替考拉寧臨床應(yīng)用

1、對糖肽類抗生素臨床應(yīng)用的再認(rèn)識,2,Folliculitis,Abscess,Cellulitis,Staphylococcus aureus Skin or Soft-Tissue Infections,Necrotizing pneumonia,Endocarditis,Osteomyelitis,Staphylococcus aureus Deep-Seated Infections,Intracranial infectio

2、n,當(dāng)前用于耐藥革蘭陽性菌的抗生素,藥 名屬類 MRS PRP VISA VRE毒付作用及其他 萬古霉素糖肽YYXX腎毒替考拉寧糖肽YY溶血葡萄球菌弱夫西地酸 Y Y利奈唑胺惡唑烷酮YYYY可貧血，血小板Quinupristin/鏈陽

3、霉素YYYX糞腸球菌差 Dalfopristin副作用達(dá)托霉素環(huán)酯肽 YY 　　　　　　　 呼吸道感染差替加環(huán)素　　 四環(huán)素 　 YYYY ?oritavancin糖肽ly33328　 YYYY 　 組織濃度不理想Telithromycin Ketolide YYYY 對MRSA弱,真的王牌——

4、 經(jīng)得起時間的考驗(yàn),抗G+球菌： 萬古霉素　　　　　　 替考拉寧抗G-桿菌：　多粘菌素抗真菌：　　兩性霉素B,替考拉寧對葡萄球菌屬的抗菌活性,*替考拉寧對金葡菌的抗菌活性比萬古霉素強(qiáng)2～4倍*替考拉寧對凝固酶陰性葡萄球菌的抗菌活性與萬古霉素相似,　但對溶血葡萄球菌的抗菌作用較萬古霉素差,Spencer RC,Goering R, Int J Antimicrob Agents 1995;5:

5、169-177,替考拉寧對鏈球菌屬的抗菌活性,*替考拉寧對肺炎鏈球菌和化膿性鏈球菌等的抗菌活性較萬古霉素稍強(qiáng)或相仿,Spencer RC,Goering R, Int J Antimicrob Agents 1995;5:169-177,替考拉寧對腸球菌屬的抗菌活性,Spencer RC,Goering R, Int J Antimicrob Agents 1995;5:169-177,替考拉寧的抗菌活性,耐萬古霉素腸球菌的耐藥類型

6、,替考拉寧對厭氧菌的抗菌活性,Glupczynski et al. Eur J Clin Microbiol 1984;3:50-51,MRSA菌血癥、自體瓣膜感染性心內(nèi)膜炎——糖肽類首選,MRSA菌血癥：非復(fù)雜性（迅速轉(zhuǎn)陰，迅速退熱，無心內(nèi)膜炎、遷涉灶、假體）： 萬古霉素或達(dá)托霉素2周復(fù)雜性：萬古霉素或達(dá)托霉素4~6周心內(nèi)膜炎：萬古霉素或達(dá)托霉素6周評估、處理菌血癥的來源！菌血癥者常規(guī)行心超檢查！,萬古霉素+利福平：6

7、周萬古霉素+慶大霉素：2周,MRSA人工瓣膜感染性心內(nèi)膜炎——推薦糖肽類,MRSA兒童菌血癥、感染性心內(nèi)膜炎——首選糖肽類,萬古霉素：15mg/kg q6h，2~6周鑒于替代藥物療效和安全性有限數(shù)據(jù)的考慮，不推薦利奈唑胺、克林霉素；達(dá)托霉素等選擇也需慎重,2011 IDSA糖肽類治療MRSA菌血癥與感染性心內(nèi)膜炎推薦劑量,Liu C, et al. Clinical Practice Guidelines by the In

8、fectious Diseases Society of America for the Treatment of Methicillin-Resistant Staphylococcus Aureus Infections in Adults and Children. CID 2011:52.,MRSA肺炎的推薦抗菌治療,重癥CAP（進(jìn)入ICU / 壞死或空洞浸潤 / 膿胸） 　　　　　　　經(jīng)驗(yàn)性治療 MR

