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首页 抗真菌药物PKPD

抗真菌药物PKPD.ppt

抗真菌药物PKPD

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2019-04-14 0人阅读 举报 0 0 0 暂无简介

简介:本文档为《抗真菌药物PKPDppt》,可适用于医药卫生领域

抗真菌药物PKPD研究进展刘学东青岛市市立医院呼吸科CAP肺炎链球菌支原体*InvasivefungalinfectionsIncidenceSolidorgantransplant:Bonemarrowtransplant:ICU:SinghNClinInfectDis:VincentJLIntensCareMed:CandidemiandashMortalityrateEdmondetalCID:Hospitalacquiredpathogensandtheirassociatedmortality*抗真菌药的研发、上市Year泊沙康唑(posaconazole)是伊曲康唑的衍生物于年上市的第二代三唑类抗真菌药物。抗菌谱广对于念珠菌属、荚膜组织胞浆菌、塞多孢子菌、双极菌接合菌、镰刀菌、酵母菌。包括耐氟康唑的非白色念珠菌株、新型隐球菌和曲霉菌都有强大的抑制活性尤其是对比较罕见、但威胁生命的真菌疾病(接合菌病、镰刀菌病和球孢子菌病等)也有效。本品适用于多种对两性霉素不能耐受或难治性成人侵袭性真菌感染的治疗对高危患者预防用药用于岁以上、免疫功能低下的患者特别是患有移植物抗宿主病(graftversushostdiseaseGVHD)的造血干细胞移植者、白血病患者和由于化疗而长期白细胞减少的患者。本品比对照药物氟康唑和伊曲康唑能更有效预防侵袭性曲霉菌感染并可降低侵袭性真菌感染相关的病死率。两性霉素B本品是从链霉菌(Streptomycesnodosus)的培养液中分离而得的一类多烯类抗真菌药。两性霉素B为多烯类抗真菌抗生素通过影响细胞膜通透性发挥抑制真菌生长的作用。临床上用于治疗严重的深部真菌引起的内脏或全身感染。该品可与敏感真菌细胞膜上的甾醇结合损伤膜的通透性导致细胞内重要物质如钾离子、核苷酸和氨基酸等外漏从而破坏了细胞的正常代谢而抑制其生长。通常临床治疗所达到的药物浓度对真菌为抑菌作用如药物浓度达到人体可耐受范围的高限时则对真菌起杀菌作用。醋酸卡泊芬净是一种由GlareaLozoyensis发酵产物合成而来的半合成脂肽(echinocandin)化合物。醋酸卡泊芬净能仰制许多丝状真菌和酵母菌细胞壁的一种基本成份beta()D葡聚糖的合成。哺乳类动物的细胞中不存在P(,)D葡聚糖。真菌的分类特点类酵母菌培养时为菌丝致病时为孢子也有菌丝在组织内菌丝为主培养基上产生类似葡萄球菌的菌落:念珠菌属的白念、热带、克柔等。酵母菌mdash单细胞真菌呈圆形或卵圆形:隐球菌属的新型隐球菌。霉菌产生分枝丝状菌丝:包括曲菌、毛霉菌。双相真菌:一定条件下呈酵母菌相一定条件下呈霉菌相(长毛):组织胞浆菌、球孢子菌、类球孢子菌、皮炎芽生菌等。药物在人体中的吸收、分布、代谢和清除的过程是药物作用与抗菌效果以及体外药代动力学参数与杀菌效果的关系药物在体内发挥的作用涉及药物的浓度与药理作用、毒副反应之间的关系血浆浓度时间曲线中的曲线下面积血浆中药物的峰浓度药物的半衰期MIC药效动力学(AUC)Cmax药代动力学和药效动力学(PKPD)及其参数TMIC药物血浆浓度高于MIC的时间比例杀菌效应作用的时间病原菌的清除率耐药菌的发生率药代动力学药代动力学和药效动力学(PKPD)最佳治疗方案最佳疗效减少耐药最低毒性PK微生物学PDWhatarethetargetsforantifungaltherapyCellmembraneFungiuseprincipallyergosterolinsteadofcholesterolCellWallUnlikemammaliancells,fungihaveacellwallDNASynthesisSomecompoundsmaybeselectivelyactivatedbyfungi,arrestingDNAsynthesisAtlasoffungalInfections,RichardDiamondEdIntroductiontoMedicalMycologyMerckandCo*TherearekeydifferencesbetweenmammalianandfungaleukaryoticcellsThisisthebasisofdrugselectivityCellMembraneActiveAntifungalsCellmembranebullPolyeneantibiotics多烯类AmphotericinB,lipidformulationsNystatin(topical)bullAzoleantifungalsKetoconazoleItraconazoleFluconazoleVoriconazoleMiconazole,clotrimazole(andothertopicals)*AboveareantifungalswhichtargetthecellmembraneFirstofallwewilllookattheazolefamilyThesedrugsarefarlesstoxicthanamphotericinBEffectofazolesonCalbicansBeforeexposureAfterexposure*ThiselectronmicrographshowsthefungistaticeffectoftheazolesThereisreducedbuddingfromtheparentcells氟康唑作