术后中枢神经系统感染的早期病原诊断及美罗培南治疗方案优化研究
|
摘要
第一部分中枢神经系统感染病原快速基因诊断研究
目的：评价病原快速基因检测方法在中枢神经系统感染中的可靠性与实用性,明确其临床应用价值。
方法：按入选排除标准收集神经外科术后拟诊为中枢神经系统感染患者的脑脊液,通过PCR扩增及基因芯片杂交技术检测病原菌种类,并与常规脑脊液培养的结果进行比较。
结果：共收集脑脊液标本204例,其中常规方法培养阳性者29例,基因芯片方法检测阳性者为25例。基因诊断方法与常规方法比较,符合率98.03%(200/204)敏感度为86.21%,特异度为100%。如排除因基因芯片未设置探针而检测阴性的3例标本,则符合率为99.50%(200/201),敏感度为96.15%。基因诊断较常规培养方法在病原菌的诊断时间上缩短3.24±1.22天；如就脑脊液细菌阳性病例而言,检出时间缩短2.44±0.68天；二者均有显著差异(P<0.01)。
结论：病原快速基因检测方法与常规培养方法比较,符合率高、检测时间明显缩短,方法可靠,具有临床应用价值。
第二部分人血浆及脑脊液中美罗培南浓度的HPLC测定方法研究
目的：建立人血浆及脑脊液样品中美罗培南的定量测定方法。
方法：采用高效液相色谱法,TSK-gel ODS-80TM C,8柱(150mm×4.6mm,5μm),血浆样品测定流动相为15mmol·L-1KH2P04(pH3.2)—乙腈(87：13),脑脊液样品测定流动相为lOmmol·L-1乙酸胺(PH3.86)—乙腈(90：10),紫外检测波长均为308nm。
结果：血浆样品中美罗培南保留时间为3.148分钟,在0.5mg·L-1～100mg·L血药浓度范围内线性关系良好(r=0.9999),最低检测浓度为0.5mg·L-1；各质控浓度提取回收率平均为109.1%,日内、日间RSD均<10%,方法回收率为82.6%～96.6%；-80℃冰箱保存6月内回收率稳定。脑脊液样品中美罗培南保留时间为3.810分钟,在0.25mg·L-1～50mg·L-1脑脊液药浓度范围内线性关系良好(r=0.9989),最低检测浓度为0.25 mg·L-1；各质控浓度提取回收率平均为96.8%,日内、日间RSD均<5%,方法回收率为94.3%～106.3%；-80℃冰箱保存6月内回收率稳定。血浆及脑脊液样品检测时均使用PABA(对氨基苯甲酸)为内标物。
结论：本研究建立的美罗培南检测方法灵敏度高、特异性强,适用于临床药代动力学的研究。
第三部分美罗培南在中枢神经系统感染中的PK/PD研究
目的：通过对术后中枢神经系统感染应用美罗培南患者进行血及脑脊液中美罗培南PK/PD研究,有望制定美罗培南治疗中枢神经系统感染的最佳治疗方案。
方法：根据入选排除标准选择神经外科术后使用美罗培南的患者,并收集应用美罗培南后不同时间点的血、脑脊液标本及临床资料,测定药物浓度后计算PK/PD数据,以确定最佳给药方案。
结果：美罗培南2g q8h给药方案的%T>MIC、Cmax/MIC及血脑屏障穿透率明显高于其余二组给药方案。对于鲍曼不动杆菌,当MIC值小于0.5mg/L时,三个给药方案在给药间隔内血和脑脊液药物浓度均高于MIC,%T>MIC为100%;MIC小于2mg/L时,血及脑脊液%T>MIC均大于50%左右；当MIC大于2mg/L时,脑脊液中该值不理想。当MIC值小于4mg/L时,血浆Cmax>MIC在5倍以上；与血药浓度相比,脑脊液中该值在MIC大于0.25mg/L时仅有2g q8h给药方案可达5倍的比值。
结论：美罗培南治疗中枢神经系统感染2g q8h的给药方案为最优,其次为1g q6h,1g q8h,在治疗同时去除脑室或脑脊液外引流装置有助于病原菌的清除。
Part 1 Study on the etiologic genetic diagnosis of central nervous system infections
OBJECT:To know the clinical value of genetic method in central nervous system infections.
METHODS:The cerebrospinal fluid of patients, who were suspected of central nervous system infection, was collected. The consistency rate between genetic method and traditional method were compared.
RESULTS:204 cases of cerebrospinal fluid samples were collected,29 were positive as assessed by culture and 25 were positive as assessed by PCR. Compared with the traditional method, genetic method had a sensitivity of 86.21% and specificity of 100%. If removed 3 samples whose microarray probes were not set, the compliance rate was raised to 99.50%, and the sensitivity was 96.15%. Genetic method detection can help us get the result 3.24±1.22 days before the traditional method detection (P<0.01)
CONCLUSION:We can draw the conclusion that genetic diagnostic method had good consistency with traditional method, and detection time was shortened. The new method is reliable and has clinical application value.
