多重耐药感染

多重耐药菌感染前言－“超级细菌”2010年，英国媒体爆出：南亚发现新型超级病菌NDM-1，抗药性极强可全球蔓延2013年，以英国为发源地的超级细菌已经开始在多个国家被发现。据美国媒体报道，这种超级细菌被称为LA-MASA超级细菌，主要存在于禽类体内，感染率极高，但是对人体危害很小2016年5月26日，美国卫生官员报告，美国发现首例对所有已知抗生素有抵抗力的细菌感染病例，如果这种超级细菌传播，可能造成日常感染的严重危险前言－“超级细菌”MDR致病菌定义FalagasMEetal.ClinInfectDis

2008;41:848-54.无法逃避“ESKAPE”Enterococcus faeciumStaphylococcus aureusKlebsiella pneumoniaeAcinetobacter baumanniiPseudomonas aeruginosaEscherichia coli屎肠球菌金黄色葡萄球菌肺炎克雷伯菌鲍曼不动杆菌铜绿假单胞菌大肠埃希菌抗生素发展史世界性的难题－细菌耐药肠杆菌科细菌1大肠埃希菌（2013）大肠杆菌ESBL阳性率:

门诊：35.8%，住院：52.7%，ICU：74.1%肺炎克雷伯菌（2013）大肠杆菌ESBL阳性率:

门诊：15.3%，住院：24.9%，ICU：33.1%阴沟肠杆菌（2013）奇异变形杆菌（2013）产气肠杆菌（2013）高死亡率肺炎克雷伯菌48.3%(28/58)奇异变形杆菌41.7%(10/24)产ESBL肠杆菌血流感染患者21天死亡率高达38.2%不同肠杆菌血流感染患者21天死亡率：大肠埃希菌

31.7%

(33/104)TumbarelloMetal.AntimicrobAgentsChemother.2007;;

51(6):1987-­94.起始充分治疗起始未充分治疗患者的21天死亡率是起始充分治疗患者的3倍以上起始未充分治疗显著增加产ESBL肠杆菌血流感染患者21天死亡率，因此，针对此类患者应采用起始充分治疗TumbarelloMetal.AntimicrobAgentsChemother.2007;;

51(6):1987-­94.治疗分层严重感染的病人：碳青霉烯类轻中度的感染：可选择复合制剂（舒普深等），疗效不佳时可改碳青霉烯类头霉素也可应用，但耐药比国外严重环丙沙星85%左右耐药阿米卡星50%左右耐药肺炎克雷伯菌对碳青霉烯类的耐药率(CHINET

2005-2015)院内常见G-菌耐药率排名（CHINET2015）CLSI(Clinical

and

laboratory

Standards

Institute)

美国【临床实验室标准化协会】非发酵菌2糖发酵试验根据细菌对各种糖的分解能力及代谢产物不同，可以鉴别细菌发酵菌一般能发酵多种单糖，如大肠杆菌能分解葡萄糖和乳糖，产生甲酸等产物，并有甲酸解氢酶，可将其分解为CO2和H2，故生化反应结果为产酸产气，以“⊕”表示非发酵菌是指一群不能利用葡萄糖或仅能以氧化形式利用葡萄糖的革兰阴性杆菌非发酵菌大多数细菌为发酵菌非发酵菌（nonfermenters）是一类临床上耐药严重的革兰阴性杆菌假单胞菌科：假单胞菌属\窄食单胞菌属\不动杆菌属（铜绿假单胞菌、不动杆菌属、产碱杆菌、

伯克霍尔德菌、黄杆菌、嗜麦芽窄食单胞菌）绿脓杆菌（2013）抗菌谱图谱MDR铜绿假单胞菌肺炎的治疗对MDR铜绿假单胞菌肺炎的治疗，2005年ATS指南推荐联合治疗方案ATS/IDSA.AmJRespirCritCareMed.

