1、-谈耐药背景下的个体化抗感染治疗,感染病患者多重耐药菌感染风险的分层Stratification of Infectious Disease Patients at Risk for MDR Organisms,武汉科技大学附属孝感市中心医院 呼吸内科 彭春燕 2016年3月9日,抗感染药物发展简史,1929 Alexander Fleming 发现青霉素,Howard Florey 和 Ernst Chain分离获得青霉素，用于动物试验。,青霉素首次用于救治战伤患者，拯救了 许多人的生命,1950s 大量抗生素用于临床。,A poster from World War II, dramati
2、cally showing the virtues of the new miracle drug, and representing the high level of motivation in the country to aid the health of the soldiers at war.,Discovery of Antibacterial Agents,CycloserineErythromycinEthionamideIsoniazidMetronidazolePyrazinamideRifamycinTrimethoprimVancomycinVirginiamycin
3、,Imipenem,1930,1940,1950,1960,1970,1980,1990,2000,PenicillinProntosil,Cephalosporin C,EthambutolFusidic acidMupirocinNalidixic acid,OxazolidinonesCecropin,Fluoroquinolones,Newer aminoglycosides,Semi-synthetic penicillins & cephalosporins,Newer carbapenems,Trinems,Synthetic approaches,Empiric screeni
4、ng,Newer macrolides & ketolides,Rifampicin,Rifapentine,Semi-synthetic glycopeptidesSemi-synthetic streptogramins,NeomycinPolymixinStreptomycinThiacetazone,Chlortetracycline,Glycylcyclines,Minocycline,Chloramphenicol,临床关注的耐药问题Resistances of Clinical Concerns,革兰阳性细菌金匍菌 MRSA, VISA, VRSAVRE (地理上差别)肺炎链球菌
5、 青霉素和大环内酯耐药 革兰阴性细菌肠杆菌科ESBLs-喹诺酮,头孢菌素,青霉素类,氨基糖苷类碳青霉烯酶（KPC, NDM-1?）-碳青酶烯耐药在中国出现和蔓延非发酵菌(假单孢菌/不动杆菌)喹诺酮, 头孢菌素,青霉素类,氨基糖苷,碳青霉烯类,Antibiotic Control and Infection Control:The Two Sides of the Resistance “Coin”,Rekha Murthy. Implementation of Strategies to Control Antimicrobial Resistance Chest 2001;119;405-4
6、11,Control of Antibiotic Resistance,经验性抗感染治疗的基本原则耐药背景下的个体化治疗,理性回归/责任所在,慢性咳嗽和黄痰-原因,哮喘 后鼻腔鼻漏病毒感染后气道高反应性胃酸返流吸烟相关的慢性支气管炎支气管扩张症弥漫性泛细支气管炎肺泡蛋白沉积症,急性发热 -WBC不高/淋巴增高（无感染灶）病毒！ -WBC增高/中性粒增高/核左移 可能细菌！ 部位/病原体？ 原发性菌血症？慢性发热 IE、布病、慢性感染灶？结核病？ 非感染性发热 药物热、风湿病、恶性肿瘤,正确诊断是正确治疗的前提,发热的诊断与鉴别诊断,27-year-old man with acute lymp
7、hocytic leukemia.,51-year-old man with chronic myelogenous leukemia.,22-year-old woman with adult T-cell leukemia.,67-year-old woman with adult T-cell leukemia.,61-year-old man with interstitial fibrosis; patient was receiving chlorambucil for chronic lymphocytic leukemia.,COP,Rapid testsWhen availa
8、ble. Gram stain!,Start adequate antibiotic coverage(within 1 hour?)Tillou A et al. Am Surg 2004;70:841-4,Drain purulent collection,SamplingIncluding invasive procedureswhen needed (BAL),合格标本进行微生物学检查 开始经验性抗感染治疗 目标治疗,经验性治疗和目标治疗的统一,选择哪种抗菌药物 感染部位的常见病原学 选择能够覆盖病原体的抗感染药物 -抗菌谱/组织穿透性/耐药性/安全性/费用考虑药代动力学/药效动力学考
9、虑病人生理和病理生理状态 高龄/儿童/孕妇/哺乳 肾功不全/肝功不全/肝肾功能联合不全其它因素 杀菌和抑菌/单药和联合/静脉和口服/ 疗程,经验性抗感染治疗合理选择药物-considerations in choosing antibiotic for empiric therapy,评估病原体 -有的而放矢！评估耐药性 -到位不越位！,病情严重性评估,+,-个体化评估-特殊修正因子 先期抗菌药物对细菌学及其耐药性影响,不同部位感染-病原体的流行病学,从病原学认识感染性疾病,SSSS,PCP,抗菌谱(coverage)组织穿透性(tissue penetration)耐药性(resistanc
10、e, specifically local resistance) 参考代表性资料/依靠当地资料安全性(safety profile) 药物本身/制剂/工艺/杂质费用/效益(cost/effectiveness) 失败或副作用致再治疗费用更高,经验性抗感染治疗药物选择的基本原则,评价病原体耐药可能？,是否耐药菌？ -了解耐药病原体流行状况 参考代表性治疗/依靠当地资料 -个体化用药-合理用药的精髓 病人来源：社区、养老院、医院 高龄、基础疾病、近期抗菌药物、近期住院、侵袭性操作、晚发医院感染,S. aureus,Penicillin,1944,Penicillin-resistantS. au
