感染病患者多重耐药菌感染风险诊断

,Click to edit Master title style,Click to edit Master text styles,Second Level,Third Level,Fourth Level,Fifth Level,-,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, dramatically 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,Cycloserine,Erythromycin,Ethionamide,Isoniazid,Metronidazole,Pyrazinamide,Rifamycin,Trimethoprim,Vancomycin,Virginiamycin,Imipenem,1930,1940,1950,1960,1970,1980,1990,2000,Penicillin,Prontosil,Cephalosporin C,Ethambutol,Fusidic acid,Mupirocin,Nalidixic acid,Oxazolidinones,Cecropin,Fluoroquinolones,Newer aminoglycosides,Semi-synthetic penicillins & cephalosporins,Newer carbapenems,Trinems,Synthetic approaches,Empiric,screening,Newer macrolides & ketolides,Rifampicin,Rifapentine,Semi-synthetic glycopeptides,Semi-synthetic streptogramins,Neomycin,Polymixin,Streptomycin,Thiacetazone,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, VRSA,VRE,(,地理上差别,),肺炎链球菌,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,Infection,Control,Antibiotic,stewardship,VRE,MRSA,AB,ESBL,K. pneumoniae,Antibiotic Control and Infection Control:,The Two Sides of the Resistance “Coin”,Rekha Murthy.,Implementation of Strategies to Control Antimicrobial Resistance,Chest,2001;119;405-411,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 lymphocytic 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 tests,When available. Gram stain!,Start adequate antibiotic coverage,(within 1 hour?),Tillou A et al. Am Surg 2004;70:841-4,Drain purulent collection,Sampling,Including invasive procedures,when 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,(resistance, 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-resistant,S. aureus,金黄色葡萄球菌耐药的发生发展过程,Methicillin,1962,Methicillin-resistant,S. aureus,(MRSA),Vancomycin-resistant,enterococci (VRE),Vancomycin,1990,s,1997,Vancomycin,intermediate,S. aureus,(VISA),2002,Vancomycin-,resistant,S. 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,/,医院感染、前期抗菌药物使用情况,),a,Except 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. Accessed 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 Pathogens,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 Changing 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.,Pneumonia,CAP,a,HCAP,b,HAP,c,/VAP,d,Morbidity & Mortality,Risk of MDR Pathogens,a. CAP=community-acquired pneumonia,b. HCAP=healthcare-associated pneumonia,c. HAP=hospital-acquired pneumonia,d. 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; 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,CA-MRSA,爆发于不同人群,儿童中出现没有“经典”危险因素的,MRS,感染,98,MMWR,报告,4,例健康儿童死于,MRSA,感染,99,CA-MRSA,成为,SSTI,的主要原因,04,05,在美国侵袭性,MRSA,导致,18,650,死亡,Community,Acquired MRSA,In contrast to the rise in nosocomial MRSA from 1990 to 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, Mich,2/3 of patients were IVDU,Mid 1990s,Children,w/o identifiable 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.,JAMA.,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 surveillance study of invasive MRSA,1-,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 CAP,But has emerged as a cause of severe CAP,Compared to non-MRSA CAP, patients were,2,:,More ill (more likely to be comatose, require intubation, pressors and die in the ER),More CXR abnormalities (multiple infiltrates, cavitation),Mortality rate 14% (up to 50% in some studies),Epidemiology of MRSA Community-Acquired Pneumonia (CAP),1,Klevens JAMA 2007; 298: 1763-1771;,2,Moran CID 2012; 54:1126-33,Approach to Empiric Therapy: CAP,Empiric treatment for MRSA is recommended for severe CAP defined by:,ICU admission,Necrotizing or cavitary infiltrates,Empyema,Discontinue 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: High Prevalence of PVL+ ST398,A prospective cohort of adults with SSTI between 2009.01,2010.08 at 4 hospitals in Beijing,501 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 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-MRSA,Reservoires,-hospitals,-LTCFs,5 genetic backgrouds,H-MRSA in community,-patients with risk factors,-contact with patients with,risk factors,True community-MRSA,-no healthcare-associated,risk factors,-with PVL genes,healthcare,community,Acquired,Onset,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,Retrospective study from January 2008 to December 2011.,943 culture-positive MRSA and non-MRSA pneumonia outside the hospital,Identified risk factors associated with MRSA pneumonia.,Community-acquired pneumonia in Europe*,*Woodhead M. Eur Resp J 2002; 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,?,?,CAP due to GNB,ANSORP, 2002-2004, 912 CAP,93 (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 morbidity,and co-morbid diseases,Septic shock, malignancy, CV disease, smoking, hypoNa, dyspnea,Higher 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,90,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,-GNEB(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 VAP. Am J Respir Crit Care Med 159:188198,Rello 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 prospective 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,0,1,2,3,4,5,6,7,0,1,2,3,4,5,6,7,(American Thoracic Society. 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-onset,pneumoniapneumoniaOthers based on,(5 days) specific risks,S. pneumoniae P. aeruginosa,Anaerobic bacteria,H. influenzae,Enterobacter,spp.,Legionella pneumophila,S. aureus,Acinetobacter,spp.,Influenza A and B,Enterobacteriaceae,K. pneumoniae,RSV,S. marcescens,Fungi,E. coli,Other GNB,S. aureus,(MRSA),GNB, Gram-negative bacilli; MRSA, methicillin-resistant,Adapted from Am J Respir Crit Care Med. 2005;171:388416.,Stratification of HAP Patients at Risk 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 sensitive,Use of antibiotics (imipenem, third generation cephalosporin and quinolone) within 15 days of VAP increased PA resistance to the same agent-patient-specific abx rotation,a,P,=.0009,b,P,=.003,c,P,=.001,d,P,=.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 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,Stratification 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,LOS 4 d),Early,(,4 d),50,Leading Pathogens,Slide Library,Time of Onset,医院获得性肺炎细菌学演变,-,抗生素治疗的方向,早期,(Early),中期,(Middle),晚期,(,Late),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,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,酶抑制剂复合制剂,1 3 5 10 15 20,耐药背景下的个体化抗感染治疗,-,小结,正确诊断,是正确治疗的前提,努力实现,经验性治疗和目标治疗之统一,经验性抗感染治疗的,两种能力,-,评估病原体,流行病学,/,个体化评估,/,从病原学识别感染性疾病,-,评估耐药性,流行病学基础上的个体化评估,耐药菌感染,:,高龄,/,基础疾病,/,近期住院,(ICU)/,晚发医院感染,/,抗生素暴露,No simplistic policy,Homogenous protocol,Mixing,Thank You,