耐药GNB感染抗菌治疗课件

耐药革兰阴性菌感染的抗菌治疗

耐药革兰阴性菌感染的抗菌治疗 2Gram-negativebacilliaccountforover70%ofallclinicalisolatesinChinaGram-negativebacilli70％（62297/88778）Gram-positivecocci30％（26481/88778）CHINET2015PercentageofGram-negativebacilliintotalclinicalisolates(%)CHINETnationalbacterialresistancesurveillancedata2Gram-negativebacilliaccount革兰阴性菌的构成CHINET2007-2014革兰阴性菌的构成CHINET2007-201444ConstituentratioofA.baumannii,P.aeruginosaandK.pneumoniaeamongallclinicalisolatesinChinasince2005CHINETnationalbacterialresistancesurveillancedata%HuFP,ClinMicrobiolInfect2016;22:S9–S14P.aeruginosaK.pneumoniaeA.baumannii44ConstituentratioofA.baum55Corelationofincreasingtrendsofimipenem-resistancewith

constituentratioofK.pneumoniaeclinicalisolatesinChinasince2005Ratio%ModifiedfromHuFP,ClinMicrobiolInfect2016;22:S9–S14Imipenem-resistancerateConstituentratioCR%CHINETDATA55Corelationofincreasingtre66Corelationofincreasingtrendsofimipenem-resistancewith

constituentratioofA.baumannii

clinicalisolatesinChinasince2005Ratio%ModifiedfromHuFP,ClinMicrobiolInfect2016;22:S9–S14Imipenem-resistancerateConstituentratioCR%CHINETDATA66Corelationofincreasingtre77Corelationofincreasingtrendsofimipenem-resistancewith

constituentratioofP.aeruginosa

clinicalisolatesinChinasince2005Ratio%ModifiedfromHuFP,ClinMicrobiolInfect2016;22:S9–S14Imipenem-resistancerateConstituentratioCR%CHINETDATA77Corelationofincreasingtre8AreportofbacterialresistanceinChina2005~2014Antimicrobialresistanceinfivemostcommonbacteria:

E.coli,

K.pneumoniae,A.baumannii,P.aeruginosaandS.aureusHuFP,ClinMicrobiolInfect2016;22:S9–S148AreportofbacterialresistaMDR--Multiple-drugresistant,多重耐药：对3类或以上在抗菌谱范围内的抗菌药耐药XDR--Extensivelydrugresistant,广泛耐药：除1-2个抗菌药敏感外，均耐药PDR--Pan-drugresistant，全（泛）耐药：对当前临床应用的所有抗菌药耐药9MDR、XDR、PDR的定义主题词MagiorakosAP,ClinMicrobiolInfect2012,18:268MDR--Multiple-drugresistant,OUTLINE肠杆菌科细菌老问题：产ESBL新问题：产碳青霉烯酶非发酵糖细菌习惯了的问题：XDR鲍曼不动杆菌变化不大的问题：铜绿假单胞菌嗜麦芽窄食单胞菌OUTLINE肠杆菌科细菌肠杆菌科细菌耐药问题：

