1、MRSA的诊断及临床治疗,复旦大学华山医院抗生素研究所卫生部抗生素临床药理重点实验室复旦大学附属华山医院感染科,2,OUTLINE,MRSA的临床重要性MRSA的药物敏感性及变迁MRSA感染的抗菌治疗,问题1、MRSA的临床重要性如何？,耐药革兰阴性菌给临床带来的问题较革兰阳性菌更大，如鲍曼不动杆菌革兰阳性菌中，MRSA的临床重要性最大,3.2 million bacterial isolates from 300 clinical lab 19982005 across the United States,Styers D, et al. Ann Clin Microbiol Antimic
2、rob 2006, 5:2.,Staphylococcus aureusEscherichia coliEnterococcus spp.Coagulase-negative staphylococciPseudomonas aeruginosaKlebsiella pneumoniaeProteus mirabilisEnterobacter cloacaeSerratia marcescensAcinetobacter baumanni,Escherichia coliStaphylococcus aureusEnterococcus spp.Pseudomonas aeruginosaC
3、oagulase-negative staphylococciKlebsiella pneumoniaeProteus mirabilisEnterobacter cloacaeStreptococcus pneumoniaeCitrobacter freundii,Percentage of all bacterial isolates encountered,Percentage of all bacterial isolates encountered,Top ten pathogens among inpatients,Top ten pathogens among outpatien
4、ts,1.5,1.6,2.9,3.1,6.1,10.3,12.7,12.7,17.3,18.8,0,5,10,15,20,25,30,35,40,1.0,1.0,1.5,4.2,6.2,6.3,6.5,8.8,14.9,38.6,0,5,10,15,20,25,30,35,40,S. aureus is a leading cause of bacterial infections in hospitals and community in the US,中国革兰阳性菌菌种分布,CHINET 2011,金葡菌是临床最常见的革兰阳性菌,MRSA可引起各类感染,骨髓炎,食物中毒,皮肤烫伤综合征,T
5、中毒休克综合征,脓疱病,疖,肺炎,眼内炎,心内膜炎,蜂窝织炎,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感染的死亡病例数高于AIDS的死亡病例数,8,S. aureus is the most common pathogen of HAP (n=656),Kim JM. Am J Infect Control 2000;28:454-8.,
6、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conducted in 12 hospitals in China from 2008 to 2010 to know the incidence and causative pathogens of HAP.,Liu YN, unpublished data by personal communication,Doern GV et al: Diagn Microbiol Infe
7、ct Dis 1999;34:65Brook I: Int J Surg 2008;6:328Chira S, Miller LG: Epidemiol Infect 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 are unc
8、ommonPolymicrobial infections are encountered:Especially with deeper soft tissue infections,Microbiology in Skin/Soft Tissue Infections,金葡菌是皮肤软组织感染的最常见病原菌,11,OUTLINE,MRSA的临床重要性MRSA的药物敏感性及变迁MRSA感染的抗菌治疗,Prevalence of MRSA and MRCNS in Shanghai region since 1999,问题2、MRSA对万古霉素的耐药性如何？ 是否存在MIC漂移（MIC creep
9、）？,MSSA(2954株)与MRSA(3033株)的耐药率（%）,CHINET 2011,耐药监测数据显示，MRSA对万古霉素、利奈唑胺100敏感,15,Twelve VRSA (Vancomycin resistant S. 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
10、factorsAAC 2009; 53: 4580-7,16,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 MIC64 mg/L, vanA positive (Saha B, et al. J Med Microbiol 2008; 57, 7279)Ira
11、n: 2 strainsOne isolate had a vancomycin MIC of 64 mg/LOther one had a vancomycin MIC of 512 mg/L and vanA positive ( Aligholi M, et al. Med Princ Pract 2008; 17(5): 432),17,异质性万古霉素中介金葡菌（hVISA）在中国的发生情况,1012株MRSA于2002-7年（主要为05-07）分离自14个城市检测方法：含药平皿及MET初筛，菌群分析策略-曲线下面积方法确认,2007年分离自14个城市315株MRSA，hVISA 9.
