mrsa抗菌治療進展

1、MRSA的診斷及臨床治療,復(fù)旦大學(xué)華山醫(yī)院抗生素研究所衛(wèi)生部抗生素臨床藥理重點實驗室復(fù)旦大學(xué)附屬華山醫(yī)院感染科,2,OUTLINE,MRSA的臨床重要性MRSA的藥物敏感性及變遷MRSA感染的抗菌治療,問題1、MRSA的臨床重要性如何？,耐藥革蘭陰性菌給臨床帶來的問題較革蘭陽性菌更大，如鮑曼不動桿菌革蘭陽性菌中，MRSA的臨床重要性最大,3.2 million bacterial isolates from 300 clini

2、cal lab 1998–2005 across the United States,Styers D, et al. Ann Clin Microbiol Antimicrob 2006, 5:2.,Staphylococcus aureusEscherichia coliEnterococcus spp.Coagulase-negative staphylococciPseudomonas aeruginosaKlebsi

3、ella pneumoniaeProteus mirabilisEnterobacter cloacaeSerratia marcescensAcinetobacter baumanni,Escherichia coliStaphylococcus aureusEnterococcus spp.Pseudomonas aeruginosaCoagulase-negative staphylococciKlebsiell

4、a pneumoniaeProteus mirabilisEnterobacter cloacaeStreptococcus pneumoniaeCitrobacter freundii,Percentage of all bacterial isolates encountered,Percentage of all bacterial isolates encountered,Top ten pathogens among

5、inpatients,Top ten pathogens among outpatients,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,1.5,1.6,2.9,3.1,6.1,10.3,12.7,12.7,17.3,18.8,0,5,10,15,20,25,30,35,40,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,1.0,1.0,1.5,4.2,6.2,6.3,6.5,8.8,14.9,

6、38.6,0,5,10,15,20,25,30,35,40,S. aureus is a leading cause of bacterial infections in hospitals and community in the US,中國革蘭陽性菌菌種分布,CHINET 2011,金葡菌是臨床最常見的革蘭陽性菌,MRSA可引起各類感染,骨髓炎,食物中毒,皮膚燙傷綜合征,T中毒休克綜合征,膿皰病,癤,肺炎,眼內(nèi)炎,心內(nèi)膜炎,蜂窩

7、織炎,Annual Death Rates in the United StatesSelected Infectious Diseases,No. of patients died,Boucher HW and Corey GR. Clin Infect Dis 2008;46:S344-9.,MRSA感染的死亡病例數(shù)高于AIDS的死亡病例數(shù),8,S. aureus is the most common pathogen of HA

8、P (n=656),Kim JM. Am J Infect Control 2000;28:454-8.,91% of S. aureus were MRSA,9,MRSA is the third most common pathogen of HAP in China,,A multi-center survey conducted in 12 hospitals in China from 2008 to 2010 to know

9、 the incidence and causative pathogens of HAP.,Liu YN, unpublished data by personal communication,Doern GV et al: Diagn Microbiol Infect Dis 1999;34:65Brook I: Int J Surg 2008;6:328Chira S, Miller LG: Epidemiol In

10、fect 2010;138:313,Gram-positive organisms predominate (60-70%)S. aureus - 48% in one studyGroup A ?-hemolytic streptococci - 26%Gram-negative organisms involved in 25-35% of infectionsAnaerobic and fungal organisms

11、are uncommonPolymicrobial infections are encountered:Especially with deeper soft tissue infections,Microbiology in Skin/Soft Tissue Infections,金葡菌是皮膚軟組織感染的最常見病原菌,11,OUTLINE,MRSA的臨床重要性MRSA的藥物敏感性及變遷MRSA感染的抗菌治療,Prevalen

12、ce of MRSA and MRCNS in Shanghai region since 1999,,問題2、MRSA對萬古霉素的耐藥性如何？ 是否存在MIC漂移（MIC creep）？,MSSA(2954株)與MRSA(3033株)的耐藥率（%）,CHINET 2011,耐藥監(jiān)測數(shù)據(jù)顯示，MRSA對萬古霉素、利奈唑胺100％敏感,15,Twelve VRSA (Vancomycin resistant S

13、. aureus) reported in the US,Twelve cases from USAPositive for the vanA geneMedian vancomycin MIC: 512 mg/LAll patients had prior MRSA colonization or infectionsAll had severe underlying factorsAAC 2009; 53: 4580-7,

14、16,Five VRSA reported in Asia,India: 3 strains 2 strains: vancomyicn MIC 32 or 64 mg/L, vanA negative in addition, found 6 VISA strains (Tiwari HK, BMC Infect Dis 2006; 6: 156)One VRSA vancomycin MIC≥6

