抗菌藥物經(jīng)驗(yàn)用藥的精準(zhǔn)化

1、抗菌藥物經(jīng)驗(yàn)用藥的精準(zhǔn)化,卓超廣州呼吸疾病研究所chaosheep@sina.com,全球重要的耐藥菌,,,,,中國(guó)耐藥菌的主要問(wèn)題,革蘭陽(yáng)性菌 相對(duì)樂(lè)觀的問(wèn)題：甲氧西林耐藥金葡菌MRSA 相對(duì)較小的問(wèn)題：萬(wàn)古霉素耐藥腸球菌屬VRE 革蘭陰性菌? 腸桿菌科細(xì)菌（大腸埃希菌、克雷伯菌屬）不易解決的老問(wèn)題：對(duì)頭孢菌素的耐藥：產(chǎn)ESBL愈演愈烈的新問(wèn)題：對(duì)碳青霉烯類耐藥CRE非發(fā)酵糖細(xì)菌（銅綠假單胞菌、不動(dòng)桿菌屬）變化不大

2、的問(wèn)題：銅綠假單胞菌耐藥習(xí)慣了的老問(wèn)題：不動(dòng)桿菌屬耐藥,Changes of antiobiotic resistance of bacteria in China,CHINET & Mohnarin data,產(chǎn)ESBL菌檢出率(%),1、汪復(fù),等.中國(guó)感染與化療雜志.2006;6(5):289-295. 2、汪復(fù).中國(guó)感染與化療雜志.2008年;8(1):1-9.3、汪復(fù) 等.中國(guó)感染與化療雜志.2008;8

3、(5):325-333. 4、汪復(fù)等.中國(guó)感染與化療雜志.2009;9(5):321-330.5、汪復(fù)等.中國(guó)感染與化療雜志.1010;10(5):325-334. 6、朱德妹,等.中國(guó)感染與化療雜志.2011;11(5):321-330.7、胡付品,等.中國(guó)感染與化療雜志.2012;12(5):321-330. 8、汪復(fù) 等.中國(guó)感染與化療雜志.2013;13(5):321-330.,The prevale

4、nce of ESBLs in Enterobacter clinical isolates in China during 2005 to 2013,中國(guó)鄉(xiāng)村醫(yī)療機(jī)構(gòu)耐藥菌發(fā)生情況,Microbes and Infection (2015),,CR-KPN from blood in China in 2013,Zhuo C, et al .CMI 2015, accepted,耐藥菌：基于微生物的精準(zhǔn)化治療,以藥物敏感率指導(dǎo)藥物選

5、擇（正確）敏感率提示可選藥物，耐藥率提示可排除藥物、以藥物MIC和耐藥機(jī)制指導(dǎo)用藥（準(zhǔn)確）同類藥物，MIC越低，體外抗菌活性越強(qiáng)契合PK/PD原則,Forest plot depicting the risk ratios (RR) of all-cause mortality of patients with infection with high-MIC versus low-MIC Gram-negative isolat

6、es.,Falagas M E et al. Antimicrob. Agents Chemother. 2012;56:4214-4222,ESBLs菌株感染治療,1. 碳青霉烯類 (嚴(yán)重感染 ?)2. 復(fù)合制劑（輕中度感染?)3. 頭霉素?4. 頭孢他定？頭孢吡肟？4. 其他藥物？----環(huán)丙沙星85%耐藥；阿米卡星50%左右耐藥。,全國(guó)產(chǎn)ESBL大腸埃希菌藥敏MIC比較,Zhuo C, plos one 2014, 9(

7、7): e100707,與碳?xì)涿瓜┫啾?，TZP治療ESBL菌血癥的生存率仍難逾越 --從感染類型與嚴(yán)重程度,TZP與碳?xì)涿瓜┲委烢SBL的定位--從病原菌種類,對(duì)ESBL-EC感染療效優(yōu)于其它腸桿菌（肺克）其它耐藥機(jī)制存在，OXA-30或AmpC合并存在接種效應(yīng),Clinical Infectious Diseases Advance Access published January 13, 2015,與β-

8、內(nèi)酰胺類/ β-內(nèi)酰胺酶抑制劑劑相比,碳青霉烯治療產(chǎn)ESBL細(xì)菌感染有降低全因死亡率的趨勢(shì)3,,一項(xiàng)納入21個(gè)RCT的meta分析報(bào)道，與β-內(nèi)酰胺類/ β-內(nèi)酰胺酶抑制劑相比，碳青霉烯組治療ESBL感染有全因死亡率更低的趨勢(shì)3,3. Vardakas KZ, et al. J Antimicrob Chemother. 2012 Dec;67(12):2793-803.,一項(xiàng)針對(duì)21項(xiàng)RCT研究的薈萃分析結(jié)果顯示：,不利于β-內(nèi)酰胺

