多重耐药菌感染的治疗标准课件.ppt

1、多重耐药菌感染的治疗MDR定义定义v无公认的定义无公认的定义v对现行之标准治疗产生耐药之细菌对现行之标准治疗产生耐药之细菌第三代第三代头孢菌素耐药肠杆菌科细菌头孢菌素耐药肠杆菌科细菌青霉素耐药肺炎链球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铜绿假单胞菌碳青霉烯类耐药不动杆菌碳青霉烯类耐药不动杆菌VREMRSA,VISA,VRSA-革兰阳性菌革兰阳性菌PRSPv青霉素青霉素0.190%Jauregui,CID Nov 15,2005Clinical Efficacy of Weekly Dalbavancin vs Standard-of-Care Antimicrobia

2、ls for SSSIsStandard-of-care antibiotics included cefazolin,vancomycin,clindamycin,ceftriaxone,and piperacillin/tazobactam.Seltzer E et al.Clin Infect Dis.2003;37:1298-1303.Dalbavancin(Zeven)v与万古霉素比较与万古霉素比较?v治疗治疗GPC所致导管相关性所致导管相关性BSI 临床有效率临床有效率:Dalbavancin=87%万古霉素万古霉素=50%Raad et al,CID Feb 2005Telava

3、ncinv新一代糖肽类新一代糖肽类v治疗治疗 CSSSI 细菌清除率细菌清除率:Telavancin=92%万古霉素万古霉素=68%Stryjewski et al,AAC Mar 2006Telavancin新一代糖肽类新一代糖肽类对对GPC呈浓度依赖性快速杀菌作用呈浓度依赖性快速杀菌作用vMRSA,MRSE,VRE,VISA,VRSA随即对照双盲随即对照双盲 III 期临床试验期临床试验(n=167)Telavancin QD vs 耐酶青霉素耐酶青霉素 QID 或万古霉素或万古霉素 BIDStryjewski ME et al.Clin Infect Dis.2005;40:1601-1

4、607.Oritavancin新一代糖肽类新一代糖肽类v作用机制同万古霉素作用机制同万古霉素对对GPC呈浓度依赖性杀菌作用呈浓度依赖性杀菌作用vMRSA,MRSE,VRE消除半衰期消除半衰期 132-356 hrsv临床试验临床试验QD给药，但给药，但 Q week 更好更好2 项治疗项治疗 cSSSIs临床试验疗临床试验疗效良好效良好Guay DR.Pharmacotherapy.2004;24:58-68.Ceftobiprolev四代后头孢菌素四代后头孢菌素v对对 MRSA具有活性具有活性v对对GNB活性与活性与3/4 GCs 相仿相仿v适应证：适应证：2008,3,19 FDA 批准批

5、准复杂性皮肤软组织感染复杂性皮肤软组织感染临床有效率临床有效率替加环素(Tygacil)注意部分产ESBLs菌株体外可对2、3GCs敏感，但对头孢他啶耐药；万古霉素耐药肠球菌（VRE）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VRE感染，包括合并菌血症9%in pure infection and 63.适应证：2008,3,19 FDA 批准覆盖大多数耐药GPB、GNB和厌氧菌MRSA,VISA,VRSANichols RL et al.colistin as monotherapy for the treatment of multidrug resistant Aci

6、netobacter baumannii ventilator-associated pneumoniaTigecyclineAminoglycosides(at times)Study 1:Q/D(7.达托霉素(Cubicin)6%(including 33%nephrotoxicity)for the COL group and 30.晚霉素(evernimicin)*vancomycin 1 g q12h IV could be substituted if the pathogen was suspected or confirmed MRSA or the patient was a

7、llergic to penicillin,cephalosporins,or carbapenems.达托霉素，替加环素体外有效Dalbavancin(Zeven)ceftaroline fosamil(PPI-0903,TAK-599)v新一代头孢菌素新一代头孢菌素v对对MRSA，MDRSP和和GNB均具抗菌活性均具抗菌活性vII期临床试验与万古霉素比较治疗期临床试验与万古霉素比较治疗cSSSI 获获满意疗效满意疗效 vIII期临床试验中期临床试验中SAN FRANCISCO Calif.September 29 2006,46th ICAAC粪肠球菌(万古霉素敏感株)A clinical

