中国老年患者万古霉素相关急性肾损伤的临床特点及危险因素的回顾性分析
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- 英文论文题名：Retrospective analysis of possible vancomycin nephrotoxicity in elderly Chinese patients
- 论文作者：刘艳 ; 刘昕竹 ; 姚慧娟 ; 李莉霞 ; 陆晓彤 ; 张健 ; 卜书红 ; You Yin
- 英文论文作者：Yan Liu ; You Yin ; Xin Zhu Liu ; Hui Juan Yao ; Li Xia Li ; Xiao Tong Lu ; Shu Hong Bu ; Jian Zhang ; Department of Pharmacy ; Xinhua Hospital ; Shanghai Jiaotong University School of Medicine ; Department of Neurology ; Changzheng Hospital Affiliated to Second Military Medical University
- 年：2016
- 作者机构：上海交通大学医学院附属新华医院药学部;Department of Neurology,Changzheng Hospital Affiliated to Second Military Medical University;
- 论文关键词：老年患者 ; 万古霉素 ; 肾损伤 ; 危险因素 ; 感染
- 英文论文关键词：Nephrotoxicity ; Trough levels ; Vancomycin ; Risk factor ; MRSA
- 会议召开时间：2016-09-27
- 会议录名称：中国药学会第十三届青年药学科研成果交流会论文集
- 语种：英文
- 分类号：R692
- 学会代码：YYWS
- 会议名称：中国药学会第十三届青年药学科研成果交流会
- 会议地点：中国江西南昌
- 主办单位：中国药学会
- 学会名称：中国药学会
- 页数：9
- 文件大小：722k
- 原文格式：O
- 会议级别：全国
摘要
背景:万古霉素是治疗MRSA感染的经典药物,其肾毒性是临床用药过程中关注重要问题。研究提示万古霉素的谷浓度与其相关的肾毒性发生有关,推荐临床使用时监测其血药浓度。目前关于中国人群万古霉素的研究缺乏,尤其针对60岁以上的老年患者的研究更为罕见。目的:探讨中国老年患者发生万古霉素相关急性肾损伤(AKI)的临床特点以及相关因素分析。方法:选择2013年1月至2014年8月间上海交通大学医学院附属新华医院使用万古霉素治疗的患者。入选条件为:(①年龄≥18周岁②接受万古霉素抗感染治疗≥48小时③基础肌酐清除率正常。排除标准:①万古霉素用药前7天使用造影剂;②参与研究前30天内行肾脏替代治疗;③慢性肾脏病5期;本研究共入选患者124例,监测万古霉素谷浓度、血肌酐和肌酐清除率,并记录患者诊断、基础状态、万古霉素的用药剂量及疗程、合并用药情况,并进行分析。结果:①肾功能损害发生率为29%,肾功能受损组(A组)的用药前肌酐清除率(78.91±12.52)低于非受损组(B组)(98.56±10.42ml/min)。用药前基础血肌酐高的患者(≥63.5mL/min)发生损害的可能性增加。②A组的患者中合并疾病如高血压、心衰、是否为ICU病人多于B组,A组的患者使用ARB类药物和利尿剂明显多于B组。④万古霉素谷浓度影响肾功能损害的发生率。A组患者平均万古霉素谷浓度较B组患者高,当万古霉素谷浓度<15μg/mL时,肾功能损害发生率为16.8%,随着谷浓度的增加,发生肾功能损害的几率显著增加。当谷浓度≥30μg/mL时,肾功能损害发生率为60.2%。结论:老年患者肾脏功能损害发生率高,且万古霉素谷浓度、高血压、休克、充血性心力衰竭是万古霉素相关急性肾损伤的危险因素,合并用药也会影响到万古霉素相关急性肾损伤的发生。因此,用药期间需定期检测血药浓度,同时严密关注肾功能相关指标。
Background:Although a causal relationship has not been firmly established,vancomycin,a key antibiotic in the management of severe Gram-positive infections,is associated with nephrotoxicity.Objective:This study investigates nephrotoxicity in elderly Chinese patients after exposure to vancomycin and other nephrotoxic risk factors.Methods:This was a retrospective,single-center,observational cohort study.The evaluation group was patients≥ 60 years of age,had normal baseline serum creatinine values and received vancomycin for ≥ 48 hrs between January 1,2013 and August 30,2014.Patients' age,sex,weight,serum creatinine,creatinine clearance(CrCl),vancomycin serum trough concentrations,comorbid conditions and concomitant medications were obtained from automated hospital,microbiology and pharmacy databases.Results:Nephrotoxicity occurred in 29%of 124 patients.A baseline CrCl ≥ 63.5 mL/min was more common in the nephrotoxic group.Patients with high(≥ 15 mg/L) rather than low(< 15 mg/L) average vancomycin troughs had elevated nephrotoxicity(47.2%vs.27.3%,p =.0001).Of the comorbid conditions evaluated,there were more patients with shock(p = 0.001),hypertension(p = 0.020) and congestive heart failure(p = 0.04) in the nephrotoxic group.Drugs frequently given at the same time as vancomycin,such as angiotensin receptor blockers and furosemide,were associated with increased nephrotoxic risk.Conclusions:Nephrotoxicity was frequently observed in patients with concurrent vancomycin trough concentrations ≥ 15μg/mL and hypertension,shock,congestive heart failure,and drugs given with the vancomycin also influence the renal function.Therefore,renal function and vancomycin serum troughs should be closely monitored,especially patients with other renal injury risk factors.