Part 2 Determination of meropenem in human cerebrospinal fluid and plasma by HPLC
OBJECT:To establish a HPLC method for determination of meropenem in human cerebrospinal fluid.
METHODS:Chromatorgraphic separation was performed on a TSK-gel 0DS-80TM C18 column. Mobile phase of CSF was ammonium acetate and acetonetrile (90:10, v/v), Mobile phase of Plasma was KH2PO4 and acetonetrile (87:13, v/v). Ultraviolet absorption at 308nm was used for detection. The temperature of column was 35℃.After protein was precipitated by acetonetrile,the derivatized sample was eluted and 20μL injected. Para-aminobenzoic acid (PABA) was used as an internal standard.
RESULTS In human cerebrospinal fluid, the retention time of meropenem was 3.810min and the detector response was linear over the concentration range of 0.25-50mg·L-1. The recovery was 94.3-106.3%, and relate standard deviation (RSD) of intra-day and inter-day assays were all less than 5%. In human plasma, the retention time of meropenem was 3.148min and the detector response was linear over the concentration range of 0.5-100mg·L-(?)The recovery was 82.6-96.6%, and relate standard deviation (RSD) of intra-day and inter-day assays were all less than 10%. CSF and plasma stored at-80℃for six months at various concentrations in cerebrospinal fluid, meropenem did not reveal any appreciable degradation.
CONCLUSION The method is simple, sensitive and accurate, and can be used for the pharmacokinetic study.
Part 3 PK/PD of meropenem in central nervous system infections
OBJECT:To explore the PK/PD of meropenem in Central Nervous System Infections.Thus we can optimize the treatment of meropenem.
METHODS:Neurosurgical patients, who were treated by meropenem, were selected based on inclusion criteria and exclusion. We collected blood and CSF samples on schedule, and got drug concentration by HPLC. At the same time, we collected their clinical data. Then we calculated PK/PD data, and determined the optimal dosage regimen.
RESULTS:The dosage group which was received 2g(q8h) of meropenem has a maximum value of %T>MIC and Cmax/MIC, and also has the best blood-brain barrier penetration. For Acinetobacter baumannii, when MIC<0.5mg/L, the plasma concentrations and CSF concentration of three groups were higher than MIC in the dosing interval (%T>MIC was 100%).When MIC<2mg/L, the value of %T>MIC(both in the plasma and csf)was more than 50%. If MIC2mg/L, the value of %T>MIC (csf) was not ideal. When the MIC value is less than 4mg/L, the Cmax>MIC (plasma) in more than 5 times. But only in 2g q8h dosage group, the Cmax>MIC(CSF) is 5 times when MIC.25mg/L.
CONCLUSION:To cure Central Nervous System Gram-negative Bacterial Infections,2g q8h dosage regimen is the best, followed by 1g q6h, 1g q8h. removing the drainage system would be useful of pathogen removal.
目的：评价病原快速基因检测方法在中枢神经系统感染中的可靠性与实用性,明确其临床应用价值。
方法：按入选排除标准收集神经外科术后拟诊为中枢神经系统感染患者的脑脊液,通过PCR扩增及基因芯片杂交技术检测病原菌种类,并与常规脑脊液培养的结果进行比较。
结果：共收集脑脊液标本204例,其中常规方法培养阳性者29例,基因芯片方法检测阳性者为25例。基因诊断方法与常规方法比较,符合率98.03%(200/204)敏感度为86.21%,特异度为100%。如排除因基因芯片未设置探针而检测阴性的3例标本,则符合率为99.50%(200/201),敏感度为96.15%。基因诊断较常规培养方法在病原菌的诊断时间上缩短3.24±1.22天；如就脑脊液细菌阳性病例而言,检出时间缩短2.44±0.68天；二者均有显著差异(P<0.01)。
结论：病原快速基因检测方法与常规培养方法比较,符合率高、检测时间明显缩短,方法可靠,具有临床应用价值。
第二部分人血浆及脑脊液中美罗培南浓度的HPLC测定方法研究
目的：建立人血浆及脑脊液样品中美罗培南的定量测定方法。
方法：采用高效液相色谱法,TSK-gel ODS-80TM C,8柱(150mm×4.6mm,5μm),血浆样品测定流动相为15mmol·L-1KH2P04(pH3.2)—乙腈(87：13),脑脊液样品测定流动相为lOmmol·L-1乙酸胺(PH3.86)—乙腈(90：10),紫外检测波长均为308nm。
结果：血浆样品中美罗培南保留时间为3.148分钟,在0.5mg·L-1～100mg·L血药浓度范围内线性关系良好(r=0.9999),最低检测浓度为0.5mg·L-1；各质控浓度提取回收率平均为109.1%,日内、日间RSD均<10%,方法回收率为82.6%～96.6%；-80℃冰箱保存6月内回收率稳定。脑脊液样品中美罗培南保留时间为3.810分钟,在0.25mg·L-1～50mg·L-1脑脊液药浓度范围内线性关系良好(r=0.9989),最低检测浓度为0.25 mg·L-1；各质控浓度提取回收率平均为96.8%,日内、日间RSD均<5%,方法回收率为94.3%～106.3%；-80℃冰箱保存6月内回收率稳定。血浆及脑脊液样品检测时均使用PABA(对氨基苯甲酸)为内标物。
结论：本研究建立的美罗培南检测方法灵敏度高、特异性强,适用于临床药代动力学的研究。
第三部分美罗培南在中枢神经系统感染中的PK/PD研究
目的：通过对术后中枢神经系统感染应用美罗培南患者进行血及脑脊液中美罗培南PK/PD研究,有望制定美罗培南治疗中枢神经系统感染的最佳治疗方案。
方法：根据入选排除标准选择神经外科术后使用美罗培南的患者,并收集应用美罗培南后不同时间点的血、脑脊液标本及临床资料,测定药物浓度后计算PK/PD数据,以确定最佳给药方案。
