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1、多重耐药菌感染的治疗,李光辉复旦大学华山医院抗生素研究所,MDR定义,无公认的定义对现行之标准治疗产生耐药之细菌第三代头孢菌素耐药肠杆菌科细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不动杆菌VREMRSA, VISA, VRSA-,革兰阳性菌,PRSP,青霉素0.1 MIC 2.0 mg/L头孢噻肟/头孢曲松大剂量青霉素或氨苄西林用于非脑膜感染泰利霉素评注亚胺培南、厄他培南、头孢吡肟、头孢泊肟、头孢呋辛亦具活性美罗培南作用不及亚胺培南吉米沙星、莫西沙星、左氧氟沙星具良好作用,PRSP,青霉素MIC 4.0 mg/L万古霉素 利福平非脑膜感染头孢噻肟/头孢曲松大剂量氨苄西林亚
2、胺培南、厄他培南 FQ (吉米沙星、莫西沙星、左氧氟沙星),MDRSP,MDRSP: 对青霉素、红霉素、四环素、氯霉素、SMZ-TMP耐药万古霉素 利福平吉米沙星、左氧氟沙星、莫西沙星泰利霉素用于非脑膜感染,泰利霉素 (Ketek),酮内酯类 (结构与大环内酯类相关)抗菌谱A、B、C和 G 组链球菌，肺炎链球菌（包括MDRSP）, MSSA李斯特菌、脑膜炎球菌、卡他莫拉菌、流感嗜血杆菌军团菌、支原体、衣原体对 MRSA, VRE, 及肠道革兰阴性菌无活性适应证轻、中度社区获得性肺炎,MRSA感染的治疗,MRSA首选：万古霉素、去甲万古霉素可选药物：替考拉宁、利奈唑胺、达托霉素、替加环素或Q/D
3、 、dalbavancin、SMZ-TMP（依据药敏）、多西环素及米诺环素（部分菌株）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,万古霉素耐药性,1997 日本首次报道 VISA 2002年美国首次报道 VRSAMMWR July 20021st 例 Michigan 导管及糖尿病溃疡培养2nd 例 Pennsylvania Tenover et al 2004足根溃疡先前无万古霉素暴露Whitener et al 2004,VISA 和 VRSA,利奈唑胺 (Zyvox)Q/D (Synercid)达托霉素 (Cubicin)替加环素 (Tygacil)Dalbavanc
4、in (Zeven)USA：临床已发现9株VRSA，通常对SMZ-TMP、氯霉素、利奈唑胺、米诺环素、利福平、AG、Q/D仍然敏感,利奈唑胺 (Zyvox),噁唑烷酮类抗菌谱及适应证VRE感染，包括合并菌血症MSSA、 MRSA或肺炎链球菌（包括MDRSP）所致HAPMSSA、或 MRSA、化脓性链球菌、或无乳链球菌所致复杂性SSTI，包括糖尿病足感染伴或不伴骨髓炎MSSA、或化脓性链球菌所致单纯性SSTI肺炎链球菌（包括 MDRSP）或MSSA所致CAP，包括合并菌血症,Meta-analyses of treatment success for clinically assessed pa
5、tients with SSTI,Meta-analyses of treatment success for clinically assessed patients with bacteraemia,Meta-analyses of treatment success for clinically assessed patients with pneumonia,奎奴普丁/达福普汀 (Synercid),链阳性菌素类，为Q-D 30:70 的复合剂Q-D与细菌核糖体50s 亚基不可逆地结合，阻断蛋白质合成抗菌谱VREPRSPMRSA、MRCNS粪肠球菌耐药适应证菌血症 - 万古霉素耐药屎肠
6、球菌金葡菌和化脓性链球菌所致cSSTI,奎奴普丁达福普汀疗效,Design: 2 randomized, open-label, controlled clinical trials in cSSSIStudy 1: Q/D (7.5 mg/kg q12h IV) vs oxacillin (2 g q6h IV)* Study 2: Q/D (7.5 mg/kg q12h IV) vs cefazolin (1 g q8h IV)*,*vancomycin 1 g q12h IV could be substituted if the pathogen was suspected or co
7、nfirmed MRSA or the patient was allergic to penicillin, cephalosporins, or carbapenems. Patients cured or improved. Results are combined from the 2 clinical trials. Statistical conclusions could not be reached due to the small number of patients in the subsets.CE=clinically evaluable; cSSSI=complica