最需关注的β-内酰胺酶是ESBLs•超广谱β-内酰胺酶(ESBLs)•高产头孢菌素酶(AmpC酶)•产碳青霉烯酶（KPC、NDM-1等）

MDRXDR

orPDR肠杆菌科细菌耐药问题：•超广谱β-内酰胺酶(ESBLs) MPrevalenceofESBLinEnterobacteracae

肠杆菌科细菌ESBL检出率CHINETDataPrevalenceofESBLinEnteroba产与非产ESBLs大肠埃希菌的耐药率（%）ComparisonofantimicrobialresistancebetweenESBL+andESBL-isolates抗菌药物耐药率抗菌药物耐药率产ESBL(9210株)非产ESBL(7301株)产ESBL(9210株)非产ESBL(7301株)阿米卡星5.42.1头孢哌酮/舒巴坦7.42.8庆大霉素54.336.7头孢西丁16.110.2哌拉西林94.841.4亚胺培南0.61.3哌拉西林/他唑巴坦3.63.2美罗培南0.61.3头孢唑林99.127.9厄他培南1.01.5头孢呋辛98.016.5环丙沙星71.442.7头孢噻肟98.514.0复方磺胺甲噁唑67.448.3头孢他啶44.58.6磷霉素10.43.5头孢吡肟44.57.2呋喃妥因6.74.1替加环素0.60.4CHINET2014胡付品,中国感染与化疗杂志2015;15(5):401产与非产ESBLs大肠埃希菌的耐药率（%）抗菌药物耐药率抗菌产与非产ESBLs克雷伯菌属的耐药率（%）抗菌药物耐药率抗菌药物耐药率产ESBL(3369株)非产ESBL(7895株)产ESBL(3369株)非产ESBL(7895株)阿米卡星13.17.2头孢哌酮/舒巴坦24.212.4庆大霉素53.811.9头孢西丁22.78.3哌拉西林94.824.2亚胺培南11.510哌拉西林/他唑巴坦19.311.6美罗培南14.013.1头孢唑林97.928.5厄他培南9.811.3头孢呋辛96.622.1环丙沙星40.114.6头孢噻肟97.721.3复方磺胺甲噁唑66.114.1头孢他啶56.216.2呋喃妥因50.731.5头孢吡肟48.211.5替加环素9.35.3CHINET2014产与非产ESBLs克雷伯菌属的耐药率（%）抗菌药物耐药率抗菌产ESBL菌株感染的抗菌药物选择

碳青霉烯类（亚胺培南、美罗培南、帕尼培南、厄他培南、比阿培南）：为最有效的药物，用于重症及/或有基础疾病感染患者酶抑制剂合剂：用于轻中度感染头霉素类：临床疗效不满意，用于腹腔、盆腔手术的预防用药阿米卡星、环丙沙星：多用于联合用药15产ESBL菌株感染的抗菌药物选择

碳青霉烯类（亚胺培南、美罗碳青霉烯类耐药肠杆菌科细菌CRE=carbapenam-resistantenterobacteriacaeCPE=carbapenamase-producingenterobacteriacae16主题词碳青霉烯类耐药肠杆菌科细菌CRE=carbapenam-re17Increasingtrendofcarbapenem-resistantKlebsiellaspp.

碳青霉烯类耐药克雷伯菌属（CRE）显著上升趋势CHINETData17Increasingtrendofcarbapen肠杆菌科细菌与鲍曼不动杆菌的比较鲍曼不动杆菌肠杆菌科细菌（肺炎克雷伯菌大肠埃希菌）检出率最为常见近年上升趋势毒力不强强病死率较低高耐药菌治疗药物少更少18肠杆菌科细菌与鲍曼不动杆菌的比较鲍曼不动杆菌肠杆菌科细菌检出XDR、PDR肠杆菌科细菌的抗菌治疗多黏菌素（国内无供应）替加环素（常需合用）磷霉素的联合治疗（多粘、替加、碳青霉烯、氨基糖苷）（头孢他啶、头孢吡肟）＋克拉维酸（对KPC有一定的抑制作用）？氨曲南＋阿米卡星？（产金属酶包括NDM-1部分菌株仍对此2药敏感）新抗菌药：头孢他啶/阿维巴坦19结论：治疗CRE尚无理想的抗菌药物XDR、PDR肠杆菌科细菌的抗菌治疗多黏菌素（国内无供应）120各治疗方案对产碳青霉烯酶肺炎克雷伯菌感染的失败率A,≥2种抗菌药联合，包括碳青霉烯类B,≥2种抗菌药联合，不包括碳青霉烯类

C,单用氨基糖苷类D,单用碳青霉烯类E,单用替加环素F,单用黏菌素G,无有效治疗药物ClinMicrobiolRev2012;

25:

