不同给药途径下万古霉素的脑脊液和血液药物浓度及其疗效比较
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摘要
研究背景及目的
革兰氏阳性菌是医院内感染和社区获得性感染的重要病原菌，也是神经外科感染的主要致病菌。万古霉素(Vancomycin hydrochloride)是来自东方链霉菌(streptomyces orientalis)的糖肽类抗生素，专门用于革兰氏阳性菌感染，尤其是近年来逐渐增多的耐甲氧西林葡萄球菌(MRS)感染。静脉注射万古霉素仅在发生脑膜炎时才能透过血脑屏障，并且其穿透性是不可预知的。临床上经常采取鞘内给药或脑室内给药的方法治疗脑膜炎，但关于万古霉素的脑脊液中给药，在剂量、疗程及毒理方面仍缺乏大宗病例研究及实验研究。本研究采用前瞻性随机对照设计，旨在通过对静脉输注联合鞘内注射万古霉素治疗革兰氏阳性菌脑膜炎时的血液和脑脊液中的药物浓度进行测定，达到以下目的：
1．获得鞘内注射万古霉素治疗革兰氏阳性菌脑膜炎时的血液和脑脊液中的药物峰、谷浓度；
2．比较单纯静脉输注和静脉输注联合鞘内注射万古霉素两种给药途径的疗效；
3．通过临床观察药物不良反应和3～12个月的随访观察，总结鞘内给药的安全性。
资料和方法
本院经确诊和经验性诊断革兰氏阳性菌脑膜炎共26例随机分为2组，治疗组13例，对照组13例。其中，男性17例，女性9例，年龄为24～67岁。26例患者均有发热症状，伴头痛、呕吐症状的11例，脑膜刺激征9例。病因包括脑室腹腔分流术11例，颅脑损伤11例(其中行开颅手术7例)，肿瘤开颅手术4例。CSF常规检查均有白细胞计数升高，平均386.63个／μL，最高3200个／μL，CSF细菌涂片见革兰氏阳性菌21例，另5例为经验性拟诊。脑脊液培养加药敏结果为耐甲氧西林葡萄球菌(MRS)5例，其中耐甲氧西林金黄色葡萄球菌(MRSA)3例，耐甲氧西林表皮葡萄球菌(MRSE)2例，均对万古霉素敏感，另外16例培养结果为阴性。26例患者受试前体检心、肝、肾等功能均正常。治疗组给予盐酸万古霉素(稳可信(?)，VANCOCIN(?)，美国礼来亚洲公司，Lilly)静脉注射，每次0.5g，每日4次，输液时间控制为60min(1例90min)。另加用鞘内注射万古霉素20mg，每日1次。对照组仅静脉给予与治疗组相同的万古霉素。治疗过程中收集万古霉素的脑脊液和血液标本，应用荧光偏振免疫分析法进行药物浓度测定。本研究使用SPSS11.5统计软件进行数据处理，计量资料数据均采用均值±标准差((?)±s)表示，两样本均数比较用t检验和复式误差限图，计数资料比较采用χ~2检验，p＜0.05为差异有统计学意义。
结果
治疗组用药11.92±3.75天，对照组用药17.08±4.92天，比较两组用药时间的差异有统计学意义，治疗组用药时间少于对照组。治疗组治疗有效率100％，对照组有效率84.62％(11／13)。两组血液中万古霉素药物峰、谷浓度比较无统计学意义。治疗组CSF中峰浓度135.99±106.84mg／L，谷浓度28.01±14.12mg／L，对照组峰浓度4.21±2.28mg／L，谷浓度1.27±0.76mg／L，两组比较差异有统计学意义，治疗组CSF中万古霉素药物峰、谷浓度均明显高于对照组。用药期间在治疗组和对照组患者中，仅1例出现“红人综合症”。所有患者未见肝肾功能损害，听力下降，血细胞异常变化，腹痛腹泻，肢体抽搐，蛛网膜下腔粘连等。随访3～12个月，综合CT、MRI、实验室检查和体格检查等未见万古霉素致损表现。
结论
1鞘内注射万古霉素可达到数倍于最小抑菌浓度(MIC)的药物浓度。
2鞘内注射万古霉素是一种治疗革兰氏阳性菌感染性脑膜炎的安全、有效方法。
3鞘内注射万古霉素疗效确切，能明显缩短治疗时间，减少治疗费用。
Background and purposes of the research
Gram-positive bacteria is the important pathogen of hospital-acquired infections and community-acquired infections. Vancomycin is a glycopeptide antibiotic that was isolated in 1956 from the actinomycetes Streptomyces orientalis and is used to treat gram-positive bacteria, especially to methicillin-resistant Staphylococcus (MRS) infections that is increasing recent years. Vancomycin when administered intravenously cerebrospinal fluid (CSF) permeation can be finded only in the situation of meningitis, but the level of concentrations can not be predicted. So it often is used for intrathecal or intraventricular administration to cure the meningitis clinically. But, what about the dosage, course of treatment, toxicity et al of Vancomycin administration into the cerebrospinal fluidis poorly reported previously. A Prospective randomized controlled trial was performed to reach the aim:
1. to obtain the data of vancomycin intrathecal administration drug peak and trough concentrations in CSF and serum to gram- positive bacterial meningitis;
2. to compare the effect of vancomycin administration intravenously sololy and intravenously conbining with intrathecally;
3. We will evaluate the safety of intrathecal administration through clinical observation of adverse effect and the following-up.
Materials and Methods
