1、根據(jù)PK/PD理論合理使用抗菌藥,2010年CHINET監(jiān)測網細菌檢出率,G-,G+,2010年CHINET監(jiān)測網各醫(yī)院MRS檢出率（%）,近年CHINET監(jiān)測網ESBL檢出率（%）,近年CHINET監(jiān)測網泛耐藥G-桿菌檢出率（%）,中國CHINET（2010）,MSSA與MRSA的耐藥率（%）,不發(fā)酵革蘭陰性菌對所測抗菌藥物的耐藥率（%）,societal drugs societal consequences,醫(yī)療機構的責任,明確有無適應癥 選擇哪種抗菌藥物 感染部位的常見病原學 選擇能夠覆蓋病原體的抗感染藥物 -抗菌譜/耐藥性/殺菌和抑菌/組織穿透性/安全性/費用 考慮病人生理和病理生理

2、狀態(tài) 高齡/兒童/孕婦/哺乳 腎功能不全/肝功能不全/肝腎功能聯(lián)合不全 怎么給藥 單藥和聯(lián)合/靜脈和口服/療程 優(yōu)化藥代動力學/藥效動力學(PK/PD),如何合理使用抗菌藥物,病原菌,體外藥效：MIC,0,Concentration,Time (hours),AUC = Area under the concentrationtime curve Cmax = Maximum plasma concentration,PK/PD參數(shù),濃度依賴性抗菌藥物的評價指標,時間依賴性抗菌藥物的評價指標,17,9.5,9.5,9.5,8.5,8.5,8.5,7.5,7.5,7.5,6.5,6.5,6.5,

3、Control 1/4MIC MIC 4MIC 16MIC 64MIC,5.5,5.5,5.5,4.5,4.5,4.5,3.5,3.5,3.5,2.5,2.5,2.5,1.5,0 2 4 6,1.5,0 2 4 6,1.5,0 2 4 6 8,Tobramycin,Ciprofloxacin,Ticarcillin,Time (h),Log10cfu /ml,不同MIC妥布霉素、環(huán)丙沙星及替卡西林對銅綠假單胞菌的殺菌曲線,Zhanel GG, et al. Drugs, 2002, 62(1)13-59,PK/PD體外研究,W.A. Craing. Diag Microbiol Infect

4、1995,抗菌藥物的PK/PD分類,0,Concentration,Time (hours),Cmax = Maximum plasma concentration,一、氨基糖苷類：Cmax/MIC,Kashuba et al. Antimicrob Agents Chemother 1999;43:623629,Probability of resolution (%),First Cmax:MIC 10 gives 90% probability of WBC and temperature resolution,Probability of temperature resolution

5、by Day 7,Probability of white blood cell (WBC) count resolution by Day 7,0,0,20,40,60,80,100,5,10,25,30,15,20,First Cmax:MIC,氨基糖苷: Cmax/MIC 與HAP治療反應,Nicolau et al. Antimicrob Agents Chemother 1995;39:650655,氨基糖苷: QD與TID給藥,氨基糖苷類給藥方案優(yōu)化,一日一次給藥優(yōu)點： Cmax:MIC8-10，有效率90% 耐藥突變下降 減少耳、腎毒性,0,Concentration,Time

6、(hours),AUC = Area under the concentrationtime curve,二、喹諾酮類：AUC/MIC,氟喹諾酮最佳AUIC（AUC/MIC）,30,125,G+,G-,Antimicrob Agents Chemother, 2001 Oct;45(10):2793-7,Forrest et al. Antimicrob Agents Chemother 1993;37:10731081,AUIC 與嚴重感染病人治療反應,Streptococcus pneumoniae CAP AUIC 33.7,Forrest et al. Antimicrob Agent

7、s Chemother 1993;37:10731081 Mouton JW et al. Drug Resistance Updates. 2011;14:107117 Thomas KL et al. Antimicrob Agents Chemother. 1998;42:521527,107例急性CAP，使用5種方案（頭孢甲肟、頭孢他啶、環(huán)丙沙星、頭孢他啶+妥布霉素，環(huán)丙沙星+哌拉西林）,提高AUIC可以減少耐藥,Baquero 67:27-33 Cantn et al. Inter J Antimicrob Chemother 2006,氟喹諾酮給藥方案優(yōu)化,提高療效：推薦每日一次給

8、藥 Cmax/MIC 8-10 24-h AUC/MIC(AUIC) G-: AUIC 100-125 G+: AUIC 30-40 防止耐藥 Cmax MPC 爭取較高的 AUIC,三、-內酰胺類：TMIC,0,Concentration,Time (hours),Required %TMIC for cidal: 40% for carbapenems 50% for penicillins 70% for cephalosporins,Drusano GL. Clin Infect Dis. 2003;36(suppl 1):S42-S50.,Required %TMIC for sta

9、tic 20% for carbapenems 30% for penicillins 40% for cephalosporins,-lactam:optimal TMIC?,Aryun Kim et al., Pharmacotherapy. 2007 27(11):1490-7,美國康涅狄格州Hartford醫(yī)院的研究結果,背景：針對470株銅綠假單胞菌，比較哌拉西林他唑巴坦各種給藥方式的效果 目的：計算達到50%TMIC *的可能性，研究最佳給藥方式,Roberts JA, et al., International Journal of Antimicrobial Agents. 2

