從PK-PD看抗菌藥物的合理應(yīng)用

1、從從PK/PDPK/PD看抗菌藥物的合理應(yīng)用看抗菌藥物的合理應(yīng)用李光輝李光輝復(fù)旦大學(xué)附屬華山醫(yī)院復(fù)旦大學(xué)附屬華山醫(yī)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抗菌藥藥效學(xué)抗菌藥藥效學(xué) 細(xì)菌對(duì)抗菌藥的敏感性細(xì)菌對(duì)抗菌藥的敏感性 紙片擴(kuò)散法（紙片擴(kuò)散法（K-BK-B法）法） 最低抑菌濃度最低抑菌濃度( MIC)( MIC) 最低殺菌濃度最低殺菌濃度(MBC)(MBC) 藥物敏感試驗(yàn)藥物敏感試驗(yàn)1. 1.瓊脂擴(kuò)散法瓊脂擴(kuò)散法( (紙片法，紙片法，Kirby-bauer)Kirby-bauer)測(cè)抑測(cè)抑菌圈大小畫(huà)分菌圈大小畫(huà)分S,I,RS,I,R2.2.稀釋法瓊脂稀釋法，肉湯稀釋法，微量稀釋法瓊

4、脂稀釋法，肉湯稀釋法，微量稀釋法稀釋法3.3.E E測(cè)定法測(cè)定法(Epsilometer test)(Epsilometer test)測(cè)測(cè)MICMIC值值 判斷標(biāo)準(zhǔn)：通常根據(jù)判斷標(biāo)準(zhǔn)：通常根據(jù)CLSICLSI判斷結(jié)果判斷結(jié)果4.4. 自動(dòng)化藥敏測(cè)自動(dòng)化藥敏測(cè)MICMICATBATB系統(tǒng)，系統(tǒng)，VitekVitek系統(tǒng)，系統(tǒng)，Micro ScanMicro Scan等等藥敏試驗(yàn)的臨床意義藥敏試驗(yàn)的臨床意義敏感敏感(S)(S)常規(guī)劑量時(shí)的平均血濃度超過(guò)常規(guī)劑量時(shí)的平均血濃度超過(guò)MICMIC的的5 5倍以上，用常規(guī)劑量通常有效倍以上，用常規(guī)劑量通常有效中介中介(I)(I)常規(guī)劑量時(shí)的平均血濃度等于

5、或常規(guī)劑量時(shí)的平均血濃度等于或略高于略高于MICMIC，需用高劑量或?qū)λ幬餄饪s部，需用高劑量或?qū)λ幬餄饪s部位的感染可能有效位的感染可能有效耐藥耐藥(R)(R)藥物的藥物的MICMIC高于其常規(guī)劑量時(shí)的高于其常規(guī)劑量時(shí)的血濃度，通常治療無(wú)效血濃度，通常治療無(wú)效CHINET 2012CHINET 2012年年1515家醫(yī)院家醫(yī)院3127731277株腸桿菌科細(xì)菌耐藥率（株腸桿菌科細(xì)菌耐藥率（%）抗菌藥物抗菌藥物耐藥耐藥敏感敏感亞胺培南亞胺培南5.05.092.292.2美羅培南美羅培南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頭孢哌酮頭孢哌酮/ /舒巴坦舒巴坦10.510.573.973.9頭孢他啶頭孢他啶29.129.165.365.3頭孢吡肟頭孢吡肟20.220.273.273.2慶大霉素慶大霉素36.0.36.0.62.462.4CHINET 2012CHINET 2012年年1515家醫(yī)院家醫(yī)院1961319613株非發(fā)酵菌耐藥率（株非發(fā)酵菌耐藥率（%）抗菌藥物抗菌藥物耐藥耐藥敏感敏感頭孢哌酮頭孢哌酮/ /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、頭孢他啶頭孢他啶41.941.952.952.9頭孢吡肟頭孢吡肟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美羅培南美羅培南44.244.252.852.8亞胺培南亞胺培南45.145.152.052.0環(huán)丙沙星環(huán)丙沙星40.040.055.055.0各種酶抑制劑復(fù)方制劑的比較各種酶抑制劑復(fù)方制劑的比較AM-SBAM-SBAM-CLAM-CLTC-CLTC-CLCPZ-SBCPZ-SBPIP-TAZPIP-TAZ商品名商品名優(yōu)力新優(yōu)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腸桿菌科腸桿菌科2 22 22 23 33 32 2