9、類/β-內(nèi)酰胺酶抑制劑,不利于碳青霉烯類,(研究設(shè)計(jì)見(jiàn)備注),Bacteremia Caused by ESBL-Producing EnterobacteriaceaeMortality,%,Cefepime group (n=33),Lee NY, Ko WC PR, Hsueh PR. Clin Infect Dis 2012 October 22,ESBL對(duì)CAZ和FEP都存在適應(yīng)性耐藥的現(xiàn)象,CRE /KPC感染的治療,一

10、直是各領(lǐng)域討論的熱點(diǎn)聯(lián)合治療是基本認(rèn)同碳青霉烯的聯(lián)合從未被忽略觀念的博弈方案的優(yōu)化,Treatment Options for CRE/KPCCombination Therapy is the Mainstream,High-dose and prolonged-infusion carbapenem therapy as part of a combination regimen for CRE with carbapen

11、em MICs ≤4 mg/LCarbapenem-based combinationsPlus colistin, tigecycline, or an aminoglycoside Colistin-based combinationsPlus a carbapenem, tigecycline, or an aminoglycosideTigecycline-based combinationsPlus gentami

12、cin or colistinDouble-carbapenem therapy = “doripenem + ertapenem”,Tzouvelekis LS, et al. Clin Microbiol Rev 2012;25:682-707.,Outcomes of Infections Caused by KPC-KPAccording to Treatment Regimen,A: 2 active drugs with

13、 a carbapenemB: 2 active drugs, not a carbapenemC: Monotherapy with an aminoglycosideD: Monotherapy with a carbapenemE: Monotherapy with tigecyclineF: Monotherapy with colistinG: iInappropriate therapy,,,T

14、zouvelekis LS, et al. Clin Microbiol Rev 2012;25:682-707.,,歷時(shí)4年，5家大型醫(yī)院661例患者入組,對(duì)不同類型CRE感染聯(lián)合治療療效評(píng)估,對(duì)不同類型CRE感染聯(lián)合治療療效評(píng)估 （續(xù)）,對(duì)不同癥候CRE感染聯(lián)合治療療效評(píng)估,對(duì)不同耐藥狀況CRE感染聯(lián)合治療療效評(píng)估,該文獻(xiàn)將碳青霉烯的MIC放寬至8-16,CRE所致不同部位感染的治療推薦,Open Forum Infect Dis.

15、 2015 Apr; 2(2): ofv050.,,,,MIC distributions of 333 CRKP isolates from blood in 2013 in China,Zhuo C, et al .CMI 2015, in press,XDR-腸桿菌科細(xì)菌的MIC分布（Vitek 16卡）,,Treatment Options for CRE/KPCCombination Therapy is the Mai

16、nstream,High-dose and prolonged-infusion carbapenem therapy as part of a combination regimen for CRE with carbapenem MICs ≤4 mg/LCarbapenem-based combinationsPlus colistin, tigecycline, or an aminoglycoside Colistin-b

17、ased combinationsPlus a carbapenem, tigecycline, or an aminoglycosideTigecycline-based combinationsPlus gentamicin or colistinDouble-carbapenem therapy = “doripenem + ertapenem”,Tzouvelekis LS, et al. Clin Microbiol

18、Rev 2012;25:682-707.,Double-Carbapenem Therapy for Carbapenemase-Producing K. pneumoniae,Bacterial densities of KPC 354 over 24 h in the in vitro chemostat model (doripenem MIC, 4 mg/L).,Control,Ertapenemalone,Doripene

19、malone,Doripenem-plus-ertapenem,Comparative efficacies of various dosing regimens of doripenem with or without ertapenem against KPC 354 in the in vivo murine thigh infection model,Antimicrob Agents Chemother 2011;55:3

20、002–4,doripenem 2 g q8h (3-h infusion)+ ertapenem 1 g q24h,,Hypothesis: KPC’s preferential affinity for ertapenem, due to the ease of hydrolysis vs. that of doripenem; thus, ertapenem acts as an KPC consumer,Double-carb

21、apenem therapy for PDR-KPN （碳青霉烯MIC>32）,Clin Infect Dis. (2014) 58 (9): 1274-1283.,1 g ertapenem IV daily, followed 1 hour later by meropenem (2g) or imipenem (1g) every 8 hours infused over 3 hou

22、rs.,高致病性肺炎克雷伯菌,K1,K2, K5, ,K16,K20, K54, and K57 serotypesString test \ positive,,警惕：重癥感染≠耐藥菌感染,Clinical characterics,1、多見(jiàn)于亞洲，糖尿病患者2、和糖尿病密切相關(guān)，男性多3、多為全身系統(tǒng)性感染，常累及肝、肺、眼4、膿腫表現(xiàn)多，多有氣腔5、進(jìn)展快，死亡率高6、多為敏感菌2、7、高效和廣譜的抗生素，

