死亡率。所有的不良反應都會由Naranjo scale 做進一步的評估,另外會將確定和極有可能的不良反應定義為linezolid 相關的不良反應納入分析。統計方法會使用Mann-Whitney U test 來比較各個不良反應(有、無)以及臨床療效(改善、失敗)兩組間的濃度差異;同時也會使用羅吉斯回歸進行校正。濃度的切點則是由ROC 曲線搭配自助抽樣法(bootstrap)進行分析,另外在劑量調整的部分則會以描述性統計的方式呈現。最後,在代謝物可能毒性的部分則使用Mann-Whitney U test 作初步的評估。 研究結果 在納入的49 位病人中,平均年齡為61.2 歲且有49 %的病人為男性,並於研究期間進行了66 次療劑監測,大部分(80.4 %)監測時間皆在14 天內。Linezolid 標準劑量(600 mg q12h)及減半劑量(600 mg qd)的Cmin, Cmax 及AUC24 濃度中位數分別為9.19 μg/mL、24.33 μg/mL、360.98 mg/L-hr 及3.48μg/mL、21.59 μg/mL、199.97 mg/L-hr。本研究血中濃度約比仿單高1.5 至2 倍之多,然而跟過去日本文獻相比則類似。在發生的副作用中最多的為血小板低下(62 %),最少為周邊神經病變(6 %)。發生血小板低下的病人的Cmin 顯著較無 發生者高(所有不良反應:13.06 vs. 6.97 μg/mL, p=0.0292;相關之不良反應:17.55 vs. 6.97 μg/mL, p=0.0007);同時Cmin 在發生白血球低下的病人族群也顯著比無發生者高(相關之不良反應:22.54 vs. 9.62 μg/mL, p=0.0291)。在其他副作用(貧血、乳酸性酸中毒、周邊神經病變)以及臨床療效(包括死亡)的部分則未達顯著差異。在濃度切點的部分,若要維持linezolid 安全性應控制Cmin 低於9 μg/mL;此外,降低劑量且仍持續使用7 天以上似乎能改善血小板低下副作用。最後,初步評估的結果顯示代謝物毒性可能跟血小板低下、貧血、乳酸性酸中毒有關,然而需要更多研究來進一步探討其中的關聯性。 結論 Linezolid 標準劑量的血中濃度顯著高出仿單記載1.5 到2 倍,但跟日本族群類似。較高的Cmin 跟血小板低下及白血球低下有關,然而在其他副作用及臨床療效的部分則未達顯著差異。早期使用療劑監測(濃度切點:9 μg/mL)來調整linezolid劑量或許能預防相關之血小板低下及白血球低下的發生。 | zh_TW |
dc.description.abstract | Background
Linezolid is the second line in the treatment of gram-positive cocci and Mycobacterium spp. Severe adverse drug reactions (ADRs) of linezolid include myelosuppression, lactic acidosis, and peripheral neuropathy. Previous studies also showed that high plasma concentration of linezolid may induce thrombocytopenia. Only a few studies demonstrated the relationship between plasma concentration and clinical outcomes, and the appropriate method of dose adjustment still remained controversial. Further investigation is warranted. Objectives This study primarily aimed to investigate the association between concentration of linezolid, ADRs and clinical outcome. The cut-off point of linezolid concentration for therapeutic drug monitoring (TDM) was also explored. Methods A prospective observational study was performed at National Taiwan University Hospital (NTUH) between December 1, 2016, and May 15, 2017. Adult patients with TDM of linezolid were included. Linezolid peak and trough concentrations were measured using HPLC and then the concentrations used to calculate the minimum concentration (Cmin), maximum concentration (Cmax) and 24-hour area-under-the-curve (AUC). All patients’ data were collected via electronic medical charts. The safety and clinical outcomes were assessed throughout the treatment course until 7 days after the completeness of linezolid and 30-day mortality was also recorded. All ADRs were evaluated by Naranjo scale, and the definite/probable ADRs were defined as linezolid-associated adverse drug reactions in the analysis. Mann-Whitney U test was used to compare the difference