从PK-PD看抗菌药物的合理应用

1、从从PK/PDPK/PD看抗菌药物的合理应用看抗菌药物的合理应用李光辉李光辉复旦大学附属华山医院复旦大学附属华山医院PKPK .What the body does to the drug .What the body does to the drugAbsorbtion Absorbtion CmaxCmaxMetabolism Metabolism AUCAUCElimination Elimination Half-lifeHalf-lifePD.PD. What the drug does to the body What the drug does to the bodyDirect

2、 effects MIC, MBCDirect effects MIC, MBCPost-drug effects PAEPost-drug effects PAESelection effects ResistanceSelection effects ResistancePharmacokineticsPharmacokineticsConcentration vs TimeConcentration vs Time From PK to PDConc.Conc.TimeTimePharmacodynamicsPharmacodynamicsEffet vs TimeEffet vs Ti

3、meEffectEffectConc.Conc.PK/PDPK/PDEffect vs TimeEffect vs TimeEffectEffectTimeTime抗菌药药效学抗菌药药效学 细菌对抗菌药的敏感性细菌对抗菌药的敏感性 纸片扩散法（纸片扩散法（K-BK-B法）法） 最低抑菌浓度最低抑菌浓度( MIC)( MIC) 最低杀菌浓度最低杀菌浓度(MBC)(MBC) 药物敏感试验药物敏感试验1. 1.琼脂扩散法琼脂扩散法( (纸片法，纸片法，Kirby-bauer)Kirby-bauer)测抑测抑菌圈大小画分菌圈大小画分S,I,RS,I,R2.2.稀释法琼脂稀释法，肉汤稀释法，微量稀释法琼

4、脂稀释法，肉汤稀释法，微量稀释法稀释法3.3.E E测定法测定法(Epsilometer test)(Epsilometer test)测测MICMIC值值 判断标准：通常根据判断标准：通常根据CLSICLSI判断结果判断结果4.4. 自动化药敏测自动化药敏测MICMICATBATB系统，系统，VitekVitek系统，系统，Micro ScanMicro Scan等等药敏试验的临床意义药敏试验的临床意义敏感敏感(S)(S)常规剂量时的平均血浓度超过常规剂量时的平均血浓度超过MICMIC的的5 5倍以上，用常规剂量通常有效倍以上，用常规剂量通常有效中介中介(I)(I)常规剂量时的平均血浓度等于

5、或常规剂量时的平均血浓度等于或略高于略高于MICMIC，需用高剂量或对药物浓缩部，需用高剂量或对药物浓缩部位的感染可能有效位的感染可能有效耐药耐药(R)(R)药物的药物的MICMIC高于其常规剂量时的高于其常规剂量时的血浓度，通常治疗无效血浓度，通常治疗无效CHINET 2012CHINET 2012年年1515家医院家医院3127731277株肠杆菌科细菌耐药率（株肠杆菌科细菌耐药率（%）抗菌药物抗菌药物耐药耐药敏感敏感亚胺培南亚胺培南5.05.092.292.2美罗培南美罗培南4.44.494.694.6厄他培南厄他培南6.36.391.891.8阿米卡星阿米卡星7.47.490.790.

6、7磷霉素磷霉素12.212.284.984.9哌拉西林哌拉西林/ /他唑巴坦他唑巴坦8.48.484.284.2头孢哌酮头孢哌酮/ /舒巴坦舒巴坦10.510.573.973.9头孢他啶头孢他啶29.129.165.365.3头孢吡肟头孢吡肟20.220.273.273.2庆大霉素庆大霉素36.0.36.0.62.462.4CHINET 2012CHINET 2012年年1515家医院家医院1961319613株非发酵菌耐药率（株非发酵菌耐药率（%）抗菌药物抗菌药物耐药耐药敏感敏感头孢哌酮头孢哌酮/ /舒巴坦舒巴坦26.526.552.852.8阿米卡星阿米卡星28.928.967.967.9