12、5(30/315) (陈宏斌，中华检验医学杂志 2009; 32(11): 1223-7),Sun W, AAC 2009; 53(9): 3642-9,How to detect VISA and hVISA ?,19,Clinical Infectious Diseases 2007; 44:153642,VISA strains (vanco MIC 4-8 ) hVISA (vanco MIC 1-2 ) CAN NOT be detected by disk diffusion method,20,MIC testing is recommended by CLSI to deter
13、mine vancomycin susceptibility for MRSA since 2009,* BHI+6g/ml vancomycin* send to reference lab,21,Comparison of laboratory detection methods of hVISA,Benjamin P. CLINICAL MICROBIOLOGY REVIEWS. 2010; 23:99-139.,hVISA can not be detected by routine methods,Population analysis profile (PAP) is “gold
14、standard”, but it is labor-intensive and impractical for clinical lab.Testing for hVISA is not routinely recommended,Vancomycin MIC creep：地区差异,22,Journal of Antimicrobial Chemotherapy (2007) 60, 788794,23,全球九国10年（2001-2010）分离MRSA万古霉素MIC几何均数在1mg/L左右(0.661.13),Reynolds R, ECCMID 2012, P1215,Vancomycin
15、 Susceptibility 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 decreased in 2010-2The reason for this decrease is uncertain. It may be due to
16、 reduced use of V or higher drug concentrations. The targeted V trough levels were increased in early 2010 to 15-20 g/L,25,OUTLINE,MRSA引起的常见感染MRSA的药物敏感性及变迁MRSA感染的抗菌治疗,问题3、目前临床应用的治疗MRSA感染的抗菌药主要有哪些？各有什么优缺点？,抗MRSA的最主要抗菌药物,27,万古霉素的优点与缺点,优 点临床使用近50年，革兰阳性菌对其仍高度敏感治疗革兰阳性菌感染最为经典的药物临床适应证最广,缺 点MRSA敏感性下降问题组织浓度不
17、良反应,不同MRSA感染的抗菌药物选择,Liu C, Clin Infect Dis 2011; 52(3):285,2011 IDSA MRSA指南,万古霉素的临床适应证最广,万古霉素治疗药物监测（TDM）相关问题,监测血清谷浓度监测给药剂量最准确、实用；应在达到稳态后采集标本（第4-5次给药前） ；并非所有患者需要血药浓度监测；监测谷浓度对象：肾功能损害；肥胖；表观分布容积波动；,31,Trough serum vancomycin concentrations always be maintained at 10 mg/L to avoid the development of resi
18、stance (BIII)To improve clinical outcomes of hospital-acquired pneumonia caused by S. aureus, trough serum vancomycin concentrations of 1520 mg/L are recommended (Note: much higher than former concentration of 5-10 mg/L) (BIII)To achieve rapid attainment of this target concentration for seriously il
19、l patients, a loading dose of 2530 mg/kg )(1.5-1.8 g)(based on actual body weight) can be considered. (BIIITrough serum vancomycin concentrations in that range should achieve an AUC/MIC of 400 for most patients if the MIC is 580, 肠球菌感染 638，预测95患者可达临床有效,糖肽类的耳肾毒性问题,在上市之初，因纯度的问题，毒性较明显纯度提高后，耳肾毒性发生率低长疗程用
20、药需注意药物热的出现可能,利奈唑胺的优点与缺点,优 点新类别抗菌药对VRE、VISA、hVISA等具抗菌活性临床适应证较广同时有静脉及口服制剂,缺 点抑菌剂静脉导管相关血流感染疗效问题耐药性出现较快骨髓抑制,不同MRSA感染的抗菌药物选择,Liu C, Clin Infect Dis 2011; 52(3):285,2011 IDSA MRSA指南,利奈唑胺的临床适应证较广,新类别抗菌药研发困难,近年开发新类别抗菌药少利奈唑胺(linezolid)：恶唑烷酮类(oxazolidinones)达托霉素(daptomycin): 脂肽类现有类别药物的改进替利霉素(telithromycin)：酮内
21、酯类ketolides, 为大环内酯类红霉素A的衍生物替加环素(tigecycline)：甘氨酰环素类glycylcyclines为四环素类米诺环素的衍生物特拉万星(telavancin)：脂糖肽类lipoglycopeptides，为万古霉素的衍生物,利奈唑胺对革兰阳性菌具良好抗菌作用,Jones RN et al. Diagnostic Microbiology and Infectious Disease . 2009;65:404413.,2008年对24个国家64个医学中心收集的6121株G+球菌进行的耐药监测结果,利奈唑胺不推荐用于导管相关血流感染,2007年FDA向医生发出警告治
22、疗导管相关感染的研究表明2 利奈唑胺治疗首次用药后84天内的死亡率21.5%(78/363) ，而对照组为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 Disease 2009, 48:203-212.2,FDA Alert 3/18