Background:Although a causal relationship has not been firmly established,vancomycin,a key antibiotic in the management of severe Gram-positive infections,is associated with nephrotoxicity.Objective:This study investigates nephrotoxicity in elderly Chinese patients after exposure to vancomycin and other nephrotoxic risk factors.Methods:This was a retrospective,single-center,observational cohort study.The evaluation group was patients≥ 60 years of age,had normal baseline serum creatinine values and received vancomycin for ≥ 48 hrs between January 1,2013 and August 30,2014.Patients' age,sex,weight,serum creatinine,creatinine clearance(CrCl),vancomycin serum trough concentrations,comorbid conditions and concomitant medications were obtained from automated hospital,microbiology and pharmacy databases.Results:Nephrotoxicity occurred in 29%of 124 patients.A baseline CrCl ≥ 63.5 mL/min was more common in the nephrotoxic group.Patients with high(≥ 15 mg/L) rather than low(< 15 mg/L) average vancomycin troughs had elevated nephrotoxicity(47.2%vs.27.3%,p =.0001).Of the comorbid conditions evaluated,there were more patients with shock(p = 0.001),hypertension(p = 0.020) and congestive heart failure(p = 0.04) in the nephrotoxic group.Drugs frequently given at the same time as vancomycin,such as angiotensin receptor blockers and furosemide,were associated with increased nephrotoxic risk.Conclusions:Nephrotoxicity was frequently observed in patients with concurrent vancomycin trough concentrations ≥ 15μg/mL and hypertension,shock,congestive heart failure,and drugs given with the vancomycin also influence the renal function.Therefore,renal function and vancomycin serum troughs should be closely monitored,especially patients with other renal injury risk factors.
引文
1.Faibrother Rw,Williams BL.Two new antibiotics;antibacterial activity of novobiocin and vancomycin.Lancet.1956 Dec8;271(6954):1177-8.
2.Stevens DL.The role of vancomycin in the treatment paradigm.Clin Infect Dis.2006 Jan 1;42 Suppl 1:S51-7.
3.Kullar R,Davis SL,Taylor TN,Kaye KS,Rybak MJ.Effects of targeting higher vancomycin trough levels on clinical outcomes and costs in a matched patient cohort.Pharmacotherapy.2012 Mar;32(3):195-201.doi:10.1002/j.1875-9114.2011.01017.x.Erratum in:Pharmacotherapy.2012 Sep;32(9):869.
4.Rybak MJ,Lomaestro BM,Rotschafer JC,Moellering RC Jr,Craig WA,Billeter M,Dalovisio JR,Levine DP.Therapeutic monitoring of vancomycin in adults summary of consensus recommendations from the American Society of Health-System Pharmacists,the Infectious Diseases Society of America,and the Society of Infectious Diseases Pharmacists.Pharmacotherapy.2009 Nov;29(11):1275-9.Review
5.Kullar R,Davis SL,Taylor TN,Kaye KS,Rybak MJ.Effects of targeting higher vancomycin trough levels on clinical outcomes and costs in a matched patient cohort.Pharmacotherapy.2012 Mar;32(3):195-201.doi:10.1002/j.1875-9114.2011.01017.x.Erratum in:Pharmacotherapy.2012 Sep;32(9):869.