7、头孢他啶头孢他啶41.941.952.952.9头孢吡肟头孢吡肟40.440.453.353.3哌拉西林哌拉西林/ /他唑巴坦他唑巴坦38.538.552.552.5美罗培南美罗培南44.244.252.852.8亚胺培南亚胺培南45.145.152.052.0环丙沙星环丙沙星40.040.055.055.0各种酶抑制剂复方制剂的比较各种酶抑制剂复方制剂的比较AM-SBAM-SBAM-CLAM-CLTC-CLTC-CLCPZ-SBCPZ-SBPIP-TAZPIP-TAZ商品名商品名优力新优力新力百汀力百汀特美汀特美汀舒普深舒普深特治星特治星肠杆菌科肠杆菌科2 22 22 23 33 32 2

8、3 3绿脓、沙雷菌绿脓、沙雷菌2 23 33 33 3不动杆菌不动杆菌2 23 3肠球菌肠球菌2 22 22 23 3嗜麦芽窄食单胞菌嗜麦芽窄食单胞菌3 33 3 2 2头孢哌酮/舒巴坦与头孢菌素、亚胺培南特性比较肠杆菌肠杆菌科细菌科细菌铜绿假铜绿假单胞菌单胞菌鲍曼不动鲍曼不动杆菌杆菌厌氧菌厌氧菌链球菌链球菌属属MRSAMRSA特特 点点头孢哌头孢哌酮酮/ /舒巴舒巴坦坦+不动及铜绿耐药低不动及铜绿耐药低适用于经验治疗适用于经验治疗链球菌属作用差链球菌属作用差头孢他头孢他啶啶+ +耐药率高，适用于病原治耐药率高，适用于病原治疗；链球菌属、厌氧菌作疗；链球菌属、厌氧菌作用差，不适用于吸入肺炎用差

9、，不适用于吸入肺炎的治疗的治疗头孢吡头孢吡肟肟+ + + +耐药率与头孢他啶基本相耐药率与头孢他啶基本相仿，对链球菌的作用增强仿，对链球菌的作用增强亚胺培亚胺培南南+ +抗菌谱广，抗菌谱广，VAPVAP经验治疗经验治疗需注意不动杆菌耐药性需注意不动杆菌耐药性对于革兰阴性菌：+, R10%; +, R20%; +, R50%; +, R MICTime-dependent killing and minimal or moderate prolonged persistent effectsMacrolides, azithromycin, clindamycin, streptogramins

10、, tetracyclines, glycopeptides, oxazolidinonesMaximize amount of drug; 24-hr AUC/MICConc.-dependent killing and prolonged persistent effectsAminoglycosides,fluoroquinolones, daptomycin, ketolides, metronidazoleMaximize conc.; 24-hr AUC/MIC and peak/MICq根据根据PK/PDPK/PD原理制订的给药方案可以达到更高的疗效和清原理制订的给药方案可以达到

11、更高的疗效和清除病原菌的作用，并可能防止疗程中细菌产生耐药性除病原菌的作用，并可能防止疗程中细菌产生耐药性q与时间依赖型药物杀菌活力有关的与时间依赖型药物杀菌活力有关的PK/PDPK/PD参数是参数是T TMICMIC，即血药浓度达到或超过，即血药浓度达到或超过MICMIC持续的时间占持续的时间占2 2次次给药间期的百分比给药间期的百分比q与浓度依赖型药物杀菌活力有关的主要参数是与浓度依赖型药物杀菌活力有关的主要参数是AUCAUC2424/MIC/MIC或或C Cmaxmax/MIC /MIC 药效学/药动学（PK/PD）原则PK/PD参数的意义Rybak MJ. Am J Med 2006;