23、/2007.,美国 Leader program 2004-2010耐利奈唑胺的金葡菌发生率,Diagnostic Microbiology and Infectious Disease 74 (2012) 5461,全球监测显示，MRSA对利奈唑胺的耐药率低,Clinical outbreak of linezolid-resistant Staphylococcus aureusin an intensive care unit in Spain (Hospital Clinico San Carlos),Snchez Garca M, JAMA. 2010; 303(22):2260-4
24、,Mechanism of linezolid resistance,Mutations in domain V of 23S rRNAMutations in rplC (ribosomal protein L3) and rplD (L4)Mediated by Cfr methyltransferaseUnknown mechanism,问题4、治疗MRSA肺炎，利奈唑胺是否优于万古霉素？,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 EOT,MITT at EO
25、T,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*n=23,n=214*n=10,n=205*n=19,n=174*n=2,Primary endpoint,Secondary endpoint,* Number of excluded patients,Zephyr
26、 study: linezolid is superior than vancomycin in the treatment of MRSA pneumonia,Wunderink RG, CID 2012; 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,Controver
27、sy: is linezolid really 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 = 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
28、,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 excluded pts from analysis,A large number of mITT patients excluded from the statistic population,Controversy : is linezolid really better than vancomycin?,Higher proportion of ca
29、ses with MRSA bacteremia and mechanical ventilation 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,针对MRSA医院肺炎的荟萃分析提示 万古霉素的临床疗效与利奈唑胺相仿,Walkey AJ, CHEST 2010; DOL 1378
30、/1556.,达托霉素的优点与缺点,优 点新类别抗菌药快速杀菌作用对VRE、VISA、hVISA等具抗菌活性,缺 点无肺炎适应证价格较高CPK升高在中国的问题：血培养阳性率低,Bacterial Growth Phases:达托霉素对静止期细菌也具杀菌作用,Stationary-phase bacteria: are non-dividing and metabolically arrested.Associated with persistent infections (endocarditis and osteomyelitis) Associated with biofilm-relat
31、ed infections (catheters, grafts, and foreign bodies) The mechanism of action of many 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
32、4260 Vol. 51, No.12.,Drug Penetration: % Tissue/Serum,达托霉素在多数组织的浓度较高,不同MRSA感染的抗菌药物选择,Liu C, Clin Infect Dis 2011; 52(3):285,2011 IDSA MRSA指南,Daptomycin Outcomes in Patients with Severe Sepsis due to Staphylococcal Bacteremia with Vancomycin MICs of 2 mg/L,100 pts were included in the efficacy popula
33、tion (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. Holloway, MA,克林霉素（Clindamycin),FDA批准治疗葡萄球菌感染；皮肤软组织、骨骼等组织浓度高（不包括CSF）；成功治疗儿童侵袭性CA-MRSA感染（骨髓炎、关节炎、肺炎等）；妊娠用药分类B；抑菌剂，不用于血管内感染（BSI、IE）；诱导耐药，HA-MRSA敏感性？腹泻多见；,54,MRSA pne
34、umonia antimicrobial therapy regimens recommended by IDSA 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% were CA-MRSA,Liu Y, Br J D
35、ermatol 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),对葡萄球菌呈杀菌作用；胞内浓度高，透过生物膜；耐药发生快，不单独应用；用于治疗MRSA感染的地位、给药方案尚待更多研究；,SMZ-TMP (TMP-SMX),CA-MRSA对其敏感率为90%100%，MRSA对其敏感性高门诊治疗SSTI的重要选择；治疗骨、关节感染有效（
36、主要为MSSA)；少数证据支持治疗BSI、IE等侵袭性感染；慎用于老年人，尤其慢性肾功能不全或同时服用肾素-血管紧张素抑制剂患者（高钾血症）；,四环素类(Teracycline),属妊娠用药D类，不用于8岁以下儿童多西环素（doxycyline）FDA批准用于葡萄球菌感染；治疗MRSA经验有限；治疗SSTI有效；治疗其他侵袭性感染资料缺乏；米诺环素（Minocycline）；对部分多西环素耐药CA-MRSA tet(k)基因仍有效；,替加环素（tigecycline）,对MRSA、VRE、不动杆菌属均具良好抗菌活性FDA批准用于cSSTI，CAP和腹腔感染组织浓度、血浓度低,替拉万星(Telavancin),脂糖肽类药物，抑制细胞壁合成，细胞膜去极化对MRSA、VISA、VRSA呈杀菌作用FDA批准用于cSSTI肾功能损害多于万古霉素国内尚未上市,SUMMARY,MRSA是临床常见的病原菌，可引起全身各类感染MRSA对常用抗菌药的耐药性高，对糖肽类、利奈唑胺及达托霉素的敏感性高MRSA的治疗：万古霉素仍为主要推荐药物新药：利奈唑胺、达托霉素、替加环素老药：SMZco、利福平、克林霉素、四环素,
