个体化抗菌治疗策略

1、 经验性抗感染治疗的基本原则 与临床实践 个体化抗感染治疗Case study acute fever既往健康急性发热、无器官系统感染的临床表现WBC正常阿奇霉素、红霉素、白霉素、洁霉素.(基层)二代头孢、三代头孢、喹诺酮类、酶抑制剂复合制剂、厄他培南.(大医院)感冒样症状轻咳、少痰渐进性气短各种抗菌药物 -广谱+联合呼吸衰竭慢性咳嗽和黄痰-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 -细菌? 部位/病原体？ 原发性菌血症？慢性发热-IE、

2、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Mortality* Associated With Initial Inadequate Therapy in Critically Ill ICU Patients0%20%40%60%80%100%Luna, 1997Ibrahim, 2000Kollef, 1998Harbarth, 2003Rello, 1997Alvarez-Lerma, 1996Initial adequate therapyInitial inadequate therapy*Mortality refe

3、rs to crude or infection-related mortality.Alvarez-Lerma F et al. Intensive Care Med 1996;22:387-394. Rello J et al. Am J Respir Crit Care Med 1997;156:196-200. Harbarth S et al. Am J Med 2003;115:529-535. Kollef MH et al. Chest 1998;113:412-420. Ibrahim EH at al. Chest 2000;118:146-155. Luna CM et

4、al. Chest 1997;111:676-685. Valles J et al. Chest 2003;123:1615-1624.Mortality*Valles, 2003Inadequate Therapy Was Closely Associated With Antibiotic Resistance% Occurrence of PathogenKollef MH. Clin Infect Dis 2000;31(Suppl 4):S131-S138.充分初始治疗改善预后/不充分治疗与耐药紧密相关 2001年在欧洲危重病会议和ICC从“猛击策略”到“降阶梯策略” 开始的广覆盖

5、-对于重症感染 开始即使用广谱抗生素以覆盖所广谱抗生素以覆盖所有可能致病菌有可能致病菌随后的降阶梯-48-72小时后 根据微生物学检查结果调整抗生素的使用/使之更有针对性 目的和意义:防止病情迅速恶化 VSVS 防止细菌产生耐药/降低费用 “广覆盖”与“降阶梯”的有机统一 对VAP最初治疗应针对G-和G+包括MRSA，Gram涂片发现G+球菌与培养金葡萄阳性率之间高度一致。故涂片见G+菌应加用万古霉素代表方案-泰能万古48岁、男性、同种异体肾移植术后3.5个月13天前出现发热（T 38.9），继之咳嗽/无痰、进行性气短胸片先后:头孢呋辛(3d)、莫西沙星(3d)、哌拉西林/他唑巴坦(3d)、亚

6、胺培南/西司他丁万古霉素(3d)查体:发绀、RR 24/分、P 118/分、双肺未闻及干湿罗音ABG:PH 7.48、PO2 56mmHg、PCO2 30mmHgCase study-PCP 58岁、男性、既往身体健康11天前出现发热（T 38.7），继之咳嗽，少痰；胸片(见右)先后头孢唑林(3d)、哌拉西林/他唑巴坦(3d)，无效病情继续加重，呼吸衰竭ALT/AST/Bilirubins/LDH/CK-MBUrinalysis-pro (+) WBC/RBC /CAST(+)再次胸片(见右)换用碳青酶烯抗MRSA抗真菌无效，呼吸衰竭，转诊Case study-LD 58岁、女性、自述既往身体

7、“健康”1天前突然出现上消化道出血诊断:肝炎后肝硬化，食道静脉曲张出血急诊行门脉断流手术术后第二天出现发热（T 38.9），继之咳嗽、咳痰，胸片(见右)血气分析:PaO2=56mmHg（吸空气）碳青酶烯+抗MRSA+抗真菌临床转归 -呼吸衰竭好转，下一步？Case study-POP 问题在哪里？经验性抗感染治疗的基本原则与临床实践Rapid testsWhen available. Gram stain! Start adequate antibiotic coverage(within 1 hour?)Drain purulent collectionSamplingIncluding i