2005;;171:388-­416.抗绿脓药+氨基糖苷类亚胺培南与阿米卡星联合，50%的菌株出现协同或部分协同作用亚胺培南与异帕米星联合，50%的菌株出现协同或部分协同作用对24株耐药铜绿假单胞菌(对受试药物均耐药)的体外研究，评估不同联合方案的部分抑菌浓度指数之和

(FICIs)，

FICIs=联合时甲药的MIC/甲药的MIC+联合时乙药的MIC/乙药的MICFICIs≤0.5协同作用；0.5<

FICIs≤1.0

部分协同作用；

1.0<

FICIs≤4.0

无关作用；

4.0<

FICIs

拮抗作用MIC50/90:亚胺培南

64/128mg/L;;阿米卡星64/512mg/L;;异帕米星32/1024mg/LSongWetal.InternationalJournalofAntimicrobialAgents.2003;;21:

8-­12住院鲍曼不动杆菌（2013）易在医院环境存活鲍曼不动杆菌为最常见的基因型，占90%以上，同时也是最常见的耐药基因型不动杆菌属中90%以上为鲍曼不动杆菌鲍曼不动杆菌鲍曼不动杆菌营养需求简单，能在不同温度和PH值条件下生存，且能抵抗各种消毒剂的作用，因此该细菌在医院环境中的存活时间较长，易出现感染的流行1.Garnacho-­MonteroJetal.CurrOpinInfect

Dis.2010;;23:332–339可在人体各部位定植呼吸道定植皮肤定植伤口定植胃肠道定植正常菌群在宿主细胞上定居、生长和繁殖的现象称为定植在正常人体体表与外界相通的腔道如呼吸道、皮肤、胃肠道和伤口等部位定植3.NaturePublishingGroup.Naturereviews

Microbiology.2007;;5:939-­951定植多于感染Dijkshoorn

L等在Nature发表的一篇综述中指出：鲍曼不动杆菌在人体定植比感染更为常见，在鲍曼不动杆菌易感人群也如此3.NaturePublishingGroup.nature

reviews.2007;;5:939-­951鲍曼不动杆菌的临床影响鲍曼不动常出现于伴严重的基础疾病患者，因此死亡率的上升与其说是不动杆菌感染，不如说病情严重所致一些对照研究显示，鲍曼不动的感染并未增加死亡率有一些队列研究显示，伴鲍曼不动感染的患者死亡率高于对照组争议依旧……仅仅根据呼吸道标本不动杆菌培养阳性而采取治疗措施是不正确的……不动杆菌培养阳性同时需要临床表现和影像学证据治疗方案药物名称优点缺点碳青霉烯类药物对鲍曼不动杆菌的体外抗菌活性、实验室数鲍曼不动杆菌存在对碳青霉烯类耐药的菌株碳青霉烯类据及临床用药经验显示，碳青霉烯类药物可用于MDR鲍曼不动杆菌感染的治疗舒巴坦及含舒巴坦的合剂舒巴坦为β-­‐内酰胺酶抑制剂，对鲍曼不动杆菌具有很好的体外抗菌活性含舒巴坦的合剂(如氨苄西林/舒巴坦、头孢哌酮/舒巴坦)可用于鲍曼不动杆菌感染的治疗舒巴坦合剂的抗菌活性主要来自舒巴坦，氨苄西林或头孢哌酮并不能增强舒巴坦的抗菌活性近年来，鲍曼不动杆菌对舒巴坦的耐药性也逐渐增加Garnacho-­MonteroJetal.CurrOpinInfect

Dis.2010;;23:332–339舒巴坦和含舒巴坦的合剂头孢哌酮/舒巴坦：常用剂量为3.0g（头孢哌酮2.0g＋舒巴坦1.0g）q8h或q6h，静脉滴注；对于严重感染者(如MDRAB、XDRAB、PDRAB)可根据药敏结果与米诺环素、阿米卡星等药物联合用药氨苄西林/舒巴坦：给药剂量为3.0g q6h，静脉滴注；严重感染患者与其他抗菌药物联合舒巴坦：可与其他类别药物联合用于治疗XDRAB、PDRAB引起的感染治疗方案药物名称优点缺点利福平利福平在体内或体外均对鲍曼不动杆菌具有很好的抗菌活性在实验模型中，利福平单药或联合其他抗菌药物对MDR鲍曼不动杆菌肺炎或脑膜炎具有很好的疗效由于利福平可能诱导鲍曼不动杆菌对该药物的耐药性，因此在临床使用中，利福平一般不作为单药治疗多粘菌素E多粘菌素E对鲍曼不动杆菌的体外抗菌活性最强多粘菌素E对鲍曼不动杆菌感染实验模型的疗效并不理想临床研究也显示，多粘菌素E对鲍曼不动杆菌肺炎的临床疗效不佳，可能与药物的肺组织穿透力较弱相关替加环素替加环素对鲍曼不动杆菌，包括耐多粘菌素E菌株具有很好的抗菌活性目前，替加环素治疗重度鲍曼不动杆菌感染的临床研究有限，对于重度肺部感染患者，常规给药剂量可能疗效不佳Garnacho-­MonteroJetal.CurrOpinInfect