6.Mangin Ol,Urien S,Mainardi JL,Fagon JY,Faisy C.Vancomycin pharmacokinetic and pharmacodynamic models for critically ill patients with post-sternotomy mediastinitis.Clin Pharmacokinet.2014 Aug 13.[Epub ahead of print]
7.Geraci JE,Heilman FR,Nichols DR,Wellman WE.Antibiotic therapy of bacterial endocarditis.Ⅶ.Vancomycin for acute micrococcal endocarditis;preliminary report.Proc Staff Meet Mayo Clin.1958 Apr 2;33(7):172-81.
8.Hanrahan TP,Harlow G,Hutchinson J,Dulhunty JM,Lipman J,Whitehouse T,Roberts JA.Vancomycin-associated nephrotoxicity in the critically ill:A retrospective multivariate regression analysis.Crit Care Med.2014 Jul 31.
9.Rostas SE,Kubiak DW,Calderwood MS.High-dose intravenous vancomycin therapy and the risk of nephrotoxicity.Clin Ther.2014 Jul1;36(7):1098-101.
10.Gurwitz JH,Avorn J,Ros-Degnan D,Lipsitz LA.Nonsteroidal anti-inflammatory drug-associated azotemia in the very old.JAMA.1990;264(4):471-5.
11.Whelton A,Hamilton C.Nonsteroidal anti-inflammatory drugs:effects on kidney function.J Clin Pharmacol.1991;31(7):588-98.
12.Lapi F,Azoulay L,Yin H,Nessim SJ,Suissa S.Concurrent use of diuretics,angiotensin converting enzyme inhibitors,and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury:nested case-control study.BMJ.2013;346:e8525.doi:10.1136/bmj.e8525.
13.Hernandez-Diaz S,Garcia-Rodriguez A.Epidemiologic assessment of the safety of conventional nonsteroidal anti-inflammatory drags.Am JMed.2001;110(3A):20S-7S.
14.Fox CS,Larson MG,Leip EP,Culleton B,Wilson PW,Levy D.Predictors of new-onset kidney disease in a community-based population.JAMA.2004;291(7):844-50.
15.Manjunath G1,Tighiouart H,Ibrahim H,MacLeod B,Salem DN,Griffith JL,Coresh J,Levey AS,Sarnak MJ.Level of kidney function as a risk factor for atherosclerotic cardiovascular outcomes in the community.J Am Coll Cardiol.2003;41(1):47-55.
16.Manjunath G,Tighiouart H,Coresh J,Macleod B,Salem DN,Griffith JL,Levey AS,Sarnak MJ.Level of kidney function as a risk factor for cardiovascular outcomes in the elderly.Kidney Int.2003;63(3):1121-9.
17.Perazella MA.Renal vulnerability to drug toxicity.Clin J Am Soc Nephrol.2009;4(7):1275-83.
18.Guo X,Nzerue R.How to prevent,recognize,and treat druginduced nephrotoxicity.Cleve Clin J Med.2002;69(4):289-90.
19.Mehta RL,Kellum JA,Shah SV,Molitoris BA,Ronco C,Warnock DG,Levin A,the acute kidney injury network:acute kidney injury network:report of an initiative to improve outcomes in acute kidney injury.Crit Care 2007,11:R31.
20.Cappelletty D,Jablonski A,Jung R.Risk factors for acute kidney injury in adult patients receiving vancomycin.Clin Drug Investig.2014 Mar;34(3):189-93.
21.Kralovicova K,Spanik S,Halko J,Netriova J,Studena-Mrazova M,Novotny J,Grausova S,Koren P,Krupova I,Demitrovicova A,Kukuckova E,Krcmery V Jr.Do vancomycin serum levels predict failures of vancomycin therapy or nephrotoxicity in cancer patients?J Chemother.1997;9:420-426.
22.Zimmermann AE,Katona BG,Plaisance KI.Association of vancomycin serum concentrations with outcomes in patients with gram-positive bacteremia.Pharmacotherapy.1995;15:85-91.
23.Downs NJ,Neihart RE,Dolezal JM,Hodges GR.Mild nephrotoxicity associated with vancomycin use.Arch Intern Med.1989;149:1777-1781.