10、010. 35: 156-163,Roberts JA, et al., International Journal of Antimicrobial Agents. 2010. 35: 156-163,P=0.04,間斷輸注組：特治星3.375g q4h或q6h 30分鐘輸注N=41 延長輸注組：特治星3.375g q8h 4h輸注N=38,Thomas P, et al., Clinical Infectious Diseases 2007;44:357-63,美國紐約Albany醫(yī)學中心的研究結果-降低死亡率,192例銅綠假單胞菌感染患者,critically ill patients

11、with an APACHE II score17,一日多次給藥，爭取TMIC 40-50% 注意：多數(shù)半衰期僅1h左右的-內酰胺類，對重癥患者或耐藥菌感染，Q12h/Q8h的給藥方式不能獲得40-50%的TMIC 優(yōu)化-內酰胺類的給藥方式 加大劑量：受腎功能限制可能需要調整劑量 增加給藥次數(shù)：Q8h轉為Q6h 采用持續(xù)靜脈滴注/延長滴注時間,-內酰胺類給藥方案優(yōu)化,S. aureus,MIC,0.1,10,100,1000,1,Concentration (g/mL),0,12,24,20,4,8,16,Time (hours),頭孢他啶：1g / 2g tid的比較,增加給藥劑量,增加給藥

12、頻率,T MIC比較,Mouton JW, et al., Drug Resistance Updates, 2011;14:107-17,Dandekar PK et al. Pharmacotherapy. 2003;23:988-991.,Meropenem 500 mg Administered as a 0.5 h or 3 h Infusion,MIC,0,2,4,6,8,0.1,1.0,10.0,100.0,Concentration (mcg/mL),Time (h),Rapid Infusion (30 min),延長輸注時間,美羅培南不同給藥方式PTA,Journal of

13、 Antimicrobial Chemotherapy. 2009;64:142-150,3G/D,6G/D,美羅培南：延長滴注時間治療多耐洋蔥伯克霍爾德菌,Meropenem 2 g infused over 3 hours q 8 h,Time (h),Concentration (mcg/mL),0,8,16,24,32,40,0.1,1,10,100,MIC = 16 mcg/mL,TMIC exposure was 40% of the dosing interval at the MIC of 16 mcg/mL,Kuti JL et al. Pharmacotherapy. 20

14、04;24:1641-1645,Journal of Antimicrobial Chemotherapy. 2009;64:142-150,延長輸注提高敏感折點,對不敏感菌株更有意義,持續(xù)輸注的問題,藥品常溫下穩(wěn)定性 長期占據(jù)一條輸液管路 導管相關感染的發(fā)生,延長給藥問題,藥師多次調劑 護師多次配藥,指南推薦用法 (2005 ATS HAP/VAP/HCAP),HAP,指南推薦用法 (2008加拿大指南 HAP/VAP),VAP,四、大環(huán)內酯類,4種大環(huán)內酯類藥物對肺炎鏈球菌的殺菌曲線 結果表明2種酮內酯類藥物Telithromycin和ABT-773呈濃度依賴性,大環(huán)內酯類為時間依賴性，但

15、其中的酮內酯類屬濃度依賴性。,五、萬古霉素,(a)在萬古霉素2, 4, 8, 16, 和64倍MIC對 S. aureus ATCC29213 的KCs. (b)在萬古霉素2, 4, 8, 16和64倍MIC對 S. epidermidisATCC29886 的KCs 結果提示萬古霉素屬于時間依賴性抗菌藥物 。,Figure 2 Relationship between pharmacokinetic/pharmacodynamic indices for vancomycin and bacteriologic efficacy against methicillin-susceptible

16、 Staphylococcus aureus. This plot, which delineates the change in colony-forming units (cfu) in an experimental mouse infection model 3 different ways, suggests that the area under the curve divided by the MIC (AUC/MIC) is the most valuable pharmacokinetic/pharmacodynamic parameter for predicting th

17、e activity of vancomycin against methicillin-susceptible S. aureus.,Rybak MJ. The pharmacokinetic and pharmacodynamic properties of vancomycin. Clin Infect Dis 2006;42(Suppl. 1):S359.,Moise-Broder PA, et al. Clin Pharmacokinet. 2004;43(13):925-42,萬古霉素在金葡菌引起的LRTI的藥效學,圖：LINEZOLID治療大鼠股部肺炎鏈球菌感染 PK/PD參數(shù)與

18、細菌學療效關系 可見LINEZOLID TMIC與細菌學療效相關系數(shù)最高為84，當TMIC為40即可達到良好的細菌學療效。,六、利奈唑胺,嚴重感染病人： Group I: 600mg/q12h Group C: D1 300mg loading+900 C, D2 1200mg/d,Adembri C, et al.International Journal of Antimicrobial Agents. 2008;31:1229.,Adembri C, et al.International Journal of Antimicrobial Agents. 2008;31:1229.,Current Opinion in Pharmacology 2011, 11:470 476,延長輸注內酰胺類藥物未解決問題,適用于人體的最佳值(fTMIC)，要比臨床前值更高嗎？ 需要進行血藥濃度監(jiān)測進行個體化用藥嗎？缺乏資料 哪種細菌多少MICs最適合延長給藥時間需要臨床試驗證實群體藥動學和Monte Carlo 模擬 何種病人會最大受益需要在嚴重敗血癥病人和具多種并發(fā)癥病人中進行臨床試驗 持續(xù)給藥對靶細菌耐藥的影響如何目前缺乏臨床資料,The opening line of the introduction of this book