结果：美罗培南2g q8h给药方案的%T>MIC、Cmax/MIC及血脑屏障穿透率明显高于其余二组给药方案。对于鲍曼不动杆菌,当MIC值小于0.5mg/L时,三个给药方案在给药间隔内血和脑脊液药物浓度均高于MIC,%T>MIC为100%;MIC小于2mg/L时,血及脑脊液%T>MIC均大于50%左右；当MIC大于2mg/L时,脑脊液中该值不理想。当MIC值小于4mg/L时,血浆Cmax>MIC在5倍以上；与血药浓度相比,脑脊液中该值在MIC大于0.25mg/L时仅有2g q8h给药方案可达5倍的比值。
结论：美罗培南治疗中枢神经系统感染2g q8h的给药方案为最优,其次为1g q6h,1g q8h,在治疗同时去除脑室或脑脊液外引流装置有助于病原菌的清除。
Part 1 Study on the etiologic genetic diagnosis of central nervous system infections
OBJECT:To know the clinical value of genetic method in central nervous system infections.
METHODS:The cerebrospinal fluid of patients, who were suspected of central nervous system infection, was collected. The consistency rate between genetic method and traditional method were compared.
RESULTS:204 cases of cerebrospinal fluid samples were collected,29 were positive as assessed by culture and 25 were positive as assessed by PCR. Compared with the traditional method, genetic method had a sensitivity of 86.21% and specificity of 100%. If removed 3 samples whose microarray probes were not set, the compliance rate was raised to 99.50%, and the sensitivity was 96.15%. Genetic method detection can help us get the result 3.24±1.22 days before the traditional method detection (P<0.01)
CONCLUSION:We can draw the conclusion that genetic diagnostic method had good consistency with traditional method, and detection time was shortened. The new method is reliable and has clinical application value.
Part 2 Determination of meropenem in human cerebrospinal fluid and plasma by HPLC
OBJECT:To establish a HPLC method for determination of meropenem in human cerebrospinal fluid.
METHODS:Chromatorgraphic separation was performed on a TSK-gel 0DS-80TM C18 column. Mobile phase of CSF was ammonium acetate and acetonetrile (90:10, v/v), Mobile phase of Plasma was KH2PO4 and acetonetrile (87:13, v/v). Ultraviolet absorption at 308nm was used for detection. The temperature of column was 35℃.After protein was precipitated by acetonetrile,the derivatized sample was eluted and 20μL injected. Para-aminobenzoic acid (PABA) was used as an internal standard.
RESULTS In human cerebrospinal fluid, the retention time of meropenem was 3.810min and the detector response was linear over the concentration range of 0.25-50mg·L-1. The recovery was 94.3-106.3%, and relate standard deviation (RSD) of intra-day and inter-day assays were all less than 5%. In human plasma, the retention time of meropenem was 3.148min and the detector response was linear over the concentration range of 0.5-100mg·L-(?)The recovery was 82.6-96.6%, and relate standard deviation (RSD) of intra-day and inter-day assays were all less than 10%. CSF and plasma stored at-80℃for six months at various concentrations in cerebrospinal fluid, meropenem did not reveal any appreciable degradation.
CONCLUSION The method is simple, sensitive and accurate, and can be used for the pharmacokinetic study.
Part 3 PK/PD of meropenem in central nervous system infections
OBJECT:To explore the PK/PD of meropenem in Central Nervous System Infections.Thus we can optimize the treatment of meropenem.
METHODS:Neurosurgical patients, who were treated by meropenem, were selected based on inclusion criteria and exclusion. We collected blood and CSF samples on schedule, and got drug concentration by HPLC. At the same time, we collected their clinical data. Then we calculated PK/PD data, and determined the optimal dosage regimen.
RESULTS:The dosage group which was received 2g(q8h) of meropenem has a maximum value of %T>MIC and Cmax/MIC, and also has the best blood-brain barrier penetration. For Acinetobacter baumannii, when MIC<0.5mg/L, the plasma concentrations and CSF concentration of three groups were higher than MIC in the dosing interval (%T>MIC was 100%).When MIC<2mg/L, the value of %T>MIC(both in the plasma and csf)was more than 50%. If MIC2mg/L, the value of %T>MIC (csf) was not ideal. When the MIC value is less than 4mg/L, the Cmax>MIC (plasma) in more than 5 times. But only in 2g q8h dosage group, the Cmax>MIC(CSF) is 5 times when MIC.25mg/L.