8、 investigation of MRSA infections to study the efficacy of arbekacin was carried in 115 institutions in Japan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Stryjewski et al,AAC Mar 20068%耐酶青霉素 90.1997 日本首次报道 VISAcSSTI可评价患者902 例J Antimicrob Chemother.CeftobiproleOritavancin第一代:万古霉素,替考拉宁5%(8/13)in the COL and Amp/Sul

9、b groups目前III期临床试验用于治疗耐药革兰阳性菌感染CPK 达托霉素组11 例,对照组8 例VRE感染，包括合并菌血症Clin Infect Dis.氨苄西林/舒巴坦、头孢哌酮/舒巴坦(舒巴坦对不动杆菌具高度活性),或Pharmacotherapy.亚胺培南、美罗培南、帕尼培南克拉普林克拉普林(iclaprim）v新二氢叶酸还原酶抑制剂新二氢叶酸还原酶抑制剂v广谱抗菌作用广谱抗菌作用抗革兰阳性菌活性较强抗革兰阳性菌活性较强vMRSA,VISA/VRSA 和大环内酯类、氟喹诺酮类和和大环内酯类、氟喹诺酮类和TMP耐药菌株耐药菌株v肺炎链球菌，包括青霉素、红霉素、左氧氟沙星和肺炎链球菌，

10、包括青霉素、红霉素、左氧氟沙星和SMZ-TMP耐药菌株耐药菌株对对GNB和不典型病原体具有活性和不典型病原体具有活性v期临床试验与万古霉素比较获满意效果期临床试验与万古霉素比较获满意效果v正在进行正在进行期临床试验期临床试验 晚霉素晚霉素(evernimicin)v晚霉素晚霉素(evernimicin,Ziracin)抗抗MRSA与与VRE活性优于万古霉素与活性优于万古霉素与synercidv静脉给药，静脉给药，t1/2 1.22 hv正在进行正在进行期临床试验期临床试验 AurograbvAurograb为抗为抗MRSA单抗和万古霉素结合药单抗和万古霉素结合药物物v主要用于治疗主要用于治疗M

11、RSA的感染的感染 v正处于正处于期临床试验阶段期临床试验阶段 Arbekacinva derivative of dibekacin,is an aminoglycosidevdeveloped and used in Japan for the treatment MRSA infections Nationwide investigation in Japan on the efficacy of arbekacin in MRSA infections vA clinical investigation of MRSA infections to study the efficacy

12、of arbekacin was carried in 115 institutions in Japanv348 patients were evaluated.74 patients were treated with ABK alone and 274 with ABK in combination with other compoundsvBacteriological clinical efficacy was 75.6%/67.9%in pure infection and 63.6%/71.3%in polymicrobial infectionvAdverse effects

13、were seen in 4.76%/5.7%,but no case was serious.Abnormal laboratory findings were noted in 15.4%of casesDrugs Exp Clin Res.1994;20(6):225-32.6%(including 33%nephrotoxicity)for the COL group and 30.Aminoglycosides(at times)2008 Jun;61(6):目前III期临床试验用于治疗耐药革兰阳性菌感染达托霉素(Cubicin)CE=clinically evaluable;cSS

14、SI=complicated SSSI.第一代:万古霉素,替考拉宁青霉素或氨苄西林庆大霉素（全身感染）;磷霉素,呋喃妥因（仅用于UTI）2nd 例 Pennsylvania Tenover et al 2004注意部分产ESBLs菌株体外可对2、3GCs敏感，但对头孢他啶耐药；Who have renal insufficiency2008 Feb;61(2):417-20Patients cured or improved.2008 Jun;56(6):432-6Aminoglycosides(at times)第三代头孢菌素耐药肠杆菌科细菌达托霉素(Cubicin)第一代:万古霉素,替考拉

