研究背景
萬古黴素開發至今已歷時超過半世紀，經常用在抗藥性革蘭氏陽性菌株（如ORSA）感染的治療。且依據早期藥物動態學與藥理學相關研究，經腎功能調量後，血液透析病患可採取每五至七天靜脈注射1g的全身給藥方式。因此，萬古黴素挾著理想的有效性、便利性與較低廉的平均每日藥價，在抗藥性菌株較盛行的醫療院所，便成為血液透析病患經驗性抗生素與治療革蘭氏陽性菌株感染的熱門選擇。但也由於此類病患的萬古黴素半衰期較長，需耗時較久以達穩定態濃度；長期以來臨床上對血液透析病患都缺乏良好的濃度監測作業模式，而以個別醫師經驗性調整給藥劑量為主。
但自2000年以來，許多菌株對萬古黴素的MIC值開始有悄悄升高的現象，各國出現萬古黴素抗藥性菌株感染的案例也逐漸增加。許多感染症的治療準則，或醫療院所內定的萬古黴素建議波谷濃度，因此有隨之往上修正的趨勢。因此，血液透析病患是否仍能依早期訂定的用藥方式給藥，以及該如何在給藥前期作濃度監測以確保療效、降低菌株出現萬古黴素抗藥性的機會、提高治療成功率並降低復發率，便成為目前亟需解答的問題。

研究目的
本研究以臨床容易取得的藥物濃度，了解血液透析病患給第一、二劑萬古黴素時之血中濃度、藥物動態學參數與臨床治療效果，並找出可能影響濃度與藥物動態學參數的因子。另外將根據本研究結果與文獻回顧，提出適當的給藥方法與監測建議。

研究方法
本研究為前瞻性觀察研究，收集民國96年11月20日至97年5月31日於成大醫院住院，且接受穩定血液透析和萬古黴素五天注射1g療程之成年病患。收案的11天內，接受兩次以上萬古黴素注射者，將於三次血液透析前、兩次給藥後第五日時，抽血監測萬古黴素血中濃度。接受一次注射者，將於三次血液透析前監測之。除此之外，記錄收案病患十一日內之體溫、白血球數量、細菌培養結果、臨床治療效果與可能影響藥物動態學參數的因子。

研究結果
本研究共納入38位病患。其中27位在收案期間接受兩次以上萬古黴素注射，共得到101個血中濃度值；11位接受一次萬古黴素注射，共得到28個血中濃度值。收案病患平均年齡為66.8歲，女性佔42.1%，平均給藥劑量為18.1mg/kg；其中4位為ORSA菌血症，MIC值皆為1.5 mcg/ml。
在第一、二次給藥後五日的濃度數值中，分別有81.3%和38.9%低於10 mcg/ml，半衰期分別為126.3、177.6小時。第一次給藥後推估之AUC24平均值為293.1 mcg/ml；若以MIC值為1.5 mcg/ml推測AUIC，則第一次給藥後預估AUIC為195.4 mcg/ml。在治療成效方面，收案結束時共84.2%病患初始感染症狀獲得完全或部分緩解，其中77.3%無發燒，52.6%無白血球過高的現象。
另外，本研究發現依體重校正後，劑量（mg/kg）會明顯影響濃度、濃度-時間曲線下面積，另外每日平均尿量較多者半衰期明顯較短（P= 0.003），肌胺酸酐清除率較高者萬古黴素清除率亦明顯較高（P= 0.001）。

結論與建議
本研究顯示，每五至七日靜脈注射1 g萬古黴素的給藥方式，在第一、二次給藥後將有一定比例的病患濃度低於10 mcg/ml，推估的AUC24、AUIC亦偏低，可能無法達到臨床需求。且劑量經體重校正後，明顯與濃度、曲線下面積相關。因此本研究建議，萬古黴素應依體重和預期達到之波谷濃度改變給藥劑量：若預期將波谷濃度維持在10 mcg/ml以上，則40公斤以下、40~60公斤、60公斤以上者，可分別給予1g、1~1.25g、1.5~2g的劑量，或依濃度、曲線下面積的臨床需求，微調給藥劑量。此外，須注意平均每日尿量較多者，半衰期會較短；肌胺酸酐清除率較大者，萬古黴素清除率亦會較大。
另外本研究發現血液透析病患使用萬古黴素時，藥物動態學參數可能存在較大的變異；因此應對血液透析病患進行濃度監測，以確實掌握個別病患狀況。監測時機以第一次給藥後、第一次血液透析前最佳；濃度值和推估曲線下面積較高者，治療效果（退燒比率、臨床反應）有較佳的趨勢。

Background
Vancomycin is one of the most common antimicobial agents against methicillin-resistant Staphylococcus aureus (MRSA) infections. As the susceptibility of MRSA to vancomycin reduced gradually, there were increasing reports of poor response to therapy among patients infected by MRSA isolates with higher minimal inhibitory concentrations (MICs, 1~2 μg/mL) or lower values of area under the inhibitory curve (AUIC < 350~400; AUIC= AUC/MIC). Patients on hemodialysis are particularly at high risks of treatment failure. This study is to investigate whether the current treatment regimen, i.e. vancomycin 1g every 5 days, is adequate among patients on hemodialysis in the “MIC creep” era, and try to establish an applicable method of vancomycin concentration monitoring.

