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Volume 39 Issue 6
Nov.  2021
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DAI Qing, CHENG Lin, HU Xianfei, LIU Fang. Study on the relationship between cystatin C level and the plasma trough concentration of teicoplanin[J]. Journal of Pharmaceutical Practice and Service, 2021, 39(6): 569-572. doi: 10.12206/j.issn.1006-0111.202103027
Citation: DAI Qing, CHENG Lin, HU Xianfei, LIU Fang. Study on the relationship between cystatin C level and the plasma trough concentration of teicoplanin[J]. Journal of Pharmaceutical Practice and Service, 2021, 39(6): 569-572. doi: 10.12206/j.issn.1006-0111.202103027

Study on the relationship between cystatin C level and the plasma trough concentration of teicoplanin

doi: 10.12206/j.issn.1006-0111.202103027
  • Received Date: 2021-03-18
  • Rev Recd Date: 2021-09-01
  • Available Online: 2021-12-27
  • Publish Date: 2021-11-25
  •   Objective  To investigate the relationship between cystatin C level and the plasma trough concentration of teicoplanin, so as to provide a reference for the rational application of teicoplanin in clinical practice.   Methods  The clinical data of the patients receiving teicoplanin, who admitted to our hospital from October 2017 to July 2020 were retrospectively analyzed. The distribution of teicoplanin concentration, the difference of teicoplanin concentration under different cystatin C level, and influence factors for teicoplanin concentration (<15 µg/ml) were analyzed.   Results  A total of 98 patients including 65 males and 33 females, aged 19 to 94 (52.2±16.2) years old, with 141 trough concentrations were enrolled. The trough concentration of teicoplanin was 11.51 (8.35, 19.07) µg/ml, and the range was 3.57-41.93 µg/ml. 95 cases (67.38%) had teicoplanin concentration <15 µg/ml. When the concentration of cystatin C was >1.05 mg/L, the trough concentration of teicoplanin were 11.37 (8.96, 20.52) µg/ml, significantly higher than those when the concentration of cystatin C was in normal [8.68 (6.34, 11.79) µg/ml, Z=−2.636, P<0.05]. Logistic regression analysis showed that cystatin C level was the influencing factor for teicoplanin trough concentration does not meet the standard (OR=1.529, 95%CI=1.001-2.336, P<0.05).   Conclusion  The concentration of teicoplanin is significantly increased when the cystatin C level is higher than the normal. Cystatin C level is the influence factor for teicoplanin trough concentration not meeting the standard. The cystatin C level may be considered as a reference for teicoplanin dosage adjustment in clinical practice.
  • [1] 沈琮, 陈文倩, 张相林. 替考拉宁治疗药物监测进展[J]. 中国医院用药评价与分析, 2019, 19(7):890-894,896.
    [2] ZHOU L J, GAO Y Q, CAO W, et al. Retrospective analysis of relationships among the dose regimen, trough concentration, efficacy, and safety of teicoplanin in Chinese patients with moderate-severe Gram-positive infections[J]. Infect Drug Resist,2018,11:29-36. doi:  10.2147/IDR.S146961
    [3] 何丹, 董娜, 朱怀军, 等. 基于替考拉宁群体药物代谢动力学模型的个体化给药研究进展[J]. 临床药物治疗杂志, 2020, 18(5):38-42. doi:  10.3969/j.issn.1672-3384.2020.05.008
    [4] 梁培, 郭晓芳. 重症感染患者替考拉宁血药谷浓度68例次监测分析[J]. 实用药物与临床, 2018, 21(5):553-556.
    [5] 张荣格, 张瑞霞, 张弋. 替考拉宁的血药浓度监测及影响因素分析[J]. 中国药学杂志, 2019, 54(8):654-658.
    [6] 吕佩瑜, 邓方斌, 林玮玮, 等. 替考拉宁在中国成人患者中的群体药动学研究[J]. 中国药学杂志, 2020, 55(8):616-622.
    [7] 李芳, 蔡乐, 毛智, 等. 重症感染患者负荷剂量替考拉宁的血药浓度监测[J]. 临床药物治疗杂志, 2019, 17(11):44-48. doi:  10.3969/j.issn.1672-3384.2019.11.010
    [8] DHARNIDHARKA V R, KWON C, STEVENS G. Serum cystatin C is superior to serum creatinine as a marker of kidney function: a meta-analysis[J]. Am J Kidney Dis,2002,40(2):221-226. doi:  10.1053/ajkd.2002.34487
    [9] 周丽娟, 刘嘉, 曹巍, 等. 替考拉宁血药浓度监测对肺炎患者用药方案的指导意义探讨[J]. 中国医院药学杂志, 2017, 37(8):771-775.
    [10] 胡萨萨, 尤海生, 金建霞, 等. 中性粒细胞缺乏伴发热患者应用替考拉宁抗感染的剂量监测及优化[J]. 河北医药, 2019, 41(23):3654-3658. doi:  10.3969/j.issn.1002-7386.2019.23.035
    [11] 王冉冉, 马婧, 黄晓会. 重症感染患者替考拉宁血药谷浓度不达标的相关因素分析[J]. 中国药师, 2020, 23(3):494-496. doi:  10.3969/j.issn.1008-049X.2020.03.021
    [12] KASAI H, TSUJI Y, HIRAKI Y, et al. Population pharmacokinetics of teicoplanin in hospitalized elderly patients using cystatin C as an indicator of renal function[J]. J Infect Chemother,2018,24(4):284-291. doi:  10.1016/j.jiac.2017.12.002
    [13] KOZONO A, HIRAKI Y, ADACHI R, et al. Comparison of predictive accuracy of teicoplanin concentration using creatinine clearance and glomerular filtration rate estimated by serum creatinine or cystatin C[J]. J Infect Chemother,2016,22(5):314-318. doi:  10.1016/j.jiac.2016.01.024
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Study on the relationship between cystatin C level and the plasma trough concentration of teicoplanin