15、宁1997 日本首次报道 VISA吉米沙星、莫西沙星、左氧氟沙星具良好作用肠球菌感染的治疗肠球菌感染的治疗v首选首选青霉素或氨苄西林青霉素或氨苄西林庆大霉素（全身感染）庆大霉素（全身感染）;磷霉素磷霉素,呋呋喃妥因（仅用于喃妥因（仅用于UTI）v青霉素耐药或过敏青霉素耐药或过敏糖肽类糖肽类FQ、氯霉素、氯霉素、RFP或多西环素（根据药敏）或多西环素（根据药敏）v糖肽类耐药糖肽类耐药 利奈唑胺利奈唑胺600mg po或或IV q12hQ-D 7.5mg/kg IV q8h,达托霉素，替加环素体外有效达托霉素，替加环素体外有效呋喃妥因或磷霉素对呋喃妥因或磷霉素对UTI有效有效 VanB菌株：替考拉

16、宁联合菌株：替考拉宁联合AG。临床试验。临床试验Q-D有效率有效率70，利奈唑胺相仿，利奈唑胺相仿万古霉素耐药肠球菌（万古霉素耐药肠球菌（VRE）v最新趋势最新趋势利奈唑胺耐药增多：匹兹堡利奈唑胺耐药增多：匹兹堡13Daptomycin耐药出现耐药出现v建议常规作利奈唑胺药敏，建议常规作利奈唑胺药敏，Daptomycin应应作作E-test革兰阴性菌革兰阴性菌耐药菌感染的治疗耐药菌感染的治疗产产ESBL肠杆菌科细菌，耐肠杆菌科细菌，耐3GCs或氨曲南或氨曲南 v重症感染：碳青霉烯类、重症感染：碳青霉烯类、FQAGv尿路感染：尿路感染：SMZ-TMP、AM-CL、呋喃妥因、呋喃妥因、FQv备注备

17、注头孢吡肟、头孢吡肟、TC/CL、PIP/TAZ体外具有活性，但动物实验体外具有活性，但动物实验效果差，部分高产效果差，部分高产ESBLs菌株对菌株对TC/CL、PIP/TAZ原发原发耐药耐药注意部分产注意部分产ESBLs菌株体外可对菌株体外可对2、3GCs敏感，但对头敏感，但对头孢他啶耐药；此类菌株所致感染用孢他啶耐药；此类菌株所致感染用2、3GCs治疗无效治疗无效如对如对FQ敏感，可能有效敏感，可能有效注意注意KPC菌株菌株少数菌株仅对多粘菌素敏感少数菌株仅对多粘菌素敏感Carbapenemase-Producing Klebsiella pneumoniae vOrganisms tha

18、t produce KPC have similar resistance profiles to most ESBLs,but with the addition of carbapenem resistance.vTreatment optionsTigecyclinePolymyxinsOther tetracyclines(at times)Aminoglycosides(at times)Pharmacotherapy.2008;28(2):235-249 铜绿假单胞菌铜绿假单胞菌v治疗选择治疗选择抗假单胞菌青霉素类抗假单胞菌青霉素类v哌拉西林、哌拉西林哌拉西林、哌拉西林/他唑巴坦、

19、替卡西林他唑巴坦、替卡西林/克拉维酸克拉维酸抗假单胞菌头孢菌素类抗假单胞菌头孢菌素类v头孢他啶、头孢哌酮、头孢哌酮头孢他啶、头孢哌酮、头孢哌酮/舒巴坦、头孢吡肟舒巴坦、头孢吡肟碳青霉烯类碳青霉烯类v亚胺培南、美罗培南、帕尼培南亚胺培南、美罗培南、帕尼培南氨基糖苷类氨基糖苷类v庆大霉素、妥布霉素、阿米卡星、异帕米星庆大霉素、妥布霉素、阿米卡星、异帕米星氟喹诺酮类氟喹诺酮类v环丙沙星、左氧氟沙星环丙沙星、左氧氟沙星v除尿路感染外通常联合用药，除尿路感染外通常联合用药，内酰胺类（内酰胺类（AG或或FQ）耐药菌感染的治疗耐药菌感染的治疗铜绿假单胞菌铜绿假单胞菌:耐亚胺培南及美罗培南耐亚胺培南及美罗培南

