多重耐药菌感染的治疗.

多重耐药菌感染的治疗李光辉复旦大学华山医院抗生素研究所[e-mail]定义无公认的定义对现行之标准治疗产生耐药之细菌第三代头孢菌素耐药肠杆菌科细菌青霉素耐药肺炎链球菌碳青霉烯类耐药铜绿假单胞菌碳青霉烯类耐药不动杆菌VREMRSA,VISA,VRSA---------------革兰阳性菌PRSP青霉素耐药肺炎链球菌MDRSP多重耐药肺炎链球菌MRSA甲氧西林耐药金葡菌VISA万古霉素中介金葡菌VRSA万古霉素耐药金葡菌VRE万古霉素耐药肠球菌PRSP青霉素0.1MIC2.0mg/L头孢噻肟/头孢曲松大剂量青霉素或氨苄西林用于非脑膜感染泰利霉素评注亚胺培南、厄他培南、头孢吡肟、头孢泊肟、头孢呋辛亦具活性美罗培南作用不及亚胺培南吉米沙星、莫西沙星、左氧氟沙星具良好作用PRSP青霉素MIC4.0mg/L万古霉素利福平非脑膜感染头孢噻肟/头孢曲松大剂量氨苄西林亚胺培南、厄他培南FQ(吉米沙星、莫西沙星、左氧氟沙星)MDRSPMDRSP:对青霉素、红霉素、四环素、氯霉素、SMZ-TMP耐药万古霉素利福平吉米沙星、左氧氟沙星、莫西沙星泰利霉素用于非脑膜感染泰利霉素(Ketek®)酮内酯类(结构与大环内酯类相关)抗菌谱A、B、C和G组链球菌，肺炎链球菌（包括MDRSP）,MSSA李斯特菌、脑膜炎球菌、卡他莫拉菌、流感嗜血杆菌军团菌、支原体、衣原体对MRSA,VRE,及肠道革兰阴性菌无活性适应证轻、中度社区获得性肺炎MRSA感染的治疗MRSA首选：万古霉素、去甲万古霉素可选药物：替考拉宁、利奈唑胺、达托霉素、替加环素或Q/D、dalbavancin、SMZ-TMP（依据药敏）、多西环素及米诺环素（部分菌株）夫西地酸、磷霉素、利福平可能有效，但必须联合用药以防耐药性发生万古霉素耐药性1997日本首次报道VISA2002年美国首次报道VRSAMMWRJuly20021st例–Michigan导管及糖尿病溃疡培养2nd例–PennsylvaniaTenoveretal2004足根溃疡先前无万古霉素暴露Whiteneretal2004VISA和VRSA利奈唑胺(Zyvox®)Q/D(Synercid®)达托霉素(Cubicin®)替加环素(Tygacil®)Dalbavancin(Zeven®)USA：临床已发现9株VRSA，通常对SMZ-TMP、氯霉素、利奈唑胺、米诺环素、利福平、AG、Q/D仍然敏感利奈唑胺(Zyvox®)噁唑烷酮类抗菌谱及适应证VRE感染，包括合并菌血症MSSA、MRSA或肺炎链球菌（包括MDRSP）所致HAPMSSA、或MRSA、化脓性链球菌、或无乳链球菌所致复杂性SSTI，包括糖尿病足感染伴或不伴骨髓炎MSSA、或化脓性链球菌所致单纯性SSTI肺炎链球菌（包括MDRSP）或MSSA所致CAP，包括合并菌血症Meta-analysesoftreatmentsuccessforclinicallyassessedpatientswithSSTIMeta-analysesoftreatmentsuccessforclinicallyassessedpatientswithbacteraemia,Meta-analysesoftreatmentsuccessforclinicallyassessedpatientswithpneumonia奎奴普丁/达福普汀(Synercid®)链阳性菌素类，为Q-D30:70的复合剂Q-D与细菌核糖体50s亚基不可逆地结合，阻断蛋白质合成抗菌谱VREPRSPMRSA、MRCNS粪肠球菌耐药适应证菌血症-万古霉素耐药屎肠球菌金葡菌和化脓性链球菌所致cSSTI奎奴普丁／达福普汀疗效Design:2randomized,open-label,controlledclinicaltrialsincSSSIStudy1:Q/D(7.5mg/kgq12hIV)vsoxacillin(2gq6hIV)*Study2:Q/D(7.5mg/kgq12hIV)vscefazolin(1gq8hIV)*Q/D(n=450)Comparator(n=443)Study1(US)49.5%51.9%Study2(International)66.4%64.2%Postoperativeinfections‡14/38(36.8%)24/42(57.1%)Traumaticwoundinfections‡33/55(60.0%)33/55(60.0%)*vancomycin1gq12hIVcouldbesubstitutedifthepathogenwassuspectedorconfirmedMRSAorthepatientwasallergictopenicillin,cephalosporins,orcarbapenems.†Patientscuredorimproved.‡Resultsarecombinedfromthe2clinicaltrials.Statisticalconclusionscouldnotbereachedduetothesmallnumberofpatientsinthesubsets.CE=clinicallyevaluable;cSSSI=complicatedSSSI.EfficacyintheCEPopulation†Synercid®IV(quinupristin/dalfopristinforinjection)[packageinsert].Bristol,Tenn:MonarchPharmaceuticals,Inc;2002.