CONCLUSION:To cure Central Nervous System Gram-negative Bacterial Infections,2g q8h dosage regimen is the best, followed by 1g q6h, 1g q8h. removing the drainage system would be useful of pathogen removal.
引文
1. Kim KS. Pathogenesis of bacterial meningitis:from bacteraemia to neuronalinjury. Nat Rev Neurosci.2003;4:376-385.
2.Scarborough M, Thwaites GE. The diagnosis and management of acute bacterial meningitis in resource-poor settings. Lancet Neurol. 2008:7:637-648.
3. van de Beek D, de Gans J, Tunkel AR, et al. Community-acquired bacterial meningitis in adults. N Engl J Med.2006:354:44-53.
4. van de Beek D, de Gans J, Spanjaard L, et al. Clinical features and prognostic factors in adults with bacterial meningitis. N Engl J Med.2004:351:1849-59.
5.赵继宗。神经外科手术精要与并发症。北京：北京大学医学出版社.2004：27-36。
6. Sharma MS, Vohra A, Thomas P, et al. Effect of risk-stratified, protocol-based perioperative chemoprophylaxis on nosocomial infection rates in a series of 31927 consecutive neurosurgical procedures (1994-2006). Neurosurgery.2009;64(6):1123.
7. Diederik van de Beek, James M. Drake, B. Ch, et al. Nosocomial Bacterial Meningitis. N Engl J Med.2010; 362:146-154.
8. Reichert MC,Medeiros EA, Ferraz FA. Hospital-acquired meningitis in patients undergoing craniotomy:incidence, evolution, and risk factors. Am J Infect Control,2002,30(3):158-164.
9. De Bels D, Korinek AM, Bismuth R, et al. Empirical treatment of adult post surgical nosocomial meningitis. Acta Neurochir (Wien),2002 144(10):989-995.
10.舒航,李昭杰,林志俊,等.脑室冲洗治疗颅脑术后继发颅内感染.实用医学杂志,2000,16(5)：386-387.
11.尚爱加,程东源,周定标.清洁开颅术后颅内感染的治疗.中华医院感染学杂志,2002,12(2)：84-86.
12.侯铁英,黄德弘。颅脑手术后医院感染经济损失的病例对照研究。中国感染控制杂志。2005；4(2)：124-126。
13. Roghmann MC. Predicting methicillin resistance and the effect of inadequate empiric therapy on survival in patients with Staphylococcus aureus bacteremia[J]. Arch Intern Med,2000,160(7):1001-1004.
14.毛红菊,林东昉,徐晓刚,张宏莲,张婴元,汪复,赵建龙。利用基因芯片快速检测多种临床常见致病菌及其耐药性基因。中华传染病杂志,2006.24(6)：372-377。
15.林东昉,徐晓刚,朱德妹,汪复,张婴元。23SrRNA基因在常见病原菌鉴定中的应用。中华检验医学杂志,2005.29(1)：79-81。
16.李光辉,朱德妹,张婴元,汪复。1995—2004年上海地区部分医院脑脊液分离菌的分布及耐药性。中华医院感染学杂志。2007,17(10)：1278-1281。
17. Tunkel A R, Hartman B J, Kaplan S L, et al. Practice guideline for the management of bacterial meningitis. Clin Infect Dis,2004,39:1267-1284.
18. Ramos-Martinez A, de Las Heras-Carballo T, Fernandez-Mateos C, et al. Postsurgical meningitis. Differential characteristics of aseptic postsurgical meningitis[J]. Neurocirugia(Astur).2009,20(2):103-109.
19.王辉,张悦娴,谢秀丽,徐英春,陈民钧。血培养凝固酶阴性葡萄球菌阳性的临床意义。中国抗感染化疗杂志,2001,1(2)：79-82。
20. Sanford, J. P. The Sanford guide to antimicrobial therapy 2009—2010 (39TM Edition).2009:170.
21. T. P. Lodise, R. Nau, M. Kinzig, G. L. Drusano, R. N. Jones and F. Sorgel. Pharmacodynamics of ceftazidime and meropenem in cerebrospinal fluid:results of population pharmacokinetic modelling and Monte Carlo simulation. Journal of Antimicrobial Chemotherapy,2007,60:1038-1044.
22. Kazuro Ikawa, Norifumi Morikawa, Kayo Ikeda. Considerations of meropenem dosage for bacterial meningitis based on pharmacodynamics in cerebrospinal fluid. International Journal of Antimicrobial Agents,32, 2008:96-98.