twenty six adult patients with gram-positive bacterial meningitis or diagnosed empirically were randomly divided into two groups: therapied group ( 13 cases) and controlled group (13 cases), range 24—67 years, 17 men and 9 women. All patients had the symptom of fever, with headache and emesis in 11 cases, and meningeal irritation sign in nine. Etiopathogenisis include ventriculoperitoneal shunt in 11 cases, cerebral trauma in 11cases (craniotomy in 7cases), and craniotomy in 4cases with tumors. All the routine examination of CSF has the result of leucocyte count rising, mean count is 386.63/μL and the highest is 3200/μL. The result of CSF bacterial stain smear is Gram-positive bacteria in 21 cases, diagnosed empirically in else 5 cases.The result of CSF culture and drug sensitivity test is 5 strains of methicillin resistant staphylococcus (MRS) , including three methicillin resistant staphylococcus aureus (MRSA) and two methicillin resistant staphylococcus epidermidis (MRSE). All the MRS strains are sensitive to vancomycin and the results of CSF culture are negative of else 16 cases. All the 26 patients'function of heart, liver and kidney was normal before our treatment. Vancomycin was administered intravenously and intrathecally in therapied group and only intravenously in controlled group daily. Vancomycin intravenously was administered at a daily dose of 2g in four administration (500 mg intravenously over 60 min every 6 h), and intrathecally at a daily dose of 20mg once. The samples of blood and CSF were collected, the concentration of vancomycin in serum and CSF was determined by fluorescence polarization immunoassay (FPIA) method. Statistical analysis was done with the software program SPSS 11.5, quantitative results presented are the mean±standard deviation (SD) ((?)±s), comparison means was used with Independent-Samples T Test and the Clustered Error Bar, comparison numeration data was done with Chi-Square Test, a probability value (p value ) of less than 0.05 was considered significant.
Results
The administration time of therapied group was 11.92±3.75 days, and controlled group was 17.08±4.92 days, there was significant difference between the two groups (P=0.006) , therapied group was shorter than controlled group. The effective power of therapied group was 100%, and controlled group was 84.62% ( 11/13 ). There was no significant difference between the two groups at the peak and trough concentrations of vancomycin in serum. The peak concentration of vancomycin in therapied group was 135.99±106.84mg/L , trough concentration was 28.01±14.12mg/L, The peak concentration of vancomycin in controlled group was 4.21±2.28mg/L, trough concentration was1.27±0.76mg/L, there was significant difference between the two groups (P=0.000, 0.000) , Both the peak and trough concentrations of vancomycin in CSF of therapied group were higher than those of controlled group. There was no adverse effect except one patient with "Red man syndrome" in the period of administration of all patients, and no evidence of functional lesion of liver and kidney, hearing functional lesion, abnormal changing in hematocyte, abdominal pain, diarrhoea, epilepsy and subarachnoid cavity adherence. In the following-up 3 to 12 months, combination with the examinations of CT, MRI, laboratory and physical was no evidence of vancomycin toxical injury.