8、3 3綠膿、沙雷菌綠膿、沙雷菌2 23 33 33 3不動(dòng)桿菌不動(dòng)桿菌2 23 3腸球菌腸球菌2 22 22 23 3嗜麥芽窄食單胞菌嗜麥芽窄食單胞菌3 33 3 2 2頭孢哌酮/舒巴坦與頭孢菌素、亞胺培南特性比較腸桿菌腸桿菌科細(xì)菌科細(xì)菌銅綠假銅綠假單胞菌單胞菌鮑曼不動(dòng)鮑曼不動(dòng)桿菌桿菌厭氧菌厭氧菌鏈球菌鏈球菌屬屬M(fèi)RSAMRSA特特 點(diǎn)點(diǎn)頭孢哌頭孢哌酮酮/ /舒巴舒巴坦坦+不動(dòng)及銅綠耐藥低不動(dòng)及銅綠耐藥低適用于經(jīng)驗(yàn)治療適用于經(jīng)驗(yàn)治療鏈球菌屬作用差鏈球菌屬作用差頭孢他頭孢他啶啶+ +耐藥率高，適用于病原治耐藥率高，適用于病原治療；鏈球菌屬、厭氧菌作療；鏈球菌屬、厭氧菌作用差，不適用于吸入肺炎用差

9、，不適用于吸入肺炎的治療的治療頭孢吡頭孢吡肟肟+ + + +耐藥率與頭孢他啶基本相耐藥率與頭孢他啶基本相仿，對(duì)鏈球菌的作用增強(qiáng)仿，對(duì)鏈球菌的作用增強(qiáng)亞胺培亞胺培南南+ +抗菌譜廣，抗菌譜廣，VAPVAP經(jīng)驗(yàn)治療經(jīng)驗(yàn)治療需注意不動(dòng)桿菌耐藥性需注意不動(dòng)桿菌耐藥性對(duì)于革蘭陰性菌：+, 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根據(jù)根據(jù)PK/PDPK/PD原理制訂的給藥方案可以達(dá)到更高的療效和清原理制訂的給藥方案可以達(dá)到

11、更高的療效和清除病原菌的作用，并可能防止療程中細(xì)菌產(chǎn)生耐藥性除病原菌的作用，并可能防止療程中細(xì)菌產(chǎn)生耐藥性q與時(shí)間依賴(lài)型藥物殺菌活力有關(guān)的與時(shí)間依賴(lài)型藥物殺菌活力有關(guān)的PK/PDPK/PD參數(shù)是參數(shù)是T TMICMIC，即血藥濃度達(dá)到或超過(guò)，即血藥濃度達(dá)到或超過(guò)MICMIC持續(xù)的時(shí)間占持續(xù)的時(shí)間占2 2次次給藥間期的百分比給藥間期的百分比q與濃度依賴(lài)型藥物殺菌活力有關(guān)的主要參數(shù)是與濃度依賴(lài)型藥物殺菌活力有關(guān)的主要參數(shù)是AUCAUC2424/MIC/MIC或或C Cmaxmax/MIC /MIC 藥效學(xué)/藥動(dòng)學(xué)（PK/PD）原則PK/PD參數(shù)的意義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抗菌藥發(fā)揮作用所必需的抗菌藥發(fā)揮作用所必需的 Time Time MICMIC抗生素抗生素B BA A（%）給藥間隔的多少給藥間隔的多少%合適？合適？ B BA A （%） B : Time above MIC B : Time above MIC 時(shí)間時(shí)間A: A: 給藥間隔時(shí)間給藥間隔時(shí)間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細(xì)菌學(xué)療效：細(xì)菌學(xué)療效：青霉素：青霉素：TMIC%40%TMIC%40%頭孢菌素：頭孢菌素：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藥效學(xué)/藥動(dòng)學(xué)（PK/PD）原則頭孢哌酮-舒巴坦復(fù)合制劑中頭孢哌酮PK/PD參數(shù)比較不動(dòng)桿不動(dòng)桿菌屬菌屬大腸埃大腸埃希菌希菌銅綠假銅綠假

