替考拉寧與肺炎

1、替考拉寧治療 MRSA 肺部感染的優(yōu)勢(shì),,檢出率%,,2009年 CHINET 43670 株臨床分離株中前十位細(xì)菌,2009-CHINET資料,,我國(guó)CHINET耐藥監(jiān)測(cè)顯示葡萄球菌耐藥率較高,Fu Wang et al. Chin J Infect Chemother 2009;9(5):321-329.,金黃色葡萄球菌及凝固酶陰性葡萄球菌中甲氧西林耐藥菌株比例分別為 55.7% 和 75.9%,11052 株 G+ 菌菌株,亞洲

2、國(guó)家HAP病原學(xué)研究提示金葡菌是主要致病菌,Asian HAP Working Group. Am J Infect Control 2008;36:S83-92.,,,,VISA,VISA,VISA,VRSA,VRSA,VRSA,MRSA,VSSA,VSSA,VSSA,,,,,,,1999年1,2000年,2001年2,2005年3,三期臨床時(shí)出現(xiàn)2株LRE,利奈唑胺上市,出現(xiàn)3株LRSA,美國(guó)匹茲堡大學(xué)醫(yī)療中心ICU出

3、現(xiàn)74株LRCNS,LRSA（耐利奈唑胺金葡菌）出現(xiàn)情況,1. Venikata G,Gold HS. Antimicrobial resistance to Linezolid.Clinical Infectious Diseases 2004, 39:1010-1015.2. Tsiodras S, Gold HS,Sakoulas G,et al.Linezolid resistance in a clinical isola

4、te of Staphylococcus aureus. Lancet 2001, 358:207-208.3. Poloski BA, Adams J,Clarke L,et al. Epidemiological Profile of Linezolid-Resistant Coagulase-Negative Staphylocucci.Clinical Infectious Diseases 2006, 43:165-17

5、1.4.An outbreak of colonization with linezolid-resistant Staphylococcus epidermidis in an intensive therapy unitKelly S, Collins J,, Maguire M.Journal of Antimicrobial Chemotherapy,2008, 61, 901–9075. Yurika Ikeda-Dan

6、tsuji ? Hideaki Hanaki ? Fuminori Sakai ,et al.Linezolid-resistant Staphylococcus aureus isolated from 2006 through 2008 at six hospitals in Japan, J Infect Chemother,published online:07 july 2010.6.Sánchez Garc

7、37;a M, De la Torre MA, Morales G, Clinical Outbreak of Linezolid-Resistant Staphylococcus aureus in an Intensive Care Unit. JAMA. 2010 Jun 9;303(22):2260-4.,2006年4,2006～08年5,愛爾蘭一醫(yī)院ICU 出現(xiàn)16株LRSE,日本上市后兩年內(nèi)連續(xù)出現(xiàn)13株LRSA,2008

8、年6,西班牙一ICU出現(xiàn)15 株LRSA，其中6例患者 死亡,作用于核糖體單一抑菌機(jī)制的利奈唑胺的耐藥,Vancomycin 、Linezolid MIC creep,Journal of Antimicrobial Chemotherapy (2007) 60, 788–794,Clatworthy AE, Pierson E, Hung DT,et al.Targeting virulence: a new paradigm

9、for antimicrobial therapy.Nature chemical biology.2007,3(9):541-548,抗生素的耐藥發(fā)展史，新藥迅速耐藥值得重視,,MRSA 病原藥物之肺穿透比較,萬古霉素治療 MRSA 肺炎失敗率高,治療成功率(%),Moise,DeRyke,ClinEval,lIT,Wunderink,N=35,N=42,N=18,N=20,N=54,,Fagon,萬古霉素治療MRSA所致呼吸機(jī)相關(guān)肺

10、炎失敗率高,Wunderink RG.Sem Respir Criti Care Med.2006;27:92-103,替考拉寧,萬古霉素的結(jié)構(gòu)升級(jí),萬古霉素,替考拉寧,,,,糖基修飾,脂肪酸側(cè)鏈,分子量：1486,分子量：1891,替考拉寧應(yīng)運(yùn)而生,抗耐藥陽(yáng)性菌藥物的組織穿透比較,,,? 30%的金葡感染必須考慮 metastatic infection，不適合使用 vancomycin? Teicoplanin 組織穿透力強(qiáng)，對(duì)m

11、etastatic infection之治療優(yōu)於vancomycin,,,,,,,European Glycopeptide Susceptibility Survey 2008,,,分離株%,MIC分布－MRSA（n＝2852）,,,,European Glycopeptide Susceptibility Survey 1995,,,,MIC分布－腸球菌屬（n＝1695）,分離株%,替考拉寧良好的體外抗菌活性,對(duì)金葡菌的抗菌活性比萬

12、古霉素強(qiáng) 2~4 倍對(duì)凝固酶陰性葡萄球菌的作用與萬古霉素相仿對(duì)鏈球菌(包括肺炎鏈球菌)的抗菌活性優(yōu)于萬古霉素對(duì)腸球菌的抗菌活性比萬古霉素強(qiáng) 4~8 倍耐萬古霉素的 VanB, VanC 等 VRE 對(duì)本品仍敏感,,糖肽類目標(biāo)濃度,,對(duì)13例 SICU 內(nèi) MRSA-VAP 應(yīng)用 Teicoplanin 12mg/kg 30min IV q12h ×2d, 此后12mg/kg gd 4-6d 同時(shí)測(cè)