6827单用粘菌素单用替加环素20各治疗方案对产碳青霉烯酶肺炎克雷伯菌感染的失败率A,≥21两药联合三药联合1.替加环素为基础的联合：替加环素+氨基糖苷类替加环素+碳青霉烯类替加环素+磷霉素替加环素+多粘菌素2.多粘菌素为基础的联合：多粘菌素+碳青霉烯类多粘菌素+磷霉素3.其他联合：磷霉素+氨基糖苷类（头孢他啶或头孢吡肟）+阿莫西林克拉维酸氨曲南+氨基糖苷类替加环素+多粘菌素+碳青霉烯类XDR肠杆菌科细菌感染的联合治疗方案ChineseXDRConsensusWorkingGroup.ClinMicrobiolInfect2016;22:S15–S2521两药联合三药联合1.替加环素为基础的联合：替加环素+22粘菌素异质性耐药和鲍曼不动杆菌耐药率全球报告JAntimicrobChemother2012;67:1607–1615异质性耐药率为19～100%耐药率为0～46%问题、异质性耐药22粘菌素异质性耐药和鲍曼不动杆菌耐药率全球报告JAnti23替加环素治疗MDR肺炎克雷伯和鲍曼不动杆菌感染的优缺点KollefM,CritCare2013;FreireADiagnMicrobiolInfectDis2010;PoulakouGJournalInfect2009;PournarasS.UAA2010;SouliMCID2010;WiskirchenDEAAC2011;BurkhardtO,IJAA2009;KoomanachaiPAAC2009;GiamarellouandPoulakouExpertOpinDrugMetabToxicol2011HirschandTamm2010.替加环素对革兰阴性菌为抑菌作用在血液、尿液和肺泡上皮衬液中的药物浓度较低对VAP的试验结果欠佳在体外与美罗培南和粘菌素有协同作用加大剂量可达到目标PK/PD替加环素联合给药在临床应用中得到满意疗效高剂量治疗HAP的Ⅱ期临床研究显示出满意疗效(-)(+)23替加环素治疗MDR肺炎克雷伯和鲍曼不动杆菌感染Kolle24碳青霉烯类不单用治疗MIC>4mg/L菌株的感染，≤4mg/L菌株尽量避免单用碳青霉烯类治疗CRE应注意以下几点：碳青霉烯类MIC≤8mg/L与其他抗菌药联合应用如多粘菌素、替加环素、氨基糖苷类大剂量、延长输注时间（3~4小时）Daikos&Markogiannakis.ClinMicrobiolInfect2011;17:1135.碳青霉烯类可用于CRE的治疗但是带“尾巴”24碳青霉烯类不单用治疗MIC>4mg/L菌株的感染，Da25产KPC肺克对磷霉素的敏感率高包括替加环素和/或粘菌素不敏感菌株*CLSI：≤64μg/ml定义为敏感EUCAST：≤32μg/ml定义为敏感EndimianiA,etal.AAC2010;54:526-9FalagasME,etal.IJAA2010;35:240国内，CR-Kp的敏感率40%~50%25产KPC肺克对磷霉素的敏感率高*CLSI：≤64μg新抗菌药：β内酰胺酶抑制剂

Avibactam(NXL104)对A类及C类β内酰胺酶具广谱抑制作用包括KPC碳氢酶烯酶Avibactam与头孢他啶的合剂对多重耐药肠杆菌科细菌包括产ESBL及丝氨酸碳氢霉烯酶KPC有效Avibactam与头孢他啶的合剂（Azycaz）美国FDA2015.2.25批准上市Avibactam与ceftaroline的合剂正在进行治疗复杂性尿路感染及复杂性腹腔感染的临床试验26新抗菌药：β内酰胺酶抑制剂

Avibactam(NXL10例、CRE血流感染男，45y头颈部、双侧上肢大面积烧伤继发感染：皮肤、肺部、血流三个部位细菌培养：XDR鲍曼不动杆菌药敏：替加环素S、多粘菌素S、阿米卡星S、头孢哌酮舒巴坦S，其他均耐药抗菌治疗：替加环素+头孢哌酮舒巴坦热退好转，1周后又出现发热27例、CRE血流感染男，45y27例、CRE血流感染血培养为碳青霉烯类耐药肺炎克雷伯菌，此前2天皮肤分泌物、痰培养同样细菌血肌酐值180umol/L药敏：多粘菌素S、阿米卡星S，其他均R问题：如何调整用药？多粘菌素28例、CRE血流感染血培养为碳青霉烯类耐药肺炎克雷伯菌，此前2例、CRE血流感染与哪个抗菌药联合？加做抗菌药MIC碳青霉烯类：美罗培南或亚胺培南磷霉素其他SMZco阿米卡星29例、CRE血流感染与哪个抗菌药联合？29OUTLINE肠杆菌科细菌老问题：产ESBL新问题：产碳青霉烯酶非发酵糖细菌习惯了的问题：XDR鲍曼不动杆菌变化不大的问题：铜绿假单胞菌嗜麦芽窄食单胞菌OUTLINE肠杆菌科细菌31Treadsofpercentagesof3principalnon-fermenterbacteriaamongnon-fermentersinShanghairegionDecreasingtrendforP.aeruginosaIncreasingtrendforAcinetobacterspp.RelativelystableforS.maltophiliaChangingtrendsofconstituentratioofP.aeruginosa,Acinetobacterspp.andS.maltophiliainGram-negativebacilliinShanghai