Methods
From Nov. 2007 to May 2008, patients aged ≥ 20 years under hemodialysis and treated with vancomycin were prospectively enrolled at National Cheng Kung University Hospital. After initial vancomycin dosing, serum vancomycin concentrations would be measured before the following three hemodialysis procedures and 5 days after each vancomycin infusion. Clinical responses, pharmacokinetic information and laboratory data were recorded.

Results
A total of 38 patients and 129 serum concentration data were collected. 81.3% had concentrations less than 10 μg/mL during inclusion period. In the first 5 days, mean 24-h area under the concentration-time curve (AUC24) was 293.1 92.0 g-hr/ml. Mean half-life after first and second dose was 126.3 45.0 h and 177.6 150.5 h, decreased among patients with daily urine output ≥ 100, 200, 300, 500 ml/day (p=0.01, p<0.001, p=0.002, p=0.001). Clearance of vancomycin was 6.5  2.7 ml/min and was associated with creatinine clearance (p<0.01). Blood cultures yielded ORSA in four patients. The MICs of four bacteremic ORSA isolates were 1.5 μg/mL, and the AUICs were 170, 213, 345 and 351, respectively. Except one patient insisted discharge early and was not evaluable, the remaining three patients got complete remission of infection. Among 38 patients enrolled, 21 had complete response to vancomycin. The estimated AUIC of the study patients was 197.1 ± 63.1.

Conclusions
Perhaps because of the limited number of patients enrolled and ORSA isolated, our study did not show relationship between AUIC and clinical response. However, as MIC creeps and the estimated AUIC < 200 in our study, the current regimen of vancomycin (1g q5d) might not provide satisfied concentrations in hemodialysis patients. Dosage should be increased according to body weight: recommended loading dosage of patients with body weight less than 40kg, 40~60kg, and more than 60kg are 1 g, 1~1.25 g and 1.5~2 g. In addition, concentrations should be closely monitored during therapy.

1.Levine DP. Vancomycin: a history. Clin Infect Dis 2006;42 Suppl 1:S5-12.
2.Darko W, Medicis JJ, Smith A, Guharoy R, Lehmann DE. Mississippi mud no more: cost-effectiveness of pharmacokinetic dosage adjustment of vancomycin to prevent nephrotoxicity. Pharmacotherapy 2003;23(5):643-50.
3.Karam CM, McKinnon PS, Neuhauser MM, Rybak MJ. Outcome assessment of minimizing vancomycin monitoring and dosing adjustments.[erratum appears in Pharmacotherapy 1999 May;19(5):674]. Pharmacotherapy 1999;19(3):257-66.
4.Matzke GR, McGory RW, Halstenson CE, Keane WF. Pharmacokinetics of vancomycin in patients with various degrees of renal function. Antimicrob Agents Chemother 1984;25(4):433-7.
5.Steinkraus G, White R, Friedrich L. Vancomycin MIC creep in non-vancomycin-intermediate Staphylococcus aureus (VISA), vancomycin-susceptible clinical methicillin-resistant S. aureus (MRSA) blood isolates from 2001-05. J Antimicrob Chemother 2007;60(4):788-94.
