替加環(huán)素文獻(xiàn)匯報(bào)

1、,,替加環(huán)素PK/PD特點(diǎn)及臨床應(yīng)用,,,,匯 報(bào) 人：培訓(xùn)專業(yè)：指導(dǎo)老師：,目錄,2,目錄,3,四環(huán)素概述--1,4,一、發(fā)現(xiàn)史：,1948年自金色鏈絲菌（Streptomyces aurao faciens）的培養(yǎng)液中分離得到 金霉素—第一個(gè)天然四環(huán)素類抗生素。1950年從皸裂鏈絲菌培養(yǎng)液中分離出土霉素。 1953年發(fā)現(xiàn)將金霉素脫去氯原子，可得到四環(huán)素。隨后發(fā)現(xiàn)用在不含氯 的培養(yǎng)基中生長(zhǎng)的鏈霉菌菌株發(fā)酵可

2、生產(chǎn)四環(huán)素。,四環(huán)素概述--2,5,二、基本結(jié)構(gòu),四環(huán)素類抗生素是由放線菌產(chǎn)生的一類口服廣譜抗生素。為四并苯（Naphthacene）衍生物，具有十二氫化并四苯基本結(jié)構(gòu) 。,四環(huán)素概述--3,6,二、基本結(jié)構(gòu),6位去氧5位加氧,6位去氧，去甲基7位加N(CH3)2,多西環(huán)素,四環(huán)素概述--3,7,二、基本結(jié)構(gòu),9位加甘氨?；?替加環(huán)素,四環(huán)素概述--4,8,三、分類,目錄,9,替加環(huán)素簡(jiǎn)介,10,替加環(huán)素：第一個(gè)甘氨酰環(huán)素類抗生素

3、,既可維持四環(huán)素類的抗菌作用，又能對(duì)抗四環(huán)素類藥物的耐藥性機(jī)制,老虎素,,替加環(huán)素簡(jiǎn)介,11,Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae,Acinetobacter baumanni, Pseudomonas aeruginosa Enterobacter species,,ESKAPE,11,替加環(huán)素簡(jiǎn)介,12,Enterococcus

4、 faecium, Staphylococcus aureus,Clostridium difficile，Acinetobacter baumanni, Pseudomonas aeruginosa Enterobacter species,,ESCAPE,12,替加環(huán)素PD特點(diǎn),13,1. Shao, Y., et al., Prevalence of plasmid-mediated quinolone resistan

5、ce determinants in Citrobacter freundii isolates from Anhui province, PR China. J Med Microbiol, 2011. 60(Pt 12): p. 1801-5.,MRSA:耐甲氧西林金黃色葡萄球菌；VRE:耐萬(wàn)古霉素腸球菌；ESBL:超廣譜β內(nèi)酰胺酶；CR-AB:耐碳青霉烯鮑曼不動(dòng)桿菌；CRE:耐碳青霉烯腸桿菌#：不包含真菌；√：具有抗菌活性，臨

6、床敏感率＞60%；X：代表臨床無(wú)效、無(wú)數(shù)據(jù)或敏感率＜30%； *：替加環(huán)素對(duì)G-菌中銅綠假單胞菌天然耐藥；?： 部分基因型的VRE對(duì)替考拉寧敏感,替加環(huán)素PD特點(diǎn),14,替加環(huán)素抗菌譜：G+,G-.非典型病原體，厭氧菌,替加環(huán)素通過(guò)與核糖體30S 亞單位結(jié)合、阻止氨?；痶RNA分子進(jìn)入核糖體A 位而抑制細(xì)菌蛋白質(zhì)合成,對(duì)多數(shù)細(xì)菌為抑菌劑，對(duì)軍團(tuán)菌和肺炎鏈球菌為殺菌劑,2. Petersen PJ, Jacobus NV, Weiss

7、WJ, et al. In vitro and in vivo antibacterial activities of a novel glycylcycline, the 9-t-butylglycylamido derivative of minocycline (GAR-936). Antimicrob Agents Chemother 1999;43:738-44,替加環(huán)素PD特點(diǎn),15,有效對(duì)抗多種耐藥機(jī)制