15、4 mg/L, vanA positive (Saha B, et al. J Med Microbiol 2008; 57, 72–79)Iran: 2 strainsOne isolate had a vancomycin MIC of 64 mg/LOther one had a vancomycin MIC of 512 mg/L and vanA positive ( Aligholi

16、 M, et al. Med Princ Pract 2008; 17(5): 432),17,異質(zhì)性萬古霉素中介金葡菌（hVISA）在中國的發(fā)生情況,1012株MRSA于2002-7年（主要為05-07）分離自14個城市檢測方法：含藥平皿及MET初篩，菌群分析策略-曲線下面積方法確認(rèn),2007年分離自14個城市315株MRSA，hVISA 9.5％(30/315) (陳宏斌，中華檢驗醫(yī)學(xué)雜志 2009; 32(11): 1223

17、-7),Sun W, AAC 2009; 53(9): 3642-9,,How to detect VISA and hVISA ?,19,Clinical Infectious Diseases 2007; 44:1536–42,VISA strains (vanco MIC 4-8 ) hVISA (vanco MIC 1-2 ) CAN NOT be detected by disk diffusion method,20,MIC

18、 testing is recommended by CLSI to determine vancomycin susceptibility for MRSA since 2009,* BHI+6μg/ml vancomycin** send to reference lab,,21,Comparison of laboratory detection methods of hVISA,Benjamin P. CLINICAL MI

19、CROBIOLOGY REVIEWS. 2010; 23:99-139.,hVISA can not be detected by routine methods,Population analysis profile (PAP) is “gold standard”, but it is labor-intensive and impractical for clinical lab.Testing for hVISA is no

20、t routinely recommended,Vancomycin MIC creep：地區(qū)差異,22,Journal of Antimicrobial Chemotherapy (2007) 60, 788–794,23,全球九國10年（2001-2010）分離MRSA萬古霉素MIC幾何均數(shù)在1mg/L左右(0.66~1.13),,Reynolds R, ECCMID 2012, P1215,Vancomycin Suscepti

21、bility in MRSA Over 10 Years: MIC Decrease After a Transient Creep,ICAAC 2012. C2-1391 R. Khatib, Grosse Pointe Woods, MI,677 isolates tested. Van MIC was stable between 2002-3 and 2005-6, increased in 2008-9 and decreas

22、ed in 2010-2The reason for this decrease is uncertain. It may be due to reduced use of V or higher drug concentrations. The targeted V trough levels were increased in early 2010 to 15-20 μg/L,25,OUTLINE,MRSA引起的常見感染MRS

23、A的藥物敏感性及變遷MRSA感染的抗菌治療,,問題3、目前臨床應(yīng)用的治療MRSA感染的抗菌藥主要有哪些？各有什么優(yōu)缺點？,抗MRSA的最主要抗菌藥物,27,萬古霉素的優(yōu)點與缺點,優(yōu) 點臨床使用近50年，革蘭陽性菌對其仍高度敏感治療革蘭陽性菌感染最為經(jīng)典的藥物臨床適應(yīng)證最廣,缺 點MRSA敏感性下降問題組織濃度不良反應(yīng),不同MRSA感染的抗菌藥物選擇,Liu C, Clin Infect Dis 2011; 52(3):

24、285,2011 IDSA MRSA指南,萬古霉素的臨床適應(yīng)證最廣,萬古霉素治療藥物監(jiān)測（TDM）相關(guān)問題,監(jiān)測血清谷濃度監(jiān)測給藥劑量最準(zhǔn)確、實用；應(yīng)在達到穩(wěn)態(tài)后采集標(biāo)本（第4-5次給藥前） ；并非所有患者需要血藥濃度監(jiān)測；監(jiān)測谷濃度對象：腎功能損害；肥胖；表觀分布容積波動；,31,Trough serum vancomycin concentrations always be maintained at >10 mg

25、/L to avoid the development of resistance (BIII)To improve clinical outcomes of hospital-acquired pneumonia caused by S. aureus, trough serum vancomycin concentrations of 15–20 mg/L are recommended (Note: much higher th

26、an former concentration of 5-10 mg/L) (BIII)To achieve rapid attainment of this target concentration for seriously ill patients, a loading dose of 25–30 mg/kg )(1.5-1.8 g)(based on actual body weight) can be considered.