12、 119:S37-S44.TimeConc.MICPAET MICAUC / MICCmax / MICFluoroquinolonesFluoroquinolonesDaptomycinDaptomycinFluoroquinolonesMacrolidesKetolidesGlycopeptidesLipopeptidesTimeAntibacterial concentration (g/ml)2Drug ADrug BADrug A present at concentration of 2 g/ml for 50% of dosing intervalDrug B present a

13、t concentration of 2 g/ml for 30% of dosing interval4680Time above MICXBDosing intervalTime above MICTime above MICCorrelation of serum pharmacokinetics with MIC Correlation of serum pharmacokinetics with MIC (susceptibility) of an organism(susceptibility) of an organism MIC Scand J Infect Dis Suppl

14、 96:11-16,1995Scand J Infect Dis Suppl 96:11-16,1995抗菌药发挥作用所必需的抗菌药发挥作用所必需的 Time Time MICMIC抗生素抗生素B BA A（%）给药间隔的多少给药间隔的多少%合适？合适？ B BA A （%） B : Time above MIC B : Time above MIC 时间时间A: A: 给药间隔时间给药间隔时间Pharmacodynamic Goals (TMIC as percent of Interval) Pharmacodynamic Goals (TMIC as percent of Interva

15、l) with Beta-Lactams with Beta-Lactams MaximumClass Organism Stasis KillingCephalosporins GNR, pneumo 40-50 70-80 Staph 20-30 40-50Penicillins GNR, pneumo 30-40 60-70 Staph 20-30 40-50Carbapenems GNR, staph 20-30 40-50 Pneumo 10-20 25-40Craig 1999020406080100020406080100Time above MIC (%)Penicillins

16、CephalosporinsMortality after 4 days of therapy (%)Craig. Diagn Microbiol Infect Dis 1996; 25:213217Relationship between Time above MIC Relationship between Time above MIC and efficacy in animal infection models and efficacy in animal infection models infected with S. pneumoniaeinfected with S. pneu

17、moniae细菌学疗效：细菌学疗效：青霉素：青霉素：TMIC%40%TMIC%40%头孢菌素：头孢菌素：TMIC%50%TMIC%50%Relationship Between TMIC and Efficacy for Cephalosporins (Yellow), Penicillins (Aqua) and Carbapenems (Red)MIC：64mg/LMIC：16mg/L8. Okamura K, et al. Acta Urol Jpn. 1989;35:727-734.9. Suzuyama Y, et al. Chemotherapy. 1984;32(S-4):355

18、-367.10. Aoyama H, et al. Jpn J Antibiot. 1988;41:1279-1284.11. Tsuyuki K, et al. Chemotherapy. 1984;32(S-4):404-41212. Cho N, et al. World Gynecol. 1984;36(8):649-675.13. Nakagawa K, et al. Surg Care. 1990;32(6):875-879.14. Hayasaki M, et al. Chemotherapy. 1984;32(S-4):649-665.15 Cetobid Product Mo

19、nograph. Physicians Desk Reference(53th ed.)16 Warnke IP, et al. Int J Clin Pharmacol Ther 1998;36(5):253-25717 Foulds G, et al. Antimicrob Agents Chemother 1997;31(11):1703-170518 Stahl JP, et al. Rev Infect Dis 1986;8(5):S612-S616药效学/药动学（PK/PD）原则头孢哌酮-舒巴坦复合制剂中头孢哌酮PK/PD参数比较不动杆不动杆菌属菌属大肠埃大肠埃希菌希菌铜绿假铜绿假

20、单胞菌单胞菌产气肠产气肠杆菌杆菌TMICTMIC9090(%)(%)头孢哌酮头孢哌酮- -舒巴坦舒巴坦2 2克克q8hq8h和和3 3克克q12hq12h在难治的革兰阴性耐药菌中在难治的革兰阴性耐药菌中TMICTMIC9090%均达到均达到5050以上以上嗜麦芽窄食嗜麦芽窄食单胞菌单胞菌阴沟肠阴沟肠杆菌杆菌舒致病菌MICMIC9090(mg/ml)(mg/ml)金黄色葡萄球菌1616(产b-内酰胺酶)铜绿假单胞菌8 8金黄色葡萄球菌2 2肺炎克雷伯菌2 2阴沟肠杆菌1 1大肠埃希菌鲍曼不动杆菌0 01 12 210102020舒巴坦头孢哌酮肺组织内平均药物浓度(mg/ml)舒普深在静注2g后在

