1、多重耐药菌感染的治疗多重耐药菌感染的治疗李光辉李光辉复旦大学华山医院抗生素研究所复旦大学华山医院抗生素研究所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PRSP青霉素耐药肺炎链球菌青霉素耐药肺炎链球菌MDRSP多重耐药肺炎链球菌多重耐药肺炎链球菌MRSA甲氧西林耐药金葡菌甲氧西林耐药金
2、葡菌VISA万古霉素万古霉素 中介金葡菌中介金葡菌VRSA万古霉素耐药金葡菌万古霉素耐药金葡菌VRE万古霉素万古霉素 耐药肠球菌耐药肠球菌PRSPv青霉素青霉素0.190%Jauregui, CID Nov 15, 2005Clinical Efficacy of Weekly Dalbavancin vs Standard-of-Care Antimicrobials for SSSIsStandard-of-care antibiotics included cefazolin, vancomycin, clindamycin, ceftriaxone, and piperacillin/
3、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 2005Telavancinv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 2006Tela
4、vancin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;40:1601-1607.nTelavancin Comparator*S aureus10280%77%MRSA clin cure4882%69%MRSA micro cure4884%74%Ori
5、tavancin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 批准批准复杂
6、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
7、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，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.
8、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MRSA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
9、in MRSA infections vA clinical investigation of MRSA infections to study the efficacy 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
10、75.6%/67.9% in pure infection and 63.6%/71.3% in polymicrobial infectionvAdverse effects 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. 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,
11、 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
12、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产产ESBL-肠杆菌肠杆菌科细菌科细菌大肠埃希菌、克雷伯菌属、变形杆大肠埃希菌、克雷伯菌属、变形杆菌属等菌属等MDR-PA多重耐药铜绿假单胞菌多重耐药铜绿假单胞菌MDR-AB多重耐药鲍曼不动杆菌多重耐药鲍曼不动杆菌PDR泛耐药铜绿假单胞菌泛耐药铜绿假单胞菌/鲍曼不动杆菌鲍曼不动杆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、FQAG
13、v尿路感染：尿路感染：SMZ-TMP、AM-CL、呋喃妥因、呋喃妥因、FQv备注备注头孢吡肟、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-Produ
14、cing Klebsiella pneumoniae vOrganisms that 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
15、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、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
16、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
17、 (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
18、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, 12061215JAC (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. 2
19、008 Jun;61(6): J Antimicrob Chemother. 2008 Jun;61(6): Efficacy and safety of high-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 patient
20、s with VAP Amp/Sulb (9 g every 8h) or COL (3 MIU every 8h) intravenously vRESULTSA total 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) a
21、nd failure in 26.6% (4/15) vs. 23% (3/13Bacteriologic success was achieved in 66.6% (10/15) vs. 61.5% (8/13) 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% nephrotoxicit
22、y) for the COL group and 30.7% (15.3% nephrotoxicity) for the Amp/Sulb group (p=NS)vCONCLUSIONColistin and high-dose AM/SB were comparably safe and effective treatments for critically ill patients with MDR A. baumannii VAP J Infect. 2008 Jun;56(6):432-6 Management of MDR PathogensvIf P aeruginosa, c
23、ombination 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 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.