8、nvasive procedureswhen needed (BAL)经验性治疗和目标治疗的统一留取标本进行微生物学检查开始经验性抗感染治疗目标治疗选择哪种抗菌药物(which antibiotic?) 感染部位的常见病原学(possible pathogens on site of infection) 选择能够覆盖病原体的抗感染药物(antibiotics requirement) -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(PK/PD)考虑病人生理和病理生理状态( physiologic and pathophysiology) 高龄/儿童/孕妇/哺乳(adva

9、nced age/children/pregnant women/breast feeding) 肾功能不全/肝功能不全/肝肾功能联合不全(renal/heptic dysfunction/combined)其它因素(other considerations) 杀菌和抑菌/单药和联合/静脉和口服/疗程 (cidal vs static/ mono vs combination/ IV vs PO/ duration)经验性抗感染治疗药物选择-considerations in choosing antibiotic for empiric therapy l培养结果前依据基本信息选择抗感染药物

10、 choosing Abx before culture result感染部位和可能病原体的关系 association of pathogen with site of infectionGram染色结果-与上述病原体是否符合？ Gram stain-in accordance with suspected pathogen?l某些病原体易于造成某些部位的感染 Some pathogen easily cause some site of infection 经验性抗感染治疗药物选择-considerations in choosing antibiotic for empiric ther

11、apy 不同感染部位的常见感染性病原体Possible pathogens on site of infectionM outh Peptococcus Peptostreptococcus Actinom yces Skin/Soft T issue S. aureus S. pyogenes S. epiderm idis Pasteurella B one and Joint S. aureus S. epiderm idis Streptococci N . gonorrhoeae G ram -negative rods A bdom en E. coli, Proteus K le

12、bsiella Enterococcus Bacteroides sp. U rinary Tract E. coli, Proteus K lebsiella Enterococcus Staph saprophyticus U pper R espiratory S. pneum oniae H . influenzae M . catarrhalis S. pyogenes Low er R espiratory C om m unity S. pneum oniae H . influenzae K . pneum oniae Legionella pneum ophila M yco

13、plasm a, Chlam ydia Low er R espiratory H ospital K . pneum oniae P. aeruginosa Enterobacter sp. Serratia sp. S. aureus M eningitis S. pneum oniae N . m eningitidis H . influenza G roup B Strep E. coli Listeria 注意特殊修正因子/特别是先期抗菌药物对细菌学的影响 不同感染部位的常见感染性病原体Possible pathogens on site of infection关注特殊病原体肺孢

14、子菌肺炎 -免疫缺陷 -相对特异临床 -积极病原学检查重症军团菌肺炎发热、少痰多肺叶、多肺段受累肺外表现抗菌谱(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 病人来源：社区

15、、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. aureusPenicillin1944Penicillin-resistantS. aureus金黄色葡萄球菌耐药的发生发展过程金黄色葡萄球菌耐药的发生发展过程Methicillin1962Methicillin-resistantS. aureus (MRSA)Vancomycin-resistantenterococci (VRE)Vancomycin1990s1997VancomycinintermediateS. aureus(VISA)2002Vancomycin-resistantS. aur

16、eusCDC, MMWR 2002;51(26):565-5671960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 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 % 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？细菌耐药监测结果如何解读？2002-2004: SMART - ESBL in community in China20022

17、0032004E. coli48h21/5936%47/7860%48/8259%Klebsiella48r12/3238%12/3336%18/3551%Study done in referral tertiary university hospitals in ChinaPrevious antibiotic exposure may select more ESLB-producerSMART China might overestimate ESBL prevalence in China实验室药物敏感性监测的意义及缺陷实验室药物敏感性监测的意义及缺陷意义-反映了耐药趋势/告诫我们要

18、慎重使用抗菌药物 -在制定用药方案时考虑耐药性导致的治疗失败缺陷 -实验室收集到的菌株/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/不利用于个体化用药 (年龄、基础疾病、社区/医院感染、前期抗菌药物使用) Prevalence of rectal carriage of Extended-Spectrum -lactamase-producing Escherichia Coli among elderly people in a community setting in Shenyang Cross sectional study-276 elderly、rec