Conclusions
I The results of our study demonstrate that vancomycin intrathecal administration can reach the level of drug concentrations that is several times than minimum inhibitory concentration (MIC) within the CSF.
2 The results of our study demonstrate that vancomycin intrathecal administration is a safe and efficacious treatment modality in gram-positive bacterial meningitis.
3 The results of our study demonstrate that vancomycin intrathecal administration can cure gram-positive bacterial meningitis with much shorter treatment time and lower costs.
革兰氏阳性菌是医院内感染和社区获得性感染的重要病原菌，也是神经外科感染的主要致病菌。万古霉素(Vancomycin hydrochloride)是来自东方链霉菌(streptomyces orientalis)的糖肽类抗生素，专门用于革兰氏阳性菌感染，尤其是近年来逐渐增多的耐甲氧西林葡萄球菌(MRS)感染。静脉注射万古霉素仅在发生脑膜炎时才能透过血脑屏障，并且其穿透性是不可预知的。临床上经常采取鞘内给药或脑室内给药的方法治疗脑膜炎，但关于万古霉素的脑脊液中给药，在剂量、疗程及毒理方面仍缺乏大宗病例研究及实验研究。本研究采用前瞻性随机对照设计，旨在通过对静脉输注联合鞘内注射万古霉素治疗革兰氏阳性菌脑膜炎时的血液和脑脊液中的药物浓度进行测定，达到以下目的：
1．获得鞘内注射万古霉素治疗革兰氏阳性菌脑膜炎时的血液和脑脊液中的药物峰、谷浓度；
2．比较单纯静脉输注和静脉输注联合鞘内注射万古霉素两种给药途径的疗效；
3．通过临床观察药物不良反应和3～12个月的随访观察，总结鞘内给药的安全性。
资料和方法
本院经确诊和经验性诊断革兰氏阳性菌脑膜炎共26例随机分为2组，治疗组13例，对照组13例。其中，男性17例，女性9例，年龄为24～67岁。26例患者均有发热症状，伴头痛、呕吐症状的11例，脑膜刺激征9例。病因包括脑室腹腔分流术11例，颅脑损伤11例(其中行开颅手术7例)，肿瘤开颅手术4例。CSF常规检查均有白细胞计数升高，平均386.63个／μL，最高3200个／μL，CSF细菌涂片见革兰氏阳性菌21例，另5例为经验性拟诊。脑脊液培养加药敏结果为耐甲氧西林葡萄球菌(MRS)5例，其中耐甲氧西林金黄色葡萄球菌(MRSA)3例，耐甲氧西林表皮葡萄球菌(MRSE)2例，均对万古霉素敏感，另外16例培养结果为阴性。26例患者受试前体检心、肝、肾等功能均正常。治疗组给予盐酸万古霉素(稳可信(?)，VANCOCIN(?)，美国礼来亚洲公司，Lilly)静脉注射，每次0.5g，每日4次，输液时间控制为60min(1例90min)。另加用鞘内注射万古霉素20mg，每日1次。对照组仅静脉给予与治疗组相同的万古霉素。治疗过程中收集万古霉素的脑脊液和血液标本，应用荧光偏振免疫分析法进行药物浓度测定。本研究使用SPSS11.5统计软件进行数据处理，计量资料数据均采用均值±标准差((?)±s)表示，两样本均数比较用t检验和复式误差限图，计数资料比较采用χ~2检验，p＜0.05为差异有统计学意义。
结果
治疗组用药11.92±3.75天，对照组用药17.08±4.92天，比较两组用药时间的差异有统计学意义，治疗组用药时间少于对照组。治疗组治疗有效率100％，对照组有效率84.62％(11／13)。两组血液中万古霉素药物峰、谷浓度比较无统计学意义。治疗组CSF中峰浓度135.99±106.84mg／L，谷浓度28.01±14.12mg／L，对照组峰浓度4.21±2.28mg／L，谷浓度1.27±0.76mg／L，两组比较差异有统计学意义，治疗组CSF中万古霉素药物峰、谷浓度均明显高于对照组。用药期间在治疗组和对照组患者中，仅1例出现“红人综合症”。所有患者未见肝肾功能损害，听力下降，血细胞异常变化，腹痛腹泻，肢体抽搐，蛛网膜下腔粘连等。随访3～12个月，综合CT、MRI、实验室检查和体格检查等未见万古霉素致损表现。
结论
1鞘内注射万古霉素可达到数倍于最小抑菌浓度(MIC)的药物浓度。
2鞘内注射万古霉素是一种治疗革兰氏阳性菌感染性脑膜炎的安全、有效方法。
3鞘内注射万古霉素疗效确切，能明显缩短治疗时间，减少治疗费用。
Background and purposes of the research
Gram-positive bacteria is the important pathogen of hospital-acquired infections and community-acquired infections. Vancomycin is a glycopeptide antibiotic that was isolated in 1956 from the actinomycetes Streptomyces orientalis and is used to treat gram-positive bacteria, especially to methicillin-resistant Staphylococcus (MRS) infections that is increasing recent years. Vancomycin when administered intravenously cerebrospinal fluid (CSF) permeation can be finded only in the situation of meningitis, but the level of concentrations can not be predicted. So it often is used for intrathecal or intraventricular administration to cure the meningitis clinically. But, what about the dosage, course of treatment, toxicity et al of Vancomycin administration into the cerebrospinal fluidis poorly reported previously. A Prospective randomized controlled trial was performed to reach the aim:
1. to obtain the data of vancomycin intrathecal administration drug peak and trough concentrations in CSF and serum to gram- positive bacterial meningitis;
2. to compare the effect of vancomycin administration intravenously sololy and intravenously conbining with intrathecally;
3. We will evaluate the safety of intrathecal administration through clinical observation of adverse effect and the following-up.
Materials and Methods
twenty six adult patients with gram-positive bacterial meningitis or diagnosed empirically were randomly divided into two groups: therapied group ( 13 cases) and controlled group (13 cases), range 24—67 years, 17 men and 9 women. All patients had the symptom of fever, with headache and emesis in 11 cases, and meningeal irritation sign in nine. Etiopathogenisis include ventriculoperitoneal shunt in 11 cases, cerebral trauma in 11cases (craniotomy in 7cases), and craniotomy in 4cases with tumors. All the routine examination of CSF has the result of leucocyte count rising, mean count is 386.63/μL and the highest is 3200/μL. The result of CSF bacterial stain smear is Gram-positive bacteria in 21 cases, diagnosed empirically in else 5 cases.The result of CSF culture and drug sensitivity test is 5 strains of methicillin resistant staphylococcus (MRS) , including three methicillin resistant staphylococcus aureus (MRSA) and two methicillin resistant staphylococcus epidermidis (MRSE). All the MRS strains are sensitive to vancomycin and the results of CSF culture are negative of else 16 cases. All the 26 patients'function of heart, liver and kidney was normal before our treatment. Vancomycin was administered intravenously and intrathecally in therapied group and only intravenously in controlled group daily. Vancomycin intravenously was administered at a daily dose of 2g in four administration (500 mg intravenously over 60 min every 6 h), and intrathecally at a daily dose of 20mg once. The samples of blood and CSF were collected, the concentration of vancomycin in serum and CSF was determined by fluorescence polarization immunoassay (FPIA) method. Statistical analysis was done with the software program SPSS 11.5, quantitative results presented are the mean±standard deviation (SD) ((?)±s), comparison means was used with Independent-Samples T Test and the Clustered Error Bar, comparison numeration data was done with Chi-Square Test, a probability value (p value ) of less than 0.05 was considered significant.