8、ted SSSI.,Efficacy in the CE Population,Synercid IV (quinupristin/dalfopristin for injection) package insert. Bristol, Tenn: Monarch Pharmaceuticals, Inc; 2002.,奎奴普丁达福普汀疗效,Design: 2 randomized, open-label, controlled clinical trials in cSSSI,*Results are combined from the 2 clinical trials. Patients
9、 cured or improved in the CE population. Overall and by-pathogen bacteriologic eradication rates in the microbiologically evaluable population.Nichols RL et al. J Antimicrob Chemother. 1999;44:263-273.,达托霉素 (Cubicin),环脂肽类（Cyclic lipopeptide ）抗菌谱MSSA, MRSA, 化脓性链球菌, 无乳链球菌, Streptococcus dysgalactiae s
10、ubsp. equisimilis, and粪肠球菌 (万古霉素敏感株) 批准 (IV, 4 mg/kg q24h)用于敏感GPB所致CSSTI金葡菌血流感染，包括右侧心内膜炎 (MSSA或MRSA) (自身瓣膜),达托霉素临床试验,cSSTI可评价患者902 例对照药：耐酶青霉素或万古霉素 10% MRSA 12% 为糖尿病足临床有效率达托霉素 81.1%达托霉素 87.3%万古霉素 73.8%耐酶青霉素 90.5%CPK 达托霉素组11 例, 对照组8 例达托霉素组2 例中停Arbiet et al 2004,替加环素 (Tygacil),甘氨酰环素米诺环素的衍生物广谱抗菌药覆盖大多数耐药
11、GPB、GNB和厌氧菌对假单胞菌属无活性体外、体内对MSSA, MRSA, 和 VISA均具活性,替加环素 (Tygacil),适应证复杂性皮肤软组织感染大肠埃希菌粪肠球菌 (万古霉素敏感株)金葡菌 (甲氧西林敏感或耐药)无乳链球菌咽峡炎链球菌. 化脓性链球菌脆弱拟杆菌,复杂性腹腔感染弗氏柠檬酸杆菌阴沟肠杆菌大肠埃希菌克雷伯菌属粪肠球菌 (万古霉素敏感株)金葡菌 (甲氧西林敏感或耐药)咽峡炎链球菌. 脆弱拟杆菌产气荚膜杆菌消化链球菌,替加环素 (Tygacil),III 期临床试验替加环素 vs. 万古霉素/氨曲南治疗CSSTI可评价患者833 例临床有效率: 替加环素 86.5% ，对照药
12、88.6%替加环素组胃肠道反应发生率高恶心 34.5% v 8.2%呕吐 19.6% v 3.6%,Ellis-Grosse et al. CID Sept 1, 2005,Dalbavancin (Zeven),第二代糖肽类第一代: 万古霉素, 替考拉宁抗菌谱葡萄球菌、链球菌梭菌属、消化链球菌、放线菌、棒状杆菌、枯草杆菌 对绝大部分GNB无作用对Van A 耐药肠球菌无作用治疗地位目前III期临床试验用于治疗耐药革兰阳性菌感染,Dalbavancin (Zeven),新一代糖肽类每周一次，静脉给药Dalbavancin vs 利奈唑胺治疗 CSSSIDalba 首剂1 gm， 7日后再用 5
13、00 mg利奈唑胺600mg q12h IV 或 po 14 d两组疗效均 90%Jauregui, CID Nov 15, 2005,Clinical Efficacy of Weekly Dalbavancin vs Standard-of-Care Antimicrobials for SSSIs,Standard-of-care antibiotics included cefazolin, vancomycin, clindamycin, ceftriaxone, and piperacillin/tazobactam.,Seltzer E et al. Clin Infect Di
14、s. 2003;37:1298-1303.,Dalbavancin (Zeven),与万古霉素比较?治疗GPC所致导管相关性BSI 临床有效率:Dalbavancin = 87%万古霉素 = 50%Raad et al, CID Feb 2005,Telavancin,新一代糖肽类治疗 CSSSI 细菌清除率:Telavancin = 92%万古霉素 = 68%Stryjewski et al, AAC Mar 2006,Telavancin,新一代糖肽类对GPC呈浓度依赖性快速杀菌作用MRSA, MRSE, VRE, VISA, VRSA随即对照双盲 III 期临床试验 (n=167)Tel