11、reus,金黄色葡萄球菌耐药的发生发展过程,Methicillin,1962,Methicillin-resistantS. aureus (MRSA),Vancomycin-resistantenterococci (VRE),Vancomycin,1990s,1997,VancomycinintermediateS. aureus(VISA),2002,Vancomycin-resistantS. aureus,CDC, MMWR 2002;51(26):565-567,1960,评价病原体耐药可能？,是否耐药菌？ -了解耐药病原体流行状况 参考代表性治疗/依靠当地资料 -个体化用药-合理
12、用药的精髓 病人来源：社区、养老院、医院 高龄、基础疾病、近期抗菌药物、近期住院、侵袭性操作、晚发医院感染,中国大陆ESBL的发生率,%,Wang H, Chen M. Diagnos Microbiol Infect Dis, 2005, 51, 201-208CMSS/SEANIR/CARES.,year,细菌耐药监测结果如何解读？,实验室药物敏感性监测的解读,意义 -反映了耐药趋势/告诫要谨慎使用抗菌药物 -影响选择药物/考虑耐药性对疗效的影响不足 -实验室收集菌株/大型教学医院/ICU 抗生素选择压力导致耐药性高估！ -没有临床背景资料/不能用于指导个体化用药 (年龄、基础疾病、社区/
13、医院感染、前期抗菌药物使用情况),aExcept nonfermenters/non-Pseudomonas species.Adapted from Carmeli Y. Predictive factors for multidrug-resistant organisms. In: Role of Ertapenem in the Era of Antimicrobial Resistance newsletter. Available at: www.invanz.co.il/secure/downloads/IVZ_Carmeli_NL_2006_W-226364-NL.pdf. A
14、ccessed 7 April 2008; Dimopoulos G, Falagas ME. Eur Infect Dis. 2007;4951; Ben-Ami R, et al. Clin Infect Dis. 2006;42(7):925934; Pop-Vicas AE, DAgata EMC. Clin Infect Dis. 2005;40(12):17921798; Shah PM. Clin Microbiol Infect. 2008;14(suppl 1):175180.,Stratification for Risk for MDR Gram-Negative Pat
15、hogens,重症感染 耐药菌感染！重症感染 革兰阴性肠杆菌科细菌感染！肺炎链球菌、化脓性链球菌、军团 菌、肺孢子菌等均可致重症感染,PCP,LD,对于选择抗菌药物-耐药性 VS 严重性哪个更重要？,PCP,LD,耐药菌感染 VS 严重感染-PCP和LD告诉我们什么？,观点: -耐药性判断 对于合理选择抗菌药物更重要！ 包括重症感染 -即使重症感染,抗感染治疗方案 仍需根据病原体及其耐药性评估 来制定,经验性抗感染治疗的基本原则耐药背景下的个体化治疗以CAP/HAP为例,22,Craven DE. Curr Opin Infect Dis. 2006;19:153-160.,The Chang
16、ing Spectrum of PneumoniaCAP, HCAP, HAP,Healthcare-associated pneumonia is a relatively new clinical entity that includes a spectrum of adult pts who have a close association with acute-care hospitals or reside in chronic-care settings that increase their risk for pneumonia caused by MDR pathogens.,
17、a. CAP=community-acquired pneumoniab. HCAP=healthcare-associated pneumoniac. HAP=hospital-acquired pneumoniad. VAP=ventilator-associated pneumonia,H. influenzae,K. pneumoniae,S. pneumoniae,M. pneumoniae,L. pneumophila,C. pneumoniae,Community-acquired pneumonia in Europe*,*Woodhead M. Eur Resp J 2002
18、; 20: Suppl. 36, 20-27,病原体排序肺链 S pneumoniae非典型病原体 atypicals 流感嗜血杆菌 H infuenzae卡他莫拉菌 M catarrhalis金葡菌 S aureus革兰阴性肠杆菌 GNB,流感流行后/坏死性肺炎 MRSA?,?,?,History of MRSA in U.S.,59,青霉素上市,第一个MRSA菌株出现,Healthcare associated MRSA,CA-MRSA,CommunityAcquired MRSA,In contrast to the rise in nosocomial MRSA from 1990 t
19、o the present, growing awareness of community-acquired MRSA has occurred through published reports of MRSA outbreaks for which traditional risk factors were not identified.,Necrotizing pneumonia,United States and Europe,1980,Outbreak in Detroit, Mich2/3 of patients were IVDU,Mid 1990s,Childrenw/o id
20、entifiable risk factors,Late 1990s,1998 - Athletes/sports teams 1999 - Native Americans,2000,Prison and jail populations,2003,IVDU=intravenous drug users.,Groom AV et al. JAMA. 2001;286:1201-1205. Herold BC et al. JAMA. 1998;279:593-598. CDC. Morb Mortal Wkly Rep. 2001;50:919-922.,Naimi TS et al. JA