23.徐明,王强,史中华等。美罗培南静脉持续泵人时血液和脑脊液药物浓度的测定。首都医科大学学报。2007,28(5)：584-586。
24. Cunha BA. Antibiotic essential. New York:Pysician Press,2005:19-27.
25.张小江,徐英春,俞云松等。2009年中国CHINET鲍曼不动杆菌细菌耐药性监测。中国感染与化疗杂志。2010,10(06)：。
26. Ikawa K., Tsumura R., Morikawa N., Ikeda K., Shibukawa M., Iida K., Kurisu K. Cerebrospinal fluid penetration and pharmacodynamic exposure of meropenem prophylactically administered to neurosurgical patients.18th European Congress of Clinical Microbiology and Infectious Diseases. Barcelona, Spain,19-22 April 2008.
27. Roland N, Cheristoph L, Martina K, et al. Disposition and Elimination of Meropenem in Cerebrospinal Fluid of Hydrocephalic Patients with External Ventriculostomy. Antimicrobial agents and chemotherapy. 1998:2012-2016.
1. Kim KS. Pathogenesis of bacterial meningitis:from bacteraemia to neuronalinjury. Nat Rev Neurosci.2003;4:376-385.
2.Scarborough M, Thwaites GE. The diagnosis and management of acute bacterial meningitis in resource-poor settings. Lancet Neurol. 2008:7:637-648.
3. van de Beek D, de Gans J, Tunkel AR, et al. Community-acquired bacterial meningitis in adults. N Engl J Med.2006:354:44-53.
4. van de Beek D, de Gans J, Spanjaard L, et al. Clinical features and prognostic factors in adults with bacterial meningitis. N Engl J Med.2004:351:1849-59.
5.赵继宗。神经外科手术精要与并发症。北京：北京大学医学出版社.2004：27-36。
6.侯铁英,黄德弘。颅脑手术后医院感染经济损失的病例对照研究。中国感染控制杂志。2005；4(2)：124-126。
7. CDC NNIS System. National Nosocomial Infections Surveil lance (NNIS) System Report, data summary from January 1992 through June 2004, issued October 2004. Am J infect Control.2004; 32:470-485.
8. Sharma MS, Vohra A, Thomas P, et al. Effect of risk-stratified, protocol-based perioperative chemoprophylaxis on nosocomial infection rates in a series of 31927 consecutive neurosurgical procedures (1994-2006). Neurosurgery.2009:64(6):1123.
9.刘旭,穆锦江,陈亚民。86例神经外科术后颅内感染分析.中华医院感染学杂志。2004；14：635。
10.王利君,黄桃芝,瞿伟军。674例神经外科患者医院感染临床调查分析.。实用预防医学。2003；10：352。
11.周忠清,郑今兰,张劲松,刘荣,石祥恩。开颅术后颅内感染的诊断与治疗.中华医院感染学杂志。2005；15(4)：402-404。
12.赵新亮,申长虹,甄自刚。神经外科术后颅内感染的临床研究。中华医院感染学杂志。2006；16：27-280。
13. Diederik van de Beek, James M. Drake, B. Ch, et al. Nosocomial Bacterial Meningitis. N Engl J Med.2010; 362:146-154.
14. Korinek AM, Baugnon T, Golmard JL, van Effenterre R, Coriat P, Puybasset L. Risk factors for adult nosocomial meningitis after craniotomy:role of antibiotic prophylaxis. Neurosurgery.2006;59:126-133.
15. McClelland S, Hall WA. Postoperative central nervous system infection: incidence and associated factors in 2111 neurosurgical procedures. Clin Infect Dis.2007;45:55-59.
16. Conen A, Walti LN, Merlo A, Fluckiger U, Battegay M, Trampuz A. Characteristics and treatment outcome of cerebrospinal fluid shunt-associated infections in adults:a retrospective analysis over an 11-year period. Clin Infect Dis.2008:47:73-82.
17. Vinchon M, Dhellemmes P. Cerebrospinal fluid shunt infection:risk factors and long-term follow-up. Childs Nerv Syst.2006;22:692-697.
18. Sorensen P, Ejlertsen T, Aaen D, Poulsen K. Bacterial contamination of surgeons gloves during shunt insertion:a pilot study. Br J Neurosurg, 2008:22:675-677.
19. Lozier AP, Sciacca RR, Romagnoli MF. Ventriculostomy-related infections:a critical review of the literature. Neurosurgery 2008:62:688-700.
20. Wong GK, Poon WS, Wai S, Yu LM, Lyon D, Lam JM. Failure of regular external ventricular drain exchange to reduce cerebrospinal fluid infection:result of a randomised controlled trial. J Neurol Neurosurg Psychiatry.2002;73:759-761.
21. Governale LS, FeinN, Logsdon J, Black PM. Techniques and complications of external lumbar drainage for normal pressure hydrocephalus. Neurosurgery.2008;63:Suppl 2:379-384.
22. Baltas I, Tsoulfa S, Sakellariou P, Vogas V, Fylaktakis M, Kondodimou A. Posttraumatic meningitis:bacteriology, hydrocephalus, and outcome, Neurosurgery.1994;35:422-426.
23. Bullock MR, Chesnut R, Ghajar J, et al. Surgical management of depressed cranial fractures. Neurosurgery.2006;58:Suppl:S56-S60.