of concentration between two groups of ADRs or clinical outcomes and the logistic regression was applied to adjust the potential confounders. Receiver operating characteristic (ROC) curve and bootstrap methods were used to calculate the cut-off points. The effect of dose adjustment was performed by descriptive analysis. Finally, the possible toxicity of metabolites was preliminarily evaluated by Mann-Whitney U test. Results Among 49 patients enrolled in the study, mean age were 61.2 years old and 49 % were male. There were 66 linezolid TDMs collected, and most (80.4%) were performed within 14 days. The median Cmin, Cmax and AUC24 of standard dose (600 mg twice daily) and reduced dose (600 mg daily) were 9.19 μg/mL, 24.33 μg/mL, 360.98 mg/L-hr and 3.48 μg/mL, 21.59 μg/mL, 199.97 mg/L-hr, respectively. Plasma concentrations were 1.5- to 2 folds higher than which in the prescribing information but similar to the results in Japanese studies. Thrombocytopenia was the most common adverse drug reactions (62 %) and peripheral neuropathy appeared infrequent (6 %). Median Cmin concentration was significantly higher in patients with thrombocytopenia compared with patients without thrombocytopenia (total ADRs: 13.06 vs. 6.97 μg/mL, p=0.0292; related ADRs: 17.55 vs. 6.97 μg/mL, p=0.0007). Median Cmin level was also significantly higher in patients with related leukopenia ADR than patients without leukopenia (22.54 vs. 9.62 μg/mL, p=0.0291). No association was identified between plasma concentration and anemia, lactic acidosis, peripheral neuropathy or clinical outcomes including mortality. The cut-off point for the upper limit of Cmin in terms of thrombocytopenia was 9 μg/mL. Dose adjustment might be useful for improving thrombocytopenia if that continued linezolid for at least 7 days or more. Preliminary results demonstrated that metabolites-associated possible toxicities were thrombocytopenia, anemia and lactic acidosis and further studies to explore the association was recommended. Conclusions Plasma concentrations of standard dose of linezolid were 1.5- to 2 folds higher than which in the prescribing information, but similar to the results in Japanese studies. Higher Cmin was associated with thrombocytopenia and leukopenia; however, no significant difference was observed between linezolid concentration and other ADRs or clinical outcome. Dose adjustment tailored by early TDM (cut-off point: 9 μg/mL) may be considered to prevent linezolid associated thrombocytopenia and leukopenia. | en |
dc.description.provenance | Made available in DSpace on 2021-06-17T01:46:47Z (GMT). No. of bitstreams: 1 ntu-106-R04451002-1.pdf: 3967317 bytes, checksum: ff5f15ee63ab4ee80df01e78e5eb0ce5 (MD5) Previous issue date: 2017 | en |