Dis.2010;;23:332–339给药剂量药物名称给药剂量给药途径亚胺培南500mgq6h—1g

q6-­8hIV美罗培南500mgq8h—1gq8hIV多利培南500mgq8hIV舒巴坦6g/dIV多粘菌素E500mg/kg/d

分2-­4次给药1-­3百万单位

q8hIV吸入替加环素首次给药100mg，随后50mg

q12hIVFishbainJetal.ClinicalInfectiousDiseases2010;;

51(1):79–84MDR鲍曼不动杆菌肺炎的治疗对MDR鲍曼不动杆菌肺炎的治疗，2005年ATS指南推荐联合治疗方案ATS/IDSA.AmJRespirCritCareMed.

2005;;171:388-­416.抗菌药物的合理使用3细菌对抗生素的耐药机制(通透性改变）(G+菌的主要耐药机制)渗透障碍细胞壁 (通透性改变）外排泵细胞壁靶位改变细胞膜产酶胞质腔(作用位置)最常见的耐药机制抗菌药物合理使用的原则抗菌药物临床应用是否合理，基于以下两方面：有无抗菌药物应用指征选用的品种及给予方案是否适宜抗菌药物应用基本原则：诊断为细菌性感染者方有指征应用抗菌药物；尽早查明感染病原，根据病原种类及药敏结果选择抗菌药物抗菌药物的经验性治疗按照药物的抗菌作用及体内代谢特点选择用药综合患者的病情，病原菌的种类及抗菌药物特点制定方案抗菌药物的PK/PD分类耐药菌的处理在病原治疗中，大多数治疗药物推荐按耐药和非耐药进行处理多重耐药菌及泛耐药菌感染时需要抗生素联合治疗诊疗感染性疾病的立足点NicolauDP.AmJManag

Care.2000;6(suppl):S1202-S1210.DelacherS,DerendorfH,HollensteinU,etal.JAntimicrobChemother.

2000;46:733-739.回本溯源：生物圈的轮回从容应对，挽救生命始终从三个角度关注和考虑抗生素在重症患者的治疗方案：细菌-患者：是否危及生命细菌-药物：是否存在MDR感染风险药物-患者：是否依循PK/PD的原理用药重症感染患者-降阶梯治疗时间窗窄:干预措施要及时早期有效扼制理论:集中优势兵力,解决主要矛盾以时间换空间，为后续治疗创造条件对干预措施的风险与效益进行评估及时作出阶段性评估调整方案降阶梯的概念降阶梯策略（de-escalation）初始经验性治疗必须覆盖所有可能的病原，如有假单孢菌要联合用药，48-72小时后一旦获得可靠的病原学诊断即改为选择性的目标治疗，有助于降低重症感染的病死率，防止广谱联合治疗不适当长时间使用导致耐药与其它不良后果降阶梯治疗的本质广谱 早期 足量 静脉大剂量！？AbstractBackground:Theaimofthisstudywastoassesstheefficacyoftigecyclineinthetreatmentofinfectionsduetocarbapen-emase-producingKlebsiellapneumoniae(CPKP)incriticallyillpatients.Methods:AretrospectiveobservationalstudywasconductedincriticallyillpatientsreceivingdifferenttigecyclinedosesforsevereCPKPinfections.Weevaluateddemo-graphicdata,localizationandseverityofinfection,responsetotherapy,andmortality.Results:Fifteenpatientsreceivedtigecyclinefor16episodesofCPKPinfection.Themaininfectionswerepneumonia(31%),urinarytractinfection(31%),peritonitis(20%),catheter-relatedbacteraemia(12%),andmeningitis(6%).Mostinfectionswerecomplicatedwithseveresepsis(44%),septicshock(12%),and/orbacteraemia(19%).Thedailymaintenancedoseoftigecyclinewas200mgin10episodesand100mgin6episodes.Theoverall30-daymortalityratewas25%.Univariateanalysisshowedthatmortalitywassignificantlyassociated(p<0.01)withmeanAPACHEIIandSOFAscoresandthepresenceofimmunosuppression,butnotwiththetigecyclinedose.Conclusions:TigecyclineappearstobeaneffectivetherapyforsevereinfectionsduetoCPKPincriticallyillpatients.Mortalityisrelatedtotheseverityoftheunderlyingdisease.Weobservednobenefitfromahighermaintenancedoseoftigecycline,althoughthenumberofpatientsincludedinthestudywastoosmalltodrawanygeneralconclusionsinthis