6.American Thoracic S, Infectious Diseases Society of A. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia.[see comment]. Am J Respir Crit Care Med 2005;171(4):388-416.
7.陳淑君. 臺大醫院住院病人使用萬古黴素 (vancomycin) 起始給藥方法之評估及藥物動力學參數之分析. 台灣大學 臨床藥學研究所碩士論文 2002.
8.Reynolds PE. Structure, biochemistry and mechanism of action of glycopeptide antibiotics. Eur J Clin Microbiol Infect Dis 1989;8(11):943-50.
9.Mohr JF, Murray BE. Point: Vancomycin is not obsolete for the treatment of infection caused by methicillin-resistant Staphylococcus aureus. [see comment]. Clin Infect Dis 2007;44(12):1536-42.
10.Chambers HF. Protein Synthesis Inhibitors and Miscellaneous Antibacterial Agents. In: Laurence L. Brunton, John S. Lazo, Parker. KL, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 11 ed. New York: McGraw-Hill, 2006:2021.
11.Finch RG, Eliopoulos GM. Safety and efficacy of glycopeptide antibiotics. J Antimicrob Chemother 2005;55 Suppl 2:ii5-13.
12.Murray BE, Nannini EC. Glycopeptides (Vancomycin and Teicoplanin), Streptogramins (Quinupristin-Dalfopristin), and Lipopeptides (Daptomycin). In: Gerald L. Mandell JEB, Raphael Dolin, ed. Mandell, Douglas, and Bennett's principles and practice of infectious diseases 6th ed. New York Elsevier, 2005.
13.Leader WG, Chandler MH, Castiglia M. Pharmacokinetic optimisation of vancomycin therapy. Clin Pharmacokinet 1995;28(4):327-42.
14.Larsson AJ, Walker KJ, Raddatz JK, Rotschafer JC. The concentration-independent effect of monoexponential and biexponential decay in vancomycin concentrations on the killing of Staphylococcus aureus under aerobic and anaerobic conditions. J Antimicrob Chemother 1996;38(4):589-97.
15.Ambrose PG, Jr., Owens RC, Grasela D. Antimicrobial pharmacodynamics. Med Clin North Am 2000;84(6):1431-46.
16.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(19):2138-44.
17.Tenover FC, Moellering RC, Jr. The rationale for revising the Clinical and Laboratory Standards Institute vancomycin minimal inhibitory concentration interpretive criteria for Staphylococcus aureus. Clin Infect Dis 2007;44(9):1208-15.
18.Sakoulas G, Moise-Broder PA, Schentag J, Forrest A, Moellering RC, Jr., Eliopoulos GM. Relationship of MIC and bactericidal activity to efficacy of vancomycin for treatment of methicillin-resistant Staphylococcus aureus bacteremia. J Clin Microbiol 2004;42(6):2398-402.
19.Amsden GW, Ballow CH, JR. JSB, Kashuba ADM. Pharmacokinetics and Pharmacodynamics of Anti-infective Agents. In: Gerald L. Mandell JEB, Raphael Dolin, ed. Mandell, Douglas, and Bennett's principles and practice of infectious diseases New York: Elsevier, 2005.
20.Hyatt JM, McKinnon PS, Zimmer GS, Schentag JJ. The importance of pharmacokinetic/pharmacodynamic surrogate markers to outcome. Focus on antibacterial agents. Clin Pharmacokinet 1995;28(2):143-60.
21.Rybak MJ. The pharmacokinetic and pharmacodynamic properties of vancomycin. Clin Infect Dis 2006;42 Suppl 1:S35-9.
22.Moise-Broder PA, Forrest A, Birmingham MC, Schentag JJ. Pharmacodynamics of vancomycin and other antimicrobials in patients with Staphylococcus aureus lower respiratory tract infections. Clin Pharmacokinet 2004;43(13):925-42.
23.Rybak MJ. Pharmacodynamics: relation to antimicrobial resistance. Am J Med 2006;119(6 Suppl 1):S37-44; discussion S62-70.