doi: 10.12206/j.issn.1006-0111.202103027

Abstract:   Objective  To investigate the relationship between cystatin C level and the plasma trough concentration of teicoplanin, so as to provide a reference for the rational application of teicoplanin in clinical practice.   Methods  The clinical data of the patients receiving teicoplanin, who admitted to our hospital from October 2017 to July 2020 were retrospectively analyzed. The distribution of teicoplanin concentration, the difference of teicoplanin concentration under different cystatin C level, and influence factors for teicoplanin concentration (<15 µg/ml) were analyzed.   Results  A total of 98 patients including 65 males and 33 females, aged 19 to 94 (52.2±16.2) years old, with 141 trough concentrations were enrolled. The trough concentration of teicoplanin was 11.51 (8.35, 19.07) µg/ml, and the range was 3.57-41.93 µg/ml. 95 cases (67.38%) had teicoplanin concentration <15 µg/ml. When the concentration of cystatin C was >1.05 mg/L, the trough concentration of teicoplanin were 11.37 (8.96, 20.52) µg/ml, significantly higher than those when the concentration of cystatin C was in normal [8.68 (6.34, 11.79) µg/ml, Z=−2.636, P<0.05]. Logistic regression analysis showed that cystatin C level was the influencing factor for teicoplanin trough concentration does not meet the standard (OR=1.529, 95%CI=1.001-2.336, P<0.05).   Conclusion  The concentration of teicoplanin is significantly increased when the cystatin C level is higher than the normal. Cystatin C level is the influence factor for teicoplanin trough concentration not meeting the standard. The cystatin C level may be considered as a reference for teicoplanin dosage adjustment in clinical practice.