Results
The administration time of therapied group was 11.92±3.75 days, and controlled group was 17.08±4.92 days, there was significant difference between the two groups (P=0.006) , therapied group was shorter than controlled group. The effective power of therapied group was 100%, and controlled group was 84.62% ( 11/13 ). There was no significant difference between the two groups at the peak and trough concentrations of vancomycin in serum. The peak concentration of vancomycin in therapied group was 135.99±106.84mg/L , trough concentration was 28.01±14.12mg/L, The peak concentration of vancomycin in controlled group was 4.21±2.28mg/L, trough concentration was1.27±0.76mg/L, there was significant difference between the two groups (P=0.000, 0.000) , Both the peak and trough concentrations of vancomycin in CSF of therapied group were higher than those of controlled group. There was no adverse effect except one patient with "Red man syndrome" in the period of administration of all patients, and no evidence of functional lesion of liver and kidney, hearing functional lesion, abnormal changing in hematocyte, abdominal pain, diarrhoea, epilepsy and subarachnoid cavity adherence. In the following-up 3 to 12 months, combination with the examinations of CT, MRI, laboratory and physical was no evidence of vancomycin toxical injury.
Conclusions
I The results of our study demonstrate that vancomycin intrathecal administration can reach the level of drug concentrations that is several times than minimum inhibitory concentration (MIC) within the CSF.
2 The results of our study demonstrate that vancomycin intrathecal administration is a safe and efficacious treatment modality in gram-positive bacterial meningitis.
3 The results of our study demonstrate that vancomycin intrathecal administration can cure gram-positive bacterial meningitis with much shorter treatment time and lower costs.
引文
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[24] 李家泰，齐慧敏，李耘，等．2002-2003年中国医院和社区获得性感染革兰阳性细菌耐药监测研究．中华检验医学杂志，2005，28(3)：254-266．
[25] Bingena E, Mariani-Kurkdjiana P, Nebbadb B. Optimal vancomycin serum level in Staphylococcus aureus infections. Medecine et maladies infectieuses, 2006, 36: 439-442.
[26] Jacques A, Marc L, Bernard B, et al. Cerebrospinal Fluid Penetration and Pharmacokinetics of Yancomycin Administered by Continuous Infusion to Mechanically Ventilated Patients in an Intensive Care Unit. Animicrobial Agents and Chemotherapy, 2000, 44(5): 1356-1358.
[27] Wysocki M, Delatour F, Faurisson F, et al. Continuous versus intermittent infusion of vancomycin in severe Staphylococcal infections: prospective multicenter randomized study. Antimicrob Agents Chemother, 2001, 45: 2460-2467.
[28] 王强，郑一，赵立红，等．神经外科手术后病人使用万古霉素时的脑脊液浓度．北京医学，2002，5：318-320．
[29] Shah SS, Sinkowitz CRL, Keyserling HL, et al. Vancomycin use in pediatric neurosurgery patients. American Journal of Infection Control, 1999, 27(6): 482-487.
[30] Markus N, Claudia N, Josef H. Bactericidal Activity of Vancomycin in Cerebrospinal Fluid. Antimicrobial Agents and Chemotherapy, 1999, 8: 1932-1934.
[31] Gatta FMd, Calvo V, HernandezJM, et al. Cost-effectiveness analysis of serum vancomycin concentration monitoring in patients with haematological malignancies. Clinical Pharmacology and Therapeutics, 1996, 60: 332-340.
[32] Catherine A, Hammett-Stabler, Thomas J. Laboratory guidelines for monitoring of antimicrobial drugs. Clinical Chemistry, 1998, 44(5): 1129-1140.
[33] Tan WH, Brown N, Kelsall AW, et al. Dose regimen for vancomycin not needing serum peak levels? Arch Dis Child Fetal Neonatal Ed, 2002, 87: F214-F216.
[34] Valero R, Gomar C, Fita G, et al. Adverse reactions to vancomycin prophylaxis in cardiac surgery. J Cardiothorac Vasc Anesth, 1991, 5(6): 574-576.
[35] 金少鸿，马越．国内细菌耐药性监测研究的回顾与展望．中国抗生素杂志，2005，5：257-259，283．
[36] NNIS System. National Nosocomial Infections Surveillance (NNIS) System Report, data summary from January 1992 through June 2004, issued October 2004. Am J Infect Control, 2004, 32(12): 470-485.
[37] CDC. Reduced susceptibility of Staphylococcus aureus to vancomycin - Japan, 1996. MMWR, 1997, 46: 624-626.
[38] CDC. Interim guidelines for prevention and control of staphylococcal infection associated with reduced susceptibility to vancomycin. MMWR, 1997, 46: 626-628, 635.