20、單胞菌單胞菌產(chǎn)氣腸產(chǎn)氣腸桿菌桿菌TMICTMIC9090(%)(%)頭孢哌酮頭孢哌酮- -舒巴坦舒巴坦2 2克克q8hq8h和和3 3克克q12hq12h在難治的革蘭陰性耐藥菌中在難治的革蘭陰性耐藥菌中TMICTMIC9090%均達(dá)到均達(dá)到5050以上以上嗜麥芽窄食嗜麥芽窄食單胞菌單胞菌陰溝腸陰溝腸桿菌桿菌舒致病菌MICMIC9090(mg/ml)(mg/ml)金黃色葡萄球菌1616(產(chǎn)b-內(nèi)酰胺酶)銅綠假單胞菌8 8金黃色葡萄球菌2 2肺炎克雷伯菌2 2陰溝腸桿菌1 1大腸埃希菌鮑曼不動(dòng)桿菌0 01 12 210102020舒巴坦頭孢哌酮肺組織內(nèi)平均藥物濃度(mg/ml)舒普深在靜注2g后在

21、肺組織內(nèi)的平均濃度與對(duì)常見(jiàn)致病菌的MIC90值比較*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 *基于舒普深藥代動(dòng)力學(xué)參數(shù)計(jì)算。2. 舒普深說(shuō)明書(shū)；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 頭孢哌酮頭孢哌酮/ /舒巴坦舒巴坦(2:1)3(2:1)3種給藥方案對(duì)非發(fā)酵菌不種給藥方案對(duì)非發(fā)酵菌不同同MICMIC值時(shí)值時(shí)%T%TMICMIC（頭孢哌酮）（頭孢哌酮）給藥方案給藥方案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鮑曼：療程天，臨床治愈率為鮑曼：療程天，臨床治愈率為79.3%79.3%（23/2923/29） ；微生物學(xué)治愈率為；微生物學(xué)治愈率為69.0%69.0%（20/2920/29）l銅綠：療程天，臨床治愈率為銅綠：療程天，臨床治愈率為68.2%68.2%（15/2215/22）；微生物學(xué)治愈率為）；微生物學(xué)治愈率為19.0%19.0%（4/2

25、14/21），），l混合感染：臨床治愈率：混合感染：臨床治愈率：2/32/3；微生物學(xué)治愈率：其中；微生物學(xué)治愈率：其中2 2例銅綠未清除例銅綠未清除舒普深舒普深3g,q8h,3g,q8h,療程療程1414天治療鮑曼不動(dòng)桿菌天治療鮑曼不動(dòng)桿菌HAPHAP患患者者PK/PDPK/PD參數(shù)與臨床療效關(guān)系的研究（參數(shù)與臨床療效關(guān)系的研究（n=12)n=12)患者號(hào)患者號(hào)MICs(g/mL) MICs(g/mL) %TMIC%TMIC臨床臨床療效療效細(xì)菌學(xué)細(xì)菌學(xué)療效療效綜合綜合療效療效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 失敗失敗未清除未清除失敗失敗13134848242444 44 10 10 失敗失敗未清

27、除未清除失敗失敗2 24848242435 35 0 0 失敗失敗未清除未清除失敗失敗7 74848242430 30 0 0 失敗失敗未清除未清除失敗失敗23234848242452 52 10 10 失敗失敗未清除未清除失敗失敗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 替加環(huán)素替加環(huán)素PK/PDPK/PD特性特性 抗生素后效應(yīng)（抗生素后效應(yīng)（PAEPAE）l 體外體外PAEPAE金葡菌：金葡菌： 4.0 h4.0 h大腸埃希菌：大腸埃希菌：2.9 h2.9 hl 體內(nèi)體內(nèi)PAEPAE 大腸桿菌：大腸桿菌：4.9 h4.9 h 肺炎鏈球菌：肺炎鏈球菌：8.9 h8.9 h 中一長(zhǎng)時(shí)效的中一長(zhǎng)時(shí)效的PAEPAE PK/PD PK/PD參數(shù)：參數(shù)：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硫酸鹽：口服給藥、局部給藥硫酸鹽：口服給藥、局部給藥l 多粘菌素多粘菌素E E甲磺酸鹽（甲磺酸鹽（CMSCMS）：靜脈注射、）：靜脈注射、肌內(nèi)注射，霧化吸入或鞘內(nèi)注射肌內(nèi)注射，霧化吸入或鞘內(nèi)注射l 多粘菌素多粘菌素B B硫酸鹽：靜脈注射，肌內(nèi)注射，硫酸鹽：靜脈注射，肌內(nèi)注射，霧化吸入霧化吸入濃度依賴(lài)性：濃度依賴(lài)性：AUC/MICAUC/MICPK/PDPK/PD靶值：肺部感染中細(xì)菌數(shù)減少靶值：肺部感染中細(xì)菌數(shù)減少1 1個(gè)個(gè) lgcfulgcfuAUC/MICAUC/MIC銅綠假單胞菌：；鮑曼不動(dòng)桿菌：銅綠假單胞菌：；鮑曼不動(dòng)桿菌：大環(huán)內(nèi)酯類(lèi)大環(huán)內(nèi)酯類(lèi)PK/

