萬古黴素在神經外科病人之藥品動態學研究

Pharmacokinetics of Vancomycin in Neurosurgical Patients

楊婷雅(Ting-Ya Yang)

指導教授 ： 沈麗娟

共同指導教授 ： 林淑文

國立臺灣大學/醫學院/臨床藥學研究所/碩士(2011年)

https://doi.org/10.6342/NTU.2011.02532

摘要

背景及目的
臨床上觀察神經外科病人在使用傳統劑量之萬古黴素時，常被測量到低於理想的血中濃度數值。本研究的目的在於描述神經外科病人之萬古黴素藥品動態學特性。

方法
回溯性分析一醫學中心之神經外科成年病人於2009年1月至2010年10月的療劑監測資料，此研究排除腎衰竭、不穩定腎功能、肥胖、休克或第三容積體液堆積之病人。病人的基本資料、併用甘露醇（mannitol）治療、腦脊髓液引流及尿液體積被列為可能影響萬古黴素藥品動態學之相關因子，並使用相關性分析及複線性迴歸分析評估各因子之貢獻度。本研究使用SASR 9.1軟體進行統計分析，以p < 0.05作為統計顯著水準。

結果
從73位病人共取得98套萬古黴素血清濃度數值進行分析，病人之平均年齡為54 ± 16歲，平均血清肌酸酐廓清率（ClCr）為78 ± 26 mL/min，其平均萬古黴素廓清率（ClV）及分佈體積（Vd）為101 ± 41 mL/min（為ClCr之1.30 ± 0.38倍）及0.93 ± 0.27 L/kg。在次組分析中觀察到加護病房病人之ClV高於一般病房病人（分別為ClCr之1.57 ± 0.34倍及1.16 ± 0.32倍，p < 0.05），但兩組間之Vd並無差異。複線性迴歸分析中發現加護病房病人之ClV經ClCr校正後與尿液體積和腦脊髓液引流具有正相關性。
最後得到的藥品動態學模式如下：(1)對於神經外科加護病房病人ClV (mL/min) = -19.6 + 1.5 ClCr (mL/min) + 0.4 UO (mL/kg/day)，調整後之判定係數（adjR2）為0.738。(2)對於神經外科一般病房病人 ClV (mL/min) = 13.6 + 1.0 ClCr (mL/min)，adjR2為0.530。(3)對於全體神經外科病人 V_d (L)=21×e^((0.009×BW))×e^((0.005×Age))×e^((0.149×Sex))，adjR2為0.222。其中ClCr係以Cockcroft-Gault公式計算，UO為療劑監測當天病人之尿液體積，BW為體重（公斤），Age為年紀（歲），Sex為性別（男性以1代入、女性以0代入）。
利用本研究建立之藥品動態學模型可計算出符合此類病人族群特性之萬古黴素建議劑量，其中不論神經外科加護病房病人或普通病房病人所需劑量皆顯著大於傳統給藥劑量，且加護病房病人所需劑量又顯著高於普通病房病人所需劑量。

結論
神經外科病人與過去文獻報告相比具有較高之萬古黴素廓清率，本研究針對此類病人建立較為合適之藥品動態學模型，但仍需要後續研究進行模型驗證及了解萬古黴素廓清率增加之機轉。

關鍵字

萬古黴素 ； 藥品動態學 ； 神經外科

並列摘要

Background and objective
Inadequate vancomycin peak/trough concentrations were observed in neurosurgical patients using conventional vancomycin dosage. The aim of the study was to characterize the pharmacokinetic properties of vancomycin for adult neurosurgical patients.

Methods
Retrospective analysis of vancomycin pharmacokinetic parameters was performed for adult neurosurgical patients from routine therapeutic drug monitoring (TDM) data in a medical center during 2009/01-2010/10. Patients were excluded if they were with renal failure, unstable renal function, obesity, shock, or third space fluid accumulation. Patients’ demographic characteristics, mannitol use, cerebrospinal fluid (CSF) drainage, and urine output were recorded as candidate covariates. Pearson’s and Spearman’s correlation tests followed by multiple linear regression analysis were used to assess the contribution of each covariate. SASR 9.1 was used for statistical analysis, and statistical tests were performed at the 0.05 level of significance.

Results
A total of 98 sets peak/trough serum concentrations obtained from 73 patients were analyzed. Their mean age was 54 ± 16 years old, with an average creatinine clearance (ClCr) level of 78 ± 26 mL/min. The mean vancomycin clearance (ClV) and volume of distribution (Vd) were 101 ± 41 mL/min (1.30 ± 0.38 folds of Cl¬Cr) and 0.93 ± 0.27 L/kg in the neurosurgical patients. In subgroup analysis, a significantly higher ClV was observed in ICU patients than in general ward patients, 1.57 ± 0.34 folds vs. 1.16 ± 0.32 folds of ClCr in each group (p < 0.05). No difference was observed in the Vd between ICU and general ward patients. Multiple linear regression of Cl¬V in the ICU subpopulation showed that urine output and CSF drainage were positively associated with ClCr adjusted ClV.
The final models selected in the study are as follows: (1) ClV (mL/min) = -19.6 + 1.5 ClCr (mL/min) + 0.4 UO (mL/kg/day) for ICU patients, adjusted R2 (adjR2) 0.738. (2) ClV (mL/min) = 13.6 + 1.0 ClCr (mL/min) for general ward patients, adjR2 0.530. (3) V_d (L)=21×e^((0.009×BW))×e^((0.005×Age))×e^((0.149×Sex)) for all neurosurgical patients, adjR2 0.222. In the models, ClCr is calculated by the Cockcroft-Gault method. UO represents the urine output volume on TDM day, BW is body weight in kg, age is in year, and sex is 1 for male and 0 for female.
Using the pharmacokinetic models built in this study, the neurosurgical patients needed significantly more vancomycin dose than conventional dosage, no matter patients in ICU or general ward. Besides, the calculated empirical dose for neurosurgical ICU patients was also significantly higher than that for general ward patients.

Conclusion
The ClV in adult neurosurgical patients is significantly elevated when adjusted by individual ClCr. The equations newly generated in our study may provide more appropriate models in these patients. Further studies are necessary to validate the equations and investigate the mechanism of this phenomenon.

並列關鍵字

Vancomycin ； Pharmacokinetics ； Neurosurgery

參考文獻

1. van de Beek D, Drake JM, Tunkel AR. Nosocomial Bacterial Meningitis. N Engl J Med 2010;362:146-54.

2. Huang WC, Lee CH, Liu JW. Clinical Characteristics and Risk Factors for Mortality in Patients with Meningitis Caused by Staphylococcus aureus and Vancomycin Minimal Inhibitory Concentrations Against These Isolates. J Microbiol Immunol Infect 2010;43:470-7.

3. Akins PT, Belko J, Banerjee A, et al. Perioperative management of neurosurgical patients with methicillin-resistant Staphylococcus aureus. J Neurosurg 2010;112:354-61.

4. Scheithauer S, Burgel U, Ryang YM, et al. Prospective surveillance of drain associated meningitis/ventriculitis in a neurosurgery and neurological intensive care unit. J Neurol Neurosurg Psychiatry 2009;80:1381-5.

5. De Bels D, Korinek AM, Bismuth R, Trystram D, Coriat P, Puybasset L. Empirical treatment of adult postsurgical nosocomial meningitis. Acta Neurochir (Wien) 2002;144:989-95.