兩種不同速效劑量下teicoplanin血中濃度的比較

Abstract

研究背景：作為第一線治療多重抗藥性菌種所造成感染的重要抗生素之一，teicoplanin的療效取決於藥品濃度超過致病菌之最低抑制濃度（minimum inhibitory concentration，MIC）的時間長短，有鑑於臺灣近年格蘭氏陽性菌的抗藥性日益嚴重，臨床MRSA (methicillin-resistant Staphylococcus aureus)分離菌株對於teicoplanin的MIC逐漸增加至2 mg/L，藥品血中濃度建議至少維持在10 mg/L，甚至20 mg/L以上。然而，teicoplanin為一高蛋白結合率藥品，臺灣目前所使用的速效劑量3-6 mg/Kg未必可及時達到理想濃度，又欠缺商業化方法進行療效監測，考量到延誤有效治療不利於治療結果，臨床上也曾觀察到治療期間致病菌的敏感性逐漸下降，感染不斷發生，因此希望找出恰當的速效劑量，使血中濃度盡快達到10 mg/L。 研究方法：本研究為一前瞻性、單盲的臨床試驗，在臺大醫院進行。首先在2004年2月至2005年1月納入十位病患，利用high performance liquid chromatography檢測teicoplanin的血中濃度，觀察投藥後達到理想濃度的比例，計算試驗所需的人數。接著在2005年6月至2006年1月納入懷疑中度格蘭氏陽性菌感染患者，將其盡量隨機分配進入兩組，接受速效劑量6或12 mg/Kg（前三劑相隔12小時，第三劑24小時後再補一劑），自第四天起投予維持劑量6 mg/Kg，給藥間隔依照肌酸酐廓清率(CLCr)調整，每個人在分別在給予第三、四、五劑前，以及第九天和十四天的給藥前抽血，以fluorescence polarization immunoassay方式檢測。 研究結果與討論：兩組各有12位患者，藥品血中濃度值在前五劑達到10 mg/L的比例有顯著差異（第三劑18% vs. 92%；第四劑17% vs. 91%；第五劑33% vs. 82%）；高速效劑量組中，在CLCr¬小於20 mL/min/1.73m2與血液透析患者濃度更超過20 mg/L。顯然起始劑量具有決定性影響，實際體重與理想體重間比值（β=21.61, p=0.0008）和經體表面積校正後的肌酸酐清除率（β=-0.11, p=0.0043）對於第三天的血中濃度也有顯著影響，顯示實際體重可能不是計算劑量最適當的方法。 此外，觀察兩週內teicoplanin谷濃度的變化，相較於低速效劑量組大部分起伏不大，半數谷濃度不超過8.5 mg/L；高速效劑量組起初都超過10 mg/L，隨後又逐漸下降，最終有三位濃度降至目標濃度之下，因此維持劑量可能還需要提高一點。給藥間隔對於CLCr在60以上、40-60和小於40 mL/min/1.73 m2的患者，可分別調整為一、二與三天。至於血液透析患者每三天投予6 mg/Kg可使血中濃度維持在10 mg/L以上；但連續血液過濾期間，病患隔天接受6 mg/Kg則略嫌不足。試驗期間共有7位（29%）患者發生8件副作用，不過並未發現與血中濃度的高低有任何關連。 結論：投予速效劑量12 mg/Kg可使病患在療程前期達到10 mg/L以上，CLCr小於20 mL/min/1.73m2與血液透析患者甚至可超過20 mg/L。之後維持劑量6 mg/Kg可能還需要提高，給藥間隔在CLCr介於40-60和小於40 mL/min/1.73m2調整為兩天和三天可能是恰當的；針對血液透析患者，每三天接受一次6 mg/Kg的投予是恰當的；連續血液過濾期間，隔天投藥6 mg/Kg則略顯不足。不過因為個體間血中teicoplanin濃度變化大，建議病人應進行臨床療效監測，以作為調整劑量的依據。

Background: As one of the first-line therapy for multiresistant Gram-positive infections, teicoplanin exhibits time-dependant killing. Due to the reduced susceptibility to teicoplanin within the past decade, the minimum inhibitory concentrations of clinical methicillin-resistant Staphylococcus aureus isolates increased to 2 mg/L in these years. It is the gold standard to maintain a trough concentration at least 10 mg/L, even 20 mg/L. However, it is known that teicoplanin is high protein binding. Current standard dose, 3-6 mg/Kg, often produces a serum trough level of < 10 mg/L. There is also no commercially avalible drug monitoring method in Taiwan. Because delay in effective therapy is detrimental to clinical outcomes, this study was designed to identify appropriate loading dose to obtain therapeutic concentrations as soon as possible. Methods: A prospective, single-blinded clinical trial was carried out in a medical center. The sample size was determined by a preliminary observation performed during Febunary 2004 to January 2005. The drug concentrations of these 10 patients were analyzed by high performance liquid chromatography. Patients with suspected moderate gram-positive infections were enrolled during June 2005 to January 2006. A loading dose of 6 or 12 mg/Kg was given every 12 hours for three times and then 24 hours after the third dose. From day 4, patients received a maintenance dose of 6 mg/Kg. The dosing interval was 1 to 3 days according to their creatinine clearance (CLCr). Serum samples before dose 3, 4, 5 and day 9 and 14 were collected to determine the trough concentrations of teicoplanin by fluorescence polarization immunoassay. Results: Twelve patients were allocated to each group as randomly as possible. The proportions of patints achieving 10 mg/L or higher during the first five doses differed significantly between two groups (18% vs. 92% before the third dose; 17% vs. 91% before the fourth dose; 33% vs. 82% before the fifth dose). Hemodialysis patients or those with CLCr < 20 mL/min/1.73m2 even achieved > 20 mg/L in the higher loading dose group. Obviously, loading dose was the crucial factor for the serum teicoplanin concentrations. Creatinine clearance (β=-0.11, p=0.0043) and the ratio of actual body weight and ideal body weight (β=21.61, p=0.0008) also influenced the trough levels on the third day, indicating actual body weight might not be the approapriate dosing weight. Besides, looking into the pattern of the changes in the trough concentrations further, higher maintenance dose might be necessary. Patients receiving loading dose of 6 mg/Kg had consitantly low trough concentrations, which half was not higher than 8.5 mg/L. Those in the other group declined over time. A total of 3 patients had trough concentrations below 10 mg/L in two weeks. Dosing interval was determined by creatinine clearance. The cutpoint was 60 and 40 mL/min/1.73m2. Hemodialysis patients kept target concentrations when they received 6 mg/Kg every three days. But 6 mg/Kg every other day might be too small to keep the target trough concentrations during continuous hemofiltration. A total of 8 adverse effects occurred on 7 study subjects (29%). There were no relationship between serum trough concentrations and the occurance of side effects. Conclusion: Loading doses of 12 mg/Kg would achieve the serum trough concentrations higher than 10 mg/L, even higher than 20 mg/L on patients with CLCr < 20 mL/min/1.73m2 or during hemodialysis in the early treatment period. Higher maintenance dose might be necessary. It was acceptable to adjust the dosing interval of maintainence dose to two and three days for patients with CLCr 40-60 and <40 mL/min/1.73m2, respectively. As for hemodialysis patients, 6 mg/Kg every 3 days was enough. But 6 mg/Kg every other day was not enough to keep target concentrations during continuous hemofiltration. In view of large variation of serum teicoplanin concentrations in different patients, therapeutic drug monitoring was recommended.