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抗菌药物临床应用抗生素细菌人体RESISTANCEBACTERICIDEINFECTIONIMMUNITYSIDEEFFECTSPHARMACOKINETICS抗菌药物临床应用2抗生素选择时需考虑的因素药物感染部位浓度对细菌MIC结果微生物学•抗菌机制•抗

菌谱•耐药性药代动力学•吸收、分布、代谢、排泄•给药方案药效学•时间/浓度依赖型•杀菌剂/抑菌剂•组织渗透•抗菌时效•临床效果•细菌清除•患者依从性•耐受性•时效•价格抗菌药物临床应用3抗菌药物临床应用◼抗菌药物基础知识◼各类抗菌药物特点◼β-内酰胺类抗菌药物◼

喹诺酮类药物◼抗阳性菌药物抗菌药物临床应用4◼抗生素药代动力学药效学毒理学特殊抗生素应用◼细菌耐药机制特别细菌◼感染（人体）抗生素应用基础理论抗菌药物临床应用5抗生素抗菌作用机制抗菌药物临床应用6抗生素药效学•细菌敏感性(MI

C/MBC)•抗菌谱(抗菌机制)•抗菌特征（杀菌/抑菌）•抗生素后效应(PAE)•抗生素联合抗菌药物临床应用7MIC/MBC◼MIC:体外培养基中孵育18-24小时后，能抑制细菌生长的最低抗生素浓度。◼MBC:体外培养基中孵育18-24小时后，能杀灭99

.9%细菌的最低抗生素浓度。抗菌药物临床应用8G(+)CG(-)CG(+)BG(-)EBG(-)BspirochetsmycoplasmachlamydiaothersG(+)CG(-)CG(+)BG(-)E

BG(-)BspirochetsmycoplasmachlamydiaothersG(+)CG(-)CG(+)BG(-)EBG(-)Bspirochetsmycoplasmachlamydiaothers抗生素针对菌万古霉素氟喹诺酮类谱（SPECTRUM）抗菌药物临床应用9不同类别

抗生素联合效应1.抗菌效果分类：杀菌剂：ß-内酰胺,氨基甙类，喹诺酮类抑菌剂：四环素,磺胺,林可酰胺类,大环内酯类2.联合效应一般原则杀菌剂+杀菌剂：协同杀菌剂+抑菌剂：拮抗抗菌药物临床应用10联合用药的优点1.取得协同

抗菌作用磺胺+TMP青霉素+氨基甙类两性霉素B+氟胞密啶2.处理混合性感染3.减少耐药菌产生4.严重感染的经验治疗抗菌药物临床应用11联合用药的缺点1.可能的拮抗作用2.增加毒副反应3.增加费用4.不恰当使用可能

增加耐药菌产生抗菌药物临床应用12药代动力学（Pharmacokinetics）CmaxCluVdTmaxA、ßT1/2、AUCC=Ae-at-Be-bt抗菌药物临床应用13抗生素药代动力学参数：T1/2CmaxSiteconcentrationsExcretio

n抗菌药物临床应用14抗生素药代动力学◼特殊人群：老人儿童肾功不良者肝功不良者孕妇哺乳期抗菌药物临床应用15药代动力学vs药效学◼Cmax/MIC◼AUC/MIC抗菌药物临床应用16不同药物不同浓度杀菌曲线1.52.53.54.55.56.

57.58.59.502461.52.53.54.55.56.57.58.59.502461.52.53.54.55.56.57.58.59.502468control1/4MICMIC4MIC16MIC64MICTime（h）LogCFUTobramycinCiprofloxaci

nTicarcillin抗菌药物临床应用17抗生素PK/PD参数T(h)Con.Cmax/MICAUC/MICMICT>MIC抗菌药物临床应用18浓度依赖性抗生素（AUC/MIC）01020304050607080901000-62.562.5

-125125-250250-500>500clincurebacteriologicAUC/MICEffectiverates抗菌药物临床应用191.抗生素的抗菌活性随药物浓度增加而增加;2.临床用药目的：取得抗生素Cmax/MIC>10;3.这类药物有：氨基

甙类、喹诺酮类、阿奇霉素、四环素、链阳霉素、万古霉素。浓度依赖性抗菌作用抗菌药物临床应用20浓度非依赖性抗生素（T>MIC）抗菌药物临床应用21浓度非依赖性抗菌作用1.抗生素的抗菌作用与药物浓度关系不密切，而与抗生素浓度维持在细菌

MIC之上有关;2.临床用药目的在于维持药物浓度在细菌MIC之上一定时间。一般为40%给药间歇以上;3.这类药物有：ß-内酰胺类、红霉素、克拉霉素、可林霉素、恶唑烷酮.抗菌药物临床应用22抗生素药效学与药代动力学分类抗生素类别PK/PD参数药物时间依赖性（短PAE）T>MIC青霉素类、头孢菌