24.Moellering RC Jr,Krogstad DJ,Greenblatt DJ.Vancomycin therapy in patients with impaired renal function:a nomogram for dosage.Ann Intern Med.1981;94:343-346.
25.Cimino MA,Rotstein C,Slaughter RL,Emrich LJ.Relationship of serum antibiotic concentrations to nephrotoxicity in cancer patients receiving concurrent aminoglycoside and vancomycin therapy.Am J Med.l987;83:1091-1097.
26.Rybak MJ,Albrecht LM,Boike SC,Chandrasekar PH.Nephrotoxicity of vancomycin,alone and with aminoglycoside J Antimicrob Chemother.1990;25:679-687.
27.Meghan N.Jeffres,PharmD1;Warren Isakow,MD2;Joshua A.Doherty,BS3;Scott T.Micek,PharmD1;and Marin H.Kollef,MD2.A retrospective analysis of possible renal toxicity associated with vancomycin in patients with health care-associated methicillin-resistant staphylococcus aureus pneumonia.Clin Ther.2007 Jun;29(6):1107-15.
28.Thomas P.Lodise,Ben Lomaestro,Jeffrey Graves,and G.L.Drusano.Larger Vancomycin Doses(at Least Four Grams per Day)Are Associated with an Increased Incidence of Nephrotoxicity.Antimicrobial agents and chemotherapy.2008 Apr;52(4):1330-6.doi:10.1128/AAC.01602-07.Epub 2008 Jan 28.
29.McKamy S1,Hernandez E,Jahng M,Moriwaki T,Deveikis A,Le J.Incidence and Risk cddceeeeeeeeeFactors Influencing the Development of Vancomycin Nephrotoxicity in Children.J Pediatr.2011 Mar;158(3):422-6.doi:10.1016/j.jpeds.2010.08.019.
30.Hidayat LK,Hsu DI,Quist R,Shriner KA,Wong-Beringer A.High dose vancomycin therapy for methicillin-resistant Staphylococcus aureus infections:efficacy and toxicity.Arch Intern Med 2006;166:2138-44.
31.Fanos V,Cataldi L.Renal transport of antibiotics and nephrotoxicity:areview.J Chemother.2001;13:461-72.
32.Oktem F,Arslan MK,Ozguner F,et al.In vivo evidences suggesting the role of oxidative stress in pathogenesis of vancomycin-induced nephrotoxicity:protection by erdosteine.Toxicology.2005;215:227-33.
33.Dieterich C,Puey A,Lin S,et al.Gene expression analysis reveals new possible mechanisms of vancomycin-induced nephrotoxicity and identifies gene markers candidates.Toxicol Sci.2009;107:258-69.
34.Hong S,Valderrama E,Mattana J,et al.Vancomycin-induced acute granulomatous interstitial nephritis:therapeutic options.Am J Med Sci.2007;334:296-300.
35.Lodise TP,Lomaestro B,Graves J,Drusano GL.Larger vancomycin doses(at least four grams per day)are associated with an increased incidence of nephrotoxicity.Antimicrob Agents Chemother.2008;52:1330-6.
36.Spapen HD1,Janssen van Doorn K,Diltoer M,Verbrugghe W,Jacobs R,Dobbeleir N,Honore PM,Jorens PG.Retrospective evaluation of possible renal toxicity associated with continuous infusion of vancomycin in critically ill patients.Ann Intensive Care.2011 Jul 19;1(1):26.doi:10.1186/2110-5820-1-26.
37.Wong-Beringer Al,Joo J,Tse E,Beringer P.Vancomycin-associated nephrotoxicity:a critical appraisal of risk with high-dose therapy.Int J Antimicrob Agents.2011 Feb;37(2):95-101.doi:10.1016/j.ijantimicag.2010.10.013.
2.Stevens DL.The role of vancomycin in the treatment paradigm.Clin Infect Dis.2006 Jan 1;42 Suppl 1:S51-7.
3.Kullar R,Davis SL,Taylor TN,Kaye KS,Rybak MJ.Effects of targeting higher vancomycin trough levels on clinical outcomes and costs in a matched patient cohort.Pharmacotherapy.2012 Mar;32(3):195-201.doi:10.1002/j.1875-9114.2011.01017.x.Erratum in:Pharmacotherapy.2012 Sep;32(9):869.