27、 (BIIITrough serum vancomycin concentrations in that range should achieve an AUC/MIC of >400 for most patients if the MIC is <1 mg/L.,Rybak MJ. Clin Infect Dis 2009; 49:325-7,Therapeutic vancomycin dose adjustment

28、 and drug monitoring,AUC24/MIC即給藥劑量：決定去甲萬古霉素治療革蘭陽性菌感染療效的主要指標(biāo),Zhang J, Eur J Clin Microbial Infect Dis 2008; 27: 275,葡萄球菌感染AUC24/MIC >580, 腸球菌感染 >638，預(yù)測95％患者可達臨床有效,糖肽類的耳腎毒性問題,在上市之初，因純度的問題，毒性較明顯純度提高后，耳腎毒性發(fā)生率低長療程用藥需

29、注意藥物熱的出現(xiàn)可能,利奈唑胺的優(yōu)點與缺點,優(yōu) 點新類別抗菌藥對VRE、VISA、hVISA等具抗菌活性臨床適應(yīng)證較廣同時有靜脈及口服制劑,缺 點抑菌劑靜脈導(dǎo)管相關(guān)血流感染療效問題耐藥性出現(xiàn)較快骨髓抑制,不同MRSA感染的抗菌藥物選擇,Liu C, Clin Infect Dis 2011; 52(3):285,2011 IDSA MRSA指南,利奈唑胺的臨床適應(yīng)證較廣,新類別抗菌藥研發(fā)困難,近年開發(fā)新類別抗菌藥少

30、利奈唑胺(linezolid)：惡唑烷酮類(oxazolidinones)達托霉素(daptomycin): 脂肽類現(xiàn)有類別藥物的改進替利霉素(telithromycin)：酮內(nèi)酯類ketolides, 為大環(huán)內(nèi)酯類紅霉素A的衍生物替加環(huán)素(tigecycline)：甘氨酰環(huán)素類glycylcyclines為四環(huán)素類米諾環(huán)素的衍生物特拉萬星(telavancin)：脂糖肽類lipoglycopeptides，為萬古霉素的衍生物

31、,利奈唑胺對革蘭陽性菌具良好抗菌作用,Jones RN et al. Diagnostic Microbiology and Infectious Disease . 2009;65:404–413.,2008年對24個國家64個醫(yī)學(xué)中心收集的6121株G+球菌進行的耐藥監(jiān)測結(jié)果,利奈唑胺不推薦用于導(dǎo)管相關(guān)血流感染,2007年FDA向醫(yī)生發(fā)出警告治療導(dǎo)管相關(guān)感染的研究表明2 利奈唑胺治療首次用藥后84天內(nèi)的死亡率21.5%(78/

32、363) ，而對照組為16.6%(58/363),1,Wilcox MH, Tack KJ,Bouza E,et al. Complicated skin and skin –structure infections and Catheter –Related Bloodstream Infections Noninferiority of Linezolid in Phase 3 Sutdy.Clinical Infectious

33、 Disease 2009, 48:203-212.2,FDA Alert [3/18/2007].,[美國 Leader program 2004-2010]耐利奈唑胺的金葡菌發(fā)生率,Diagnostic Microbiology and Infectious Disease 74 (2012) 54–61,全球監(jiān)測顯示，MRSA對利奈唑胺的耐藥率低,Clinical outbreak of linezolid-resistant

34、 Staphylococcus aureusin an intensive care unit in Spain (Hospital Clinico San Carlos),Sánchez García M, JAMA. 2010; 303(22):2260-4,Mechanism of linezolid resistance,Mutations in domain V of 23S rRNAMutations

35、 in rplC (ribosomal protein L3) and rplD (L4)Mediated by Cfr methyltransferaseUnknown mechanism,,問題4、治療MRSA肺炎，利奈唑胺是否優(yōu)于萬古霉素？,,,,,,,,,57.6,54.8,83.3,80.1,46.6,44.9,69.9,67.8,0,20,40,60,80,100,PP at EOS,MITT at EOS,PP at

36、EOT,MITT at EOT,Proportion of patients with successful response (%),,Linezolid,,Vancomycin,,P = 0.04295%CI 0.5-21.6,P = 0.04995%CI 0.1-19.8,P = 0.002,,P = 0.004,n=165*n=7,n=180*n=3,n=186*n=2,n=186 *n=38,n=201

37、*n=23,n=214*n=10,n=205*n=19,n=174*n=2,Primary endpoint,,Secondary endpoint,* Number of excluded patients,Zephyr study: linezolid is superior than vancomycin in the treatment of MRSA pneumonia,Wunderink RG, CID 2

38、012; 54: 621-9,60 Days Kaplan-Meier Survival rates were similar between two groups for mITT Population,94 subject deaths ( 15.7%) in linezolid arm100 subject deaths (17.0%) in vancomycin arm,Controversy: is linezolid r

39、eally better than vancomycin?,,,,,,,,,57.6,54.8,83.3,80.1,46.6,44.9,69.9,67.8,0,20,40,60,80,100,PP at EOS,MITT at EOS,PP at EOT,MITT at EOT,Proportion of patients with successful response (%),,Linezolid,,Vancomycin,,P =