8、 對(duì)常見(jiàn)致病菌(包括耐藥菌)抗菌活性強(qiáng),與其他四環(huán)素類或其他抗菌藥物不易產(chǎn)生交叉耐藥,核糖體保護(hù)機(jī)制,外排泵機(jī)制,外排泵無(wú)法識(shí)別替加環(huán)素，不會(huì)將其泵出排出蛋白無(wú)法識(shí)別或是排出蛋白誘導(dǎo)不足,結(jié)合位點(diǎn)不同，結(jié)合方式獨(dú)特具有很高的結(jié)合力,,,FDA批準(zhǔn)替加環(huán)素適應(yīng)癥,,,,16,替加環(huán)素已獲FDA批準(zhǔn)的適應(yīng)癥：,治療18歲(含)以上由敏感菌株引起的成人復(fù)雜性皮膚和皮膚軟組織感染(cSSSI) 社

9、區(qū)獲得性細(xì)菌性肺炎（CAP）治療18歲(含)以上由敏感菌株引起的成人復(fù)雜性腹腔內(nèi)感染(cIAI),Off lable indicationsMDR（多重耐藥感染）感染嚴(yán)重復(fù)雜性難治性艱難梭菌性腸炎,17,復(fù)雜性闌尾炎,復(fù)雜性膽囊炎,腹腔膿腫,腸穿孔,復(fù)雜性憩室炎,胃/十二指腸穿孔,腹膜炎,其他,234263 262,7069 74,40 3551 45,38 2951 40,23 3032 42,

10、23 2325 25,16 1818 20,2 33 5,n=,治愈率(%),N=,替加環(huán)素治療不同疾病類型的腹腔感染具有較好的臨床治愈率,95% CI： 1.1 % (6.8 % to 4.6 %),95% CI： 2.5% (6.4% to 11.4%),95% CI： 0.7% (17.0% to 18.8%),95% CI： 2.0% (17.0% to 21.8%),95% CI： 0.4 % (22.1

11、%to 21.7%),95% CI： 0.0% (20.6% to 20.6%),95% CI： 1.1% (27.4% to 23.8%),95% CI： 6.7% (56.6% to 60.0%),3. Babinchak, T., et al., The efficacy and safety of tigecycline for the treatment of complicated intra-abdominal infec

12、tions: analysis of pooled clinical trial data. Clin Infect Dis, 2005. 41 Suppl 5: p. S354-67.,替加環(huán)素臨床研究,18,19,4. Purdy J, Jouve S, Yan JL, et al. Pharmacokinetics and safety profile of tigecycline in children aged 8 to 11

13、 years with selected serious infections: a multicenter, open-label, ascending-dose study. Clin Ther 2012;34:496-507,一項(xiàng)多中心、開(kāi)放式 II 期臨床試驗(yàn)研究了58例8-11歲的兒童患者推薦1.2mg/kg Q12h可以達(dá)到滿意AUC/MIC.,替加環(huán)素臨床研究,,20,替加環(huán)素PK特點(diǎn),替加環(huán)素是首個(gè)經(jīng)非腸道的甘氨酰環(huán)類抗

14、生素,初始劑量為100mg，然后50mgQ12h維持治療，可用0.9%氯化鈉注射液，5%葡萄糖注射液，或者林格氏液稀釋最少滴注30——60min治療cIAI及cSSSI推薦5-14天，治療CAP推薦7-14天,用法用量及療程,ADME,21,替加環(huán)素PK特點(diǎn),替加環(huán)素廣泛分布于身體各組織 替加環(huán)素的穩(wěn)定狀態(tài)分布容積約為7.2 -- 8.6 L/kg，且其分布范圍要超過(guò)血漿的分布容積可廣泛分布到全身各個(gè)組織根據(jù)臨床研究觀察(0.1

15、至1.0 μg/mL)，替加環(huán)素的體外血漿蛋白結(jié)合率約為71%至89%,5. Peterson, L.R., A review of tigecycline--the first glycylcycline. Int J Antimicrob Agents, 2008. 32 Suppl 4: p. S215-22.,ADME,22,替加環(huán)素PK特點(diǎn),替加環(huán)素呈線性PK特點(diǎn)首劑給予100mg后續(xù)50mgQ12h可達(dá)Cmax為866 &

