替加环素在感染患者中的血药浓度监测方法
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摘要
目的建立液相色谱-串联质谱(LC-MS/MS)法监测感染患者血浆中替加环素浓度。方法以替加环素-d9为内标,血浆样品用蛋白沉淀法处理,沉淀剂为甲醇。色谱柱为Waters X Select HSS T3 C_(18)柱(2. 1 mm×50 mm,3. 5μm),流动相为甲醇-水(含0. 1%甲酸v/v),梯度洗脱,流速为0. 4 m L·min~(-1)。离子源为AJS-ESI,正离子模式,多反应监测(MRM),替加环素和内标的定量离子对分别为m/z 586. 3→m/z 513. 1,m/z 595. 2→m/z 514. 2。结果替加环素在50～2000 ng·mL~(-1)线性关系良好(R~2=0. 998 4),50,100,500,1600ng·mL~(-1)4个质量浓度质控样品的批内精密度(RSD)<4. 56%,批间精密度(RSD)<7. 84%。4例感染患者替加环素谷浓度平均值分别为115. 46(48. 27～189. 91),245. 19(218. 17～294. 35),185. 40(163. 94～206. 86),55. 87(51. 4～60. 86) ng·mL~(-1)。2例患者鲍曼不动杆菌的抑菌圈分别为12和13mm。结论该方法准确、快速、灵敏,可用于替加环素血药浓度监测及药代动力学研究。
Objective To develop a HPLC-MS/MS method for the monitoring of tigecycline concentration in patients with infection.Methods Plasma samples were precipitated by methanol with tigecycline-d9 as internal standard,then the supernatant was seperated on a waters X Select HSS T3 C_(18) column( 2. 1 mm × 50 mm,3. 5 μm) and eluted by methanol and 0. 1% formic acid in water at a flow rate of 0. 4 m L· min~(-1). A tandem mass spectrometer equipped with electrospray ionization source was used as detector and operated in positive ion mode. The detection was operated by multiple reaction monitoring( MRM)of the transitions of m/z 586. 3 → m/z 513. 1 for tigecycline and m/z595. 2→m/z 514. 2 for tigecycline-d9( IS),respectively. Results The calibration curves were linear ranging from 50 to 2000 ng · m L~(-1)( R~2= 0. 998 4) with a lower limit of quantification of 50 ng · m L~(-1).Both the inter-day and intra-day RSD were satisfactory( less than4. 56% and 7. 84% respectively). The mean trough concentration of tigecycline in 4 patients with infection were 115. 46( 48. 27-189. 91),245. 19( 218. 17-294. 35),185. 40( 163. 94-206. 86) and 55. 87( 51. 4-60. 86) ng·m L~(-1),respectively. The inhibition zone of acinetobacter baumannii in 2 patients were 12 and 13 mm respectively.Conclusion This method is accurate, quick and sensitive for the determination of tigecycline in human plasma. It could be widely used for therapeutic drug monitoring( TDM) and pharmacokinetic study of tigecycline.
Objective To develop a HPLC-MS/MS method for the monitoring of tigecycline concentration in patients with infection.Methods Plasma samples were precipitated by methanol with tigecycline-d9 as internal standard,then the supernatant was seperated on a waters X Select HSS T3 C_(18) column( 2. 1 mm × 50 mm,3. 5 μm) and eluted by methanol and 0. 1% formic acid in water at a flow rate of 0. 4 m L· min~(-1). A tandem mass spectrometer equipped with electrospray ionization source was used as detector and operated in positive ion mode. The detection was operated by multiple reaction monitoring( MRM)of the transitions of m/z 586. 3 → m/z 513. 1 for tigecycline and m/z595. 2→m/z 514. 2 for tigecycline-d9( IS),respectively. Results The calibration curves were linear ranging from 50 to 2000 ng · m L~(-1)( R~2= 0. 998 4) with a lower limit of quantification of 50 ng · m L~(-1).Both the inter-day and intra-day RSD were satisfactory( less than4. 56% and 7. 84% respectively). The mean trough concentration of tigecycline in 4 patients with infection were 115. 46( 48. 27-189. 91),245. 19( 218. 17-294. 35),185. 40( 163. 94-206. 86) and 55. 87( 51. 4-60. 86) ng·m L~(-1),respectively. The inhibition zone of acinetobacter baumannii in 2 patients were 12 and 13 mm respectively.Conclusion This method is accurate, quick and sensitive for the determination of tigecycline in human plasma. It could be widely used for therapeutic drug monitoring( TDM) and pharmacokinetic study of tigecycline.
引文
[1]CHINET中国细菌耐药监测网.CHINET中国细菌耐药监测(2018年1-6月)[EB/OL].上海:复旦大学附属华山医院抗生素研究所,2018-10-17[2018-10-25].www.chinets.com.
[2]黄勋,邓子德,倪语星,等.多重耐药菌医院感染预防与控制中国专家共识[J].中国感染控制杂志,2015,14(1):1-9.
[3]陈佰义,何礼贤,胡必杰,等.中国鲍曼不动杆菌感染诊治与防控专家共识[J].中国医药科学,2012,2(8):3-8.
[4]梅和坤,王瑾,柴栋,等.替加环素临床研究现状的分析[J].中国临床药理学杂志,2018,34(10):1236-1239.
[5]DE PASCALE G,MONTINI L,PENNISI M A,et al.High dose tigecycline in critically ill patients with severe infections due to multidrug-resistant bacteria[J].Crit Care,2014,18(3):R90.
[6]US FOOD AND DRUG ADMINISTRATION(FDA).Tygacil(tigecycline for injection)[EB/OL].US:FDA,2009-02-10[2018-09-22].https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021821s016lbl.pdf.
[7]何渊慧,张凌云,李耘,等.不同Mueller-Hinton培养基对鲍曼不动杆菌替加环素体外药敏结果的影响[J].中国临床药理学杂志,2018,34(9):1060-1063.
[8]BHAVNANI S M,RUBINO C M,HAMMEL J P,et al.Pharmacological and patient-specific response determinations in patients with hospital-acquired pneumonia treated with tigecycline[J].Antimicrob Agents Chemother,2012,56(2):1065-1072.
[2]黄勋,邓子德,倪语星,等.多重耐药菌医院感染预防与控制中国专家共识[J].中国感染控制杂志,2015,14(1):1-9.
[3]陈佰义,何礼贤,胡必杰,等.中国鲍曼不动杆菌感染诊治与防控专家共识[J].中国医药科学,2012,2(8):3-8.
[4]梅和坤,王瑾,柴栋,等.替加环素临床研究现状的分析[J].中国临床药理学杂志,2018,34(10):1236-1239.
[5]DE PASCALE G,MONTINI L,PENNISI M A,et al.High dose tigecycline in critically ill patients with severe infections due to multidrug-resistant bacteria[J].Crit Care,2014,18(3):R90.
[6]US FOOD AND DRUG ADMINISTRATION(FDA).Tygacil(tigecycline for injection)[EB/OL].US:FDA,2009-02-10[2018-09-22].https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021821s016lbl.pdf.
[7]何渊慧,张凌云,李耘,等.不同Mueller-Hinton培养基对鲍曼不动杆菌替加环素体外药敏结果的影响[J].中国临床药理学杂志,2018,34(9):1060-1063.
[8]BHAVNANI S M,RUBINO C M,HAMMEL J P,et al.Pharmacological and patient-specific response determinations in patients with hospital-acquired pneumonia treated with tigecycline[J].Antimicrob Agents Chemother,2012,56(2):1065-1072.