奎奴普丁／达福普汀疗效Design:2randomized,open-label,controlledclinicaltrialsincSSSISummaryofClinicalandMicrobiologicResults*Q/D(n=450)Comparator(n=443)Clinicalefficacy†68.2%70.7%Microbiologiceradication‡66.6%77.7%MSSA64.3%76.6%MRSA77.8%50.0%Gram-positivecoccionly56.3%69.7%*Resultsarecombinedfromthe2clinicaltrials.†PatientscuredorimprovedintheCEpopulation.‡Overallandby-pathogenbacteriologiceradicationratesinthemicrobiologicallyevaluablepopulation.NicholsRLetal.JAntimicrobChemother.1999;44:263-273.达托霉素(Cubicin®)环脂肽类（Cycliclipopeptide）抗菌谱MSSA,MRSA,化脓性链球菌,无乳链球菌,Streptococcusdysgalactiaesubsp.equisimilis,and粪肠球菌(万古霉素敏感株)批准(IV,4mg/kgq24h)用于敏感GPB所致CSSTI金葡菌血流感染，包括右侧心内膜炎(MSSA或MRSA)(自身瓣膜)达托霉素临床试验cSSTI可评价患者902例对照药：耐酶青霉素或万古霉素~10%MRSA~12%为糖尿病足临床有效率达托霉素81.1%达托霉素87.3%万古霉素73.8%耐酶青霉素90.5%CPK–达托霉素组11例,对照组8例达托霉素组2例中停Arbietetal2004替加环素(Tygacil®)甘氨酰环素米诺环素的衍生物广谱抗菌药覆盖大多数耐药GPB、GNB和厌氧菌对假单胞菌属无活性体外、体内对MSSA,MRSA,和VISA均具活性替加环素(Tygacil®)适应证复杂性皮肤软组织感染大肠埃希菌粪肠球菌(万古霉素敏感株)金葡菌(甲氧西林敏感或耐药)无乳链球菌咽峡炎链球菌.化脓性链球菌脆弱拟杆菌复杂性腹腔感染弗氏柠檬酸杆菌阴沟肠杆菌大肠埃希菌克雷伯菌属粪肠球菌(万古霉素敏感株)金葡菌(甲氧西林敏感或耐药)咽峡炎链球菌.脆弱拟杆菌产气荚膜杆菌消化链球菌替加环素(Tygacil)III期临床试验替加环素vs.万古霉素/氨曲南治疗CSSTI可评价患者833例临床有效率:替加环素86.5%，对照药88.6%替加环素组胃肠道反应发生率高恶心34.5%v8.2%呕吐19.6%v3.6%Ellis-Grosseetal.CIDSept1,2005Dalbavancin(Zeven®)第二代糖肽类第一代:万古霉素,替考拉宁抗菌谱葡萄球菌、链球菌梭菌属、消化链球菌、放线菌、棒状杆菌、枯草杆菌对绝大部分GNB无作用对VanA耐药肠球菌无作用治疗地位目前III期临床试验用于治疗耐药革兰阳性菌感染Dalbavancin(Zeven)新一代糖肽类每周一次，静脉给药Dalbavancinvs利奈唑胺治疗CSSSIDalba首剂1gm，7日后再用500mg利奈唑胺600mgq12hIV或po×14d两组疗效均90%Jauregui,CIDNov15,2005ClinicalEfficacyofWeeklyDalbavancinvsStandard-of-CareAntimicrobialsforSSSIs90.590.594.194.176.28176.2810102030405060708090100EOT-ITTFU-ITTEOT-EvalFU-EvalSuccessRatesDalbavancinStandardofCareStandard-of-careantibioticsincludedcefazolin,vancomycin,clindamycin,ceftriaxone,andpiperacillin/tazobactam.SeltzerEetal.ClinInfectDis.2003;37:1298-1303.Dalbavancin(Zeven)与万古霉素比较??治疗GPC所致导管相关性BSI临床有效率:Dalbavancin=87%万古霉素=50%Raadetal,CIDFeb2005Telavancin新一代糖肽类治疗CSSSI细菌清除率:Telavancin=92%万古霉素=68%Stryjewskietal,AACMar2006Telavancin新一代糖肽类对GPC呈浓度依赖性快速杀菌作用MRSA,MRSE,VRE,VISA,VRSA随即对照双盲III期临床试验(n=167)TelavancinQDvs耐酶青霉素QID或万古霉素BIDStryjewskiMEetal.ClinInfectDis.2005;40:1601-1607.nTelavancinComparator*Saureus10280%77%MRSA–clincure4882%69%MRSA–microcure4884%74%Oritavancin新一代糖肽类作用机制同万古霉素对GPC呈浓度依赖性杀菌作用MRSA,MRSE,VRE消除半衰期132-356hrs临床试验QD给药，但Qweek更好2项治疗cSSSIs临床试验疗效良好GuayDR.Pharmacotherapy.2004;24:58-68.Ceftobiprole四代后头孢菌素对MRSA具有活性对GNB活性与3/4GCs相仿适应证：2008,3,19FDA批准复杂性皮肤软组织感染90.590.281.980.8020406080100TOCITTCeftobiproleVan/caz临床有效率％ceftarolinef