21、MA. 2003;290:2976-2984.Zetola N et al. Lancet Infect Dis. 2005;5:275-286.Levine DP et al. Ann Intern Med. 1982;97:330-338. CDC. Morb Mortal Wkly Rep. 2003;52:793-795.,Gillet Y et al. Lancet. 2002;359:753-759. CDC. Morb Mortal Wkly Rep. 1999;48:707-710.,Remains an uncommon cause of CAP -CDC surveilla
22、nce study of invasive MRSA1- 0.74/100,000 -EMERGEncy ID NET Study Group (12 U.S. ERs) 2 MRSA accounted for 2.4% of all CAP; 5% of ICU CAPBut has emerged as a cause of severe CAP Compared to non-MRSA CAP, patients were2:More ill (more likely to be comatose, require intubation, pressors and die in the
23、 ER)More CXR abnormalities (multiple infiltrates, cavitation)Mortality rate 14% (up to 50% in some studies),Epidemiology of MRSA Community-Acquired Pneumonia (CAP),1Klevens JAMA 2007; 298: 1763-1771; 2Moran CID 2012; 54:1126-33,Approach to Empiric Therapy: CAP,Empiric treatment for MRSA is recommend
24、ed for severe CAP defined by:ICU admissionNecrotizing or cavitary infiltratesEmpyemaDiscontinue empiric Rx if cultures do not grow MRSA,Liu CID 2011; 52; 285-322,中国社区MRSA流行病学？我们怎么办？,Valentini Ann of Clin Micro 2008,Characterization of CA-MRSA Associated with Skin and Soft Tissue Infection in Beijing
25、: High Prevalence of PVL+ ST398,A prospective cohort of adults with SSTI between 2009.01 2010.08 at 4 hospitals in Beijing501 SSTI patients were enrolled -Cutaneous abscess (40.7%); impetigo (6.8%); cellulitis (4.8%)S. aureus accounted for 32.7% (164/501) -5 isolates (5/164, 3.0%) were CA-MRSA -most
26、 dominant ST was ST398 (17.6%) -prevalence of PVL gene was 41.5% (66/159) in MSSA.,王辉 PLoS ONE,2012; 7(6): e38577.,到目前为止CA-MRSA所致CAP尚无报告,Epidemiology of MRSA,H-MRSAReservoires -hospitals -LTCFs5 genetic backgrouds,H-MRSA in community -patients with risk factors -contact with patients with risk facto
27、rs,True community-MRSA -no healthcare-associated risk factors -with PVL genes,healthcare,community,AcquiredOnset,H-MRSA 感染危险因素: 年龄65岁， 严重基础疾病， 伤口 广谱抗生素使用， 住院时间延长， 多次住院 侵袭性操作（气管插管、切开/植入血管导管）,合理使用抗MRSA药物糖肽类/利奈唑胺,Prediction of MRSA in Patients with Non-Nosocomial pneumonia,BMC Infectious Diseases 2013,
28、 13:370 doi:10.1186/1471-2334-13-370,Retrospective study from January 2008 to December 2011. 943 culture-positive MRSA and non-MRSA pneumonia outside the hospitalIdentified risk factors associated with MRSA pneumonia.,Community-acquired pneumonia in Europe*,*Woodhead M. Eur Resp J 2002; 20: Suppl. 3
29、6, 20-27,病原体排序肺链 S pneumoniae非典型病原体 atypicals 流感嗜血杆菌 H infuenzae卡他莫拉菌 M catarrhalis金葡菌 S aureus革兰阴性肠杆菌 GNB,?,?,CAP due to GNB,ANSORP, 2002-2004, 912 CAP93 (10.1%) were caused by GNB肠杆菌科-K. pneumoniae (59), Enterobacter spp. (7), S. marcescens (1)非发酵菌-P. aeruginosa (25), A. baumannii (1), Higher morb
30、idity and co-morbid diseasesSeptic shock, malignancy, CV disease, smoking, hypoNa, dyspneaHigher mortality 18.3% vs 6.1% (p5 days)HAP或 MDR病原体的危险因素,否,是,窄谱抗菌药物,广谱抗菌药物-针对MDR病原体,HAP初始经验性抗菌药物选择的流程图,ATS. Am J Respir Crit Care Med 2005;171:388-416,既往90天内曾经使用过抗菌药物住院时间为5天或更长在社区或其他医疗机构抗生素耐药出现的频率高存在HCAP相关危险因素9