24. Baer ET. Post-dural puncture bacterial meningitis. Anesthesiology. 2006;105:381-393.
25.卢岩,彭松林。神经外科颅内感染危险因素的病例对照研究。中国感染控制杂志。2008：6：396-398。
26.周建新,王强,唐明忠等。神经外科患者脑脊液细菌流行病学和耐药性监测。中华医院感染学杂志。2006；16：154-157。
27. Thomas KE, Hasbun R, Jekel J, et al. The diagnostic accuracy of Kernig' s sign, Brudzinski's sign, and nuchal rigidity in adults with suspected meningitis. Clin Infect Dis.2002; 35:46-52.
28. Mayhall CG, Archer NH, Lamb VA, et al. Ventriculostomy-related infections:a prospective epidemiologic study.N Engl J Med.1984:310:553-559.
29. La Scolea LJ Jr, Dryja D. Quantitation of bacteria in cerebrospinal fluid and blood of children with meningitis and its diagnostic significance. J Clin Microbiol.1984 Feb;19(2):187-190.
30. Banks JT, Bharara S, Tubbs RS, et al. Polymerase chain reaction for the rapid detection of cerebrospinal fluid shunt or ventriculostomy infections. Neurosurgery.2005;57:1237-1243.
31. Roland Nau, Fritz Sorge, Hilmar W. Prange。Pharmacokinetic Optimisation of the Treatment of Bacterial Central Nervous System Infections。 Clin Pharmacokinet.1998,35 (3):223-246.
32. Small PM, Tauber MG, Hackbarth CJ, et al. Influence of body temperature on bacterial growth rates in experimental pneumococcal meningitis in rabbits. Infect Immun.1986; 52:484-7.
33. Ronny Beer, Bettina Pfausler, Erich Schmutzhard 。Infectious intracranial complications in the neuro-ICU patient population。 Current Opinion in Critical Care.2010,16:117-122.
34. Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis.2004; 39:1267-84.
35. Yuliya Nudelman and Allan R. Tunkel. Bacterial Meningitis Epidemiology, Pathogenesis and Management Update. Drugs.2009,69(18): 2577-2596.
36. Falagas ME, Bliziotis IA, Tam VH. Intraventricular or intrathecal use of polymyxins in patients with gram-negative meningitis:a systematic review of the available evidence. Int J Antimicrob Agents.2007;29:9-25.
37. Katragkou A, Roilides E. Successful treatment of multidrug-resistant Acinetobacter baumannii central nervous system infections with colistin. J Clin Microbiol.2005:43:4916-4917.
38.中华医学会外科学分会,中华外科杂志编辑委员会。围手术期预防应用抗菌药物指南。中华外科杂志,2006；44：1594-1596。
39. Sanford, J. P. The Sanford guide to antimicrobial therapy 2009 — 2010 (39TH Edition).2009:170.
2.Scarborough M, Thwaites GE. The diagnosis and management of acute bacterial meningitis in resource-poor settings. Lancet Neurol. 2008:7:637-648.
3. van de Beek D, de Gans J, Tunkel AR, et al. Community-acquired bacterial meningitis in adults. N Engl J Med.2006:354:44-53.
4. van de Beek D, de Gans J, Spanjaard L, et al. Clinical features and prognostic factors in adults with bacterial meningitis. N Engl J Med.2004:351:1849-59.
5.赵继宗。神经外科手术精要与并发症。北京：北京大学医学出版社.2004：27-36。
6. Sharma MS, Vohra A, Thomas P, et al. Effect of risk-stratified, protocol-based perioperative chemoprophylaxis on nosocomial infection rates in a series of 31927 consecutive neurosurgical procedures (1994-2006). Neurosurgery.2009;64(6):1123.
7. Diederik van de Beek, James M. Drake, B. Ch, et al. Nosocomial Bacterial Meningitis. N Engl J Med.2010; 362:146-154.
8. Reichert MC,Medeiros EA, Ferraz FA. Hospital-acquired meningitis in patients undergoing craniotomy:incidence, evolution, and risk factors. Am J Infect Control,2002,30(3):158-164.
9. De Bels D, Korinek AM, Bismuth R, et al. Empirical treatment of adult post surgical nosocomial meningitis. Acta Neurochir (Wien),2002 144(10):989-995.
10.舒航,李昭杰,林志俊,等.脑室冲洗治疗颅脑术后继发颅内感染.实用医学杂志,2000,16(5)：386-387.
11.尚爱加,程东源,周定标.清洁开颅术后颅内感染的治疗.中华医院感染学杂志,2002,12(2)：84-86.
12.侯铁英,黄德弘。颅脑手术后医院感染经济损失的病例对照研究。中国感染控制杂志。2005；4(2)：124-126。
13. Roghmann MC. Predicting methicillin resistance and the effect of inadequate empiric therapy on survival in patients with Staphylococcus aureus bacteremia[J]. Arch Intern Med,2000,160(7):1001-1004.