23、以及局部引流,Lancet Infect Dis. 2012 Nov;12(11):881-7,Clostridium difficile Escherichia coli (O104:H4) CA-MRSA---------,由于進(jìn)展快，死亡高，無(wú)論表型如何，碳?xì)涿瓜└采w很重要，并尋找膿腫灶，外科處理,Recommendations on Nosocomial Pneumonia caused by CR, XDR or PDR

24、 Ab.,Conventional agentsCarbapenems (imipenem, meropenem and doripenem) prolonged infusion plus sulbactam (6-8g/d) or sulbactam-containing agentsAlternative agentsIV colisin (2 MU every 8h) plus IV rifampicin (10 mg/k

25、g) or carbapenemTigecycline (high dose) plus carbapenemTigecycline (high dose) plus colistin,Pharmacother 2011; 12: 2145-8.,Colistin dosing: high dosesA loading dose of 300 to 400 mg CBA followed by a maintenance dos

26、e of 150mg twice (CID 2013; 56: 398-404),,基于CPM的聯(lián)合治療時(shí)，即使CPM的MIC>32, 對(duì)死亡率不構(gòu)成危險(xiǎn)因素。,Crit Care Med 2015; 43:1194–1204,對(duì)于多粘菌素耐藥的鮑曼不動(dòng)桿菌感染,以碳青霉烯、多粘菌素和舒巴坦的聯(lián)合治療的死亡率最低，優(yōu)于基于替加環(huán)素+舒巴坦的聯(lián)合治療方案,Clinical Infectious Diseases 2015;60(9)

27、:1295–303,對(duì)于多粘菌素耐藥的鮑曼不動(dòng)桿菌感染,替加環(huán)素對(duì)鮑曼不動(dòng)桿菌的MIC≥1mg/L,Ni WT, et al. Pak J Pharm Sci. 2014;27(3):463-7.,MIC<1mg/L時(shí)，大、小劑量臨床達(dá)標(biāo)率相近,MIC≥1mg/L時(shí)，小劑量替加環(huán)素的臨床達(dá)標(biāo)率顯著低于大劑量替加環(huán)素,臨床達(dá)標(biāo)率（%）,替加環(huán)素對(duì)鮑曼不動(dòng)桿菌的MIC(mg/L),,通過(guò)蒙特卡羅模型計(jì)算臨床達(dá)標(biāo)率與MIC間的

28、關(guān)系，對(duì)多種耐藥（MDR）鮑曼不動(dòng)桿菌感染的院內(nèi)肺炎進(jìn)行給替加環(huán)素不同劑量治療的分析,針對(duì)CRE或XDR的聯(lián)合治療方案,Expert Rev. Anti Infect. Ther. 11(12), 1333–1353 (2013),美羅培南與舒巴坦協(xié)同針對(duì)CRAB,新近研究，舒巴坦作用AB的靶位為PBP1 和 PBP3，而PBP3極少發(fā)生變異美羅培南作用AB的靶位以PBP2和 PBP1a，而對(duì)銅綠假單胞菌以PBP1 和 PBP3為主

29、兩者聯(lián)合時(shí)，即保證對(duì)鮑曼的協(xié)同性，同時(shí)兼顧了對(duì)銅綠合并感染的覆蓋。,Antimicrob Agents Chemother. 2015,59(3):1680-9.,New Microbiologica, 38, 67-73, 2015,碳?xì)涿瓜┞?lián)合藥物的時(shí)間-殺菌效應(yīng)（CRAB）,對(duì)于ABA和PA,MEM較IMP有更窄的MSW,The Scientific World Journal Volume 2014

30、0;(2014), Article ID 979648,,MEM的T>MSW更容易達(dá)標(biāo),,,Facing the Gram-Negative MDROOptimizing Antibiotic Empiricism,AB, A. baumannii; HI, H. influenzae; MC, M. catarrhalis; PA, P. aeruginosa; SP, S. pneumoniae; CR, ca

31、rbapenem-susceptible; CR, carbapenem-resistant,carbpenem,Enterobacteriaceae(CS: ESBL, AmpC, MDR…),Anaerobes,HI, MC,PA, AB (CS),CRAB,CRPA,SulbactamCefoperazone- or ampicillin-),Colistin,Fosfomycin,Ciprofloxacin,Extende

32、d coverage,Synergy resistance,Amikacin,,Tigecycline,Rifampin,+,,,KPC,總結(jié),我國(guó)細(xì)菌耐藥“陰盛陽(yáng)衰”ESBL在腸桿菌科細(xì)菌耐藥中將長(zhǎng)期占重要地位。CRE總體比例較低，CRAB/XDRAB仍然挑戰(zhàn)臨床以藥物MIC，結(jié)合細(xì)菌耐藥機(jī)制、PK/PD指導(dǎo)合理用藥，是當(dāng)前耐藥菌治療的重要依據(jù)碳青霉烯藥物使用到位不越位是門藝術(shù)。,人的收入達(dá)到何種水平最幸福？,,收入高人