用靶点:真菌细胞膜上的alpha固醇去甲基酶DoddsAshleyES,etalClinInfectDis:S氟康唑通过特异性抑制真菌细胞膜上的alpha固醇去甲基酶的活性来减少真菌细胞膜麦角固醇的合成TriazolesactascytochromePalphademethylaseinhibitorsThisenzymeisinvolvedintheconversionoflanosteroltoergosterolwhichishelpfulinthecellwallsynthesisInthismechanismthebasicnitrogenoftheazoleringistightlyboundtothehemeironofthefungalcytochromePpreventingsubstrateandoxygenbindingInhibitionofthealphademethylaseresultsinaccumulationofsterolsandcausespermeabilitychangeandmalfunctionofmembraneproteins注:PAE抗生素后效应T半衰期AUC药时曲线下面积MIC最低抑菌浓度Cmax峰浓度各类抗真菌药物药代动力学比较AmB两性霉素BLAB脂质体两性霉素BAUC浓度曲线下面积Cmax药物峰浓度ES空腹NA无可用数据ND无数据NE无影响Unk未知a口服液bmgdc人体d动物e活性药物或代谢物百分比。DoddsAshleyES,etalClinInfectDis(suppl):S不同抗真菌药物在不同的部位组织浓度不同汪复《实用抗感染治疗学》第版年制《药理学》教材第版*ThetimetakenforpeakserumconcentrationstobereachedishrsThisisdeterminedbyseveralfactorsincluding:disintegrationdissolutionrate(favouredbyacidicpH)GastricemptyingrateIntestinaltransittimeIntestinalmetabolism(CYPAinintestinalwall)RateofabsorptionfromtheintestineFirstPasseffect(metabolisminliver)ClearancerateFooddelaysabsorption,butdoesnotdecreasepeakserumconcentrationssignificantly对抗真菌药物PKPD的影响因素抗真菌药物的肾清除率增加:烧伤高的血液动力学使用了血液动力学活性的药物药物滥用MartaUlldemolinsetalCHEST:ndashTulienTextoris,etalEuiJAnaesthesiol:器官功能衰竭对抗菌药物PK参数的影响多器官功能衰竭对抗菌药物PK的影响胃肠道功能衰竭组织灌注不足肝功能衰竭肾功能衰竭药物吸收减少药物组织浓度下降减少高蛋白结合药物的结合率减少亲脂性药物的新陈代谢减少亲水性药物的清除率给药剂量不足需增加给药剂量药物蓄积需减少给药剂量UlldemolinsMetalChest依据PKPD的抗真菌药物分类AndesDAntimicrobAgentsChemother:介于浓度依赖和时间依赖之间氟康唑按照PKPD分类介于浓度依赖和时间依赖之间Fluconazoleexhibitstimedependent,concentrationindependentfungistaticactivityagainstCandidaExperimentalstudiesinanimalsandclinicalstudieswithfluconazoleinthetreatmentofmucosalandinvasivecandidiasissuggestthatachievingaserumfreedrugAUC:MICratioofgreaterthanistheparametermostcloselylinkedtosuccessfultreatmentCurrentConceptsinAntifungalPharmacologyPDinvestigationsoffluconazoleandCandidahavebeenundertaken,andbothinvitroandinvivomodelshavedemonstratedacorrelationbetweendrugdose,organismMIC,andoutcomeFluconazoleexhibitstimedependent,concentrationindependentfungistaticactivityagainstCandidaThisconcentrationindependentactivity,coupledwithaprolongedinvivopostantifungaleffect,increasestheimportanceofthetotalamountofdrugadministeredTheareaundertheserumconcentrationcurve(AUC)representsthetotalamountofdrugexposure,andtheAUCMICratioisthepredictivePDparameterInvivofluconazoledoserangingstudieswithCalbicansstrainsforwhichtheMICsvariedfoldfoundthatanAUCMICmagnitudenearpredictedefficacySubsequentstudieshaveincludedCalbicansstrainsforwhichMICscoveredarangeofmorethanfoldandhaveconfirmedtreatmentsuccesswithafluconazoleAUCMICrationear念珠菌药敏试验FIG(A)AmgfluconazolediskonalawnofCFUofCalbicansafterhofincubation(B)AmgfluconazolediskonalawnofCFUofCalbicansafterhofincubationInhibitoryzonediametersweremeasuredatthetransitionalpointwheregrowthabruptlydecreased(interioredgesofbars),asdeterminedbyamarkedreductionincolonysizesFluconazoleDiskDiffusionSusceptibilityTestingofCandidaSpecies念珠菌药敏试验FIGFluconazole(FL)EtestreadingpatternsforCalbicans(A)Growthofmicrocoloniesinsidetheentireinhibitionzone(ellipse)MIC,mgml(B)ClearellipseonCasitoneagarMIC,mgmlThenumbersonthescalecorrespondtothefluconazoleconcentrationsonthestrip(inmicrogramspermilliliter)FIGFluconazole(FL)EtestreadingpatternsforCglabrataAresistantsubpopulationappearsasmacrocolonieswithintheellipseonCasitoneagarMIC,mgmlThenumbersonthescalecorrespondtofluconazoleconcentrationsonthestrip(inmicrogramspermilliliter)EvaluationoftheEtestMethodforDeterminingFluconazoleSusceptibilitiesofClinicalYeastIsolatesbyUsingThreeDifferentAgarMedia念珠菌药敏试验EtestresultsofaCandidaalbicansclinicalisolatetestedagainstamphotericinB,fluconazole,itraconazole,posaconazole,andvoriconazoleNotethelawnofmicrocoloniesinsidetheellipsesoftriazolestripsaccordingtotheendpointrulerecommendedbythemanufacturer,theminimuminhibitoryconcentrationforvoriconazoleshouldbemgL,iethefirstchangeingrowth(blackarrow)念珠菌药敏结果RexJH,etalClinInfectDisOct():抑菌环直径(mm)MIC(ugml)敏感(S)gele剂量依赖敏感(SDD)耐药(R)lege氟康唑AUC或剂量MIC越高患者死亡率越低例生存者中氟康唑AUChMIC生存者也较死亡者高plusmnvsplusmnp=氟康唑AUC或剂量MIC越高患者死亡率越低例生存者中氟康唑剂量MIC显著高于例死亡患者(plusmnvsplusmnp=)fordosewnMICratiosbetweenand,toforratiosbetweenand,forratiosbetweenand,andforratiosaboveFluconazoledosewnMICratiowassignificantlyhigherforsurvivors(range,to)comparedtononsurvivors(range,to),controllingfortimetoinitiationoffluconazole(P=)MortalityratesdeclinedsignificantlywithincreasedfluconazoledosewnMICratios(P=)fromfordosewnMICratiosbetweenand,toforratiosbetweenand,forratiosbetweenand,andforratiosabove氟康唑AUC或剂量MIC越高患者死亡率越低年氟康唑对例患者分离念珠菌的体外敏感性研究并评估AUCMIC及剂量MIC与患者死亡率的关系。氟康唑AUChMIC越高患者死亡率越低折点为p=氟康唑剂量hMIC越高患者死亡率越低折点为p=氟康唑剂量MICge时临床有效率可达以上氟康唑不同给药剂量MIC比值治疗粘膜侵袭性念珠菌病总体临床治愈率PfallerMAClinicalMicrobiologyReviews():三项侵入性念珠菌病的研究及一项粘膜感染的研究的汇总结果AnAUCndashMICratioof=usingtheClinicalandLaboratoryStandardsInstitute(CLSI)MICmethodor=usingtheEuropeanCommitteeonAntimicrobialandSusceptibilityTesting(EUCAST)MICmethodhasbeenreportedtomaximisetheefficacyofFLC,withimprovedclinicaloutcomesdemonstratedinvitro,invivoandinclinicalstudies*氟康唑日剂量MIC对指导临床合理用药具有重要意义RexJH,etalClinInfectDisOct():针对白色念珠菌药敏提示MIC为mgL时:敏感的念珠菌引起的菌血症需氟康唑X=mg天如针对光滑念珠菌药敏提示MIC为mgL时:剂量依赖型敏感的念珠菌引起的菌血症需氟康唑X=mg天抑菌环直径(mm)MIC(ugml)敏感(S)gele剂量依赖敏感(SDD)耐药(R)lege念珠菌耐药机制防突变浓度(mutantpreventionconcentration,MPC)突变选择窗(muantselectionwindow,MSW):以MPC为上界、MIC为下界的浓度范围当血清或组织液药物浓度低于MIC时治疗无效但也不会导致耐药突变体的选择性富集药物浓度高于MPC时细菌要生长须同时发生两次或两次以上耐药突变因而不仅治疗成功而且也很难出现耐药突变体的选择性富集药物浓度处于MSW内时即使临床有很高的治疗成功率但也很容易出现耐药突变体的选择性富集传统的超过MIC的药物推荐治疗剂量很可能使药物浓度落在MSW内导致耐药突变体的选择性富集目前大多数抗菌药物的药物浓度正好位于MSW内解释目前广泛而严重的抗菌药物耐药问题限制耐药发生的策略CurrentConceptsinAntifungalPharmacologyAdjustedCLSICBPsforFLUandCalbicans,Cparapsilosis,Ctropicalis(S,lemcgmlSDD,mcgmlR,gemcgml),andCglabrata(SDD,lemcgmlR,gemcgml)shouldbemoresensitivefordetectingemergingresistanceamongcommonCandidaspeciesandprovideconsistencywithEUCASTCBPsCLSI:ClinicalandLaboratoryStandardsInstituteEUCAST:EuropeanCommitteeonAntimicrobialSusceptibilityTestingCBPs:clinicalbreakpoints抑菌环直径(mm)MIC(ugml)敏感(S)gele剂量依赖敏感(SDD)耐药(R)legeS(mcgml)SDD(mcgml)R(mcgml)CalbicanslegeCparapsilosislegeCtropicalislegeCglabratalegeCurrentConceptsinAntifungalPharmacologyDrugResistUpdatDec():EpubNovForexample,isolateswithfluconazoleMICsoforgreaterwouldbedifficulttotreatwithastandarddosageofmgkgdaily(ie,mgdosewithanAUCofghperliter)becausetheAUC:MICfallsbelowatthisMICwiththestandarddosageTherefore,isolateswithfluconazoleMICsoftougmLarecategorizedasldquosusceptibledosedependentrdquoinsteadofldquointermediaterdquobecausetheymaystillbetreatableprovidedhigherdailydosagesoffluconazoleareused(ie,mgkgdailyorapproximatelymgd)isolateswithMICsgreaterthanugmLwouldrequirefluconazoledosagesofmgdorgreaterandthereforeareclassifiedasldquoresistantrdquoIDSA年念珠菌指南中氟康唑给药剂量治疗性应用:mg首剂mgqd:念珠菌血症、疑似念珠菌病的经验治疗、慢性播散性念珠菌病、骨髓炎、化脓性关节炎~mgqd:中枢神经系统感染、心包炎或心肌炎、植入起搏器等感染、化脓性血栓性静脉炎、眼内炎~mgqd:食道念珠菌病、膀胱炎、肾盂肾炎~mgqd:口咽部念珠菌病mgSD:外阴阴道念珠菌病PappasPG,ClinInfectDis:腎功能不全的病人氟康唑使用方法★單一劑量的治療無調整之需要★多劑量治療者在第一天及第二天應給予正常劑量隨後視CCr來調整每日劑量或給藥間隔調整方式為:★三小時的血液透析可降低血漿濃度定期進行血液透析的病人每次透析後給與一次建議劑量CCr(mlmin)劑量間隔每日劑量hrs正常劑量hrs或正常劑量的≦hrs或正常劑量的总结根据PKPD原理给药可增加疗效根据PKPD原理给药可减少耐药根据PKPD原理给药可增加安全性药代动力学和药效动力学(PKPD)最佳治疗方案最佳疗效减少耐药最低毒性PK微生物学PD谢谢*ThebiggestthingIhopewehavecommunicatedtodayisthatbiofilmsplayamajorroleinthepathologyofchronicwoundsTheslough,thatharmlesslittlebunnythatisfelttobeanuisance,isnotanuisancendashitistheproblemndashapainful,deadlyproblemAndthatisthebiofilmsurpriseThatthereisorganizedbacteriabiofilm,whichlookslikeaninnocuousslimeyetitcantotallydestroyourimmuneresponsemuchlikethisbunnydestroyedthewolfThesurpriseforwoundcarewastofindthattheenemyisbiofilm问题:四代喹诺酮类的特点为什么莫西沙星作为耳鼻喉科感染一线用药(鼻窦炎和上呼吸道感染)为什么用降阶梯治疗CAP肺炎链球菌支原体**泊沙康唑(posaconazole)是伊曲康唑的衍生物于年上市的第二代三唑类抗真菌药物。