32、PDPK/PD研究研究4 4種大環(huán)內(nèi)酯類(lèi)藥物對(duì)肺炎鏈球菌的殺菌曲線(xiàn)種大環(huán)內(nèi)酯類(lèi)藥物對(duì)肺炎鏈球菌的殺菌曲線(xiàn)結(jié)果表明結(jié)果表明2 2種酮內(nèi)酯類(lèi)藥物種酮內(nèi)酯類(lèi)藥物TelithromycinTelithromycin和和ABT-773ABT-773呈濃度依賴(lài)性呈濃度依賴(lài)性大環(huán)內(nèi)酯類(lèi)為時(shí)間依賴(lài)性，但其中的酮內(nèi)酯類(lèi)屬濃度依賴(lài)性。大環(huán)內(nèi)酯類(lèi)為時(shí)間依賴(lài)性，但其中的酮內(nèi)酯類(lèi)屬濃度依賴(lài)性。糖肽類(lèi)抗生素糖肽類(lèi)抗生素 PK/PDPK/PD研究研究(a)(a)在萬(wàn)古霉素在萬(wàn)古霉素2, 4, 8, 16,2, 4, 8, 16, 和和6464倍倍MICMIC對(duì)對(duì) S. aureusS. aureusATCC29213ATC

33、C29213 的的KCs. KCs. (b)(b)在萬(wàn)古霉素在萬(wàn)古霉素2, 4, 8, 162, 4, 8, 16和和6464倍倍MICMIC對(duì)對(duì) S. epidermidisS. epidermidisATCC29886ATCC29886 的的KCsKCs 結(jié)果提示萬(wàn)古霉素屬于時(shí)間依賴(lài)性抗菌藥物結(jié)果提示萬(wàn)古霉素屬于時(shí)間依賴(lài)性抗菌藥物 。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治療大鼠股部肺炎鏈球菌感染治療大鼠股部肺炎鏈球菌感染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參數(shù)與細(xì)菌學(xué)療效關(guān)系參數(shù)與細(xì)菌學(xué)療效關(guān)系可見(jiàn)可見(jiàn)LINEZOLIDLINE

36、ZOLID TMICTMIC與細(xì)菌學(xué)療效相關(guān)系數(shù)最高為與細(xì)菌學(xué)療效相關(guān)系數(shù)最高為8484，當(dāng)，當(dāng)TMICTMIC為為4040即可達(dá)到良好的細(xì)菌學(xué)療效。即可達(dá)到良好的細(xì)菌學(xué)療效。Andes D, et al. Antimicrob Agents Chemother 2002;46:3484-9.斯沃斯沃AUCAUC2424/MIC 100/MIC 100臨床療效卓越臨床療效卓越利奈唑胺利奈唑胺PTAPTA結(jié)果結(jié)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氨基糖苷類(lèi)日劑量單次給藥氨基糖苷類(lèi)日劑量單次給藥 1 1、提高抗菌活性、提高抗菌活性 氨基糖苷類(lèi)屬于濃度依賴(lài)型抗生素，氨基糖苷類(lèi)氨基糖苷類(lèi)屬于濃度依賴(lài)型抗生素，氨基糖苷類(lèi)C Cmaxmax/MIC/MIC與臨床療效呈正相關(guān)。與臨床療效呈正相關(guān)。 在日劑量不變的情況

47、下，單次給藥可以獲得較多次給藥在日劑量不變的情況下，單次給藥可以獲得較多次給藥更高的更高的C Cmaxmax，使使C Cmaxmax/MIC/MIC比值增大，從而明顯提高抗菌活比值增大，從而明顯提高抗菌活性和臨床療效。但應(yīng)注意性和臨床療效。但應(yīng)注意C Cmaxmax不得超過(guò)最低毒性劑量。不得超過(guò)最低毒性劑量。2 2、降低耐藥性發(fā)生、降低耐藥性發(fā)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、降低腎毒性、降低腎毒性 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