40、0.04295%CI 0.5-21.6,P = 0.04995%CI 0.1-19.8,P = 0.002,,P = 0.004,n=165*n=7,n=180*n=3,n=186*n=2,n=186 *n=38,n=201*n=23,n=214*n=10,n=205*n=19,n=174*n=2,Primary endpoint,,Secondary endpoint,,*Unknown exc

41、luded pts from analysis,A large number of mITT patients excluded from the statistic population,Controversy : is linezolid really better than vancomycin?,Higher proportion of cases with MRSA bacteremia and mechanical ven

42、tilation in the vancomycin arm,The baseline clinical characteristics of vancomycin arm are seems to be more complicated and severe,Controversy: is linezolid really better than vancomycin?,47,針對MRSA醫(yī)院肺炎的薈萃分析提示 萬古霉素的臨床療效與

43、利奈唑胺相仿,Walkey AJ, CHEST 2010; DOL 1378/1556.,達托霉素的優(yōu)點與缺點,優(yōu) 點新類別抗菌藥快速殺菌作用對VRE、VISA、hVISA等具抗菌活性,缺 點無肺炎適應(yīng)證價格較高CPK升高在中國的問題：血培養(yǎng)陽性率低,Bacterial Growth Phases:達托霉素對靜止期細(xì)菌也具殺菌作用,Stationary-phase bacteria: are non-dividin

44、g and metabolically arrested.Associated with persistent infections (endocarditis and osteomyelitis) Associated with biofilm-related infections (catheters, grafts, and foreign bodies) The mechanism of action of many

45、 bactericidal antibiotics requires ongoing cell division (log phase)Normally bactericidal antibiotics (e.g. , beta-lactams) may display limited activity against stationary phase cells,Mascio et al., AAC 2007 p. 4255–42

46、60 Vol. 51, No.12.,Drug Penetration: % Tissue/Serum,達托霉素在多數(shù)組織的濃度較高,不同MRSA感染的抗菌藥物選擇,Liu C, Clin Infect Dis 2011; 52(3):285,2011 IDSA MRSA指南,Daptomycin Outcomes in Patients with Severe Sepsis due to Staphylococcal Bacterem

47、ia with Vancomycin MICs of ≥2 mg/L,100 pts were included in the efficacy population (15 of which had septic shock) 72 pts received vancomycin prior to DAP, and of those, 27 (38%) failed therapy.,ICAAC 2012. K-1635 K. Ho

48、lloway, MA,克林霉素（Clindamycin),FDA批準(zhǔn)治療葡萄球菌感染；皮膚軟組織、骨骼等組織濃度高（不包括CSF）；成功治療兒童侵襲性CA-MRSA感染（骨髓炎、關(guān)節(jié)炎、肺炎等）；妊娠用藥分類B；抑菌劑，不用于血管內(nèi)感染（BSI、IE）；誘導(dǎo)耐藥，HA-MRSA敏感性？腹瀉多見；,54,MRSA pneumonia antimicrobial therapy regimens recommended by I

49、DSA guideline 2011,Liu C, Clin Infect Dis 2011; 52(3):285,Therapy duration: 7-21 days,55,High resistance rate of clindamycin against CA-MRSA in Mainland China,984 strains of S. aureus from impetigo children, 2003-071.1%

50、 were CA-MRSA,Liu Y, Br J Dermatol 2009; 161(6):1347,Clindamycin is NOT suitable for the treatment of MRSA infections in some regions where resistance rate to this drug is high,利福平 (Rifampin),對葡萄球菌呈殺菌作用；胞內(nèi)濃度高，透過生物膜；耐藥

51、發(fā)生快，不單獨應(yīng)用；用于治療MRSA感染的地位、給藥方案尚待更多研究；,SMZ-TMP (TMP-SMX),CA-MRSA對其敏感率為90%~100%，MRSA對其敏感性高門診治療SSTI的重要選擇；治療骨、關(guān)節(jié)感染有效（主要為MSSA)；少數(shù)證據(jù)支持治療BSI、IE等侵襲性感染；慎用于老年人，尤其慢性腎功能不全或同時服用腎素-血管緊張素抑制劑患者（高鉀血癥）；,四環(huán)素類(Teracycline),屬妊娠用藥D類，不用于8歲以

52、下兒童多西環(huán)素（doxycyline）FDA批準(zhǔn)用于葡萄球菌感染；治療MRSA經(jīng)驗有限；治療SSTI有效；治療其他侵襲性感染資料缺乏；米諾環(huán)素（Minocycline）；對部分多西環(huán)素耐藥CA-MRSA [tet(k)基因]仍有效；,替加環(huán)素（tigecycline）,對MRSA、VRE、不動桿菌屬均具良好抗菌活性FDA批準(zhǔn)用于cSSTI，CAP和腹腔感染組織濃度、血濃度低,替拉萬星(Telavancin),脂糖肽類藥