4.Rybak MJ,Lomaestro BM,Rotschafer JC,Moellering RC Jr,Craig WA,Billeter M,Dalovisio JR,Levine DP.Therapeutic monitoring of vancomycin in adults summary of consensus recommendations from the American Society of Health-System Pharmacists,the Infectious Diseases Society of America,and the Society of Infectious Diseases Pharmacists.Pharmacotherapy.2009 Nov;29(11):1275-9.Review
5.Kullar R,Davis SL,Taylor TN,Kaye KS,Rybak MJ.Effects of targeting higher vancomycin trough levels on clinical outcomes and costs in a matched patient cohort.Pharmacotherapy.2012 Mar;32(3):195-201.doi:10.1002/j.1875-9114.2011.01017.x.Erratum in:Pharmacotherapy.2012 Sep;32(9):869.
6.Mangin Ol,Urien S,Mainardi JL,Fagon JY,Faisy C.Vancomycin pharmacokinetic and pharmacodynamic models for critically ill patients with post-sternotomy mediastinitis.Clin Pharmacokinet.2014 Aug 13.[Epub ahead of print]
7.Geraci JE,Heilman FR,Nichols DR,Wellman WE.Antibiotic therapy of bacterial endocarditis.Ⅶ.Vancomycin for acute micrococcal endocarditis;preliminary report.Proc Staff Meet Mayo Clin.1958 Apr 2;33(7):172-81.
8.Hanrahan TP,Harlow G,Hutchinson J,Dulhunty JM,Lipman J,Whitehouse T,Roberts JA.Vancomycin-associated nephrotoxicity in the critically ill:A retrospective multivariate regression analysis.Crit Care Med.2014 Jul 31.
9.Rostas SE,Kubiak DW,Calderwood MS.High-dose intravenous vancomycin therapy and the risk of nephrotoxicity.Clin Ther.2014 Jul1;36(7):1098-101.
10.Gurwitz JH,Avorn J,Ros-Degnan D,Lipsitz LA.Nonsteroidal anti-inflammatory drug-associated azotemia in the very old.JAMA.1990;264(4):471-5.
11.Whelton A,Hamilton C.Nonsteroidal anti-inflammatory drugs:effects on kidney function.J Clin Pharmacol.1991;31(7):588-98.
12.Lapi F,Azoulay L,Yin H,Nessim SJ,Suissa S.Concurrent use of diuretics,angiotensin converting enzyme inhibitors,and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury:nested case-control study.BMJ.2013;346:e8525.doi:10.1136/bmj.e8525.
13.Hernandez-Diaz S,Garcia-Rodriguez A.Epidemiologic assessment of the safety of conventional nonsteroidal anti-inflammatory drags.Am JMed.2001;110(3A):20S-7S.
14.Fox CS,Larson MG,Leip EP,Culleton B,Wilson PW,Levy D.Predictors of new-onset kidney disease in a community-based population.JAMA.2004;291(7):844-50.
15.Manjunath G1,Tighiouart H,Ibrahim H,MacLeod B,Salem DN,Griffith JL,Coresh J,Levey AS,Sarnak MJ.Level of kidney function as a risk factor for atherosclerotic cardiovascular outcomes in the community.J Am Coll Cardiol.2003;41(1):47-55.
16.Manjunath G,Tighiouart H,Coresh J,Macleod B,Salem DN,Griffith JL,Levey AS,Sarnak MJ.Level of kidney function as a risk factor for cardiovascular outcomes in the elderly.Kidney Int.2003;63(3):1121-9.
17.Perazella MA.Renal vulnerability to drug toxicity.Clin J Am Soc Nephrol.2009;4(7):1275-83.
18.Guo X,Nzerue R.How to prevent,recognize,and treat druginduced nephrotoxicity.Cleve Clin J Med.2002;69(4):289-90.
19.Mehta RL,Kellum JA,Shah SV,Molitoris BA,Ronco C,Warnock DG,Levin A,the acute kidney injury network:acute kidney injury network:report of an initiative to improve outcomes in acute kidney injury.Crit Care 2007,11:R31.
20.Cappelletty D,Jablonski A,Jung R.Risk factors for acute kidney injury in adult patients receiving vancomycin.Clin Drug Investig.2014 Mar;34(3):189-93.