[39] Fred CT, James WB, Michael VL, et al. Increasing Resistance to Vancomycin and Other Glycopeptides in Staphylococcus aureus. Emerging Infectious Diseases, 2001, 7(2): 327-332.
[40] CDC. Staphylococcus aureus Resistant to Yancomycin-United States, 2002. MMWR, 2002, 51: 565-567.
[41] Vicente P, Carmen C, Santiago M, et al. Enterococcal Meningitis A Clinical Study of 39 Cases and Review of the Literature. Medicine, 2003, 82(5): 346-364.
[42] Tammy SL, Jack DS. Antibiotics for gram-positive bacterial infcctions: vancomycin, quinupristin-dalfopristin, linezolid, anddaptomycin. Infect DisClin N Am, 2004, 18: 651-668.
[43]Pedro FV, Francisco G, Josef ina L, et al. Evaluation of Vancomycin for Therapy of Adult Pneumococcal Meningitis. Animicrobial Agents and Chemotherapy, 1991, 35(12): 2467-2472.
[44]Anselmo C, Mariano P, Aldo M, et al. Levels of vancomycin in the cerebral interstitial fluid after severe head injury. Intensive Care Med, 2006, 32(1): 325-328.
[45]Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice guidelines for the management of bacterial meningitis. Clinical Infectious Diseases, 2004, 39(9): 1267-1284.
[46]Thomson RBJ, Bertram H. Laboratory diagnosis of central nervous system infections. Infectious Disease Clinics of North America. 2001, 15(4): 1047-1071.
[47] O' connel JEA. Vascular factor in intracranial pressure and maintenance of cerebrospinal fluid circulation. Brain, 1943, 66: 204-228.
[48]Duboulay GH. Pulsatile movements in the CSF pathways. BR J Radiol, 1966, 39: 255-262.
[49]Dichiro G. Observation on the circulation of the cerebrospinal fluid. Acta Radiol Diag, 1966, 5: 988-1002.
[50] MilhoratTH, Hammock MK, Fenstermacher JD, et al. Cerebrospinal Fluid Production by the Choroid Plexus and Brain. Science, 1971, 173(994): 330-332.
[51]Greitz D, Greitz T. The pathogenesis and hemodynamics of hydrocephalus: proposal for a new understanding. IJNR, 1997, 3: 367-375.
[52]Morton NS. Bacterial meningitis—a view of the past 90 years. N Engl J Med, 2004, 351(18): 1826-1828.
[53]Buzon LM, Guerrero A, Romero J, et al. Penicillin-resistant Streptococcus pneumoniae meningitis treated with vancomycin. Eur J Clin Microbiol, 1984, 3: 442.
[54]Linares J , Perez JL , Garau J , et al. Comparative susceptibilities of penicillin-resistant pneumococci to co-trimoxazol, vancomycin, rifampin and fourteen beta-lactam antibiotics. J Antimicrob Chemother, 1984, 13: 353-359.
[55] Bettina P, tteinrich S, Ronny B. Treatment of staphylococcal ventriculitis associated with external cerebrospinal fluid drains: a prospective randomized trial of intravenous compared with intraventricular vancomycin therapy. J Neurosurg, 2003, 98(5): 1040-1044.
[56] 蔡望青，钟伟健，刘安民，等．持续万古霉素灌洗治疗4例颅内葡萄球凶感染．中国神经精神疾病杂志，2005，31(6)：469-470．
[57] Klibanov OMK, Joanne EF. Sensorineural Hearing Loss Associated with Intrathecal Vancomycin. Ann Pharmacother, 2003, 37(1): 61-65.
[58] Grabb PA, Albright AL. Intraventricular Vancomycin-induced Cerebrospinal Fluid Eosinophila: Report of Two Patients. J Neurosurgery, 1992, 30(4): 630-635.
[59] Roland N, Wolfgang B. Neuronal injury in bacterial meningitis:mechanisms and implications for therapy. Trends in Neuroscience, 2002, 25(1): 38-45.
[60] Finchl RG, Eliopoulos GM. Safety and efficacy of glycopeptide antibiotics. Journal of Antimicrobial Chemotherapy, 2005, 55: S2, ii5-ii13.