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MRSA 的诊断及临床治疗 PowerPoint Presentation
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MRSA 的诊断及临床治疗

MRSA 的诊断及临床治疗

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MRSA 的诊断及临床治疗

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  1. MRSA的诊断及临床治疗 王明贵 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

  3. MRSA引起的常见感染 • MRSA为医院获得性感染的常见致病菌 • MRSA引起的常见感染: • 皮肤软组织感染 • 肺炎 • 骨髓炎、关节炎 • 中枢神经系统感染 • 心内膜炎

  4. MRSA is one of the major pathogens of HAP in Asia Charmla R. Am J Infect Control 2008; 36:s93-100

  5. S. aureus is the most common pathogen of HAP (n=656) 91% of S. aureus were MRSA Percentage(%) P aeruginosa E coli CoNS Others S aureus MRSA K pneumoniae Enterococcus spp E. faecalis Candida spp C. albicans Acinetobacter spp A. baumannii Enterobacter spp E. cloacae S. marcescens S. maltophilia C. freundii Kim JM. Am J Infect Control 2000;28:454-8.

  6. MRSA is the third most common pathogen of HAP in China The incidence of HAP varies from 0.9-4.1% in different hospitals in China A. baumannii S. aureus C. albicans E. coli C. Tropical CoNS P. aeruginosa S. maltophilia E. cloacae A. fumigatus K. pneumoniae A multi-center survey conducted in 12 hospitals in China from 2008 to 2010 to know the incidence and causative pathogens of HAP. Percentage(%) Liu YN, unpublished data by personal communication

  7. 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 7

  8. Prevalence of MRSA and MRCNS in Shanghai region since 1999

  9. MSSA(2954株)与MRSA(3033株)的耐药率(%) CHINET 2011

  10. Nine VRSA (Vancomycin resistant S. aureus) reported in the US • Nine cases from USA • Seven from Michigan (first reported in 2002) • One from Pennsylvania • One from New York • Positive for the vanA gene • Median vancomycin MIC: 512 mg/L • All patients had prior MRSA colonization or infection • All had severe underlying factors AAC 2009;53: 4580-7

  11. 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≥64 mg/L, vanA positive (Saha B, et al. J Med Microbiol 2008; 57, 72–79) Iran: 2 strains One isolate had a vancomycin MIC of 64 mg/L Other one had a vancomycin MIC of 512 mg/L and vanA positive ( Aligholi M, et al. Med Princ Pract 2008; 17(5): 432)

  12. 目前hVISA在中国的发生情况Sun W, AAC 2009; 53(9): 3642-9 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 9.5%(30/315) (陈宏斌,中华检验医学杂志 2009; 32(11): 1223-7) 12

  13. Correlation between vancomycin Etest MIC and heteroresistance for MRSA The proportion of hVISA isolates increases with increasing vancomycin MICs within the susceptible range N=74 N=355 N=50 N=10 Percentage of hVISA (%) hVISA hVISA hVISA Vancomycin MIC Howden BP, CLINICAL MICROBIOLOGY REVIEWS. 2010;23:99

  14. hVISA对临床治疗的影响 以色列16例hVISA感染患者,均以恰当的万古霉素给药方案治疗(谷浓度均>5 mg/L) 7例存在持续血流感染(血培养持续阳性5天以上),12例(75%)死亡,其中8例与hVISA的感染直接相关。 结论:hVISA感染的预后差 Maor Y, J Clin Microbiol, 2007, 45:1511–4 14

  15. How to detect VISA and hVISA ?

  16. Disc diffusionand E-Test 17mm zone “S” 17mm zone “S” 17mm zone “S” 17mm zone “S” 17mm zone “S” MIC– 8ug/ml “I” MIC– 8ug/ml “I” MIC– 8ug/ml “I” MIC– 8ug/ml “I” MIC– 8ug/ml “I” MIC– 8ug/ml “I” E-Test: MIC 2, but disc diffusion: for “S” E-Test: MIC =2, but disc diffusion: for “S” E-Test: MIC>2, but disc diffusion: for “S” VISA strains (vanco MIC 4-8 ) hVISA (vanco MIC 1-2 ) CAN NOT be detected by disk diffusion method • VISA was identified as "S“ by disc diffusion Clinical Infectious Diseases 2007; 44:1536–42

  17. MIC testing is recommended by CLSI to determine vancomycin susceptibility for MRSA since 2009 * BHI+6μg/ml vancomycin ** send to reference lab

  18. Comparison of laboratory detection methods of hVISA 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 not routinely recommended Benjamin P. CLINICAL MICROBIOLOGY REVIEWS. 2010; 23:99-139.