21、肺组织内的平均浓度与对常见致病菌的MIC90值比较*Deguchi K, Yokota N, koguchi m,et al,. b-lactamase activty in sputum of patients withcommunity-agguired lower respiratory tract infections. Jon J antibiot 1994; 47:161-169.34舒普深舒普深(2:1) 3g q6h(2:1) 3g q6h的的PK/PDPK/PDMICMIC%TMIC%TMIC* *646443 43 323270 70 161696 96 8 8123 12

22、3 4 4150 150 2 2176 176 1 1203 203 0.50.5230 230 0.250.25256 256 0.1250.125283 283 0.06250.0625310 310 *基于舒普深药代动力学参数计算。2. 舒普深说明书；3. REITBERG DP, MARBLE DA, SCHULTZ RW, et al. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 1988, p. 503-509；5. REITBERG DP, WHALL TJ, CHUNG M, et al. ANTIMICROBIAL AGENTS AND CH

23、EMOTHERAPY, Jan. 1988, p. 42-46 头孢哌酮头孢哌酮/ /舒巴坦舒巴坦(2:1)3(2:1)3种给药方案对非发酵菌不种给药方案对非发酵菌不同同MICMIC值时值时%T%TMICMIC（头孢哌酮）（头孢哌酮）给药方案给药方案MIC(mg/L)MIC(mg/L)4 48 81616323264643gq8h3gq8h (1.5h )(1.5h )10010010010010010065659 93gq8h3gq8h (2h)(2h)100100100100100100575715153gq6h3gq6h (2h)(2h)1001001001001001007171222

24、23gq12h3gq12h (2h)(2h)1001009696666635354 4lMICMIC16mg/L:3g,q8h16mg/L:3g,q8h、 3g,q12h 3g,q12h ；MICMIC 32mg/L:3g,q6h32mg/L:3g,q6hl鲍曼：疗程天，临床治愈率为鲍曼：疗程天，临床治愈率为79.3%79.3%（23/2923/29） ；微生物学治愈率为；微生物学治愈率为69.0%69.0%（20/2920/29）l铜绿：疗程天，临床治愈率为铜绿：疗程天，临床治愈率为68.2%68.2%（15/2215/22）；微生物学治愈率为）；微生物学治愈率为19.0%19.0%（4/2

25、14/21），），l混合感染：临床治愈率：混合感染：临床治愈率：2/32/3；微生物学治愈率：其中；微生物学治愈率：其中2 2例铜绿未清除例铜绿未清除舒普深舒普深3g,q8h,3g,q8h,疗程疗程1414天治疗鲍曼不动杆菌天治疗鲍曼不动杆菌HAPHAP患患者者PK/PDPK/PD参数与临床疗效关系的研究（参数与临床疗效关系的研究（n=12)n=12)患者号患者号MICs(g/mL) MICs(g/mL) %TMIC%TMIC临床临床疗效疗效细菌学细菌学疗效疗效综合综合疗效疗效CPZCPZSULSULCPZCPZSULSUL10101.51.50.750.75304 304 128 128 治

26、愈治愈清除清除治愈治愈26264 42 2268 268 73 73 治愈治愈清除清除治愈治愈141416168 8211 211 60 60 治愈治愈清除清除治愈治愈9 924241212104 104 29 29 治愈治愈清除清除治愈治愈8 84 42 2123 123 60 60 治愈治愈菌交替菌交替治愈治愈16162 21 1100 100 100 100 治愈治愈菌交替菌交替治愈治愈181816168 868 68 0 0 治愈治愈菌交替菌交替治愈治愈5 53232161663 63 14 14 失败失败未清除未清除失败失败13134848242444 44 10 10 失败失败未清