9、SA感染HA-MRSACA-MRSA伴膿胸MRSA肺炎，抗生素+引流兒童MRSA肺炎：萬古霉素（克林霉素，替代—利奈唑胺）,,,萬古霉素利奈唑胺克林霉素,7~21天,Liu C, et al. Clinical Practice Guidelines by the Infectious Diseases Society of America for the Treatment of Methicillin-Resista

10、nt Staphylococcus Aureus Infections in Adults and Children. CID 2011:52.,,2011 IDSA糖肽類治療MRSA肺炎推薦劑量,Liu C, et al. Clinical Practice Guidelines by the Infectious Diseases Society of America for the Treatment of Methicillin

11、-Resistant Staphylococcus Aureus Infections in Adults and Children. CID 2011:52.,MRSA骨關(guān)節(jié)感染,骨髓炎：清創(chuàng)引流+萬古霉素或達(dá)托霉素、利奈唑胺、克林霉素（+利福平），﹥8周化膿性關(guān)節(jié)炎：同骨髓炎，3~4周骨關(guān)節(jié)、脊柱植入物術(shù)后感染：　　早發(fā)：同骨髓炎 （+2周 利福平）　　遲發(fā)：取出植入物兒童：萬古霉素（克林霉素，達(dá)托霉素，利奈唑胺）,MRS

12、A中樞神經(jīng)系統(tǒng)感染,腦膜炎：萬古霉素2周（+利福平） 替代治療：利奈唑胺，TMP-SMX 引流管：取出，培養(yǎng)轉(zhuǎn)陰后再置入腦膿腫、硬膜下積膿：　　　 切開引流+萬古霉素4~6周（+利福平） 替代治療：利奈唑胺，TMP-SMX海綿竇栓塞：萬古霉素4~6周（+利福平）

13、 替代治療：利奈唑胺，TMP-SMX兒童：萬古霉素,萬古霉素治療失敗怎么辦？,Impact of Increasing Vancomycin Dosage,Recommended vancomycin trough level10 – 15 mg/L or 15 – 20 mg/LAchievable by 15 mg/kg ever 12 hour

14、 Baddour LM, et al. Circulation 2005;111:e394 – 434 Gemmell CG, et al. J Antimicrob Agent 2006;57:589 – 608 Wang JT, et al. J Antimicrob Agent 2001;47:246Higher trough level?20 – 25 mg/L: n

15、o outcome differenceMore renal toxicityWysocki M, et al. Antimicrob Agents Chemother 2001;45:2460 – 7,萬古霉素治療失敗怎么辦？,清創(chuàng)引流替代一：達(dá)托霉素+（慶大霉素，利福平，利奈唑胺，SMZco）替代二：奎奴普丁/達(dá)福普丁， SMZco，利奈唑胺，特拉萬星,臺灣傳染病協(xié)會推薦替考拉寧為MRSA-HAP的經(jīng)驗(yàn)性治療,Guidel

16、ines on antimicrobial therapy of pneumonia in adults in Taiwan, revised 2006. J Microbiol Immunol Infect. 2007; 40(3): 279-283.,推薦替考拉寧作為MRSA感染的遲發(fā)性HAP和VAP的經(jīng)驗(yàn)性治療用藥對于存在多重耐藥危險因素和任何嚴(yán)重疾病的遲發(fā)性HAP (肺炎發(fā)生于入院第5天或以后)，推薦替考拉寧聯(lián)合其他抗生素作為

17、MRSA感染的經(jīng)驗(yàn)性治療用藥對于 VAP，推薦替考拉寧聯(lián)合其他抗生素作為MRSA感染的經(jīng)驗(yàn)性治療用藥,臺灣成人肺炎抗生素治療指南 (2007)臺灣傳染病協(xié)會 (IDST),,,,亞洲HAP工作組專家共識推薦替考拉寧為MRSA-HAP的一線用藥,Song JH, et al. Am J Infect Control. 2008; 36(4): S83-S92.,,,亞洲HAP工作組專家共識 (2008),,推薦萬古霉素和替考拉寧作為