  19. QUESTION: Is vancomycin MIC tested in the clinical microbiology department of your hospital? MIC may not be tested in some institutions because of the high price of E-test strips and/or the labor-intensive dilution method

  20. 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 20

  21. 不同MRSA感染的药物选择 Liu C, Clin Infect Dis 2011; 52(3):285

  22. 不同MRSA感染的药物选择 Liu C, Clin Infect Dis 2011; 52(3):285

  23. 不同MRSA感染的药物选择 Liu C, Clin Infect Dis 2011; 52(3):285

  24. 万古霉素(vancomycin) 治疗MRSA感染的支柱(Vancomycin has been the mainstay of parenteral therapy for MRSA infections); 慢效杀菌,耐药,MIC漂移; 在肺部、骨骼、CSF浓度低; 妊娠用药C类; 对MSSA疗效不如β内酰胺类药物

  25. AUC24/MIC是决定去甲万古霉素治疗革兰阳性菌感染疗效的主要指标AUC24/MIC是决定去甲万古霉素治疗革兰阳性菌感染疗效的主要指标 葡萄球菌感染AUC24/MIC >580, 肠球菌感染 >638,预测95%患者可达临床有效 Zhang J, Eur J Clin Microbial Infect Dis 2008; 27: 275

  26. 万古霉素治疗药物监测(TDM) 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;

  27. Therapeutic vancomycin dose adjustment and drug monitoring Trough serum vancomycin concentrations always be maintained at >10 mg/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 than 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. (BIII Trough 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 27

  28. QUESTION: Is serum vancomycin concentration tested in your institution? Therapeutic Drug Monitoring might not be implemented in some Asian countries and relatively low doses of vancomycin might be used in clinical practice

  29. 利奈唑胺(Linezolid) 噁唑烷酮类,抑制细菌蛋白质合成 FDA批准适应证:MRSA所致HAP、皮肤软组织感染 口服生物利用度100% 与其他药物无交叉耐药 妊娠用药分类C 不良反应:骨髓抑制,周围神经、神经损害等

  30. 利奈唑胺对革兰阳性菌具良好抗菌作用 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 Jones RN et al. Diagnostic Microbiology and Infectious Disease . 2009;65:404–413.

  31. 组织浓度 组织/血清(%) Tissue Linezolid Vancomycin Teicoplanin Linezolid Bone 7%–13% ~50%–60% 60% CSF 0%–18% ~10% 70% ELF 11%–17% 415%13 Inflammatory blister fluid 77% 104% Muscle ~30% ~40% 94% Peritoneal dialysis fluid ~20% ~40% 61% 1. Graziani 1988; 2. Matzke 1986; 3. Albanese 2000; 4. Georges 1997; 5. Lamer 1993; 6. Daschner 1987; 7. Blevins 1984; 8. Wilson 2000; 9. Stahl 1987; 10. Wise 1986; 11. Frank 1997; 12. Lovering 2002; 13. SmPC; 14. Gee 2001; 15. Gendjar 2001.

  32. 达托霉素(Daptomycin) 独特杀菌机制(细胞膜去极化,破坏细菌细胞膜离子梯度); FDA批准治疗血流感染(右心IE)、复杂性皮肤软组织感染; 妊娠用药分类B; 被肺泡表面活性物质灭活,不用于肺炎; 与万古霉素交叉耐药? CPK升高、嗜酸性细胞肺炎;

  33. 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;

  34. MRSA pneumonia antimicrobial therapy regimens recommended by IDSA guideline 2011 Therapy duration: 7-21 days 34 Liu C, Clin Infect Dis 2011; 52(3):285

  35. High resistance rate of clindamycin against CA-MRSA in Mainland China 984 strains of S. aureus from impetigo children, 2003-07 1.1% were CA-MRSA Clindamycin is NOT suitable for the treatment of MRSA infections in some regions where resistance rate to this drug is high Liu Y, Br J Dermatol 2009; 161(6):1347 35

  36. 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;

  37. SMZ-TMP (TMP-SMX) CA-MRSA对其敏感率为90%~100%; 门诊治疗SSTI的重要选择; 治疗骨、关节感染有效(主要为MSSA); 少数证据支持治疗BSI、IE等侵袭性感染; FDA未批准用于葡萄球菌感染; 妊娠用药C/D类; 不用于小于2个月婴儿; 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);

  38. 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;

  39. 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

  40. 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; 妊娠用药C类 国内尚未上市

  41. 例1 老年人MRSA肺炎的抗菌治疗 • M 78y • 医院获得性肺炎(T38.5˚C, 咳嗽、黄痰,血Wbc 13×109, P89%),3次痰培养为MRSA • DM史30年,脑梗史5年 • 治疗:万古霉素 0.5 ivgtt q12h,5天无效 • 问题: • 为何抗菌治疗无效? • 抗菌治疗方案调整: • 万古霉素加量至 0.5 q8h? • 利奈唑胺 0.6 ivgtt q12h?

  42. 例1 讨论 • 无效原因: • 病原因素:MRSA非真正致病菌? • 有DM基础疾病、3次痰培养阳性--需要考虑是致病菌 • 药物因素: • MRSA对万古霉素敏感性下降? • 万古霉素在肺组织中未达到有效浓度? • 最后确定改用利奈唑胺,体温下降

  43. 例2、肾功能减退者MRSA感染 • M, 59y • 右下肢皮肤感染、破溃10天,渗出物培养:MRSA 2次 • 糖尿病史28年,血Cr 145 µmol/L • 问题:如何选抗菌药? • 利奈唑胺0.6 ivgtt q12h • 其他选择的问题: • 万古霉素及SMZco:不良反应问题 • 磷霉素:抗菌活性问题 • 利福平:耐药问题

  44. 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,对糖肽类万古霉素的敏感性近年来有下降趋势 • 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