20、v选用药物选用药物 环丙沙星（根据药敏）环丙沙星（根据药敏）氨基糖苷类（根据药敏）氨基糖苷类（根据药敏）粘菌素静脉给药粘菌素静脉给药v备注备注许多菌株仍对氨曲南和头孢他啶或许多菌株仍对氨曲南和头孢他啶或AP Pen敏感敏感AP Pen+AG、或头孢他啶、或头孢他啶+AG可能有效可能有效鲍曼不动杆菌鲍曼不动杆菌v治疗选择治疗选择碳青霉烯类碳青霉烯类氨苄西林氨苄西林/舒巴坦、头孢哌酮舒巴坦、头孢哌酮/舒巴坦舒巴坦(舒巴坦对不动杆菌舒巴坦对不动杆菌具高度活性具高度活性),或或 氟喹诺酮类氟喹诺酮类(环丙沙星环丙沙星,左氧氟沙星左氧氟沙星)联合氨基糖苷类以预防耐药并获协同作用联合氨基糖苷类以预防耐药并

21、获协同作用v体外具有活性体外具有活性米诺环素米诺环素/多西环素多西环素替加环素替加环素多粘菌素多粘菌素鲍曼不动杆菌感染的治疗鲍曼不动杆菌感染的治疗鲍曼不动杆菌鲍曼不动杆菌:耐亚胺培南、耐亚胺培南、AP Pen或或cef、AG、FQ v选用药物：含舒巴坦制剂（舒巴坦单用对部分鲍曼不选用药物：含舒巴坦制剂（舒巴坦单用对部分鲍曼不动杆菌有效）动杆菌有效）v黏菌素有效黏菌素有效v备注：备注：6/8例鲍曼不动杆菌脑膜炎例鲍曼不动杆菌脑膜炎AM/SB治疗痊愈，其中治疗痊愈，其中7例对亚胺培南耐药例对亚胺培南耐药FQ+AG、泰能、泰能+AG或或RFP、或、或AP Pen或或AP Cef+AG对部分泛耐药株具

22、有活性对部分泛耐药株具有活性体外活性：黏菌素体外活性：黏菌素+泰能泰能+RFP,替加环素替加环素JAC(2007)60,12061215 12%为糖尿病足J Antimicrob Chemother.Study 1:Q/D(7.7%,but no case was serious.临床有效率:替加环素 86.利奈唑胺耐药增多：匹兹堡13Who have renal insufficiency对绝大部分GNB无作用达托霉素(Cubicin)*vancomycin 1 g q12h IV could be substituted if the pathogen was suspected or c

23、onfirmed MRSA or the patient was allergic to penicillin,cephalosporins,or carbapenems.Results are combined from the 2 clinical trials.Mortality rates(14 days and 28 days)were 15.CPK 达托霉素组11 例,对照组8 例1%达托霉素 87.奎奴普丁达福普汀疗效金葡菌血流感染，包括右侧心内膜炎(MSSA或MRSA)(自身瓣膜)亚胺培南、美罗培南、帕尼培南Aminoglycosides(at times)利奈唑胺600mg

24、po或IV q12hCE=clinically evaluable;cSSSI=complicated SSSI.JAC(2007)60,12061215Lancet Infect Dis 2006;6:589601J Antimicrob Chemother.2008 Feb;61(2):417-20 J Antimicrob Chemother.2008 Jul;62(1):45-55 J Antimicrob Chemother.2008 Jun;61(6):J Antimicrob Chemother.2008 Jun;61(6):Efficacy and safety of high