18、治療MRSA感染HAP的一線用藥萬古霉素具有腎毒性和耳毒性等副作用，治療時需要嚴(yán)密監(jiān)測其血藥濃度；替考拉寧嚴(yán)重不良反應(yīng)少，無需監(jiān)測血藥濃度為避免耐藥菌株選擇抗生素，利奈唑胺應(yīng)作為治療MRSA感染HAP的二線用藥,英國MRSA感染預(yù)防和治療指南推薦MRSA感染選用糖肽類治療,Gould FK, et al. Journal of Antimicrobial Chemotherapy. 2009; 63:849–861.,英國MRSA

19、感染預(yù)防和治療指南(2008),無并發(fā)癥的菌血癥推薦使用糖肽類抗生素，療程至少14 d [證據(jù)級別Ⅱ],,,,嚴(yán)重皮膚軟組織感染和/或菌血癥高危因素的住院患者，可考慮使用使用糖肽類抗生素 [證據(jù)級別ⅠA],糖肽類分子結(jié)構(gòu),萬古霉素,替考拉寧,組織濃度(% of serum concentration),◆1986-2007年265篇論文，RCT46篇，符合薈萃分析標(biāo)準(zhǔn)24篇。粒細(xì)胞減少伴發(fā)熱和非粒細(xì)胞減少伴發(fā)熱各12篇，病例數(shù)187

20、2例◆結(jié)論：替考拉寧療效與萬古霉素相似（萬古霉素MIC≤1.5），而不良反應(yīng)（腎毒性）少于萬古霉素,Syetitsky S, et al.Comparative efficacy and safety of vancomycin versus teicoplanin: systematic review and meta-analysis. Antimicrob Agents Chemother. 2009;53:4069-79.,替

21、考拉寧與萬古霉素的療效與安全性: 薈萃分析,Vancomycin Teicoplanin,- 64%,p＜0.05,Hahn-Ast C et al. Infection 2008;36:54–8.,替考拉寧腎毒性發(fā)生率低于萬古霉素,Nephrotoxicity of glycopeptides,Definations: > 50% rise in creatinine,J Chemother 2000;12(

22、supp 5):21-5,29/49,32/42,Hahn-Ast C et al. Infection 2008;36:54–8.,2/11,11/19,%,Overall,Overall,Pneumonia,Pneumonia,替考拉寧 vs 萬古霉素--肺部感染,,,Overall vs Pneumonia Clinical Efficacy in Febrile Neutropenia,C.Tascini. et.al. Jou

23、rnal of Chemotherapy. 2009;21:311-316.,,利奈唑胺與替考拉寧治療G+菌感染的回顧性研究,菌血癥及肺炎是兩組患者最常見的感染類型,C.Tascini. et al. Journal of Chemotherapy. 2009;21:311-316.,臨床有效率(%),32/37,12/15,15/22,7/10,15/16,11/14,13/16,9/14,13/14,8/13,利奈唑胺治療各部位感

24、染的臨床有效率與替考拉寧無統(tǒng)計學(xué)差異,C.Tascini. et al. Journal of Chemotherapy. 2009;21:311-316.,研究結(jié)果,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,Time,MIC90,Log Concentration,24h-AUC,Trough level: 15-20 mg/L24 h-AUC: >800 ?g h/mL (teicolanin)2

25、4 h-AUIC (AUC24/MIC): At least an AUC24/MIC >125，Better an AUC24/MIC >345 or 400,Glycopeptides Time-dependent Bacterial Killing,MIC,Dose,Dose,,,Cmax,T>MIC,,,Teicoplanin Pharmacokinetics,Teicoplanin can be given

26、 by the IV or IM routeLong serum half life (88~182 hrs)90% bound to serum albuminExcreted through the kidneys, 80% of the dose being recovered in urine and 3 % in stool in 16 days,4.98,7.64,9.4,一,,,,一,Teicoplanin Leve