抗菌谱广对于念珠菌属、荚膜组织胞浆菌、塞多孢子菌、双极菌接合菌、镰刀菌、酵母菌。包括耐氟康唑的非白色念珠菌株、新型隐球菌和曲霉菌都有强大的抑制活性尤其是对比较罕见、但威胁生命的真菌疾病(接合菌病、镰刀菌病和球孢子菌病等)也有效。本品适用于多种对两性霉素不能耐受或难治性成人侵袭性真菌感染的治疗对高危患者预防用药用于岁以上、免疫功能低下的患者特别是患有移植物抗宿主病(graftversushostdiseaseGVHD)的造血干细胞移植者、白血病患者和由于化疗而长期白细胞减少的患者。本品比对照药物氟康唑和伊曲康唑能更有效预防侵袭性曲霉菌感染并可降低侵袭性真菌感染相关的病死率。两性霉素B本品是从链霉菌(Streptomycesnodosus)的培养液中分离而得的一类多烯类抗真菌药。两性霉素B为多烯类抗真菌抗生素通过影响细胞膜通透性发挥抑制真菌生长的作用。临床上用于治疗严重的深部真菌引起的内脏或全身感染。该品可与敏感真菌细胞膜上的甾醇结合损伤膜的通透性导致细胞内重要物质如钾离子、核苷酸和氨基酸等外漏从而破坏了细胞的正常代谢而抑制其生长。通常临床治疗所达到的药物浓度对真菌为抑菌作用如药物浓度达到人体可耐受范围的高限时则对真菌起杀菌作用。醋酸卡泊芬净是一种由GlareaLozoyensis发酵产物合成而来的半合成脂肽(echinocandin)化合物。醋酸卡泊芬净能仰制许多丝状真菌和酵母菌细胞壁的一种基本成份beta()D葡聚糖的合成。哺乳类动物的细胞中不存在P(,)D葡聚糖。*TherearekeydifferencesbetweenmammalianandfungaleukaryoticcellsThisisthebasisofdrugselectivity*AboveareantifungalswhichtargetthecellmembraneFirstofallwewilllookattheazolefamilyThesedrugsarefarlesstoxicthanamphotericinB*ThiselectronmicrographshowsthefungistaticeffectoftheazolesThereisreducedbuddingfromtheparentcellsTriazolesactascytochromePalphademethylaseinhibitorsThisenzymeisinvolvedintheconversionoflanosteroltoergosterolwhichishelpfulinthecellwallsynthesisInthismechanismthebasicnitrogenoftheazoleringistightlyboundtothehemeironofthefungalcytochromePpreventingsubstrateandoxygenbindingInhibitionofthealphademethylaseresultsinaccumulationofsterolsandcausespermeabilitychangeandmalfunctionofmembraneproteins*ThetimetakenforpeakserumconcentrationstobereachedishrsThisisdeterminedbyseveralfactorsincluding:disintegrationdissolutionrate(favouredbyacidicpH)GastricemptyingrateIntestinaltransittimeIntestinalmetabolism(CYPAinintestinalwall)RateofabsorptionfromtheintestineFirstPasseffect(metabolisminliver)ClearancerateFooddelaysabsorption,butdoesnotdecreasepeakserumconcentrationssignificantlyCurrentConceptsinAntifungalPharmacologyPDinvestigationsoffluconazoleandCandidahavebeenundertaken,andbothinvitroandinvivomodelshavedemonstratedacorrelationbetweendrugdose,organismMIC,andoutcomeFluconazoleexhibitstimedependent,concentrationindependentfungistaticactivityagainstCandidaThisconcentrationindependentactivity,coupledwithaprolongedinvivopostantifungaleffect,increasestheimportanceofthetotalamountofdrugadministeredTheareaundertheserumconcentrationcurve(AUC)representsthetotalamountofdrugexposure,andtheAUCMICratioisthepredictivePDparameterInvivofluconazoledoserangingstudieswithCalbicansstrainsforwhichtheMICsvariedfoldfoundthatanAUCMICmagnitudenearpredictedefficacySubsequentstudieshaveincludedCalbicansstrainsforwhichMICscoveredarangeofmorethanfoldandhaveconfirmedtreatmentsuccesswithafluconazoleAUCMICrationearFluconazoleDiskDiffusionSusceptibilityTestingofCandidaSpeciesEvaluationoftheEtestMethodforDeterminingFluconazoleSusceptibilitiesofClinicalYeastIsolatesbyUsingThreeDifferentAgarMediaFluconazoledosewnMICratiowassignificantlyhigherforsurvivors(range,to)comparedtononsurvivors(range,to),controllingfortimetoinitiationoffluconazole(P=)MortalityratesdeclinedsignificantlywithincreasedfluconazoledosewnMICratios(P=)fromfordosewnMICratiosbetweenand,toforratiosbetweenand,forratiosbetweenand,andforratiosaboveAnAUCndashMICratioof=usingtheClinicalandLaboratoryStandardsInstitute(CLSI)MICmethodor=usingtheEuropeanCommitteeonAntimicrobialandSusceptibilityTesting(EUCAST)MICmethodhasbeenreportedtomaximisetheefficacyofFLC,withimprovedclinicaloutcomesdemonstratedinvitro,invivoandinclinicalstudies*当血清或组织液药物浓度低于MIC时治疗无效但也不会导致耐药突变体的选择性富集药物浓度高于MPC时细菌要生长须同时发生两次或两次以上耐药突变因而不仅治疗成功而且也很难出现耐药突变体的选择性富集药物浓度处于MSW内时即使临床有很高的治疗成功率但也很容易出现耐药突变体的选择性富集传统的超过MIC的药物推荐治疗剂量很可能使药物浓度落在MSW内导致耐药突变体的选择性富集目前大多数抗菌药物的药物浓度正好位于MSW内解释目前广泛而严重的抗菌药物耐药问题CurrentConceptsinAntifungalPharmacologyDrugResistUpdatDec():EpubNovForexample,isolateswithfluconazoleMICsoforgreaterwouldbedifficulttotreatwithastandarddosageofmgkgdaily(ie,mgdosewithanAUCofghperliter)becausetheAUC:MICfallsbelowatthisMICwiththestandarddosageTherefore,isolateswithfluconazoleMICsoftougmLarecategorizedasldquosusceptibledosedependentrdquoinsteadofldquointermediaterdquobecausetheymaystillbetreatableprovidedhigherdailydosagesoffluconazoleareused(ie,mgkgdailyorapproximatelymgd)isolateswithMICsgreaterthanugmLwouldrequirefluconazoledosagesofmgdorgreaterandthereforeareclassifiedasldquoresistantrdquo*ThebiggestthingIhopewehavecommunicatedtodayisthatbiofilmsplayamajorroleinthepathologyofchronicwoundsTheslough,thatharmlesslittlebunnythatisfelttobeanuisance,isnotanuisancendashitistheproblemndashapainful,deadlyproblemAndthatisthebiofilmsurpriseThatthereisorganizedbacteriabiofilm,whichlookslikeaninnocuousslimeyetitcantotallydestroyourimmuneresponsemuchlikethisbunnydestroyedthewolfThesurpriseforwoundcarewastofindthattheenemyisbiofilm问题:四代喹诺酮类的特点为什么莫西沙星作为耳鼻喉科感染一线用药(鼻窦炎和上呼吸道感染)为什么用降阶梯治疗

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