13、定血清和FLE藥物濃度結(jié)果： 血清谷濃度中位數(shù): 15.9µg/ml(8.9-29.9µg/ml) FLE濃度中位數(shù)： 4.9µg/ml（2.0-11.8µg/ml）結(jié)論：為達(dá)到穩(wěn)態(tài)時(shí)肺組

14、織中足夠的藥物谷濃度，在合并VAP的危重患者 應(yīng)用替考拉寧 12mg/kg 30min IV q12h ×2d, 此后12mg/kg gd 其肺組織濃度均可保證≥2µg/ml,Intensive Care Med 2006,32:776-779,Steady-state trough serum and epithelial lining flui

15、d concentrations of teicoplanin 12 mg/kg per day in patients with ventilator-associated pneumonia.,替考拉寧與萬古霉素的藥代動(dòng)力學(xué)比較,,,給藥途徑,彌散速度,血漿蛋白結(jié)合率,替考拉(6mg)/kg,萬古霉素500mg,指標(biāo),Clinical Efficacy and Renal Toxicity among Patients with F

16、ebrile Neutropenia Teicoplanin Vs. Vancomycin,Retrospective, comparative, single-center study100 consecutive neutropenic patients with hematological malignancies and persistent fever after 72 hours of first-line antibi

17、otic therapyGroup T: 50 patients from 8/1996 to 9/2000 received teicoplanin + piperacillin/tazobactam and gentamicinGroup V: 50 patients from 10/2000 to 4/2002 received vancomycin + meropenem and levofloxacin,Hahn-Ast

18、C et al. Infection 2008;36:54–8.,Definition of Treatment SuccessSuccess of empirical antimicrobial therapy was defined as defervescence for at least 7 days in absence of any sign of continuing infection.Patients who we

19、re still febrile at day 21 of antimicrobial treatment were classified as failures.Definition of NephrotoxicityDocumented by monitoring of serum creatinineIncrease of > 0.5 mg/dlDoubling of creatinine,Hahn-Ast C et

20、 al. Infection 2008;36:54–8.,Hahn-Ast C et al. Infection 2008;36:54–8.,Vancomycin Teicoplanin,- 64%,p＜0.05,Hahn-Ast C et al. Infection 2008;36:54–8.,替考拉寧治療 1431 例病人的不良事件,J Antimicrob Chemother 1988 Jan;21

21、Suppl A:61-7,,,Wilcox et al. J Antimicrob Chemother 2004;53:335–344,臨床治愈率,利奈唑胺與替考拉寧,C.Tascini. et.al. Journal 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,研究簡(jiǎn)介,研究目的：比較利奈唑胺與替考拉寧治療 G+ 菌感染的療效、不良反應(yīng)、患者生存率及住院時(shí)間等

22、研究方式：回顧性對(duì)照研究入選人群： 169 例使用利奈唑胺的患者，91 例使用替考拉寧的患者,C.Tascini. et al. Journal of Chemotherapy. 2009;21:311-316.,患者特征,*：p<0.007；?：p<0.002,C.Tascini. et al. Journal of Chemotherapy. 2009;21:311-316.,菌血癥及肺炎是兩組患者最常見的感染類型

23、,C.Tascini. et al. Journal of Chemotherapy. 2009;21:311-316.,臨床有效率(%),32/37,12/15,15/22,7/10,15/16,11/14,13/16,9/14,13/14,8/13,10/14,利奈唑胺治療各部位感染的臨床有效率與替考拉寧無統(tǒng)計(jì)學(xué)差異,C.Tascini. et al. Journal of Chemotherapy. 2009;21:311-316

24、.,研究結(jié)果,P<0.002,P＞0.05,不良反應(yīng)發(fā)生率比較,結(jié)果顯示：利奈唑胺組患者的不良反應(yīng)發(fā)生率略高于替考拉寧組,C.Tascini. et al. Journal of Chemotherapy. 2009;21:311-316.,兩組死亡率比較,患者死亡率(%),27/169,10/91,結(jié)果顯示：利奈唑胺組的總體死亡率略高于替考拉寧組,C.Tascini. et al. Journal of Chemotherapy

25、. 2009;21:311-316.,Comparison of Anti-MRSA Agents,? MRSA 在肺部感染中占有重要地位? 有效的治療藥物非常有限，新藥產(chǎn)生的耐藥狀態(tài)令人擔(dān)憂? 糖肽類對(duì)金葡菌的耐藥發(fā)展極其緩慢、長(zhǎng)期保持其敏感? 替考拉寧(他格適）保持萬古霉素的抗菌活性，在 PK/PD 得到優(yōu)化， 肺組織等濃度提高，不良反應(yīng)減少，療效基本等同于利奈唑胺?替考拉寧(他格適）為細(xì)菌性腦膜炎治療的可選藥物之一,小