dc.description.tableofcontents | 誌謝 i
中文摘要 ii Abstract iv 目錄 vii 圖目錄 xi 表目錄 xiii 第一章 緒論 1 第二章 文獻探討 2 2.1 Linezolid 簡介 2 2.1.1 藥理機轉與藥效作用 2 2.1.2 藥品動態學特性 4 2.1.3 適應症與使用劑量 7 2.1.4 不良反應與注意事項 10 2.1.5 Linezolid相關之嚴重副作用 11 2.1.6 藥品交互作用 12 2.2 藥品血中濃度與療劑監測(therapeutic drug monitoring, TDM) 14 2.2.1 劑量與血中濃度關係 14 2.2.2 血中濃度和不良反應關係 16 2.2.3 血中濃度和臨床療效關係 17 2.2.4 劑量調整準則 20 第三章 研究目的 21 第四章 研究方法 22 4.1 研究架構 22 4.2 研究對象、地點 23 4.3 納入及排除條件 23 4.4 資料收集 23 4.4.1 病人基本資料 23 4.4.2 Linezolid給藥及抽血時間記錄 24 4.4.3 濃度及影響濃度之因子 24 4.4.4 不良反應及臨床療效 26 4.5 Linezolid血中濃度測量方法 27 4.5.1 樣品前處理 27 4.5.2 標準品之配製 27 4.5.3 分析條件 27 4.5.4 分析條件之確效 28 4.6 不良反應評估 29 4.6.1 不良反應定義 29 4.6.2 不良反應相關性(Probability) 30 4.6.3 不良反應開始作用時間及恢復時間(Onset and recovery time) 32 4.7 臨床療效評估 32 4.8 疾病嚴重程度及共病症評估 32 4.9 統計方法 33 第五章 研究結果 35 5.1 分析方法確效 35 5.2 收案情形 43 5.3 病人基本資料(Characteristics) 44 5.3.1 病人基本資料 44 5.3.2 感染症 46 5.3.3 Linezolid劑量與療程 48 5.3.4 Linezolid血中濃度 49 5.3.4.1 TDM血中濃度 49 5.3.4.2 Linezolid劑量與血中濃度 50 5.3.4.3 不同給藥方案(dosing regimen)之血中濃度分布 55 5.4 Linezolid血中濃度與不良反應分析 59 5.4.1 不良反應評估 59 5.4.2 Linezolid血中濃度與不良反應 62 5.4.3 不良反應迴歸分析 69 5.4.3.1 血小板低下(thrombocytopenia) 69 5.4.3.2 貧血 70 5.4.3.3 白血球低下 76 5.4.3.4 乳酸性酸中毒 76 5.5 Linezolid血中濃度與臨床療效分析 82 5.5.1 臨床療效評估 82 5.5.2 Linezolid血中濃度與臨床療效 83 5.6 Linezolid濃度與影響因子分析及切點 88 5.6.1 Linezolid Cmin與影響因子 88 5.6.2 Linezolid不良反應之濃度切點 91 5.7 Linezolid多次TDM分析 92 5.7.1 持續TDM追蹤之分析 92 5.7.2 TDM調整劑量之影響 93 5.7.2.1 劑量調整與濃度 93 5.7.2.2 劑量調整與血小板減少 98 5.8 Linezolid代謝物與不良反應初步分析 101 5.9 收案病人之分析 104 5.9.1 病人基本特性及感染症 104 5.9.2 Linezolid劑量 107 5.9.3 不良反應與臨床療效 108 第六章 討論 110 6.1 藥物分析條件之確效 110 6.2 病人族群與感染症 111 6.3 Linezolid劑量與血中濃度 112 6.4 Linezolid不良反應與血中濃度 115 6.4.1 血小板低下 115 6.4.2 白血球低下 118 6.4.3 其他不良反應 118 6.4.4 影響濃度因子及切點 120 6.5 Linezolid臨床療效與血中濃度 121 6.6 Linezolid劑量調整之影響 122 6.7 Linezolid代謝物 123 6.8 收案病人之分析 125 6.9 研究限制 126 6.10 未來展望 127 第七章 結論 128 參考文獻 129 附錄 133 附錄一、各不良反應單變項迴歸分析 133 附錄二、各不良反應複迴歸分析 156 | |
dc.language.iso | zh-TW | |
dc.title | Linezolid 藥品血中濃度與不良反應之關聯性研究 | zh_TW |
dc.title | Association between Plasma Concentration of Linezolid
and Adverse Drug Reactions | en |
dc.type | Thesis | |
dc.date.schoolyear | 105-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 王振泰(Jann-Tay Wang),郭錦樺(Ching-Hua Kuo),王繼娟(Chi-Chuan Wang),吳建志(Chien-Chih Wu) | |
dc.subject.keyword | linezolid,療劑監測,不良反應,劑量調整,代謝物, | zh_TW |
dc.subject.keyword | Linezolid,therapeutic drug monitoring,adverse drug reactions,dose adjustment,metabolites, | en |
dc.relation.page | 162 | |
dc.identifier.doi | 10.6342/NTU201701975 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2017-07-26 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 臨床藥學研究所 | zh_TW |
顯示於系所單位: | 臨床藥學研究所 |
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