19、tal swab/E coli isolation/ESBL screening、genotyping and PEGFResult: prevalence of ESBL positive E Coli 7.0%（19/270） CTX-M type -CTX-M-14 63.2%, other:CTX-M-22 and CTX-M-24， 2 CTX-M-57-like -GA substitution in 865 point leading to DN subsitution in 289 point in AA ( new, sequence No.EF426798) Tian SF

20、, Chen BY.Prevalence of rectal carriage of Extended-Spectrum -lactamase -producing Escherichia Coli among elderly people in a community setting in Shenyang, China. Canadian Journal of microbiology 2008;54:15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-合理用药的核心 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

21、院、侵袭性操作、晚发医院感染 Risk factors for infection with ESBL producers (MDR) outside hospitalFactorOdds ratioRx 3 gen ceph15.8Rx 2 gen ceph10.1Hospital in last 3 months8.95Rx quinolone4.1Rx penicillins4.0Antibiotic Rx in last 3 months3.23Age 60 years2.65Diabetes2.57Colodner et al EJCMID 2004 23, 163.Univaria

22、te analysis of risk factors for carriage of ESBL-producing Escherichia coli in the community (n=270)Potential Risk factors No(%) ESBLs Total No Odds ratio(95% CI) P value Age (years) 74 16(7.4) 216 75 3(5.6) 54 0.74(0.21-2.62) 0.77 Gender Female 12(7.8) 153 Male 7(6.0) 117 0.81 (0.31-2.13) 0.81 Diab

23、etes No 11(6.3) 174 Yes 8(8.3) 96 1.35(0.52-3.47) 0.62 Hospitalization in past one year No 18(6.8) 264 Yes 1(16.7) 6 2.73(0.30-24.66) 0.34 Surgery in past one year No 19(7.1) 268 Yes 0(0) 2 0.0 0.8 Use of antibiotic in past three months No 12(5.3) 227 Yes 7(16.3) 43 3.48(1.29-9.44) .018 医院感染医院感染- -产

24、产ESBL 细菌感染的危险因素细菌感染的危险因素Prospective study of 455 episodes of K. pneumoniae bacteremia (253 nosocomial) in 12 hospitalsn30.8% 为医院获得, ICU中43.5%产ESBLsnESBLs危险因素 -先期使用氧亚氨基-内酰胺类抗菌药物 -过去14天内使用2 d (OR= 3.9). n其它危险因素 TPN, 肾功衰竭,烧伤n非ESBL危险:碳青霉烯、头孢吡肟、喹诺酮、氨基糖苷类 Paterson et al: Ann Intern Med 2004; 140:26-32.VAP

25、耐药菌感染的危险因素耐药菌感染的危险因素135 次VAP ICU变量 OR PMV7 days 6.0 .009先期ABs 13.5 7 days / prior ABsTrouillet, et al. Am J Respir Crit Care Med. 1998;157:531No Risk Factors for MDR PathogensRisk Factors for MDR EnterobacteriaceaeaRisk Factors for MDR PseudomonasHealth care contact No Yes! (eg, recent hospital admi

26、ssion, nursing home, dialysis) without invasive procedure Yes, Long hospitalization and/or infection following invasive procedures (5 days) Recent Abx No Yes! (14 days in past 90 days) Yes ! (14 days in past 90 days) Patient characteristics Young few comorbidities 65 yrs comorbidities such as TPN or

27、 renal insufficiency co-morbidities such as CF, structural lung disease, advanced AIDS, neutropenia, or other severe immunodeficiency aExcept nonfermenters/non-Pseudomonas species.Adapted from Carmeli Y. Predictive factors for multidrug-resistant organisms. In: Role of Ertapenem in the Era of Antimi

28、crobial 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)

29、:17921798; Shah PM. Clin Microbiol Infect. 2008;14(suppl 1):175180.Stratification for Risk for MDR Gram-Negative PathogensEpidemiology of MRSAH-MRSAReservoires -hospitals -LTCFs5 genetic backgroudsH-MRSA in community -patients with risk factors -contact with patients with risk factorsTrue community-