24.Tsuji BT, Rybak MJ, Lau KL, Sakoulas G. Evaluation of accessory gene regulator (agr) group and function in the proclivity towards vancomycin intermediate resistance in Staphylococcus aureus. Antimicrob Agents Chemother 2007;51(3):1089-91.
25.Mulhern JG, Braden GL, O'Shea MH, Madden RL, Lipkowitz GS, Germain MJ. Trough serum vancomycin levels predict the relapse of gram-positive peritonitis in peritoneal dialysis patients. Am J Kidney Dis 1995;25(4):611-5.
26.Zimmermann AE, Katona BG, Plaisance KI. Association of vancomycin serum concentrations with outcomes in patients with gram-positive bacteremia. Pharmacotherapy 1995;15(1):85-91.
27.Rybak MJ CD, Ruffing MJ, et al. Influence of vancomycin serum concentrations on the outcome of patients being treated for gram-positive infections. Abstracts of the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy 1997:A46.
28.郭俊男. ORSA菌血症住院病患的vancomycin血中波谷濃度與臨床療效及腎毒性之關係評估. 成功大學臨床藥學研究所 碩士論文 2006.
29.Lowdin E, Odenholt I, Cars O. In vitro studies of pharmacodynamic properties of vancomycin against Staphylococcus aureus and Staphylococcus epidermidis. Antimicrob Agents Chemother 1998;42(10):2739-44.
30.Knudsen JD, Fuursted K, Espersen F, Frimodt-Moller N. Activities of vancomycin and teicoplanin against penicillin-resistant pneumococci in vitro and in vivo and correlation to pharmacokinetic parameters in the mouse peritonitis model. Antimicrob Agents Chemother 1997;41(9):1910-5.
31.MacGowan AP. Pharmacodynamics, pharmacokinetics, and thera-peutic drug monitoring of glycopeptides. Ther Drug Monit 1998;20(5):473-7.
32.Pancorbo S, Comty C. Peritoneal transport of vancomycin in 4 patients undergoing continuous ambulatory peritoneal dialysis. Nephron 1982;31(1):37-9.
33.Nielsen HE, Sorensen I, Hansen HE. Peritoneal transport of vancomycin during peritoneal dialysis. Nephron 1979;24(6):274-7.
34.Ackerman BH OK, Padilla CB. Errors in Assuming a One- Compartment Model for Vancomycin. Ther Drug Monit 1990;12(3):304-5.
35.陳惠美. 危急尿毒症患者使用不同透析膜對萬古黴素藥物動力學的影響. 成功大學臨床藥學研究所 碩士論文 1997.
36.Ambrose PJ, Winter ME. Vancomycin. In: Winter ME, Troy DB, eds. Basic Clinical Pharmacokinetics. 4 ed. Philadelphia: Lippincott Wiliams & Wilkins, 2004:511.
37.Welty TE, Copa AK. Impact of vancomycin therapeutic drug monitoring on patient care. [see comment]. Ann Pharmacother 1994;28(12):1335-9.
38.Leonard AE, Boro MS. Vancomycin pharmacokinetics in middle- aged and elderly men. Am J Hosp Pharm 1994;51(6):798-800.
39.Ducharme MP, Slaughter RL, Edwards DJ. Vancomycin pharmaco- kinetics in a patient population: effect of age, gender, and body weight. Ther Drug Monit 1994;16(5):513-8.
40.Bearden DT, Rodvold KA. Dosage adjustments for antibacterials in obese patients: applying clinical pharmacokinetics. Clin Pharmacokinet 2000;38(5):415-26.
41.Todo A Rushing, Amssose PJ. Clinical application and evaluation of vancomycin dosing in adults. the Journal of Pharmacy Technology 2001;17.
42.Teramachi H, Hatakeyama H, Matsushita R, Imai Y, Miyamoto Ki, Tsuji A. Evaluation of predictability for vancomycin dosage regimens by the Bayesian method with Japanese population pharmacokinetic parameters. Biol Pharm Bull 2002;25(10):1333-8.
43.Aldaz A, Ortega A, Idoate A, Giraldez J, Brugarolas A. Effects of hepatic function on vancomycin pharmacokinetics in patients with cancer. Ther Drug Monit 2000;22(3):250-7.