21.Kralovicova K,Spanik S,Halko J,Netriova J,Studena-Mrazova M,Novotny J,Grausova S,Koren P,Krupova I,Demitrovicova A,Kukuckova E,Krcmery V Jr.Do vancomycin serum levels predict failures of vancomycin therapy or nephrotoxicity in cancer patients?J Chemother.1997;9:420-426.
22.Zimmermann AE,Katona BG,Plaisance KI.Association of vancomycin serum concentrations with outcomes in patients with gram-positive bacteremia.Pharmacotherapy.1995;15:85-91.
23.Downs NJ,Neihart RE,Dolezal JM,Hodges GR.Mild nephrotoxicity associated with vancomycin use.Arch Intern Med.1989;149:1777-1781.
24.Moellering RC Jr,Krogstad DJ,Greenblatt DJ.Vancomycin therapy in patients with impaired renal function:a nomogram for dosage.Ann Intern Med.1981;94:343-346.
25.Cimino MA,Rotstein C,Slaughter RL,Emrich LJ.Relationship of serum antibiotic concentrations to nephrotoxicity in cancer patients receiving concurrent aminoglycoside and vancomycin therapy.Am J Med.l987;83:1091-1097.
26.Rybak MJ,Albrecht LM,Boike SC,Chandrasekar PH.Nephrotoxicity of vancomycin,alone and with aminoglycoside J Antimicrob Chemother.1990;25:679-687.
27.Meghan N.Jeffres,PharmD1;Warren Isakow,MD2;Joshua A.Doherty,BS3;Scott T.Micek,PharmD1;and Marin H.Kollef,MD2.A retrospective analysis of possible renal toxicity associated with vancomycin in patients with health care-associated methicillin-resistant staphylococcus aureus pneumonia.Clin Ther.2007 Jun;29(6):1107-15.
28.Thomas P.Lodise,Ben Lomaestro,Jeffrey Graves,and G.L.Drusano.Larger Vancomycin Doses(at Least Four Grams per Day)Are Associated with an Increased Incidence of Nephrotoxicity.Antimicrobial agents and chemotherapy.2008 Apr;52(4):1330-6.doi:10.1128/AAC.01602-07.Epub 2008 Jan 28.
29.McKamy S1,Hernandez E,Jahng M,Moriwaki T,Deveikis A,Le J.Incidence and Risk cddceeeeeeeeeFactors Influencing the Development of Vancomycin Nephrotoxicity in Children.J Pediatr.2011 Mar;158(3):422-6.doi:10.1016/j.jpeds.2010.08.019.
30.Hidayat LK,Hsu DI,Quist R,Shriner KA,Wong-Beringer A.High dose vancomycin therapy for methicillin-resistant Staphylococcus aureus infections:efficacy and toxicity.Arch Intern Med 2006;166:2138-44.
31.Fanos V,Cataldi L.Renal transport of antibiotics and nephrotoxicity:areview.J Chemother.2001;13:461-72.
32.Oktem F,Arslan MK,Ozguner F,et al.In vivo evidences suggesting the role of oxidative stress in pathogenesis of vancomycin-induced nephrotoxicity:protection by erdosteine.Toxicology.2005;215:227-33.
33.Dieterich C,Puey A,Lin S,et al.Gene expression analysis reveals new possible mechanisms of vancomycin-induced nephrotoxicity and identifies gene markers candidates.Toxicol Sci.2009;107:258-69.
34.Hong S,Valderrama E,Mattana J,et al.Vancomycin-induced acute granulomatous interstitial nephritis:therapeutic options.Am J Med Sci.2007;334:296-300.
35.Lodise TP,Lomaestro B,Graves J,Drusano GL.Larger vancomycin doses(at least four grams per day)are associated with an increased incidence of nephrotoxicity.Antimicrob Agents Chemother.2008;52:1330-6.
36.Spapen HD1,Janssen van Doorn K,Diltoer M,Verbrugghe W,Jacobs R,Dobbeleir N,Honore PM,Jorens PG.Retrospective evaluation of possible renal toxicity associated with continuous infusion of vancomycin in critically ill patients.Ann Intensive Care.2011 Jul 19;1(1):26.doi:10.1186/2110-5820-1-26.
37.Wong-Beringer Al,Joo J,Tse E,Beringer P.Vancomycin-associated nephrotoxicity:a critical appraisal of risk with high-dose therapy.Int J Antimicrob Agents.2011 Feb;37(2):95-101.doi:10.1016/j.ijantimicag.2010.10.013.
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