14.毛红菊,林东昉,徐晓刚,张宏莲,张婴元,汪复,赵建龙。利用基因芯片快速检测多种临床常见致病菌及其耐药性基因。中华传染病杂志,2006.24(6)：372-377。
15.林东昉,徐晓刚,朱德妹,汪复,张婴元。23SrRNA基因在常见病原菌鉴定中的应用。中华检验医学杂志,2005.29(1)：79-81。
16.李光辉,朱德妹,张婴元,汪复。1995—2004年上海地区部分医院脑脊液分离菌的分布及耐药性。中华医院感染学杂志。2007,17(10)：1278-1281。
17. Tunkel A R, Hartman B J, Kaplan S L, et al. Practice guideline for the management of bacterial meningitis. Clin Infect Dis,2004,39:1267-1284.
18. Ramos-Martinez A, de Las Heras-Carballo T, Fernandez-Mateos C, et al. Postsurgical meningitis. Differential characteristics of aseptic postsurgical meningitis[J]. Neurocirugia(Astur).2009,20(2):103-109.
19.王辉,张悦娴,谢秀丽,徐英春,陈民钧。血培养凝固酶阴性葡萄球菌阳性的临床意义。中国抗感染化疗杂志,2001,1(2)：79-82。
20. Sanford, J. P. The Sanford guide to antimicrobial therapy 2009—2010 (39TM Edition).2009:170.
21. T. P. Lodise, R. Nau, M. Kinzig, G. L. Drusano, R. N. Jones and F. Sorgel. Pharmacodynamics of ceftazidime and meropenem in cerebrospinal fluid:results of population pharmacokinetic modelling and Monte Carlo simulation. Journal of Antimicrobial Chemotherapy,2007,60:1038-1044.
22. Kazuro Ikawa, Norifumi Morikawa, Kayo Ikeda. Considerations of meropenem dosage for bacterial meningitis based on pharmacodynamics in cerebrospinal fluid. International Journal of Antimicrobial Agents,32, 2008:96-98.
23.徐明,王强,史中华等。美罗培南静脉持续泵人时血液和脑脊液药物浓度的测定。首都医科大学学报。2007,28(5)：584-586。
24. Cunha BA. Antibiotic essential. New York:Pysician Press,2005:19-27.
25.张小江,徐英春,俞云松等。2009年中国CHINET鲍曼不动杆菌细菌耐药性监测。中国感染与化疗杂志。2010,10(06)：。
26. Ikawa K., Tsumura R., Morikawa N., Ikeda K., Shibukawa M., Iida K., Kurisu K. Cerebrospinal fluid penetration and pharmacodynamic exposure of meropenem prophylactically administered to neurosurgical patients.18th European Congress of Clinical Microbiology and Infectious Diseases. Barcelona, Spain,19-22 April 2008.
27. Roland N, Cheristoph L, Martina K, et al. Disposition and Elimination of Meropenem in Cerebrospinal Fluid of Hydrocephalic Patients with External Ventriculostomy. Antimicrobial agents and chemotherapy. 1998:2012-2016.
1. Kim KS. Pathogenesis of bacterial meningitis:from bacteraemia to neuronalinjury. Nat Rev Neurosci.2003;4:376-385.
2.Scarborough M, Thwaites GE. The diagnosis and management of acute bacterial meningitis in resource-poor settings. Lancet Neurol. 2008:7:637-648.
3. van de Beek D, de Gans J, Tunkel AR, et al. Community-acquired bacterial meningitis in adults. N Engl J Med.2006:354:44-53.
4. van de Beek D, de Gans J, Spanjaard L, et al. Clinical features and prognostic factors in adults with bacterial meningitis. N Engl J Med.2004:351:1849-59.
5.赵继宗。神经外科手术精要与并发症。北京：北京大学医学出版社.2004：27-36。
6.侯铁英,黄德弘。颅脑手术后医院感染经济损失的病例对照研究。中国感染控制杂志。2005；4(2)：124-126。
7. CDC NNIS System. National Nosocomial Infections Surveil lance (NNIS) System Report, data summary from January 1992 through June 2004, issued October 2004. Am J infect Control.2004; 32:470-485.
8. Sharma MS, Vohra A, Thomas P, et al. Effect of risk-stratified, protocol-based perioperative chemoprophylaxis on nosocomial infection rates in a series of 31927 consecutive neurosurgical procedures (1994-2006). Neurosurgery.2009:64(6):1123.
9.刘旭,穆锦江,陈亚民。86例神经外科术后颅内感染分析.中华医院感染学杂志。2004；14：635。
10.王利君,黄桃芝,瞿伟军。674例神经外科患者医院感染临床调查分析.。实用预防医学。2003；10：352。
11.周忠清,郑今兰,张劲松,刘荣,石祥恩。开颅术后颅内感染的诊断与治疗.中华医院感染学杂志。2005；15(4)：402-404。
12.赵新亮,申长虹,甄自刚。神经外科术后颅内感染的临床研究。中华医院感染学杂志。2006；16：27-280。
13. Diederik van de Beek, James M. Drake, B. Ch, et al. Nosocomial Bacterial Meningitis. N Engl J Med.2010; 362:146-154.
14. Korinek AM, Baugnon T, Golmard JL, van Effenterre R, Coriat P, Puybasset L. Risk factors for adult nosocomial meningitis after craniotomy:role of antibiotic prophylaxis. Neurosurgery.2006;59:126-133.