44.Dykhuizen RS, Harvey G, Stephenson N, Nathwani D, Gould IM. Protein binding and serum bactericidal activities of vancomycin and teicoplanin. Antimicrob Agents Chemother 1995;39(8):1842-7.
45.Marti R, Rosell M, Pou L, Garcia L, Pascual C. Influence of biochemical parameters of liver function on vancomycin pharmacokinetics. Pharmacol Toxicol 1996;79(2):55-9.
46.Troy DB. 15. Vancomycin. Basic Clinical Pharmacokinetics 2004; 4/e.
47.Launay-Vacher V, Izzedine H, Mercadal L, Deray G. Clinical review: use of vancomycin in haemodialysis patients. Crit Care 2002;6(4):313-6.
48.Aronoff GR. Drug prescribing in renal failure :dosing guidelines for adults and children 5ed. Philadelphia: American College of Physicians, 2007.
49.Fanos V, Cataldi L. Renal transport of antibiotics and nephrotoxicity: a review. J Chemother 2001;13(5):461-72.
50.Wilson AP. Comparative safety of teicoplanin and vancomycin. Int J Antimicrob Agents 1998;10(2):143-52.
51.Malacarne P, Bergamasco S, Donadio C. Nephrotoxicity due to combination antibiotic therapy with vancomycin and amino- glycosides in septic critically ill patients. Chemotherapy 2006;52(4):178-84.
52.Colares VS, Oliveira RB, Abdulkader RCRM. Nephrotoxicity of vancomycin in patients with normal serum creatinine. Nephrol Dial Transplant 2006;21(12):3608.
53.Elting LS, Rubenstein EB, Kurtin D, et al. Mississippi mud in the 1990s: risks and outcomes of vancomycin-associated toxicity in general oncology practice. Cancer 1998;83(12):2597-607.
54.Gendeh BS, Gibb AG, Aziz NS, Kong N, Zahir ZM. Vancomycin administration in continuous ambulatory peritoneal dialysis: the risk of ototoxicity. Otolaryngol Head Neck Surg 1998;118(4):551-8.
55.Sivagnanam S, Deleu D. Red man syndrome. [comment]. Crit Care 2003;7(2):119-20.
56.Wallace MR, Mascola JR, Oldfield EC, 3rd. Red man syndrome: incidence, etiology, and prophylaxis. J Infect Dis 1991;164(6):1180-5.
57.Hassaballa H, Mallick N, Orlowski J. Vancomycin anaphylaxis in a patient with vancomycin-induced red man syndrome. Am J Ther 2000;7(5):319-20.
58.Sorensen SJ, Wise SL, al-Tawfiq JA, Robb JL, Cushing HE. Successful vancomycin desensitization in a patient with end-stage renal disease and anaphylactic shock to vancomycin. Ann Pharmacother 1998;32(10):1020-3.
59.Chopra N, Oppenheimer J, Derimanov GS, Fine PL. Vancomycin anaphylaxis and successful desensitization in a patient with end stage renal disease on hemodialysis by maintaining steady antibiotic levels. Ann Allergy Asthma Immunol 2000;84(6):633-5.
60.Rocha JLL, Kondo W, Baptista MIDK, Da Cunha CA, Martins LTF. Uncommon vancomycin-induced side effects. Braz J Infect Dis 2002;6(4):196-200.
61.Pai MP, Mercier R-C, Koster SA. Epidemiology of vancomycin- induced neutropenia in patients receiving home intravenous infusion therapy. Ann Pharmacother 2006;40(2):224-8.
62.Smith PF, Taylor CT. Vancomycin-induced neutropenia associated with fever: similarities between two immune-mediated drug reactions. Pharmacotherapy 1999;19(2):240-4.
63.Von Drygalski A, Curtis BR, Bougie DW, et al. Vancomycin-induced immune thrombocytopenia. [see comment]. N Engl J Med 2007;356(9):904-10.
64.Okamoto H. Vancomycin-induced immune thrombocytopenia. [comment]. N Engl J Med 2007;356(24):2537; author reply -8.
65.U.S. Renal Data System, USRDS 2007 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2007.
66.Finelli L, Miller JT, Tokars JI, Alter MJ, Arduino MJ. National surveillance of dialysis-associated diseases in the United States, 2002. Semin Dial 2005;18(1):52-61.