素类、氨曲南、碳青霉烯类、大环内酯类、克林霉素、恶唑烷酮类、氟胞嘧啶时间依赖性（长PAE）AUC24/MIC链阳霉素、四环素、万古霉素、替考拉林、氟康唑、阿齐霉素浓度依赖性AUC24/MIC或Cmax/MIC氨基糖苷类、氟喹诺酮类、daptomycin、酮内酯、甲硝唑、两性霉素B%

T>MIC=ln[Dose/(Vd×MIC)]×T1/2/ln2×100/DI抗菌药物临床应用23抗菌药物临床应用◼抗菌药物基础知识◼各类抗菌药物特点◼β-内酰胺类抗菌药物◼喹诺酮类药物◼抗阳性菌药物抗菌药物临床应用24ß-内酰胺抗生

素抗菌药物临床应用25ONNHSONSNCOOHOAcNH2OMeSONNHNH2OCOOHNOHOCOOHSNNH2NSO3HONH2OONOSNNH2OCOOHNNSOOCOOHOSULBACTAMI

MIPENEMAMPICILLINCEFOTAXIMECARUMONAMNONHOCOOHOMeCOOHSNNNNHOOLATAMOXEFNSOONH2OOHCOOHLITIPENEMNNHNH2C2H5COOHClOOLORACARBIF抗菌药

物临床应用26细菌细胞壁粘肽结构抗菌药物临床应用27NSCCH3CH3ONOCOOHNSCCH3CH3ONOOCOOHNSCCH3CH3ONOCOOHNOCH3NSCCH3CH3ONOCOOHNH2青霉素G青霉素V氨苄西林苯唑西林哌拉西林NSCCH3CH3ON

OCOOHNONNC2H5OO抗菌药物临床应用28头孢菌素分代分代（组）原则♫化学结构♫药理学特征♫开发年代抗菌药物临床应用29注射用头孢菌素口服用头孢菌素00sCeftobiprole、cefotaroline5th1990s头孢吡肟、头孢匹罗、头孢噻利、头孢

唑兰、头孢喹肟、头孢瑞南4thG1980s头孢噻肟、头孢甲肟、头孢唑肟、头孢曲松、头孢他定、头孢哌酮、头孢磺啶、头孢匹胺、头孢米唑、头孢地嗪、头孢替胺3rdG头孢克肟、头孢布烯、头孢地尼、头孢他美酯、头孢泊肟酯、头孢特伦酯、头孢妥仑酯、头孢卡品酯、头孢替

胺酯70-80s头孢呋辛、头孢唑南、头孢尼西、头孢替坦、头孢西丁、头孢美唑、头孢羟唑、头孢拉宗、头孢米诺2ndG头孢呋辛酯、头孢克罗头孢丙烯、氯碳头孢1960s头孢噻吩、头孢噻定、头孢曲嗪、头孢乙嗪、头孢氮氟、头孢替唑、头孢西酮、头孢唑啉、头孢拉定、头孢硫眯IstG头孢氨苄、头孢

羟氨苄、头孢拉定头孢菌素的发展抗菌药物临床应用30•酯化头孢菌素构效关系SNR1R2OCOOH•抗菌活性•药代特征•药代特征•对酶稳定性•抗菌活性抗菌药物临床应用31分类C7位特征C3位特征药品第一代头孢菌素肠外、酶不稳定，快代谢无特别，对没不稳定乙酰甲基，快速代谢，短半衰期头孢噻

吩肠外，酶不稳定，代谢稳定无特别，对没不稳定其他基团取代乙酰甲基，代谢稳定头孢唑林口服，酶不稳定，代谢稳定酰基侧链其他基团取代乙酰甲基，代谢稳定CH3头孢氨苄第二代头孢菌素肠外，酶稳定，代谢稳定酰基侧链，对

酶稳定，抗菌谱扩大到产头孢酶细菌其他基团取代乙酰甲基头孢孟多头霉素甲氧基头孢美唑NSCONHR2R1OCOOHSCH2CH2OCOCH3NNNNCH2NNSCH2CH3SCH+NH3CHOHNNNNCH3SCH2NCCH2SCH2OCH3NNNNCH3CH2头

孢菌素的SAR抗菌药物临床应用32分类C7位特征C3位特征药品第三代头孢菌素肠外，耐酶，代谢稳定肟基不同头孢噻肟口服，酶稳定，代谢稳定肟基不同头孢布烯口服，酶稳定，代谢稳定肟基C4脂头孢泊肟第四代头孢菌素肠外，耐酶，代谢稳定肟基4价氮头孢吡肟CH2OCOCH3SNCNOCH3NH2NSNH

2COOHSNNH2NOCH3CH3OOCH3OCH3NNSNOCH3NCH2CH3+NSCONHR2R1OCOOH头孢菌素的SAR抗菌药物临床应用33各代头孢菌素大致比较代别G+MRSAG-非发酵普通酶ESBLs安全性适应症1st+