regard.Keywords:Tigecycline,criticallyill,Klebsiellapneumoniae,multidrug-resistant

Gram-negativebacteria,carbapenemase-producingEnterobacteriaceaeIntroductionTigecycline(TGC)isaglycylcyclineantibioticwithabroadspectrumofantibacterialactivity.Ithasbeenapprovedforthetherapyofskin,soft-tissue,andintra-abdominalinfections.In2008,TGCalsoreceivedapprovalforthetreatmentofcommunity-acquiredbacterialpneumonia[1].However,arecentmeta-analysisquestionedthepreviouslyobservedefficacyofTGCinclinicaltrials,concludingthatTGCisnotbetterthancomparatoragentsandthatitsuseisasso-ciatedwithexcessdeathsandtreatmentfailure[2].Most

experts

have

recommended

thatTGC

be

avoidedfor

the

treatment

of

severe

infections

and

that

it

shouldbereservedforuseasalast-resortdrug

[3].Correspondence:B.BalandínMoreno,IntensiveCareUnit,HospitalUniversitarioPuertadeHierroMajadahonda,C/ManueldeFallan

1,

28222,Majadahonda,Madrid,Spain.Tel:+34911916000.Fax:+34911916727.E-mail:

balandinmoreno@(Received4June2013;accepted23October

2013)ISSN0036-5548print/ISSN1651-1980online©2014InformaHealthcareDOI:

10.3109/00365548.2013.861608ScandinavianJournalofInfectiousDiseases,2014;46:

175–180ORIGINAL

ARTICLETigecyclinetherapyforinfectionsduetocarbapenemase-producingKlebsiellapneumoniaeincriticallyill

patientsB.BALANDINMORENO1,I.FERNÁNDEZSIMÓN1,V.PINTADO

GARCÍA2,I.SÁNCHEZ

ROMERO3,

B.ISIDORO

FERNÁNDEZ4,

M.

A.

ROMERAORTEGA1,S.ALCÁNTARACARMONA1,M.PÉREZREDONDO1&P.GALDOS

ANUNCIBAY1Fromthe1IntensiveCareUnit,HospitalUniversitarioPuertadeHierroMajadahonda,2DepartmentofInfectiousDiseases,HospitalRamónyCajal,UniversidaddeAlcaládeHenares,3DepartmentofMicrobiology,HospitalUniversitarioPuertadeHierroMajadahonda,and4DepartmentofPreventiveMedicine,HospitalUniversitarioPuertadeHierroMajadahonda,Madrid,

SpainDespitetheselimitations,TGCisausefulalterna-tiveforthetreatmentofinfectionsduetomultidrug-resistant(MDR)Gram-negativebacteria,suchascarbapenemase-producingEnterobacteriaceae(CPE).TheemergenceofCPEisaseriousproblemworld-wide,especiallyamongpatientsadmittedtointensivecareunits(ICU).Infectionsduetothesemicroorgan-ismshavelimitedtreatmentoptionsandhavebeenassociatedwithhighmortalityrates

[4].AlthoughTGCexhibitspotentinvitroactivityagainstmostclinicallyimportantpathogensisolatedfromcriticallyillpatients[5],thereislimitedexperiencewithTGCincriticallyillpatientsinfectedwithCPE[6–8].Itshouldbenotedthatnoclinicaltrialshave

beenScandJInfectDisDownloadedfrom

byTulaneUniversityon04/10/14Forpersonaluse

only.大剂量替加环素治疗产碳青霉烯酶肺克所致重症感染－系统分析大剂量！？大剂量替加环素治疗重度细菌感染的临床应用－系统分析Pleasecitethisarticleinpressas:FalagasME,etal.Effectivenessandsafetyofhigh-dosetigecycline-containingregimensforthetreatmentofseverebacterialinfections.IntJAntimicrobAgents(2014),