27、除未清除失败失败2 24848242435 35 0 0 失败失败未清除未清除失败失败7 74848242430 30 0 0 失败失败未清除未清除失败失败23234848242452 52 10 10 失败失败未清除未清除失败失败Kuti et al. Am J Health Syst Pharm 2002;59:22092215Concentration (g/mL)01101004862Time (hours)MIC = 2 g/mL; 60% TMICMIC = 4 g/mL; 46% TMICMeropenem 1 g three-times daily:5000 patient M

28、onte Carlo simulation 替加环素替加环素PK/PDPK/PD特性特性 抗生素后效应（抗生素后效应（PAEPAE）l 体外体外PAEPAE金葡菌：金葡菌： 4.0 h4.0 h大肠埃希菌：大肠埃希菌：2.9 h2.9 hl 体内体内PAEPAE 大肠杆菌：大肠杆菌：4.9 h4.9 h 肺炎链球菌：肺炎链球菌：8.9 h8.9 h 中一长时效的中一长时效的PAEPAE PK/PD PK/PD参数：参数：AUCAUC2424/MIC/MIC l CAPCAP患者患者: : f AUCf AUC0-240-24:MIC:MIC) of 12.8 were associated w

29、ith a faster ) of 12.8 were associated with a faster time to fever resolutiontime to fever resolutionl patients patients with lower drug exposures had a slower time to fever with lower drug exposures had a slower time to fever resolution (resolution (P0.05)P18) values of 100% for MICs0.25 mg/Ll goin

30、g down to 65% and 0 for an MIC of 0.5 mg/L, with 100 and 50 mg q12h respectively,A. Canut .Eur J Clin Microbiol Infect Dis (2012) 31:2227多粘菌素多粘菌素PK/PDPK/PD特性特性Phillip J. Pharmacokinetic/Pharmacodynamic Investigation of Colistin against Pseudomonas aeruginosa Using an In Vitro Model AAC Sept. 2010, p

31、. 3783l 多粘菌素多粘菌素E E硫酸盐：口服给药、局部给药硫酸盐：口服给药、局部给药l 多粘菌素多粘菌素E E甲磺酸盐（甲磺酸盐（CMSCMS）：静脉注射、）：静脉注射、肌内注射，雾化吸入或鞘内注射肌内注射，雾化吸入或鞘内注射l 多粘菌素多粘菌素B B硫酸盐：静脉注射，肌内注射，硫酸盐：静脉注射，肌内注射，雾化吸入雾化吸入浓度依赖性：浓度依赖性：AUC/MICAUC/MICPK/PDPK/PD靶值：肺部感染中细菌数减少靶值：肺部感染中细菌数减少1 1个个 lgcfulgcfuAUC/MICAUC/MIC铜绿假单胞菌：；鲍曼不动杆菌：铜绿假单胞菌：；鲍曼不动杆菌：大环内酯类大环内酯类PK/

32、PDPK/PD研究研究4 4种大环内酯类药物对肺炎链球菌的杀菌曲线种大环内酯类药物对肺炎链球菌的杀菌曲线结果表明结果表明2 2种酮内酯类药物种酮内酯类药物TelithromycinTelithromycin和和ABT-773ABT-773呈浓度依赖性呈浓度依赖性大环内酯类为时间依赖性，但其中的酮内酯类属浓度依赖性。大环内酯类为时间依赖性，但其中的酮内酯类属浓度依赖性。糖肽类抗生素糖肽类抗生素 PK/PDPK/PD研究研究(a)(a)在万古霉素在万古霉素2, 4, 8, 16,2, 4, 8, 16, 和和6464倍倍MICMIC对对 S. aureusS. aureusATCC29213ATC