27、ls in Critically Ill Patients202 Patients,J Antimicrob Chemother 2003;51: 971–5.,An appropriate loading dose of teicoplanin (6 mg/kg every 12 h for at least three doses) was administered only in 38.6% of cases

28、 41.2% with normal renal function 8.7% with moderately impaired renal function 2.2% of patients with totally impaired renal functionHypoalbuminaemic in 74.5% More rapid distribution and higher clearance,,J Antimicro

29、b Chemother 2003;51: 971–5.,4.24,6.47,10.8,6.11,11.22,8.66,Teicoplanin Levels in Critically Ill PatientsLoading Dose Is Needed,6 mg/kg every 12 h for three doses,4.98,7.64,9.4,一,,,,一,Teicoplanin Levels in Critically Ill

30、 Patients202 Patients,,J Antimicrob Chemother 2003;51: 971–5.,Niwa T et al. Int J Antimicrob Agents 2010;35:507-10.,Kanazawa N et al. J Infect Chemother 2011;17:297-300.,Matsumoto K et al. J Infect Chemother 2010;16:193

31、-9.,Ahn BJ, et al. Yonsei Med J 2011;52:616-23.,Clinical Response vs. Trough Teicoplanin Levels Ctrough ?13 mg/L on 4th Day (N=69),Matsumoto K et al. J Infect Chemother 2010;16:193-9.,,83%,20%,Teicoplanin Dosing for M

32、RSA Infections,Teicoplanin a total dose of ?36 mg/kg during the first 3 days and a trough concentration of ?13 mg/L on the fourth day,,,9%,88%,?36 mg/kg was recommended to achieve Ctrough > 13 mg/L,Matsumoto K et al.

33、 J Infect Chemother 2010;16:193-9.,13,Serum Level of Teicoplanin,12mg/kg q12h x 3 doses, followed by 12 mg/kg 24h x 1 dose,6mg/kg q12h x 3 doses, followed by 6 mg/kg 24h x 1 dose,Maintenance dose: both 6 mg/kg.day,Wang

34、 JT, et al. Manuscript prepared,,Recommended Teicoplanin Loading Doses,A loading dose of 400 mg q12h for three doses followed by 400mg once daily: None achieved the optimal teicoplanin trough concentration within 3 days

35、800 mg and 400 mg 12 h apart on Day 1 and 600 mg and 400 mg 12 h apart on Day 2, followed by a high maintenance dose of 400 mg95% of patients (21/22) showed the optimal concentration800mg on Day 1 followed by 400mg on

36、Days 2 and 3 is recommended as the initial loading doses to achieve the optimal trough concentration promptly,Niwa T et al. Int J Antimicrob Agents 2010;35:507-10.,Slide 43 of 45,Recommended Teicoplanin Loading Doses,說明書

37、對于劑量的規(guī)定：,腎功能正常的成人和老年人 ：中度感染，如皮膚和軟組織感染、泌尿系統(tǒng)感染、呼吸道感染 ：負(fù)荷量 ：第一天400 mg，靜脈注射1次。維持量 ：靜脈或肌肉注射200 mg，每日1次。嚴(yán)重感染，如骨和關(guān)節(jié)感染、敗血癥、心內(nèi)膜炎 ：負(fù)荷量 ：靜脈注射400 mg，每12小時給藥1次，連續(xù)3次。維持量 ：靜脈或肌肉注射400 mg，每日1次。某些臨床情況，如嚴(yán)重?zé)齻腥净蚪瘘S色葡萄球菌心內(nèi)膜炎病人，替考拉寧維持量可能需要達(dá)

38、到12 mg/kg。,,腎功能不全患者替考拉寧劑量調(diào)整,無尿長期血透患者替考拉寧劑量調(diào)整,替考拉寧不能被血透濾過血藥谷濃度應(yīng)維持在10mg/l以上以往：負(fù)荷劑量6mg/kg，每12小時注射三次，之后每72小時重復(fù)注射一次推薦：每次10mg/kg，每隔48-72小時注射一次,Papaioannou　MG,et al. Inter J Antimicrob Agents 2002; 19: 233-236,CRRT患者替考拉寧劑量