31Treadsofpercentagesof3p8769株不动杆菌属(鲍曼不动93.0%)的耐药率（%）ResistanceratestomostantimicrobialsinAcinetobacterspp.are>50%不动杆菌属对多数抗菌药的耐药率>50%CHINET20148769株不动杆菌属(鲍曼不动93.0%)的耐药率（%）Re不同耐药水平鲍曼不动杆菌的抗菌治疗非多重耐药菌感染敏感的β内酰胺类抗菌药根据药敏试验结果选用其他敏感抗菌药多重耐药菌感染碳青霉烯类舒巴坦或含舒巴坦合剂碳青霉烯类耐药菌感染多粘菌素与利福平等其他抗菌药合用对于有气管支气管炎或呼吸机相关性肺炎者，可用多粘菌素雾化吸入替加环素对于考虑由复数菌引起的复杂性腹腔感染及皮肤软组织感染，可作为首选药物WangMG33CurrOpinInfectDis2010;23:332不同耐药水平鲍曼不动杆菌的抗菌治疗非多重耐药菌感染WangMControversiesonthecombinationtherapyforXDRorPDRA.baumanniiinfectionsSupportNecessaryforcombination:TreatmentoptionsarelimitedPotentialadvantagesofcombination:improvedefficacyduetosynergyCombinationtherapyiscommonlyusedinclinicalpractice34OppositionLackoflargerandomizedclinicaltrialdata(evidence-baseddata)DisadvantagesofcombinationadverseeventspotentialdrivetowardsresistancePaulM,JAntimicrobChemother2014;69:2305–9Controversiesonthecombinati35XDR鲍曼不动杆菌感染的联合抗菌治疗方案两药联合三药联合1.舒巴坦或其合剂为基础的联合头孢哌酮舒巴坦+替加环素头孢哌酮舒巴坦+多西环素舒巴坦+碳青霉烯类2.替加环素为基础的联合：替加环素+碳青霉烯类替加环素+多粘菌素3.多粘菌素为基础的联合：多粘菌素+碳青霉烯类头孢哌酮舒巴坦+多西环素+碳青霉烯类头孢哌酮舒巴坦+替加环素+碳青霉烯类亚胺培南＋利福平＋多粘菌素或妥布霉素ChineseXDRConsensusWorkingGroup.ClinMicrobiolInfect2016;22:S15–S2535XDR鲍曼不动杆菌感染的联合抗菌治疗方案两药联合三药联合AntimicrobialtreatmentofXDRA.baumanniiatahospitalinShanghaiAntimicrobialtherapyof43ptswithXDRA.baumanniiwasretrospectivelyanalyzedConclusion:High-dosecefoperazone-sulbactamandcarbapenemaloneorcombinedwithotherantibioticscouldbeconsideredchoicesfortreatmentofXDRwhenotheroptionsarenotavailable.36LiY,JMicrobiolImmunolInfect2015;48,101-8AntimicrobialsEfficacyrate%Cefoperazone-sulbactam(n=8)Alone4,withAMK/ISP2,withDox/Mino262.5Carbapenem(n=19)Alone12,withDox/Mino6,withISP147.3Cefoperazone-sulbactam+carbapenem(n=7)Alone4,withDox/Mino342.9Noantimicrobialtreatment(n=7)

28.6AntimicrobialtreatmentofXDR美罗培南+头孢哌酮舒巴坦+米诺环素治疗PDR鲍曼不动杆菌重度烧伤感染9例，6M3F,38±11Y，均有吸入烧伤PDR鲍曼感染：9例首先出现肺部，6例皮肤（其中4例血流）抗菌药剂量：美罗培南6g/d头孢哌酮舒巴坦12g/d米诺环素0.2g/dPO疗效：全部有效37NingF,ChinJMed2014;127(6):1177美罗培南+头孢哌酮舒巴坦+米诺环素治疗PDR鲍曼不动杆菌重度Cefoperazone-sulbactam(CFP-SUL)andSulbactamRelativelylowresistancerateofCFP-SULinA.baumanniiTheresistancerateislowerthanampicillin-sulbactam:38%vs67%in2015(unpublishedCHINETdata)TheantimicrobialsusceptibilityofCFP-SULisroutinelytestedforgram-negativebacilliinChinaCFP-SULisavailableinseveralAsiancountriessuchasChina,Japan,Korea,ThailandandPhillipines.Sulbactamaloneavailablesince2014inChinaBreakpointsofCFP-SULused:S,≤16/8μg/ml;I,32/16μg/ml;R,≥64/32μg/ml(JonesRN,JCM1987)38CHINETnationalbacterialresistancesurveillancedataCFP-SULresistancerateinA.baumanniiR%Cefoperazone-sulbactam(CFP-SU3939A.baumannii