++-±/+-±-++2nd++-++-+/++-++++3rd+/++-+++-/+++-++++4th++-+++++++-++++5th++++++++++-？+抗菌药物临床应用34近年来头孢菌素发展情况给药方式分代药品名称商品名开发公司上市年代首市国家注射用五

代ceftobiproleJ&J2009USA五代ceftarolineAZ-PhaseII四代cefopiromeCefromHoechst1992Sweden四代cefepimeMaxipimeBMS1993Sweden四代cefozopranFirstci

nTaketa1995Japan四代cefoselisWincefFujisawa1998Japan三代cefodizimeNeucefHoechst1990Japan口服三代cefdinirCefzonFujisawa1991Japan三代ceftibudinCedaxShionoge199

3Japan三代cefpodoximeBananSankyo1990Japan三代cefetametGlobcefTaketa1992Mexico三代cefditorenMeiactMeiji1994Japan三代cefcapeneFlomoxShionoge199

7Japan二代cefotiamPansporinTaketa1991Japan二代cefprozilCefzilBMS1992US二代loracarbefLorabidKyowa1992US抗菌药物临床应用35头孢菌素体外抗菌活性比较（MIC90,mg/L）细菌头孢吡肟头

孢匹罗头孢噻利头孢克啶头孢噻肟头孢他啶MSSA3.13/500.78/6.256.25/12.512.5/50MSSE0.78/250.39/6.253.13/12.56.25/50化脓链球菌0.0150.008<0.0080.060.0080.2

5无乳链球菌0.250.006<0.060.50.060.5抗菌药物临床应用36头孢菌素体外抗菌活性比较（MIC90,mg/L）细菌头孢吡肟头孢匹罗头孢噻利头孢克啶头孢噻肟头孢他啶肺炎链球菌0.50.

015<0.0080.50.0150.5粪肠球菌6432>32>32>128>128屎肠球菌>16>128>32>128>128鸟肠球菌>100>100>100>100>100>100抗菌药物临床应用37头孢菌素体外抗菌活

性比较（MIC90,mg/L）细菌头孢吡肟头孢匹罗头孢噻利头孢克啶头孢噻肟头孢他啶大肠杆菌0.060.060.060.10.120.5肺炎杆菌0.060.060.120.20.060.5变形杆菌0.060.12<0.060.390.030.12枸橼酸菌4143.133

264抗菌药物临床应用38头孢菌素体外抗菌活性比较（MIC90,mg/L）细菌头孢吡肟头孢匹罗头孢噻利头孢克啶头孢噻肟头孢他啶产气杆菌0.50.1210.248阴沟杆菌4243.136464沙雷菌10.250.50

.3941莫根菌0.030.060.120.221抗菌药物临床应用39头孢菌素体外抗菌活性比较（MIC90,mg/L）细菌头孢吡肟头孢匹罗头孢噻利头孢克啶头孢噻肟头孢他啶绿脓杆菌3.136.2580.78>32

3.13窄食单胞菌16128>32>32128128不动杆菌1005010050流感杆菌0.060.120.250.390.060.25抗菌药物临床应用40碳青霉烯类药物发展介绍NOHOSCH2CH2NH2COOHNOHOCOOHSCH2CH

2NHCHNHNOHOCOOHSNNHCH3NOHOCOOHSCH3NHCON(CH3)2NOHOCOOHSCH3NN+NNOHOCOOHSCH3NH2+NOCOONaThienamycin1978Imipenem1987Panipenem1993Meropenem1995Biap

enem2002Ertapenem2002抗菌药物临床应用41药物发展介绍NOOCOOHR1R2O碳青霉烯类广谱、强效的原因O对β-内酰胺酶稳定（抑酶）OPD、PK影响O对DPH-I稳定抗菌药物临床应用42碳青霉烯类体外抗菌活性比较AntibioticsS.

aureus(30),MSSAS.epidermidis(46),MSSEMICrMIC50MIC90MICrMIC50MIC90Imipenem0.016-0.1250.0320.0320.008-0.0320.0160.016Meropenem0

.063-0.1250.1250.1250.0630.1250.125Biapenem0.063-0.1250.1250.1250.032-0.1250.0630.125Cefpirome0.25-1110.125-10.50.5Ceftazidi

me8-1616164-1688AAC,1998,42:94-99抗菌药物临床应用43碳青霉烯类体外抗菌活性比较AntibioticsS.pyogenes(42)S.pneumoniae(25),PRSPMICrMIC50MIC90MICrMIC50MIC9