DAI Qing, CHENG Lin, HU Xianfei, LIU Fang. Study on the relationship between cystatin C level and the plasma trough concentration of teicoplanin[J]. Journal of Pharmaceutical Practice and Service, 2021, 39(6): 569-572. doi: 10.12206/j.issn.1006-0111.202103027
Citation: DAI Qing, CHENG Lin, HU Xianfei, LIU Fang. Study on the relationship between cystatin C level and the plasma trough concentration of teicoplanin[J]. Journal of Pharmaceutical Practice and Service, 2021, 39(6): 569-572. doi: 10.12206/j.issn.1006-0111.202103027
  • 替考拉宁是一种糖肽类抗生素,临床上主要用于治疗各种严重的革兰阳性菌感染,包括不能用青霉素类和头孢菌素类其他抗生素者。该药的血药浓度与临床疗效密切相关,对于重症感染患者,监测血药浓度可以提高治愈率[1]。临床一般检测其在血浆中的稳态谷浓度,而在不同疾病中,替考拉宁谷浓度需达到对应的目标值才能满足治疗要求,但由于替考拉宁成分复杂,患者在常规剂量使用过程中低于目标谷浓度的发生率很高,因此,对替考拉宁进行血药浓度监测很有必要[2-4]。替考拉宁血浆谷浓度的检测方法目前主要为高效液相色谱(HPLC)法,需要专职人员进行,很多单位尚无条件进行检测。因此,寻找替考拉宁谷浓度的临床预测指标,探讨其与替考拉宁谷浓度的关系,就显得尤为重要。替考拉宁血浆蛋白结合率高,与白蛋白的结合率为 90%~95%,消除半衰期长,除 2%~3% 经肝脏代谢外,大部分以原型经肾脏排泄。肾功能的变化必然对替考拉宁谷浓度产生明显影响,既往研究也显示肌酐清除率会对替考拉宁谷浓度产生明显影响[5-7]。胱抑素C是一种能灵敏反映肾小球滤过率变化的内源性标志物[8],其血中浓度由肾小球滤过率决定,不受炎症反应、肌肉、性别等的影响。本研究主要探讨胱抑素C水平与替考拉宁血浆稳态谷浓度的关系,以期为临床替考拉宁的合理应用提供依据。

    • 本研究收集2017年10月−2020年7月在陆军军医大学第一附属医院进行替考拉宁血药浓度监测患者。患者纳入标准:①年龄≥18岁;②住院患者;③替考拉宁谷浓度为稳态谷浓度。排除标准:①孕妇;②未监测肝肾功能者;③血液透析者。本研究经本院伦理委员会批准(批号:KY2020109)。

    • 患者每日经静脉滴注给予替考拉宁(给药剂量为200~800 mg,qd,根据患者疗效和不良反应以及血药浓度监测结果对给药剂量进行调整;患者疗程为7~67 d),最早于第6剂(替考拉宁谷浓度达稳态)给药前30 min,用EDTA管采集静脉血4 ml,3 500 r/min室温离心5 min,取出血浆按下述高效液相色谱(HPLC)法测定其谷浓度。替考拉宁对照品溶液:取替考拉宁对照品适量,精密称定(20.00 mg)后置于10 ml棕色量瓶中,用超纯水溶解并稀释至刻度,混匀,即得。哌拉西林钠对照品溶液:取哌拉西林钠对照品(内标)适量,精密称定(15.43 mg)后置于100 ml棕色量瓶中,用甲醇溶解并稀释至刻度,混匀,即得。色谱柱:Diamonsil C18(250 mm×4.6 mm,5 µm);柱温:40 ℃;流动相:0.01 mol/L磷酸二氢钠-乙腈(76∶24,V/V);流速:1.6 ml/min;紫外检测波长为240 nm;进样量:20 µl。取待测血浆0.4 ml,加入50 µl内标甲醇液(150 µg/ ml),涡旋混匀30 s,随后再加入乙腈0.6 ml,涡旋混匀1 min,13 000 r/min,离心5 min,取出上清液0.9 ml加入0.4 ml二氯甲烷,涡旋混匀1 min,13 000 r/min,离心5 min,上清液20 µl进样测定。

      空白血浆中加入替考拉宁对照品溶液适量,再依次用空白血浆分别稀释成3.125、6.250、12.50、25.00、50.00、100.0 µg/ml系列浓度,处理后上液相色谱仪测定,记录色谱图,将替考拉宁(TA2-2)与内标的峰面积比值(R)对浓度(C)进行线性回归,得回归方程(n=6):R=0.6821C−2.186×10−2r=0.9999,线性范围:3.125~100.0 µg/ml,本试验最低定量限为3.125 µg/ml,其5次测量值的RSD为2.57 %。

    • 炎症指标、肾功能指标、肝功能指标及其他实验室检查指标均由本院检验科测定。胱抑素C的检测采用胶乳增强免疫比浊法测定。质控品按其说明书进行操作,每天进行一次质控实验。试剂空白吸光度:波长546 nm,光径10 mm,测得吸光度值A≤1.5000。线性范围:0.2~8 mg/L范围内线性相关系数r≥0.995,0.2~2.0 mg/L范围内绝对偏差≤0.2 mg/L,2.0~8 mg/L范围内相对偏差≤10.0%。准确度:相对偏差≤10.0%。分析灵敏度:样本浓度为1.0 mg/L时,吸光度差值为0.0060~0.0600。