15、avancin QD vs 耐酶青霉素 QID 或万古霉素 BID,Stryjewski ME et al. Clin Infect Dis. 2005;40:1601-1607.,Oritavancin,新一代糖肽类作用机制同万古霉素对GPC呈浓度依赖性杀菌作用MRSA, MRSE, VRE消除半衰期 132-356 hrs临床试验QD给药，但 Q week 更好2 项治疗 cSSSIs临床试验疗效良好,Guay DR. Pharmacotherapy. 2004;24:58-68.,Ceftobiprole,四代后头孢菌素对 MRSA具有活性对GNB活性与3/4 GCs 相仿适应证：200
16、8,3,19 FDA 批准复杂性皮肤软组织感染,临床有效率,ceftaroline fosamil (PPI-0903, TAK-599),新一代头孢菌素对MRSA，MDRSP和GNB均具抗菌活性II期临床试验与万古霉素比较治疗cSSSI 获满意疗效 III期临床试验中,SAN FRANCISCO Calif. September 29 2006, 46th ICAAC,克拉普林(iclaprim）,新二氢叶酸还原酶抑制剂广谱抗菌作用抗革兰阳性菌活性较强MRSA, VISA/VRSA 和大环内酯类、氟喹诺酮类和TMP耐药菌株肺炎链球菌，包括青霉素、红霉素、左氧氟沙星和SMZ-TMP耐药菌株对G
17、NB和不典型病原体具有活性期临床试验与万古霉素比较获满意效果正在进行期临床试验,晚霉素(evernimicin),晚霉素(evernimicin, Ziracin)抗MRSA与VRE活性优于万古霉素与synercid静脉给药，t1/2 1.22 h正在进行期临床试验,Aurograb,Aurograb为抗MRSA单抗和万古霉素结合药物主要用于治疗MRSA的感染 正处于期临床试验阶段,Arbekacin,a derivative of dibekacin, is an aminoglycosidedeveloped and used in Japan for the treatment MRSA
18、 infections,Nationwide investigation in Japan on the efficacy of arbekacin in MRSA infections,A clinical investigation of MRSA infections to study the efficacy of arbekacin was carried in 115 institutions in Japan348 patients were evaluated. 74 patients were treated with ABK alone and 274 with ABK i
19、n combination with other compoundsBacteriological clinical efficacy was 75.6%/67.9% in pure infection and 63.6%/71.3% in polymicrobial infectionAdverse effects were seen in 4.76%/5.7%, but no case was serious. Abnormal laboratory findings were noted in 15.4% of cases,Drugs Exp Clin Res. 1994;20(6):2
20、25-32.,肠球菌感染的治疗,首选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）青霉素耐药或过敏糖肽类FQ、氯霉素、RFP或多西环素（根据药敏）糖肽类耐药 利奈唑胺600mg po或IV q12hQ-D 7.5mg/kg IV q8h, 达托霉素，替加环素体外有效呋喃妥因或磷霉素对UTI有效 VanB菌株：替考拉宁联合AG。临床试验Q-D有效率70，利奈唑胺相仿,万古霉素耐药肠球菌（VRE）,最新趋势利奈唑胺耐药增多：匹兹堡13Daptomycin耐药出现建议常规作利奈唑胺药敏，Daptomycin应作E-test,革兰阴性菌,耐药菌感染的治疗,产ESBL肠杆菌科细
21、菌，耐3GCs或氨曲南 重症感染：碳青霉烯类、FQAG尿路感染：SMZ-TMP、AM-CL、呋喃妥因、FQ备注头孢吡肟、TC/CL、PIP/TAZ体外具有活性，但动物实验效果差，部分高产ESBLs菌株对TC/CL、PIP/TAZ原发耐药注意部分产ESBLs菌株体外可对2、3GCs敏感，但对头孢他啶耐药；此类菌株所致感染用2、3GCs治疗无效如对FQ敏感，可能有效注意KPC菌株少数菌株仅对多粘菌素敏感,Carbapenemase-Producing Klebsiella pneumoniae,Organisms that produce KPC have similar resistance p