0Imipenem<0.004-0.008<0.0040.0080.008-20.250.25Meropenem<0.004-0.0080.0080.0080.016-20.250.5Biapenem<0.004-0.010.0080.0080.016-40.250.5Cefpir

ome0.008-0.0160.0080.0080.032-20.50.5Ceftazidime0.125-0.250.1250.250.125-32832AAC,1998,42:94-99抗菌药物临床应用44碳青霉烯类体外抗菌活性比较AntibioticsE.coli(30)K.pne

umoniae(30)MICrMIC50MIC90MICrMIC50MIC90Imipenem0.063-0.250.1250.1250.063-0.250.1250.25Meropenem0.016-0.0320.0160.0160.0320.0320.032Biapenem0.03

2-0.0630.0320.0630.032-0.250.0630.125Cefpirome0.016-0.1250.0320.0630.032-0.1250.0320.063Ceftazidime0.063-10.250.2

50.063-0.50.1250.25AAC,1998,42:94-99抗菌药物临床应用45碳青霉烯类体外抗菌活性比较AntibioticsP.mirabilis(27)C.freundii(22)MICrMIC50MIC90MICrMIC50MIC90

Imipenem0.125-0.50.250.50.125-10.250.5Meropenem0.0320.0320.0320.016-0.0630.0320.032Biapenem0.032-10.1250.50.063-10.0630.125Cefpirome0.008

-0.1250.0320.0630.016-10.0320.063Ceftazidime0.032-0.50.1250.250.25-1280.51AAC,1998,42:94-99抗菌药物临床应用46碳青霉烯类体外抗菌活性比较AntibioticsE.cloacae(30)S

.marcescens(30)MICrMIC50MIC90MICrMIC50MIC90Imipenem0.125-10.250.50.25-20.251Meropenem0.016-0.1250.0320.0630.032-80.0630.125Biapenem0.032-0.50.0

630.1250.125-80.251Cefpirome0.016-40.06340.032-320.0630.5Ceftazidime0.063->1280.251280.125-1280.1250.5AAC,1998,42:94-99抗菌药物临床应用47碳青

霉烯类体外抗菌活性比较AntibioticsP.aeruginosa(83),imi-sensitiveB.cepacia(25)MICrMIC50MIC90MICrMIC50MIC90Imipenem0.25-8188-321632Meropenem0.032-80.252

2-848Biapenem0.125-80.544-16816Cefpirome2->12883216->12864128Ceftazidime0.5-1282322-1648AAC,1998,42:94-99抗菌

药物临床应用48BacteriaImiMeroBiaPaniLenaCS-834S-4661MSSA≤0.0080.060.060.030.030.120.06MRSA3216320.1283216MSCoNS<0

.0080.060.060.0150.0150.060.03MRCoNS16161614816PSSP≤0.0080.0150.0150.0150.0150.0080.008PRSP0.250.25E.faecium128<128<12

8128128128E.faecalis1441482C.difficile81811碳青霉烯类体外抗菌活性比较(MIC50)ClinPharmacokinet2000,39:185抗菌药物临床应用49BacteriaImiMeroBiaPaniLenaCS-834S-466

1H.influenzae10.060.50.50.060.12E.coli0.120.0150.030.060.030.0150.015K.pneumoniae0.120.030.120.120.060.01

50.03Proteusspp.20.0620.1220.060.25S.marcescens0.250.060.250.250.250.120.12Enterobacter0.250.030.060.

250.030.120.03Acinetobacter0.120.250.120.120.120.5P.aeruginosa10.250.520.5320.25S.maltophilia>12864>128>128>128B.fr

agilis0.250.120.250.030.250.12碳青霉烯类体外抗菌活性比较(MIC50)抗菌药物临床应用50DrugDose(mg)Cmax(mg/L)t½β(h)V(L)Cl(L/h)Pb(%)Imipenem/cilastatin50

0/50021-580.9-1.1114.4-15.911.0-12.22031-4940Panipenem/betamipron500/50027.51.17±0.3019.8±5.40.28±0.05415.60.71±0.1829.3±9.80

.71±0.17Meropenem50021-300.82-1.120.916.69Biapenem50032.4±2.3(600)1.42-3.413.36.66-9.90NALenapenem5001.43±0.1414.04±1.347.86±1.42NACS-83

41500.81±0.25NA49.5±12.916-20ertapenem10001554.50.121.895碳青霉烯类药代动力学(IV)参数比较ClinPharmacokinet2000,39(3):190-198抗菌药物临床应用51碳青霉烯类PK/

PD比较药物给药方案目标T>MICMIC>4mg/LMIC>1mg/LImipenem500mg,qid4578Meropenem1000mg,tid4671panipenem500mg,tid3652Biapenem500mg,tid5088ClinPharmacokinet

2000,39(3):190-198抗菌药物临床应用52BacterialspeciesResistantmechanismsGrampositivecocciTargetmutationEnterobacteriaceaeCephalosporinase+porinlossCarbape

nemaseP.aeruginosaPorinlossUp-regulatedeffluxCarbapenemaseAcinetobacterspp.Cephalosporinase+porinloss