    • 收集患者的人口统计学资料,包括患者性别、年龄、感染类型和病原菌,给药剂量、给药方式、替考拉宁谷浓度,与替考拉宁谷浓度监测同一时间点的炎症指标降钙素原(PCT),肾功能指标血肌酐和胱抑素C,肝功能相关指标谷丙转氨酶(ALT)、天门冬氨酸氨基转移酶(AST)、总蛋白、白蛋白、胆红素、直接胆红素,以及葡萄糖水平等。

    • 采用SPSS 18.0统计软件进行分析。对计数资料行χ2检验;对连续性变量先进行正态分布检验,对不符合正态分布的变量,以中位数(第25百分位数,第75百分位数)表示。不同胱抑素C水平下替考拉宁谷浓度不符合正态分布,行 Mann-Whitney检验;Logistic回归分析替考拉宁谷浓度不达标(<15 µg/ml)的影响因素,以P<0.05为差异有统计学意义。

    • 共入组98例患者141个谷浓度,其中男65例、女33例,年龄19~94(52.2±16.2)岁,60岁以上者32例(32.0%)。患者肺部感染57例,粒细胞缺乏伴感染14例,腹腔感染12例,感染性心内膜炎4例,其他11例;感染检出病原菌有耐甲氧西林金黄色葡萄球菌、肺炎克雷伯菌、铜绿假单胞菌、鲍氏不动杆菌、粪肠球菌、大肠埃希菌和嗜麦芽窄食单胞菌等。入组患者的炎症指标PCT的均值为2.09,说明患者的感染程度较重。患者的实验室检查指标情况见表1

      指标中位数(第25,
      第75百分位数)
      范围
      ALT(U/L)7.60(3.45,22.42)3.2~339.4
      AST(U/L)21.30(12.50,45.40)5.4~624.6
      总蛋白(g/L)60.05(54.52,67.28)42.3~103.8
      白蛋白(g/L)32.00(28.30,35.15)20.8~43.9
      胆红素(mol/L)19.70(13.10,44.20)4.8~698.78
      直接胆红素(mol/L)7.00(5.36,9.63)1.0~437.8
      血肌酐(mol/L)66.04(46.00,98.60)22.6~482.9
      胱抑素C(mg/L)1.22(0.91,1.94)0.45~6.37
      降钙素原(ng/ml)0.61(0.26,2.07)0.02~20.98
      注:表中括弧中数据为四分位中位数。
    • 患者替考拉宁谷浓度为11.51(8.35,19.07)µg/ml,范围为3.57~41.93 µg/ml,谷浓度<15 µg/ml者95例次(67.38 %)。替考拉宁给药剂量为400 mg时,谷浓度<15 µg/ml的百分比为80.90 %(72/89);替考拉宁给药剂量为800 mg时,谷浓度<15 µg/ml的百分比为42.86 %(18/42);两种给药剂量比较,差异有统计学意义(χ2=19.205,P<0.01)。

    • 胱抑素C浓度>1.05 mg/L时,替考拉宁谷浓度明显高于胱抑素C浓度在0.3~1.05 mg/L时(Z=-2.636,P=0.008),见表2

      胱抑素C(mg/L)替考拉宁浓度(µg/ml)替考拉宁浓度范围(µg/ml)
      ≤1.05 8.68(6.34,11.79)3.57~26.47
      >1.0511.37(8.96,20.52)3.73~41.93
      注:表中括弧中数据为四分位中位数。
    • 炎症指标PCT,肝功能相关指标总蛋白、白蛋白、胆红素、直接胆红素和葡萄糖水平与替考拉宁谷浓度不相关(P>0.05)。血肌酐浓度与替考拉宁谷浓度呈正相关(P<0.01),胱抑素C浓度与替考拉宁谷浓度呈正相关(P<0.05),见表3