22、rofiles to most ESBLs, but with the addition of carbapenem resistance. Treatment optionsTigecyclinePolymyxinsOther tetracyclines (at times)Aminoglycosides (at times),Pharmacotherapy. 2008;28(2):235-249,铜绿假单胞菌,治疗选择抗假单胞菌青霉素类哌拉西林、哌拉西林/他唑巴坦、替卡西林/克拉维酸抗假单胞菌头孢菌素类头孢他啶、头孢哌酮、头孢哌酮/舒巴坦、头孢吡肟碳青霉烯类亚胺培南、美罗培南、帕尼培南氨基
23、糖苷类庆大霉素、妥布霉素、阿米卡星、异帕米星氟喹诺酮类环丙沙星、左氧氟沙星除尿路感染外通常联合用药，内酰胺类（AG或FQ）,耐药菌感染的治疗,铜绿假单胞菌: 耐亚胺培南及美罗培南选用药物 环丙沙星（根据药敏） 氨基糖苷类（根据药敏） 粘菌素静脉给药备注许多菌株仍对氨曲南和头孢他啶或AP Pen敏感AP Pen+AG、或头孢他啶+AG可能有效,鲍曼不动杆菌,治疗选择碳青霉烯类氨苄西林/舒巴坦、头孢哌酮/舒巴坦 (舒巴坦对不动杆菌具高度活性) , 或 氟喹诺酮类 (环丙沙星, 左氧氟沙星)联合氨基糖苷类以预防耐药并获协同作用体外具有活性米诺环素/多西环素替加环素多粘菌素,鲍曼不动杆菌感染的治疗,鲍
24、曼不动杆菌: 耐亚胺培南、AP Pen或cef、AG、 FQ 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） 黏菌素有效备注：6/8例鲍曼不动杆菌脑膜炎AM/SB治疗痊愈，其中7例对亚胺培南耐药FQ+AG、泰能+AG或RFP、或AP Pen或AP Cef+AG对部分泛耐药株具有活性体外活性：黏菌素+泰能+RFP, 替加环素,JAC (2007) 60, 12061215,JAC (2007) 60, 12061215,Lancet Infect Dis 2006; 6:589601,J Antimicrob Chemother. 2008 Feb;61(2):417-20,J An
25、timicrob 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-dose ampicillin/sulbactam vs. colistin as monotherapy for the treatment of multidrug resistant Acinetobacter baumannii ventilator-associated pneumonia,
26、METHODSA prospective cohort study in adult critically ill patients with VAP Amp/Sulb (9 g every 8h) or COL (3 MIU every 8h) intravenously RESULTSA 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 th
27、e 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) 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
28、 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)CONCLUSIONColistin and high-dose AM/SB were comparably safe and effective treatments for critically ill patients with MDR A. baumannii VAP,J Infect. 2008
29、 Jun;56(6):432-6,Management of MDR Pathogens,If P aeruginosa, combination therapy is recommendedIf Acinetobacter spp, the most active agents are the carbapenems, sulbactam, colistin, and polymyxinAvoid monotherapy with a third-generation cephalosporin for ESBL+ EnterobacteriaceaeConsider adjunctive
30、inhaled aminoglycoside for MDR Gram-negative pneumonia in patients not improving with systemic therapyLinezolid is an alternative to vancomycin for treatment of MRSA VAPLinezolid may be preferred (but more data are needed) in patients: Who have renal insufficiency Receiving other nephrotoxic agents,ATS/IDSA. Am J Respir Crit Care Med. 2005;171:388-416.,