31、0天内住急性病院两天及以上家庭内输液治疗（含抗生素）30天内有过持续透析家庭外伤治疗家庭成员有耐多药病原体感染免疫抑制性疾病和/或免疫抑制剂治疗,阴性预计值的价值更大,Stratification of HAP Patients at Risk for MDR Organisms,The differences not firmly settled Available data indicate in spontaneously breathing pts -potentially drug resistant microorganisms may play a minor role -GNE
32、B(abx susceptible), S aureus (MSSA) and S pneumoniae as leading pathogens,-spontaneously breathing VS ventilated,Ewig S, Torres A, et al.(1999) Bacterial colonization patterns in mechanically ventilated patients with traumatic and medical head injury. Incidence, risk factors, and association with VA
33、P. Am J Respir Crit Care Med 159:188198Rello J, Torres A (1996) Microbial causes of VAP. Semin Respir Infect 11:2431,Mechanical Ventilation Is Associated With a Significantly Increased Incidence of Respiratory Tract MRSA Infection,Pujol M et al. Eur J Clin Microbiol Infect Dis. 1998;17:622-628.,A pr
34、ospective cohort study conducted to define the clinical and epidemiological characteristics of MRSA VAP acquired during a large-scale outbreak of MRSA,Time from Hospitalization (days),Time from Intubation (days),Late-onset HAP,Early-onset VAP,Late-onset VAP,Early-onset HAP,(American Thoracic Society
35、. Am J Respir Crit Care Med 2005;171:388-416),Stratification of Patients at Risk for MDR Organisms,-early onset VS late-onset,Early-onsetLate-onsetpneumoniapneumoniaOthers based on(5 days) specific risksS. pneumoniae P. aeruginosa Anaerobic bacteria H. influenzaeEnterobacter spp. Legionella pneumoph
36、ilaS. aureus Acinetobacter spp. Influenza A and B Enterobacteriaceae K. pneumoniae RSVS. marcescens Fungi E. coli Other GNB S. aureus (MRSA),GNB, Gram-negative bacilli; MRSA, methicillin-resistant S.aureus,Adapted from Am J Respir Crit Care Med. 2005;171:388416.,Stratification of HAP Patients at Ris
37、k for MDR Organisms,-early onset VS late-onset,-Recent Antibiotic Therapy and Pseudomonal Resistance,Trouillet JL et al. Clin Infect Dis. 2002;34:1047-1054.,P. aeruginosa VAP: 34 isolates piperacillin and multi-drug resistant; 101 sensitiveUse of antibiotics (imipenem, third generation cephalosporin
38、 and quinolone) within 15 days of VAP increased PA resistance to the same agent-patient-specific abx rotation,aP=.0009 bP=.003 cP=.001 dP=.05,Stratification of Patients at Risk for MDR Organisms,既往应用抗生素发生CRAB的风险比(OR),Kim YJ,et al.J Korean Med Sci. 2012 May;27(5):471-5.,碳青霉烯使用是IR-MDRAB出现的唯一独立危险因素,Ye
39、JJ, et al. PLoS One. 2010 Apr 1; 5(4):e9947,Stratification of Patients at Risk for MDR Organisms,-Recent Antibiotic Therapy and Acinetobacter Resistance,Risk Factors for Infections With Multidrug-Resistant Stenotrophomonas maltophilia in Patients With Cancer. CANCER 。2007；109（12）：2615-22,Stratificat
40、ion of Patients at Risk for MDR Organisms,-Recent Antibiotic Therapy and S maltophilia,医院获得性肺炎细菌学演变-抗生素选择性压力的体现,早期(Early),中期(Middle),晚期(Late),1 3 5 10 15 20,肺链,流感嗜血杆菌,MSSA MRSA,肠杆菌科细菌(抗生素敏感) 肠杆菌科细菌(抗生素不敏感),肺克, 大肠 肺克, 大肠,铜绿假单胞菌 MDR XDR PDR,不动杆菌 MDR XDR PDR,嗜麦芽窄食单胞菌,抗生素选择性压力,二代头孢菌素 三代头孢菌素/酶抑制剂复合制剂 碳青霉烯+抗MRSA,1 3 5 10 15 20,hospital/ICU admmission,