30、MRSA -no healthcare-associated risk factors -with PVL geneshealthcarecommunityAcquiredOnsetH-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！ PCP、军团菌、肺炎链球菌都可致重症感染是否重症? -依据临床表现/器官功能状态 -氧和、血液动力学、肾功能 肠功能PCPLD为什么随意使用广谱抗菌药物和联合使用？ SIR

31、S plus Documented 重症感染的临床判定Severe Sepsis Sepsis plus Septic shock Severe sepsis and Despite adequate ressucitationat least 2 of the followingsT 38or 90 beats/ minRR 20 breaths/minWBC 12,000 cells/ml, 10% immature formsACCP/SCCM consensus conference 1992重症感染的临床判定宿主因素-Host factorn免疫缺陷u高龄、疾病、治疗感染所致临床综合

32、征n中枢神经系统-CNSn医院获得性肺炎-HAPu呼吸机相关肺炎-VAPn菌血症-Bacteremiau肺炎-pneumoniau原发性或不明原因-Primary or unknownn严重软组织感染-Severe soft tissue infection病原体致病性/耐药性 High virulence or resistanceu金黄色葡萄球菌-S. aureusu铜绿假单孢菌-P. aeruginosau化脓性链球菌-S. pyogenes获得感染得场所-Nosocomial infectionsu病人因素-Patient factors免疫缺陷-Immunocompromized病情

33、危重-Critically illu病原体因素-Pathogen factors高致病性和/或难治性微生物 Virulent and / or difficult to treat organismsPCPLD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！ 包括重症感染选择哪种抗菌药物(which antibiotic?) 感染部位的常见病原学(possible pathogens on site of infection) 选择能够覆盖病原体的抗感染药物(antibiotics requirement) -抗菌谱/组织穿透性/耐药性/

34、安全性/费用考虑药代动力学/药效动力学(PK/PD)考虑病人生理和病理生理状态( physiologic and pathophysiology) 高龄/儿童/孕妇/哺乳(advanced age/children/pregnant women/breast feeding) 肾功能不全/肝功能不全/肝肾功能联合不全(renal/heptic dysfunction/combined)其它因素(other considerations) 杀菌和抑菌/单药和联合/静脉和口服/疗程 (cidal vs static/ mono vs combination/ IV vs PO/ duration)

35、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！评估严重性 广谱 VS 窄谱？ 单药 VS 联合？选择哪种抗菌药物(which antibiotic?) 感染部位的常见病原学(possible pathogens on site of infection) 选择能够覆盖病原体的抗感染药物(antibiotics requirement) -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(PK/PD)考虑病人生理和病理生理状态( p

36、hysiologic and pathophysiology) 高龄/儿童/孕妇/哺乳(advanced age/children/pregnant women/breast feeding) 肾功能不全/肝功能不全/肝肾功能联合不全(renal/heptic dysfunction/combined)其它因素(other considerations) 杀菌和抑菌/单药和联合/静脉和口服/疗程 (cidal vs static/ mono vs combination/ IV vs PO/ duration)经验性抗感染治疗药物选择-considerations in choosing an

37、tibiotic for empiric therapy 联合用药的理由补充单一用药的抗菌谱不足！补充单一用药的抗菌谱不足！协同作用如铜绿假单孢菌菌血症协同作用如铜绿假单孢菌菌血症减少耐药？减少耐药？2007 ATS/IDSA Guidelines: InpatientsMandell LA, et al. Clin Infect Dis 2007CAP Inpatient TherapyMedical WardIntensive Care UnitRecentAntibioticNo RecentAntibioticRespiratory FQ alone ORAdvanced macrol

38、ide + -lactamNo Pseudomonas RiskNo -lactam Allergy-lactam Allergy-lactam + advanced macrolide OR + respiratory FQ* Regimen depend on nature of recent Abx therapyRespiratory FQ + aztreonamPseudomonas RiskNo -lactam Allergy-lactam Allergy Anti-pseudomonal, antipneumococcal b- lactam /penem + Cipro/Levo 750 OR Anti-pseudomonal, antipneumococcal b- lactam /penem + aminoglycoside + Azithromycin Aztreonam + respiratory FQ + aminoglycosideAdvanced m