67.Mailloux LU, Bellucci AG, Wilkes BM, et al. Mortality in dialysis patients: analysis of the causes of death. Am J Kidney Dis 1991;18(3):326-35.
68.Zander E, Schultz B, Gums G, Lorenz G, Warzok R. Causes of death in insulin-dependent diabetic patients treated with hemodialysis. J Diabet Complications 1989;3(3):163-6.
69.Himmelfarb J. Hemodialysis complications. Am J Kidney Dis 2005;45(6):1122-31.
70.郭美娟. 尿毒症病患的感染與免疫功能. 高醫醫訊 2001;第二十一卷 第七期.
71.台灣腎臟醫學會. 台灣血液透析診療指引. 2004.
72.周康茹. 醫院內感染管制通則與血液透析室感染管制. 腎臟與透析 2005;17卷2期.
73.Lew SQ, Kaveh K. Dialysis access related infections. ASAIO J 2000;46(6):S6-12.
74.台灣腎臟醫學會. 九十三年度透析病患年度報告. 2006.
75.Horl WH. Neutrophil function and infections in uremia. Am J Kidney Dis 1999;33(2):xlv-xlviii.
76.陳建良. 血管通路感染. 腎臟與透析 2005;17(2):126-8.
77.McKibben L. Horan TC. Tokars JI. Fowler G. Cardo DM. Pearson ML. Brennan PJ. Healthcare Infection Control Practices Advisory Committee (HICPAC). Guidance on Public Reporting of Healthcare-Associated Infections. American Journal of Infection Control. 33(4):217-26, 2005 May.
78.Allon M. Dialysis catheter-related bacteremia: treatment and prophylaxis. Am J Kidney Dis 2004;44(5):779-91.
79.D'Agata EMC. Antimicrobial-Resistant, Gram-Positive Bacteria among Patients Undergoing Chronic Hemodialysis. Clin Infect Dis 2002;35:1212-8.
80.Huang AH, Yan JJ, Wu JJ. Rapid dissemination of Staphylococcus aureus with classic oxacillin resistance phenotype at a new university hospital. J Hosp Infect 2000;44(4):309-15.
81.Hsueh PR LY, Yang D, et al. Multicenter surveillance of antimicrobial resistance of major bacterial pathogens in intensive care units in 2000 in Taiwan. Microb Drug Resist 2001;7:373-82.
82.Anonymous. Recommendations for preventing the spread of vancomycin resistance: recommendations of the Hospital Infection Control Practices Advisory Committee (HICPAC). Am J Infect Control 1995;23(2):87-94.
83.行政院衛生署. 中華民國95年重大傷病住院醫療費用申報狀況. 台灣, 2007.
84.Green K, Schulman G, Haas DW, Schaffner W, D'Agata EM. Vancomycin prescribing practices in hospitalized chronic hemodialysis patients. Am J Kidney Dis 2000;35(1):64-8.
85.De Bock V, Verbeelen D, Maes V, Sennesael J. Pharmacokinetics of vancomycin in patients undergoing haemodialysis and haemofiltration. Nephrol Dial Transplant 1989;4(7):635-9.
86.DeSoi CA, Sahm DF, Umans JG. Vancomycin elimination during high-flux hemodialysis: kinetic model and comparison of four membranes. Am J Kidney Dis 1992;20(4):354-60.
87.Foote EF, Dreitlein WB, Steward CA, Kapoian T, Walker JA, Sherman RA. Pharmacokinetics of vancomycin when administered during high flux hemodialysis. Clin Nephrol 1998;50(1):51-5.
88.Alwakeel J, Najjar TA, al-Yamani MJ, Huraib S, al-Haider A, Abu-aisha H. Comparison of the effects of three haemodialysis membranes on vancomycin disposition. Int Urol Nephrol 1994;26(2):223-8.
89.Torras J, Cao C, Rivas MC, Cano M, Fernandez E, Montoliu J. Pharmacokinetics of vancomycin in patients undergoing hemodialysis with polyacrylonitrile. [see comment]. Clin Nephrol 1991;36(1):35-41.
90.Hiramatsu K. Vancomycin-resistant Staphylococcus aureus: a new model of antibiotic resistance. Lancet Infect Dis 2001;1(3):147-55.