25、-dose ampicillin/sulbactam vs.colistin as monotherapy for the treatment of multidrug resistant Acinetobacter baumannii ventilator-associated pneumonia vMETHODSA prospective cohort study in adult critically ill patients with VAP Amp/Sulb(9 g every 8h)or COL(3 MIU every 8h)intravenously vRESULTSA tota

26、l of 28 patients were enrolled(15 COL,13 Amp/Sulb).Resolution of symptoms and signs occurred in 60%(9/15)of the COL group and 61.5%(9/13)of the Amp/Sulb group,improvement in 13.3%(2/15)vs.15.3%(1/13)and failure in 26.6%(4/15)vs.23%(3/13Bacteriologic success was achieved in 66.6%(10/15)vs.61.5%(8/13)

27、in the COL and Amp/Sulb groupsMortality rates(14 days and 28 days)were 15.3%and 30%for the Amp/Sulb and 20%and 33%for the COL groupAdverse events were 39.6%(including 33%nephrotoxicity)for the COL group and 30.7%(15.3%nephrotoxicity)for the Amp/Sulb group(p=NS)vCONCLUSIONColistin and high-dose AM/SB

28、 were comparably safe and effective treatments for critically ill patients with MDR A.baumannii VAP J Infect.2008 Jun;56(6):432-6 晚霉素(evernimicin)万古霉素耐药肠球菌（VRE）对GNB活性与3/4 GCs 相仿Statistical conclusions could not be reached due to the small number of patients in the subsets.Aminoglycosides(at times)如对

29、FQ敏感，可能有效氨苄西林/舒巴坦、头孢哌酮/舒巴坦(舒巴坦对不动杆菌具高度活性),或随即对照双盲 III 期临床试验(n=167)Dalbavancin(Zeven)2003;37:1298-1303.泰利霉素(Ketek)李斯特菌、脑膜炎球菌、卡他莫拉菌、流感嗜血杆菌Adverse effects were seen in 4.1997 日本首次报道 VISAResults are combined from the 2 clinical trials.J Antimicrob Chemother.选用药物：含舒巴坦制剂（舒巴坦单用对部分鲍曼不动杆菌有效）替加环素(Tygacil)吉米沙星

30、、莫西沙星、左氧氟沙星具良好作用CID Sept 1,2005MSSA,MRSA,化脓性链球菌,无乳链球菌,Streptococcus dysgalactiae subsp.Dalbavancin(Zeven)*vancomycin 1 g q12h IV could be substituted if the pathogen was suspected or confirmed MRSA or the patient was allergic to penicillin,cephalosporins,or carbapenems.Efficacy in the CE Population2

31、005;40:1601-1607.5 mg/kg q12h IV)vs cefazolin(1 g q8h IV)*替加环素(Tygacil)Bacteriological clinical efficacy was 75.适应证：2008,3,19 FDA 批准Meta-analyses of treatment success for clinically assessed patients with pneumoniaManagement of MDR PathogensJ Antimicrob Chemother.*Results are combined from the 2 cli

32、nical trials.Daptomycin耐药出现2nd 例 Pennsylvania Tenover et al 20047%,but no case was serious.Drugs Exp Clin Res.Dalbavancin(Zeven)*vancomycin 1 g q12h IV could be substituted if the pathogen was suspected or confirmed MRSA or the patient was allergic to penicillin,cephalosporins,or carbapenems.Managem

33、ent of MDR PathogensvIf P aeruginosa,combination therapy is recommendedvIf Acinetobacter spp,the most active agents are the carbapenems,sulbactam,colistin,and polymyxinvAvoid monotherapy with a third-generation cephalosporin for ESBL+EnterobacteriaceaevConsider adjunctive inhaled aminoglycoside for

34、MDR Gram-negative pneumonia in patients not improving with systemic therapyvLinezolid is an alternative to vancomycin for treatment of MRSA VAPvLinezolid may be preferred(but more data are needed)in patients:Who have renal insufficiency Receiving other nephrotoxic agentsATS/IDSA.Am J Respir Crit Care Med.2005;171:388-416.