Carbapenemase细菌对碳青霉烯类耐药机制抗菌药物临床应用53细菌对碳青霉烯类耐药机制分子分类酶型酶解谱抑酶效应产生菌遗传物质氨基青霉素脲基青霉素广谱头孢菌素氨曲南碳青酶烯克拉维酸EDTAANmcA,Sme1-2,IMI1-2+++-++

++/--E.Cloacae,M.marcescensChromAKPC1-4++++++++++-K.pneu,EnterobacterPlasmidASHV-38+++++++++-K.pneu.PlasimdAGES1-9++++++++++-P.aeru,K.pneu,E.co

liPlasmidIntegronBIMP1-18++++++-++-+Enterobacter,Pseudo,Alcal,AcinetPlasmid,Chrom,IntegronBVIM1-11++++++-++-+P.aeru,P.putides,A.baumPlasmid,Chro

m,IntegronDOXA(23-27)+++++-++/--A.baumaniichrom,integron碳青霉烯酶比较CMI,2002,8:321,JAC,2007,60:470抗菌药物临床应用54KineticParametersofCarbapenamasesfo

rCarbapenemsEnzymeSubstratekcat(s-1)RelativekcatKm(μM)kcat/Km(μM-1s-2)Relativekcat/KmCcrAImipenem1510063240100Meropenem8.45

63822092Biapenem3.725200197.9L1Imipenem2.01002676100Meropenem0.88441180110Biapenem0.5528192938Sme-1Imipenem0.33100665.0100Meropenem0.0288.54.36.

5130Biapenem0.034105.46.3130IMI-1Imipenem100100170530100Meropenem10102638071Biapenem9.49.43229055AAC,1999,12:2904–2909抗菌药物临床应用55DrugsIMP-6IMP-1MIC*km

kcatKcat/kmMICKmKcatKcat/kmImipenem2681100.61246391.2Panipenem41802500.71250100.12meropenem64327.64.20.544301.5AAC.45.5.1343–1348.2001细菌对碳青霉烯类耐药机制*M

IC为大肠杆菌带imp基因时MIC金属碳青霉烯酶比较抗菌药物临床应用56细菌对碳青霉烯类耐药机制A组碳青霉烯酶比较（Kcat/Km）AntibioticsKPC-1KPC-2KPC-3Ampicillin0.90.91.2Nitrocefin--2.6Cephaloridine0.61.11

.4Cephalotin1.40.83.5Cefotaxime0.10.10.5Ceftazidime0.001-0.03Cefoxitin0.0020.0020.5Moxalactam--0.05Meropenem0.30.31.4Imipenem0.20.

31.9Sulbactam--0.1AAC,2005,49:4760抗菌药物临床应用57流出通道(OprM)外膜周质间隙连接脂蛋白(MexA)胞浆膜流出泵系统(MexB)膜孔蛋白(Opr)主动外排系统结构图抗菌药物临

床应用58细菌对碳青霉烯类耐药机制JInfectChemother(2002)8:371–373,JAntibiotics1995;48:89–91DrugsOprD2EffluxsystemsMexA

B-OprMMexXY-OprMMexCD-OprJImipenem√XXXBiapenem√XXXBO2727√X√XPanipenem√?√XMeropenem√√X√S4665√√√√DU6681√√√√抗菌药物临床应用591.为浓度非依赖性抗生素。2.对革兰阳性菌有一定PAE，对革兰阴性菌

没有PAE。3.T>MIC对治疗效果有较好预见作用.4.当药物浓度低于MIC时,细菌很快恢复生长.5.半衰期普遍较短,需多次给药.6.持续静脉滴注疗效可能优于间歇多次给药.同时药品经济学更优.7.不良反应不一定与恒定

血清或组织浓度有关.ß-内酰胺类药效学特点抗菌药物临床应用60喹诺酮类抗菌药物临床应用61氟喹诺酮类药物XNOOHOFR7R1R2R5R8抗菌药物临床应用62196019701980199020002010NDAcinoenoxnorfPPAoflociproLevopefllemof

lerspartosutematravclinsitagemipazubaloprulmoxigatigrepgarequininerufdifami苯吡啶奈啶酮泌尿感染阴性菌感染广谱药物呼吸喹诺酮抗菌药物临床应用63喹诺酮的分代国际分代国

内分代代表药物代表结构11/2奈啶酸,吡哌酸2a3氟哌酸,环丙沙星,氧氟沙星,左氧沙星2b斯帕沙星,格帕沙星3a4加替沙星,曲伐沙星,莫西沙星3b吉米沙星45garenoxacinNNNOOHONNOOHOFNNONOOHO

FNFNH2NNCH3CH3CH3OOHONOMeNNNOOHOCH3OOHOFNNNNH2NOMeOOHOFNFNH2NNCH3CH3CH3抗菌药物临床应用64X8NR5OCO-OR7FR1X8NR5OCO-OR7FR1X8NR5OCO-OR7FR1X8NR