16、#177; 233 mg/L半衰期長(zhǎng)為37 - 67 h在體內(nèi)并不經(jīng)過(guò)廣泛的代謝—可與其他經(jīng)肝藥酶代謝藥物合用在接受14C-替加環(huán)素的男性健康志愿者中，替加環(huán)素在尿液和糞便中發(fā)現(xiàn)主要14C 標(biāo)記物質(zhì)，但也可見(jiàn)葡萄糖醛酸苷、N-乙酰代謝產(chǎn)物和替加環(huán)素異構(gòu)體，每種成分不超過(guò)給藥劑量的10%,6. Korth-Bradley JM, Baird-Bellaire SJ,Patat AA, et al. Pharmacokinetics

17、 and safety of a single intravenous dose of the antibiotic tigecycline in patients with cirrhosis. J Clin Pharmacol 2011;51:93-101,ADME,23,雙通道排泄途徑總劑量的22%以替加環(huán)素原型經(jīng)尿液排泄代謝產(chǎn)物沒(méi)有任何活性腎功能不全患者（包括透析患者）無(wú)需調(diào)整給藥劑量，在嚴(yán)重肝功能不全患者中需要調(diào)整劑量

18、-首劑100mg后維持計(jì)量為25mgQ12h，并密切關(guān)注患者情況。,替加環(huán)素PK特點(diǎn),ADME,約有59%通過(guò)膽汁/糞便排泄消除,33%經(jīng)尿液排泄,6. Korth-Bradley JM, Baird-Bellaire SJ,Patat AA, et al. Pharmacokinetics and safety of a single intravenous dose of the antibiotic tigecycline in

19、 patients with cirrhosis. J Clin Pharmacol 2011;51:93-101,藥代動(dòng)力學(xué)特性—抗生素后效應(yīng)(PAE),替加環(huán)素為時(shí)間依賴性抗菌藥物，并具有中至長(zhǎng)時(shí)間的PAE,對(duì)肺炎鏈球菌PAE為8.9h,1、體外試驗(yàn)顯示，替加環(huán)素對(duì)各種金葡菌的PAE可持續(xù)3.4-4h，對(duì)大腸埃希菌(包括帶有特定抗藥性決定因子的菌株)可持續(xù)1.8-2.9h2、一項(xiàng)嗜中性白血球缺乏癥小鼠大腿局部感染模型研究顯示，

20、替加環(huán)素體內(nèi)的PAE持續(xù)時(shí)間極長(zhǎng)，對(duì)肺炎鏈球菌為8.9h,24,,25,替加環(huán)素臨床應(yīng)用,目錄,26,替加環(huán)素不足,27,,不推薦用于醫(yī)院獲得性肺炎（HAP）不推薦用于呼吸機(jī)相關(guān)肺炎（VAP）不推薦用于糖尿病引起的足部感染,7. Burkhardt O, Rauch K, Kaever V, et al. Tigecycline possibly underdosed for the treatment of pneumonia:

21、a pharmacokinetic viewpoint. Int J Antimicrob Agents 2009;34:101-2,28,亞胺培南(n=243),替加環(huán)素(n=268),亞胺培南(n=429）,替加環(huán)素(n=440),CE人群,c-mITT人群,亞胺培南治療HAP患者的治愈率高,8. Freire, A.T., et al., Comparison of tigecycline with imipenem/ci

22、lastatin for the treatment of hospital-acquired pneumonia. Diagn Microbiol Infect Dis, 2010. 68(2): p. 140-51.,替加環(huán)素臨床研究,在VAP患者亞胺培南明顯縮短患者住院時(shí)間,治療VAP患者的住院時(shí)間,住院天數(shù),P=0.046,替加環(huán)素臨床研究,29,8. Freire, A.T., et al., Comparison of t

23、igecycline with imipenem/cilastatin for the treatment of hospital-acquired pneumonia. Diagn Microbiol Infect Dis, 2010. 68(2): p. 140-51.,替加環(huán)素FDA警示：,30,31,,替加環(huán)素可增加VAP及HAP的病死率，重度感染需慎重選用替加環(huán)素,研究顯示藥物原因引起的病死率各組間無(wú)統(tǒng)計(jì)學(xué)差異，在治療MRS

24、A及VRE感染時(shí)表現(xiàn)出非劣性療效。,,,替加環(huán)素對(duì)于重度感染的療效不佳,31,32,,替加環(huán)素增加患者病死率，由于較低的臨床療效和抗菌能力，應(yīng)避免在重癥感染中單獨(dú)應(yīng)用替加環(huán)素。,感染類型及程度是HAP的一個(gè)重要危險(xiǎn)因素。繼發(fā)性VAP是膿毒血癥及死亡率的重要危險(xiǎn)因素。,替加環(huán)素對(duì)于重度感染的療效不佳,,,9. Kaewpoowat, Q. and L. Ostrosky-Zeichner, Tigecycline : a criti