/10.1016/j.ijantimicag.2014.01.006ARTICLEIN

PRESSG

ModelANTAGE-4251;No.ofPages

7InternationalJournalofAntimicrobialAgentsxxx(2014)

xxx–xxxContents

lists

available

at

ScienceDirectInternationalJournalofAntimicrobial

Agentsj

o

ur

nal

ho

me

pag

e:

/locate/ijantimicag

ReviewEffectivenessandsafetyofhigh-dosetigecycline-containing

regimensforthetreatmentofseverebacterial

infectionsMatthewE.Falagasa,b,c,∗,KonstantinosZ.Vardakasa,b,KonstantinosP.

Tsiveriotisa,NikolaosA.Triaridesa,b,GiannoulaS.

Tansarliaa

AlfaInstitute

of

Biomedical

Sciences

(AIBS),9

Neapoleos

Street,

151

23

Marousi,

Athens,

Greeceb

Departmentof

Internal

Medicine

–

Infectious

Diseases,

Mitera

Hospital,

Hygeia

Group,

Athens,

GreececTuftsUniversitySchoolofMedicine,Boston,MA,

USAa

r

t

i

c

l

e

i

n

f

oArticle

history:Received

14

January

2014Accepted

15

January

2014Keywords:AcinetobacterMDRPDRXDREnterobacteriaceaeIntensivecare

unita

b

s

t

r

a

c

tHere

we

review

the

effectiveness

and

safety

of

high-dose

tigecycline

(200

mg

daily).

A

systematic

searchwas

performed

in

PubMed

and

Scopus

databases

as

well

as

of

abstracts

presented

at

scientific

conferences.Eightstudies(263patients;58%criticallyill)wereincluded,comprisingonerandomisedcontrolledtrial(RCT),fournon-randomisedcohortsandthreecasereports.Klebsiellapneumoniaewasthemostcom-monlyisolatedpathogen(reportedinsevenstudies).IntheRCT,responseintheclinicallyevaluablepatients

was

85.0%

(17/20)

in

the

100

mg

every

12

h(q12

h)group

and

69.6%

(16/23)

in

the

75

mg

q12

hgroup(P=0.4).Moreepisodesofdiarrhoea,treatment-relatednauseaandvomitingdevelopedinthehigh-dosegroup(14.3%vs.2.8%,8.6%vs.2.8%and5.7%vs.2.8%,respectively;P>0.05forallcompar-isons).

Three(8.6%)and

7(19.6%)patients

died

in

the

200

mg

and

150

mg

daily

dose

groups,

respectively.Thecohortstudiesenrolledpatientswithsevereinfections,includingventilator-associatedpneumoniaandcomplicatedintra-abdominalinfections.Mortalitywithhigh-dosetigecycline(100mgq12h)inthecohort

studies

ranged

from

8.3%

to

26%;

mortality

in

the

low-dose

groups

(50

mg

q12

h)

ranged

from

8%

to61%

and

depended

on

the

severity

of

the

underlying

infection.

There

are

limited

available

data

regardingtheeffectivenessandsafetyofhigh-dosetigecycline.Mostofthedatacomefromcriticallyillpatientswithdifficult-to-treatinfections.Pharmacokinetic/pharmacodynamicpropertiesoftigecyclinesuggestthathigh-doseregimensmaybemoreeffectivethanlow-doseregimens.Candidatesforadministrationofhigh-dosetigecyclineshouldbealso

defined.©2014ElsevierB.V.andtheInternationalSocietyofChemotherapy.Allrights

reserved.1.

IntroductionNewclassesofantibioticsagainstGram-negativebacteriaarenot

available

and

resistance

to

the

currently

available

antibiotics

isspreading.Furthermore,recentstudiesshowedthathighermini-mum

inhibitory

concentrations

(MICs)

within

the

susceptible

rangebothforGram-positiveandGram-negativebacteriawereassoci-ated

with

higher

mortality

[1,2].

Tigecycline

was

approved

in

2005bytheUSFoodandDrugAdministration(FDA)forcomplicatedskin

and

soft-tissue

infections,

complicated

intra-abdominal

infec-tions(IAIs)andcommunity-acquiredpneumoniaandsincethen