includingXDRisolateshavearelativelyhighsusceptibleratetominocyclineinChinaCHINETnationalbacterialresistancesurveillancedataR%HuFP,ClinMicrobiolInfect2016;22:S9–S14nS,≤4µg/mlMICdistributionofminocyclineagainst256XDRABCARSSnationalbacterialresistancesurveillancedataXuA,ClinMicrobiolInfect2016;22:S1-83939A.baumanniiincludingXDRTheuseofMinocyclineorDoxycyclineforAcinetobacterinfectionsMinocyclineisan“olddrug”thatwasfirstintroducedinthe1960s.ItisapprovedforthetreatmentofA.baumanniiinfectionsbyFDAoftheUS.InChina,Minocyclineisonlyavailablefororalformulation,buthasbothoralandintravenouspreparationsofDoxycycline.MinocyclinesusceptibilityisroutinelytestedforAcinetobacterIntravenousdoxycyclineisusedforXDRA.baumanniiinfections.

UsuallycombinedwithCFP-SUL,carbapenems,orwithbothofthem40GoffDA&KayeKS.ClinInfectDis2014;59:s365-6TheuseofMinocyclineorDoxyWhatisthedifferencebetweendoxycylineandminocycline?MIC50,µg/mlMIC90,µg/mlSusceptibility%Minocycline1879Doxycycline2>860Imipenem>8>837Ampicillin-sulbactam>16/4>16/42641CastanheiraM.ClinInfectDis2014;59:s367-73DoxycyclinemayhavelesscentralnervousadverseeffectofdizzinessA.baumanniiclinicalisolatesarehighlysusceptibletobothofthemMinocyclinehasbetteractivity(n=5478)Whatisthedifferencebetween4242

上海地区铜绿假单胞菌对抗菌药的耐药率相对稳定

ShanghaiSurveillancedata%4242

上海地区铜绿假单胞菌对抗菌药的耐药率相对稳定Sh4343%CHINETDATAPan-drugresistance(PDR)inP.aeruginosaandA.baumannii(colistinandtigecyclinenotincludedforAST)4343%CHINETDATAPan-drugresis铜绿假单胞菌感染的抗菌药物选择青霉素类：哌拉西林、美洛西林、阿洛西林头孢菌素类：头孢他啶、头孢哌酮、头孢吡肟酶抑制剂合剂：头孢哌酮-舒巴坦哌拉西林-他唑巴坦替卡西林-克拉维酸碳青霉烯类：亚胺培南、美罗培南、帕尼培南氟喹诺酮类：环丙沙星氨基糖苷类：阿米卡星、庆大霉素铜绿假单胞菌感染的抗菌药物选择青霉素类：哌拉西林、美铜绿假单胞菌感染治疗原则

剂量足highdosage疗程足longtreatmentcourse联合combinationβ-内酰胺药物+氨基糖苷类：协同，后者不良反应大β-内酰胺药物+环丙沙星：无协同，后者组织浓度高，抑制biofilm铜绿假单胞菌感染治疗原则

剂量足highdosageXDR铜绿假单胞菌感染的治疗方案推荐两药联合三药联合多粘菌素为基础的联合：

多黏菌素+抗PAβ内酰胺类

多粘菌素+环丙沙星

多粘菌素+磷霉素抗PAβ内酰胺类为基础的联合：

抗PAβ内酰胺类+氨基糖苷类

抗PAβ内酰胺类+环丙沙星

抗PAβ内酰胺类+磷霉素环丙沙星为基础的联合：

环丙沙星+抗PAβ内酰胺类

环丙沙星+氨基糖苷类双β内酰胺类联合：

头孢他啶+哌拉西林他唑巴坦

头孢他啶+头孢哌酮舒巴坦

氨曲南+头孢他啶

氨曲南+哌拉西林他唑巴坦多粘菌素+抗PAβ内酰胺类+环丙沙星多粘菌素+抗PAβ内酰胺类+磷霉素多粘菌素静滴+碳青霉烯类+多粘菌素雾化吸入ChineseXDRConsensusWorkingGroup.ClinMicrobiolInfect2016;22:S15–S25XDR铜绿假单胞菌感染的治疗方案推荐两