5OCO-OR7FR1AABB喹诺酮类抗菌作用机制抗菌药物临床应用65氟喹诺酮构效关系XNOOHOR1R5R6R8R7DNA结合部位F>>HNH2>OH>CH3抗菌活性影响NNRNNH2HalkylG-↑G+↑G+↑N抗厌氧菌活性↑Ｃl,FO-CH3OCH2FO-CH

3耐药选择↓>>C(CH3)2FF活性增强抗菌药物临床应用66IsolatesCiproOfloLevoMoxiS.pneumoniaeCIP-S1210.25S.pneumoniaeCIP-R6432164H.influen

zae0.0160.060.030.06M.catarrhalis0.030.1250.1250.125S.aureusCIP-S0.50.50.250.06S.aureusCIP-R>12832164P.aerugin

osaCIP-S0.5428P.aeruginosaCIP-R128>128>128>128M.pneumoniae410.50.125常用氟喹诺酮类体外抗菌活性(MIC90)抗菌药物临床应用67氟喹诺酮类对E.coli活

性比较E.coli(100)MIC(mg/L)%SusceptibilityRange50%90%Ciprofloxacin≤0.03-0.12≤0.030.03100Moxifloxacin≤0.03-0.250.030.06100Gatifloxac

in≤0.03-0.50.060.12100Levofloxacin≤0.03-0.120.030.03100Pip/tazobactam0.12->1280.5490Imipenem≤0.03-0.50.12

0.25100抗菌药物临床应用68K.Pneumoniae(40)MIC(mg/L)%susceptibilityRange50%90%Ciprofloxacin≤0.03-1.00.060.12100Moxifloxacin0.06-2.00.251100Gatifloxacin0.

06-2.00.52100Levofloxacin≤0.03-1.00.060.25100Pip/tazobactam0.12-64.01890Imipenem≤0.03-1.00.120.5100氟喹诺酮类对K.pne

umoniae活性比较抗菌药物临床应用69喹诺酮的特点和副作用分代特点副作用I仅用于泌感IIaG-作用强，G+作用有限环丙对铜绿假单胞作用最强典型喹诺酮副作用IIb增强G+作用，铜绿假单胞作用减弱光毒性和QT间期延长明显IIIa增强G+作用无CYP450

抑制IIIb明显增强G+作用无光毒性低CNS毒性Ⅳ无氟,抗阳性菌作用强副作用降低?BallP.JAC2000;46:17-24抗菌药物临床应用70细菌耐喹诺酮类机制×抗菌药物临床应用71不同细菌对左氧沙星的耐药情况010203040506070809

0屎肠溶葡大肠金葡表葡鲍曼铜绿粪肠阴沟弗枸变形克肺产气化链志贺嗜麦芽流感沙雷肺球沙门R％30%抗菌药物临床应用72药物单次口服Cmaxmg/LTmax(h)T1/2(h)AUCmg·h/L生物利用度(%)蛋白结合率(%)尿回收(%)氧氟沙星400mg5.850.645.035.0

902080环丙沙星500mg2.561.254.012.07036.740左氟沙星200mg2.690.926.2419.31003280加替沙星400mg4.11.47.833.5962682莫西沙星400mg3.12.51236914025吉米沙星320mg1.481.86.659.309

056.935常用氟喹诺酮类药物PK比较抗菌药物临床应用73FQ中枢神经系统不良反应◼轻中度不良反应◼头昏\头疼◼眩晕◼失眠◼视觉异常◼重度不良反应◼神志异常◼幻觉◼抽搐/惊厥Drug,2002,62:13-59CID1999,28:352-364抗菌药物临床应用74FQ

CNS不良反应机制与率◼抑制GABA与受体结合,刺激中枢神经系统,与其7位侧链结构有关;◼其他途径:◼N-甲基-D-门冬酰腺苷受体激活;◼兴奋性氨基酸受体激活◼发生率:Trova>Norf,Gati,Moxi>Spar>Ci

pro>Oflo>Levo抗菌药物临床应用75氟喹诺酮致QTc延长比较◼TdPoccurrence:◼Ciprofloxacin:0.3/10million◼Levofloxcin:5.4/10million◼Gatiflox

acin:27/10million◼QTcprolongationefficacy:Sparfloxacin>grepafloxacin>moxifoxacin>gatifloxacin>gemifloxacin>levofloxacin>

ciprofloxacinpharmacotherapy2001.21(12):1468-72抗菌药物临床应用76torsadesdepointes(TdP)多因素效应抗菌药物临床应用77◼肝损害表现:◼转氨酶升高◼黄疸◼肝衰竭

◼药物:◼曲伐沙星:撤市◼所有药物均有,程度不同而已氟喹诺酮药物肝损害抗菌药物临床应用78FQ光毒性◼服用FQ后,暴露部分皮肤出现损害;可轻可重,轻者红癍,重者出现大疱性皮炎;◼机制:◼FQ进入皮肤;◼受光(阳光\紫外光等)照射,能量激发氧离子基团产生,启动炎症