91.Song J-H, Hiramatsu K, Suh JY, et al. Emergence in Asian countries of Staphylococcus aureus with reduced susceptibility to vancomycin. Antimicrob Agents Chemother 2004;48(12):4926-8.
92.Uttley AH, George RC, Naidoo J, et al. High-level vancomycin- resistant enterococci causing hospital infections. Epidemiol Infect 1989;103(1):173-81.
93.From the Centers for Disease Control. Staphylococcus aureus resistant to vancomycin-- United States, 2002. Jama 2002;288(7):824-5.
94.Courvalin P. Vancomycin resistance in gram-positive cocci. Clin Infect Dis 2006;42 Suppl 1:S25-34.
95.Bonten MJ, Willems R, Weinstein RA. Vancomycin-resistant enterococci: why are they here, and where do they come from? Lancet Infect Dis 2001;1(5):314-25.
96.陳志榮, 黃玉成. 對萬古黴素敏感度下降的金黃色葡萄球菌. 感染控制雜誌 2003;13(4):223-9.
97.Jones RN. Microbiological features of vancomycin in the 21st century: minimum inhibitory concentration creep, bacteri- cidal/static activity, and applied breakpoints to predict clinical outcomes or detect resistant strains. Clin Infect Dis 2006;42 Suppl 1:S13-24.
98.Rybak MJ, Akins RL. Emergence of methicillin-resistant Staphylococcus aureus with intermediate glycopeptide resistance: clinical significance and treatment options. Drugs 2001;61(1):1-7.
99.McKibben L. Horan TC. Tokars JI. Fowler G. Cardo DM. Pearson ML. Brennan PJ. Healthcare Infection Control Practices Advisory Committee (HICPAC). Guidance on Public Reporting of Healthcare-Associated Infections. American Journal of Infection Control. 33(4):217-26, 2005 May.
100.Ruano R, Martin-Reyes G, Munoz I, et al. [Monitoring of vancomycin plasma levels in patients undergoing hemodialysis]. Farm 2005;29(6):354-8.
101.Pollard TA, Lampasona V, Akkerman S, et al. Vancomycin redistribution: dosing recommendations following high-flux hemodialysis. Kidney Int 1994;45(1):232-7.
102.Welage LS, Mason NA, Hoffman EJ, et al. Influence of cellulose triacetate hemodialyzers on vancomycin pharmacokinetics. J Am Soc Nephrol 1995;6(4):1284-90.
103.Touchette MA, Patel RV, Anandan JV, Dumler F, Zarowitz BJ. Vancomycin removal by high-flux polysulfone hemodialysis membranes in critically ill patients with end-stage renal disease. Am J Kidney Dis 1995;26(3):469-74.
104.Matzke GR, O'Connell MB, Collins AJ, Keshaviah PR. Disposition of vancomycin during hemofiltration. Clin Pharmacol Ther 1986;40(4):425-30.
105.Gonzalez-Martin G, Acuna V, Perez C, Labarca J, Guevara A, Tagle R. Pharmacokinetics of vancomycin in patients with severely impaired renal function. Int J Clin Pharmacol Ther 1996;34(2):71-5.
106.Ariano RE, Fine A, Sitar DS, Rexrode S, Zelenitsky SA. Adequacy of a vancomycin dosing regimen in patients receiving high-flux hemodialysis. Am J Kidney Dis 2005;46(4):681-7.
107.Mangram AJ, Horan TC, Pearson ML, Silver LC, Jarvis WR. Guideline for Prevention of Surgical Site Infection, 1999. Centers for Disease Control and Prevention (CDC) Hospital Infection Control Practices Advisory Committee. Am J Infect Control 1999;27(2):97-132; quiz 3-4; discussion 96.
108.Sanchez-Manuel FJ, Lozano-Garcia J, Seco-Gil JL. Antibiotic prophylaxis for hernia repair.[update of Cochrane Database Syst Rev. 2004;(4):CD003769; PMID: 15495064]. Cochrane Database Syst Rev 2007(3):CD003769.
109.Pickering LKea, Diseases. AAoPCoI. Red Book 27th ed. Elk Grove Village, Ill.: American Academy of Pediatrics, 2006.