25、cal safety review. Expert Opin Drug Saf, 2015. 14(2): p. 335-42.,,替加環(huán)素FDA黑框警示,,,,33,FDA在2010年9月通告注射用替加環(huán)素可增加患者的病死率，在2013年9月將此嚴(yán)重不良反應(yīng)寫入黑色警示框。,,34,替加環(huán)素黑框警示,,,,,,影響替加環(huán)素臨床療效的原因包括,替加環(huán)素的抗菌活性主要顯示為抑制細(xì)菌生長(zhǎng),替加環(huán)素在體內(nèi)的分布容積大，在組織中的分布濃度差異大

26、。有報(bào)道顯示，替加環(huán)素在血液、肺上皮細(xì)胞襯液以及骨組織中的濃度較低。因此，替加環(huán)素治療肺炎以及DFI（糖尿病足感染）的療效可能不佳,替加環(huán)素對(duì)部分G-菌天然耐藥，因此，替加環(huán)素能否有效治療多重耐藥G-菌感染一直存在爭(zhēng)議,避免單藥使用替加環(huán)素治療重度感染，并將其作為最后考慮使用的抗菌藥物,替加環(huán)素應(yīng)用現(xiàn)狀,35,36,小結(jié),37,參考文獻(xiàn),1. Shao, Y., et al., Prevalence of plasmid-mediat

27、ed quinolone resistance determinants in Citrobacter freundii isolates from Anhui province, PR China. J Med Microbiol, 2011. 60(Pt 12): p. 1801-5.Petersen PJ, Jacobus NV, Weiss WJ, et al. In vitro and in vivo antibacteri

28、al activities of a novel glycylcycline, the 9-t-butylglycylamido derivative of minocycline (GAR-936). Antimicrob Agents Chemother 1999;43:738-44Babinchak, T., et al., The efficacy and safety of tigecycline for the treat

29、ment of complicated intra-abdominal infections: analysis of pooled clinical trial data. Clin Infect Dis, 2005. 41 Suppl 5: p. S354-67.Purdy J, Jouve S, Yan JL, et al. Pharmacokinetics and safety profile of tigecycline i

30、n children aged 8 to 11 years with selected serious infections: a multicenter, open-label, ascending-dose study. Clin Ther 2012;34:496-507Peterson, L.R., A review of tigecycline--the first glycylcycline. Int J Antimicro

31、b Agents, 2008. 32 Suppl 4: p. S215-22.Korth-Bradley JM, Baird-Bellaire SJ,Patat AA, et al. Pharmacokinetics and safety of a single intravenous dose of the antibiotic tigecycline in patients with cirrhosis. J Clin Pharm

32、acol 2011;51:93-101Burkhardt O, Rauch K, Kaever V, et al. Tigecycline possibly underdosed for the treatment of pneumonia:a pharmacokinetic viewpoint. Int JAntimicrob Agents 2009;34:101-2Freire, A.T., et al., Comparison

33、 of tigecycline with imipenem/cilastatin for the treatment of hospital-acquired pneumonia. Diagn Microbiol Infect Dis, 2010. 68(2): p. 140-51.9. Kaewpoowat, Q. and L. Ostrosky-Zeichner, Tigecycline : a crit

34、ical safety review. Expert Opin Drug Saf, 2015. 14(2): p. 335-42.Gilbert DN et al.熱病.44版，2014Infectious Diseases Society of America, IDSA 2011南非《替加環(huán)素合理用藥指南》 2010 Gilbert DN, et al.熱病.44版,2011.Debast SB, Baue

35、r MP, Kuijper EJ, et al. European society of clinical microbiology and infectious diseases: update of the treatment guidance document for clostridium difficile infection. Clin Microbiol Infect 2014;20:1-26Chemaly RF, Ha

36、nmod SS, Jiang Y,et al. Tigecycline use in cancer patients with serious infections: a report on 110 cases from a singleinstitution. Medicine (Baltimore) 2009;88:211-20Purdy J, Jouve S, Yan JL, et al. Pharmacokinetics an