反应,破坏皮肤.◼与FQ第8位基团有关.◼光毒性强度:◼Lome,Fler>Spar>Enor>Clin>Trov>Gati>Moxi>Oflo,Cipro,Norf抗菌药物临床应用79FQ8位基团与光毒药物8位基团动物致

毒剂量(mg/kg)NorfCH>300CiproCH>300OfloC-OR>300MoxiCH3OH>300GatiCH3OH>100TrovaN>100SparCF18ClinCF10抗菌药物临床应用80司帕沙星对幼龄大鼠膝关节软骨

毒性研究AAC1998,6:1470-1475高剂量喹诺酮类与幼龄动物关节软骨毒性有关剂量(mg/kg)次/天时间(天)软骨病变600110/6600140/10600180/10600210/61800115/8抗菌药物临床应用81环丙沙星/氧氟沙星对人体关节软骨作

用的体外研究AAC1997,11:2562-2565喹诺酮类对人体软骨细胞有体外毒性喹诺酮类体外孵育14天,显微镜下测量软骨细胞坏死与硫酸软骨素空泡数,药物与对照间差异明显,不同药物间没有差异抗菌药物临床应用82喹诺酮类致软骨损害◼幼龄动物产生;◼动物种属存在差异:幼犬作用最明显;◼多发生

在负重关节;◼与镁缺乏有关;◼可能发生机制:◼影响软骨细胞表面整合素及其后续反应;◼细胞内活性氧增加;◼抑制细胞DNA旋转酶?抗菌药物临床应用83•现有研究结果表明:•氟喹诺酮不引起儿童关节病或者骨骼异常;•儿童对之耐受良好;•临床感染治疗有效.•美国儿科学会感染委员

会推荐:在认真评估危险与收益的情况下,可用于:•囊性纤维化患者肺支气管感染恶化;•复杂性尿路感染;•长期用药的免疫抑制个体多重耐药革兰阴性菌感染;•慢性骨髓炎;•慢性化脓性中耳炎;•多重耐药结核杆菌感染国外儿童应用喹诺酮类

意见SeminarsinPediaricInfectiousDiseases,1999,10:31-37抗菌药物临床应用84FQ致血糖改变◼现象:◼Cipro与磺脲类合用致严重低血糖;◼Levo与糖尿病药合用致低血

糖;◼Moxi可致磺脲类浓度降低,但未见血糖改变;◼Gati与磺脲类合用致后者药效改变,但未见药物相互作用◼糖尿病者高血糖或低血糖◼正常人发生高血糖◼一般发生在用药3天之内Drug,2002,62:13-59

AmJMed,2002,1133:232-234抗菌药物临床应用85FQ致血糖改变机制与发生率◼可能与药物相互作用有关◼影响肾上腺素分泌?◼影响胰岛细胞ATP钾通道,影响胰岛素分泌血糖CiproLevoG

atiMoxi高血糖NA<1%<3%<0.1%低血糖<0.1%<0.1%<0.1%NA抗菌药物临床应用86氟喹诺酮毒性构效关系XNOOHOR1R5R6R8R7Mg2+结合,软骨毒性?FNH2,CH3遗传毒性NP450作用↑=C2H5>FF光毒性,遗传毒性NH2光毒性

↓>>alkylsubNNN<<alkylsubNNNGABA结合NN结晶尿NSAID作用bulkyP450作用↓bulkyＣl,FO-CH3结晶尿↓F>Ｃl>OCH3P450作用F>OMeQTc↑NH2>CH3>HQTc↑抗菌药物临床应用87喹诺酮副作用i副作用喹

诺酮(频率)危险人群遗传毒性？？？孕妇胃肠道氟罗，司帕，格帕(>10％)光毒性司帕，氟罗，洛美(>10％)软骨培氟，其他(2.7%)儿童，孕妇肌腱炎培氟>>左氧/氧氟>环丙老人尤其在激素治疗中，运动员VanBam

bekeF,etal.ClinMicrobiolInfect2005;11:256-280抗菌药物临床应用88副作用喹诺酮(频率)危险人群严重肝损伤曲伐(0.006%)严重CNS左氧：意识错乱(0.026%)氟罗：失眠(8%)合用

NSAID或CYP450抑制剂QT间期延长司帕(9-28ms)>格帕(10ms)>莫西(6ms)>左氧(3ms)>加替(2.9ms)合用可延长QT药或CYP450抑制剂低/高血糖加替，左氧合用口服降糖药CYP450抑制依诺>环丙>洛美

>氧氟>左氧，司帕，加替，莫西喹诺酮副作用iiVanBambekeF,etal.ClinMicrobiolInfect2005;11:256-280抗菌药物临床应用89196019701980199020002010NDAcinoenoxnorfPPAoflocip

roLevopefllemoflerspartosutematravclinsitagemipazubaloprulmoxigatigrepgarequininerufdifami苯吡啶奈啶酮泌尿感染阴性菌感染广谱药物呼吸喹诺酮抗菌药物临床应用90糖肽类药物◼万古霉素◼替考拉