15. McClelland S, Hall WA. Postoperative central nervous system infection: incidence and associated factors in 2111 neurosurgical procedures. Clin Infect Dis.2007;45:55-59.
16. Conen A, Walti LN, Merlo A, Fluckiger U, Battegay M, Trampuz A. Characteristics and treatment outcome of cerebrospinal fluid shunt-associated infections in adults:a retrospective analysis over an 11-year period. Clin Infect Dis.2008:47:73-82.
17. Vinchon M, Dhellemmes P. Cerebrospinal fluid shunt infection:risk factors and long-term follow-up. Childs Nerv Syst.2006;22:692-697.
18. Sorensen P, Ejlertsen T, Aaen D, Poulsen K. Bacterial contamination of surgeons gloves during shunt insertion:a pilot study. Br J Neurosurg, 2008:22:675-677.
19. Lozier AP, Sciacca RR, Romagnoli MF. Ventriculostomy-related infections:a critical review of the literature. Neurosurgery 2008:62:688-700.
20. Wong GK, Poon WS, Wai S, Yu LM, Lyon D, Lam JM. Failure of regular external ventricular drain exchange to reduce cerebrospinal fluid infection:result of a randomised controlled trial. J Neurol Neurosurg Psychiatry.2002;73:759-761.
21. Governale LS, FeinN, Logsdon J, Black PM. Techniques and complications of external lumbar drainage for normal pressure hydrocephalus. Neurosurgery.2008;63:Suppl 2:379-384.
22. Baltas I, Tsoulfa S, Sakellariou P, Vogas V, Fylaktakis M, Kondodimou A. Posttraumatic meningitis:bacteriology, hydrocephalus, and outcome, Neurosurgery.1994;35:422-426.
23. Bullock MR, Chesnut R, Ghajar J, et al. Surgical management of depressed cranial fractures. Neurosurgery.2006;58:Suppl:S56-S60.
24. Baer ET. Post-dural puncture bacterial meningitis. Anesthesiology. 2006;105:381-393.
25.卢岩,彭松林。神经外科颅内感染危险因素的病例对照研究。中国感染控制杂志。2008：6：396-398。
26.周建新,王强,唐明忠等。神经外科患者脑脊液细菌流行病学和耐药性监测。中华医院感染学杂志。2006；16：154-157。
27. Thomas KE, Hasbun R, Jekel J, et al. The diagnostic accuracy of Kernig' s sign, Brudzinski's sign, and nuchal rigidity in adults with suspected meningitis. Clin Infect Dis.2002; 35:46-52.
28. Mayhall CG, Archer NH, Lamb VA, et al. Ventriculostomy-related infections:a prospective epidemiologic study.N Engl J Med.1984:310:553-559.
29. La Scolea LJ Jr, Dryja D. Quantitation of bacteria in cerebrospinal fluid and blood of children with meningitis and its diagnostic significance. J Clin Microbiol.1984 Feb;19(2):187-190.
30. Banks JT, Bharara S, Tubbs RS, et al. Polymerase chain reaction for the rapid detection of cerebrospinal fluid shunt or ventriculostomy infections. Neurosurgery.2005;57:1237-1243.
31. Roland Nau, Fritz Sorge, Hilmar W. Prange。Pharmacokinetic Optimisation of the Treatment of Bacterial Central Nervous System Infections。 Clin Pharmacokinet.1998,35 (3):223-246.
32. Small PM, Tauber MG, Hackbarth CJ, et al. Influence of body temperature on bacterial growth rates in experimental pneumococcal meningitis in rabbits. Infect Immun.1986; 52:484-7.
33. Ronny Beer, Bettina Pfausler, Erich Schmutzhard 。Infectious intracranial complications in the neuro-ICU patient population。 Current Opinion in Critical Care.2010,16:117-122.
34. Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis.2004; 39:1267-84.
35. Yuliya Nudelman and Allan R. Tunkel. Bacterial Meningitis Epidemiology, Pathogenesis and Management Update. Drugs.2009,69(18): 2577-2596.
36. Falagas ME, Bliziotis IA, Tam VH. Intraventricular or intrathecal use of polymyxins in patients with gram-negative meningitis:a systematic review of the available evidence. Int J Antimicrob Agents.2007;29:9-25.
37. Katragkou A, Roilides E. Successful treatment of multidrug-resistant Acinetobacter baumannii central nervous system infections with colistin. J Clin Microbiol.2005:43:4916-4917.
38.中华医学会外科学分会,中华外科杂志编辑委员会。围手术期预防应用抗菌药物指南。中华外科杂志,2006；44：1594-1596。
39. Sanford, J. P. The Sanford guide to antimicrobial therapy 2009 — 2010 (39TH Edition).2009:170.