33、C29213 的的KCs. KCs. (b)(b)在万古霉素在万古霉素2, 4, 8, 162, 4, 8, 16和和6464倍倍MICMIC对对 S. epidermidisS. epidermidisATCC29886ATCC29886 的的KCsKCs 结果提示万古霉素属于时间依赖性抗菌药物结果提示万古霉素属于时间依赖性抗菌药物 。Non-concentration dependent killing of teicoplanin against S. aureus1234567891003691215182124hlog10 cfu/ml2xMIC4xMIC8xMIC16xMIC64x

34、MICControl210-1-2-3-430100300 10001030 100 300 100020406080 100 log10 CFU/g over 24 h24-h AUC/MICPeak/MICT MICEbert S. et al. 27th ICAAC 1987.Craig WA & Andes DR. 46th ICAAC 2006. Relationship of PK/PD for Vancomycin Bacteriologic Relationship of PK/PD for Vancomycin Bacteriologic Efficacy vs. M

35、SSA in Thighs of Neutropenic MiceEfficacy vs. MSSA in Thighs of Neutropenic MiceLINEZOLIDLINEZOLID治疗大鼠股部肺炎链球菌感染治疗大鼠股部肺炎链球菌感染Time Above MIC (%) 020406080 100Change in Log CFU/Thigh-6-4-2024R2 = 84%AUC/MIC1101001000Change in Log CFU/Thigh-6-4-2024R2 = 42%PK/PDPK/PD参数与细菌学疗效关系参数与细菌学疗效关系可见可见LINEZOLIDLINE

36、ZOLID TMICTMIC与细菌学疗效相关系数最高为与细菌学疗效相关系数最高为8484，当，当TMICTMIC为为4040即可达到良好的细菌学疗效。即可达到良好的细菌学疗效。Andes D, et al. Antimicrob Agents Chemother 2002;46:3484-9.斯沃斯沃AUCAUC2424/MIC 100/MIC 100临床疗效卓越临床疗效卓越利奈唑胺利奈唑胺PTAPTA结果结果l PTA (AUC24/MIC100) higher than 90% for MICs2 mg/L PTA (AUC24/MIC100) higher than 90% for MI

37、Cs2 mg/L l For an MIC of 4 mg/L, the PTA reached a value of about 40% For an MIC of 4 mg/L, the PTA reached a value of about 40%A. Canut .Eur J Clin Microbiol Infect Dis (2012) 31:2227Antibiotic concentrationMIC Time24-hr AUC/MIC is correlated with outcome of infection, the magnitude required for su

38、ccess and MIC at which this occurs becomes the PD breakpoint24-hr AUC/MIC and Peak/MIC Ratios24-hr AUC/MIC and Peak/MIC RatiosCorrelation of serum pharmacokinetics with MIC of an organism Correlation of serum pharmacokinetics with MIC of an organism Area under the curve to MIC ratioPeak to MIC ratio

39、Levofloxacin PK/PD Parameters Against Levofloxacin PK/PD Parameters Against S. pneumoniaeS. pneumoniae in Neutropenic Mouse Thigh Infection Modelin Neutropenic Mouse Thigh Infection Model%T MICPeak/MIC24-Hr AUC/MICHandbook of Experimental Pharmacology. Vol 127: Quinolone Antibacterials. 1998 Relatio

40、nship between 24 Hr AUC/MIC and Relationship between 24 Hr AUC/MIC and mortality for fluoroquinolones against mortality for fluoroquinolones against S. S. pneumoniaepneumoniae in immunocompetent animals in immunocompetent animalsMortality (%)24-hr AUC/MIC 1 25 10 5 2.5020406080100100 50 Relationship

41、 between 24 Hr AUC/MIC and mortality Relationship between 24 Hr AUC/MIC and mortality for fluoroquinolones against Gram-negative for fluoroquinolones against Gram-negative bacilli in immunocompromised animalsbacilli in immunocompromised animals33030010100100002040608010024 hr AUC/MICPercent Mortalit