宁◼Dalbavacin◼Oritavacin◼Telavacin抗菌药物临床应用91欧洲43家医院监测结果BacteriaYearStrainNoVancomycinTeicoplaninMICrMIC90MICrMIC90S

.aureus2005337<0.25-21<0.12-8220062200.5-210.25-4120071310.5-210.25-412008690.25-210.25-41CoNS200593<0.25-420.25-1642006810.5

-220.25->3282007810.5-220.25-842008910.25-220.12-84S.pyogenes2005410.250.25NtNt2006-----20071460.12-0.50.25<0.03-4<0.032008540.12-0.250.

25<0.03-1<0.03Enterococci20053010.125-2562560.06-256642006-----2007720.25-220.5-20.2520081070.25->12820.25-128

0.25ECCMID2009,p1620抗菌药物临床应用92Vancomycinsafety项目FarberMellorSorrelCiminoDownsRybakGoetzSalamaElting年代1983198519851987198919901993199

31998设计回顾前瞻前瞻回顾前瞻前瞻前瞻前瞻前瞻例次94335481662316991747人群医疗医疗医疗肿瘤医疗医疗医疗医疗肿瘤总体肾毒%1617715171022717单独肾毒%5901513

51908合并AG者%35714152722241432耳毒%1125-----4静脉炎%13-37-14---3皮疹%3-6-0---11Cancer1998;83:2597抗菌药物临床应用94恶唑烷酮类——利奈唑烷OC3HH

CNOONFONLinezolid(PNU-100766)抗菌药物临床应用95Linezolid抗菌机制抗菌药物临床应用96Linezolid抗菌谱Gram-positivemicroorganisms:•屎肠球菌(包

括VRE)•金黄色葡萄球菌(包括MRSA)•肺炎链球菌(包括PRSP)•无乳链球菌•化脓性链球菌•粪肠球菌(包括VRE)•表皮葡萄球菌(包括MRSE)•溶血葡萄球菌•草绿色链球菌Someanaerobicbacteria:抗菌药物临床应

用97vancomycin/aztreonamvslinezolid/aztreonamforthetreatmentofHAP01020304050607080cureratemicrobsuccessMRSAeradvanco/aztlinzol

/aztCID2001,32:402抗菌药物临床应用98注意:耐药性◼抗菌机制:50S亚基中23SrRNAV区结合◼耐药机制:23SrRNAV区点突变,G2576T◼叠加性:5-6个23SrRNA基因逐

步变异◼交叉耐药:氯霉素,链阳霉素,林可霉素◼Enterocccus,Staphylococcus◼临床菌株已有报道◼实验室筛选抗菌药物临床应用9923SrRNA点突变量与耐药关系细菌筛选次数MIC(lzd)23S变异状况rm

1rm2rm3rm4rm5T9911GGGGGT1887214GGTGGT1888228GGTGTT19003432GGTTT19104464GTTTTT201954128TTTTTT2019/50-5064TGTTTAAC2008,52(4)

:1570-1572抗菌药物临床应用100抗菌药物临床应用101其他抗阳性菌药物◼Streptogramins◼Dapotomycin◼Ketolides◼Tigecycline◼Ceftibiprole◼Ceftaroline◼Sitafloxacin◼……

抗菌药物临床应用102大环内酯类(大环内酯类,氮内酯类,酮内酯,酰内酯)抗菌药物临床应用103macrolides12-memberedring14-memberedring15-memberedri

ng16-memberedringmethymycinNaturalerythromycinA,B,CetcSemisyntheticClarthromycinDirithromycinFlurithromycinRoxithro

mycinKetolidestelithromycincethromycinAzithromycinSpiramycin大环内酯类分类抗菌药物临床应用104Pharmacokineticparametersofnewmacrolide

sDrugdosage（mg）Cmax(mg/L)Tmax(h)T1/2β(h)erythromycin5001.782.71.7Roxithromycin30010.820.93-1.311.9Azathromycin5000

.4-0.452.5-2.635-48Clarthromycin4002.141.74.73Dirothromycin5000.29432.5-44flurothromycin5000.2-21-28抗菌药物临床应用105新大环内酯类特性◼对胃酸更

稳定，生物利用度高:罗红霉素，克拉霉素;◼半衰期长:阿奇霉素,地红霉素,罗红霉素;◼组织浓度高:阿奇霉素前列腺浓度为血清浓度10倍;◼抗菌谱扩大，覆盖G+/G-球菌,嗜血杆菌，厌氧菌，部分G-杆菌，非细菌微生物;◼PAE长，约4小时;◼其

他效应：anti-biofilms;◼不良反应少。抗菌药物临床应用106谢谢抗菌药物临床应用107