      指标名称rP
      胱抑素C(mg/L)0.2250.036
      血肌酐(mol/L)0.2480.009
      降钙素原(ng/ml)0.0480.706
      总蛋白(g/L)0.0320.746
      白蛋白(g/L)0.1400.134
      胆红素(mol/L)−0.0250.798
      直接胆红素(mol/L)−0.0410.670
      葡萄糖(mmol/L)0.0840.426
    • 通过纳入替考拉宁谷浓度影响因素如患者性别、年龄、胱抑素C、血肌酐、ALT、AST、白蛋白、总蛋白、胆红素、直接胆红素进行Logistic回归分析,结果显示,替考拉宁谷浓度不达标(<15 µg/ml)的影响因素是患者年龄、胱抑素C和白蛋白水平(P<0.05),见表4

      因素OR值95%CIP
      胱抑素C1.5291.001~2.3360.049
      白蛋白1.1541.025~1.2990.018
      年龄0.9520.917~0.9890.012
    • 替考拉宁的血药浓度与临床疗效间存在较强的相关性,研究显示,治疗严重感染时,替考拉宁有效血谷浓度不应<10 mg/L,但目前临床使用中却发现其血药浓度达标率普遍偏低[3-4, 9]。2017年,注射用替考拉宁说明书的变更获批,提出重度感染时,替考拉宁谷浓度应达到15~30 mg/L。因此,本研究以替考拉宁谷浓度<15 µg/ml为不达标,而本研究中不达标患者百分比为67.38%,值得引起重视。给予标准负荷剂量6 mg/kg的替考拉宁早期均不能达到目标谷浓度,不论患者肌酐清除率正常与否;给予高负荷剂量10 mg/kg替考拉宁的低肌酐清除率者早期可达目标谷浓度[10-11]。本研究中,替考拉宁给药剂量为800 mg时,其谷浓度达标的百分比明显高于替考拉宁给药剂量为400 mg时,提示临床上应提高替考拉宁负荷剂量的使用率。

      近年来研究表明血清胱抑素C能更准确地评价患者肾功能[5]。正常情况下,胱抑素C在血清和血浆中的浓度为0.3~1.05 mg/L。当肾功能受损时,胱抑素C在血液中的浓度会升高。有研究考察了胱抑素C、肌酐清除率和肾小球滤过率3种评价指标对替考拉宁体内代谢的影响,结果显示胱抑素C是影响替考拉宁清除率最显著的协变量[12-13]。因此,本研究考察了胱抑素C水平与替考拉宁谷浓度的关系,结果显示,胱抑素C水平高于正常值上限时,替考拉宁谷浓度明显升高。另外,替考拉宁谷浓度不达标影响因素的Logistic回归分析结果显示,胱抑素C是替考拉宁谷浓度不达标的影响因素。

      研究显示,肌酐清除率显著影响替考拉宁的谷浓度[4,7,11],但血肌酐对替考拉宁谷浓度的影响无统计学意义[4]。本研究中,血肌酐浓度越高,替考拉宁谷浓度越高,但血肌酐不是替考拉宁谷浓度不达标的影响因素。有研究显示,白蛋白为影响替考拉宁清除率的主要因素[7]。本研究中,白蛋白水平虽与替考拉宁谷浓度不存在相关性,与相关研究相符[5],但白蛋白是替考拉宁谷浓度不达标的影响因素。另有研究显示,替考拉宁谷浓度与剂量的比值与炎症指标超敏 C 反应蛋白成负相关[6],本研究考察了另一炎症指标PCT与替考拉宁谷浓度的相关性,结果显示PCT与替考拉宁谷浓度不存在相关性。分析原因可能与影响替考拉宁谷浓度的其他因素,如年龄、性别、体重指数、给药剂量和肾功能差异等有关;也可能与PCT和C反应蛋白虽然同是炎症指标,但二者产生的机制,发挥的生理作用和临床预测价值不同有关。

      本研究的不足之处:由于每例患者替考拉宁谷浓度监测次数多为1~2次,本研究未考察替考拉宁谷浓度与疗效的相关性,而只是考察了替考拉宁谷浓度的影响因素。终上所述,本研究结果显示,替考拉宁给药剂量为400 mg时,谷浓度不达标<15 µg/ml的百分比明显高于替考拉宁给药剂量为800 mg时,提示临床上应提高替考拉宁负荷剂量的使用率。胱抑素C浓度高于正常值上限时替考拉宁谷浓度明显升高,是替考拉宁谷浓度不达标的影响因素,提示除肌酐清除率外,无条件进行替考拉宁血药浓度监测的单位,可以考虑将胱抑素C作为替考拉宁剂量调整的参考指标。

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