42、yMortality (%)24-hr AUC/MIC310003001003010020406080100Clinicalfailure rate 43%11.5% 1%Levofloxacin PK/PD correlations134 hospitalized patients with RTI, SSTI or UTI treated with 500 mg qd for 514 daysJacobs. Clin Microbiol Infect 2001;7:58996 Adapted from Preston et al. JAMA 1998;279:125943233100101

43、02030405060708090100No. of patientsAUC:MIC 25 Peak:MIC 100 Peak:MIC 12SuccessFailureClinical outcomeRelationship Between 24-Hr AUC/MIC and Relationship Between 24-Hr AUC/MIC and Efficacy of Ciprofloxacin in 64 Patients with Efficacy of Ciprofloxacin in 64 Patients with Serious Bacterial InfectionsSe

44、rious Bacterial Infections24-hr AUC/MICRelationship between max. Peak/MIC ratio and Relationship between max. Peak/MIC ratio and the rate of clinical response for aminoglycosidesthe rate of clinical response for aminoglycosidesMoore et.al. J Infect Dis, 1987, 155: 93Moore et.al. J Infect Dis, 1987,

45、155: 93 Maximum Peak/MIC ratioResponse rate, %Kashuba et al. Antimicrob Agents Chemother 1999;43:623629Probability of resolution (%)First Cmax:MIC 10 gives 90% probability of WBC and temperature resolutionProbability of temperature resolution by Day 7 Probability of white blood cell (WBC) count reso

46、lutionby Day 7002040608010051025301520First Cmax:MICOptimising aminoglycoside therapy Optimising aminoglycoside therapy for nosocomial pneumoniafor nosocomial pneumonia氨基糖苷类日剂量单次给药氨基糖苷类日剂量单次给药 1 1、提高抗菌活性、提高抗菌活性 氨基糖苷类属于浓度依赖型抗生素，氨基糖苷类氨基糖苷类属于浓度依赖型抗生素，氨基糖苷类C Cmaxmax/MIC/MIC与临床疗效呈正相关。与临床疗效呈正相关。 在日剂量不变的情况

47、下，单次给药可以获得较多次给药在日剂量不变的情况下，单次给药可以获得较多次给药更高的更高的C Cmaxmax，使使C Cmaxmax/MIC/MIC比值增大，从而明显提高抗菌活比值增大，从而明显提高抗菌活性和临床疗效。但应注意性和临床疗效。但应注意C Cmaxmax不得超过最低毒性剂量。不得超过最低毒性剂量。2 2、降低耐药性发生、降低耐药性发生 Gould IM,Milne K and Jason C. Gould IM,Milne K and Jason C. Drug Exp Clin Res.1990;16:6218. Drug Exp Clin Res.1990;16:6218.3

48、3、降低肾毒性、降低肾毒性 Verpooten GA,Giuliano RA,Verbist L,et al. Verpooten GA,Giuliano RA,Verbist L,et al. Clin Pharmacol Ther 1989;45:22-27 Clin Pharmacol Ther 1989;45:22-274 4、降低耳毒性降低耳毒性 Fishman D N ,Kaye K M.Fishman D N ,Kaye K M. Infect Dis Clin Nirth Am ,2000 Infect Dis Clin Nirth Am ,2000，14(2):47514(2

49、):475Daptomycin PharmacodynamicsnBactericidal in vitroanRapidnConcentration-dependent killingnKey predictors of efficacy based on animal modelsnPeak exposure: Cmax/MICnTotal exposure: AUC/MICn5 -10 h postantibiotic effectCmax=maximum plasma concentration; MIC=minimum inhibitory concentration; AUC=area under the concentration-time curve.aThe clinical significance of in vitro data has not been established.CUBICIN (daptomycin for injection) current p