耐药G+球菌的治疗课件.pptx

1、耐药G+球菌的抗菌治疗-特别关注MRSA感染常见革兰阳性球菌感染肺炎链球菌链球菌-A 组(S.pyogenes)-B 组(S.agalactiae)-草绿色链球菌肠球菌葡萄球菌-金匍菌-凝固酶阴性葡萄球菌-脑膜炎、中耳炎、咽扁桃体炎、窦炎、肺炎-皮肤、软组织感染-新生儿感染-感染性心内膜炎-IE/泌尿系统感染/CNS感染-疖/痈、SSSI、血流感染、脓毒症、心内膜炎、HAP/VAP、CRBSI丹毒蜂窝织炎猩红热脓疱病坏死性筋膜炎中毒性休克综合征病原体社区治疗入院治疗ICU发表的研究数量92313肺炎链球菌19,325,921,7流感嗜血杆菌3,34,05,1军团菌1,94,97,9金匍菌0,2

2、1,47,6GNB0,42,77,5肺炎支原体11,17,52鹦鹉热衣原体1,51,91,3病毒11,710,95,1病原学不明49,843,841,5*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?Meningitis Criteria-CARTIPS-2009ResistantSusceptible48.651.437.162.954466040Non-m

3、eningitis criteria:Nonsusceptible rateChina:10.8%;Taiwan:2.8%;Singapore:4%Wang H,Chen MC,Hsueh PR et al.Int J Antimicrob Agents 2011;38:376-83.Azithromycin nonsusceptibility:China:88.8%;Taiwan:87.3%,Singapore,56%耐药肺炎链球菌风险评估Risk Factors for Drug-Resistant S.pneumoniae近期抗生素暴露近期住院两极年龄接触托儿所儿童基础疾病HIV免疫缺陷

4、住机构病人赵春江等.中华结核和呼吸杂志.2015;1(38):1-6常见革兰阳性球菌感染目标治疗肺炎链球菌 -呼吸道感染 -脑膜炎 Pen MIC 头曲MIC链球菌肠球菌PISP 大剂量青霉素 PC过敏、不耐受PRSP 左氧、莫西 糖肽类、恶唑烷酮 青霉素 头孢菌素Sanford guide 2012CID 2009;49:1452,+RIF600mg po氨苄敏感 氨苄或青霉素 2g q4h 或q6h 万古霉素 +/-氨基糖苷 或氨苄+/-庆大1mg/kg q8h氨苄耐药 万古+/-氨基糖苷 万古15mg/kg q12h 利奈唑胺或迖托6mg/kg，qd万古敏感 +/-庆大，1mg/kg q

5、8h 氨苄耐药 利奈唑胺或迖托 利奈唑胺600mg q12h；奎奴普丁万古耐药 迖托6mg/kg，qd金葡菌 Why Worry?致病性-强 -导致疾病众多传播性-易-定植/感染皆为传播源耐药性-高-治疗药物有限疖和痈/蜂窝质炎/乳腺炎脓疱病/皮肤剥脱综合征外科伤口感染/感染性关节炎/TSS/食物性胃肠炎肺炎肺炎(CAP/HAP/VAP)(CAP/HAP/VAP)、BSI、骨髓炎/脓胸、急性或右心内膜炎、脑脓肿、硬脑膜外脓肿、肾脏痈、感染性休克From:Archer.Clin Infect Dis 1998;26:117981-内酰胺耐药(产酶)-耐酶青霉素MRSA(PBP改变)-万古霉素万古

6、霉素MIC漂移？/VRSA(全球9株)利奈唑胺上市1年出现耐药(LRSA)达托霉素上市2年出现耐药株(DRSA)定植者对于传播的意义更大Evolution of drug resistance in S.aureusS.aureusPenicillin1940sPenicillin-resistantS.aureus1Vancomycin Methicillin1958/9MRSA119972002VRSA4hVISA31950s1960s,1970s19961980sVancomycin(widely used)VISA21.Liares J.Clin Microbiol Infect 20

7、01;7(Suppl 4):815 2.MMWR Morb Mortal Wkly Rep 1997;46:624625 3.Hiramatsu K et al.Lancet 1997;350:16701673 4.MMWR Morb Mortal Wkly Rep 2002;51:5655675.Jones R.Clin Infect Dis 2006;42:S13S24 6.Tsiodras et al,Lancet 2001 7.2001LRSA62005DRSA7MRSA流行病学59青霉素上市第一个MRSA菌株出现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

8、98MMWR 报告4例健康儿童死于 MRSA感染99CA-MRSA 成为 SSTI的主要原因0405美国侵袭性MRSA导致18,650 死亡 Most Invasive MRSA Infections Are Healthcare AssociatedKlevens et al JAMA 2007;298:1763-71Most Invasive HA-MRSA Infections are Community-Onset Epidemiology of MRSAH-MRSAReservoires-hospitals-LTCFs5 genetic backgroudsH-MRSA in com

9、munity-patients with risk factors-contact with patients with risk factorsTrue community-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 侵袭侵袭性性MRSAMRSA感染的发病率（按年龄分层）感染的发病率（按年龄分层）Data from 2

10、012 Active Bacterial Core Surveillance(ABCs)Report http:/www.cdc.gov/abcs/reports-findings/survreports/mrsa12.pdf MRSA感染的主要临床表现 Data from 2012 Active Bacterial Core Surveillance(ABCs)Report http:/www.cdc.gov/abcs/reports-findings/survreports/mrsa12.pdf14Craven DE.Curr Opin Infect Dis.2006;19:153-160

11、.The Changing Spectrum of Pneumonia CAP,HCAP,HAPPneumoniaCAPaHCAPbHAPc/VAPdMorbidity&MortalityRisk of MDR Pathogensa.CAP=community-acquired pneumoniab.HCAP=healthcare-associated pneumoniac.HAP=hospital-acquired pneumoniad.VAP=ventilator-associated pneumoniaConsider HCAP in individuals meeting any on

12、e of the followings:nHospitalization for 2 days in an acute-care facility within 90 days of infectionnResidence in a nursing home or long-term care facilitynAntibiotic therapy,chemotherapy,or wound care within 30 days of current infectionnHemodialysis treatment at hospital or clinicnHome infusion th

13、erapy or home wound carenFamily member with MDR pathogensAll patients meeting these criteria should also be considered at risk for infection with atypical and/or MDR organisms Retrospective cohort study of pts with PNA admitted to 59 US hospitals 2002-2003Epidemiology of MRSA PneumoniaKollef Chest 2

14、005Remains an uncommon cause of CAPnCDC surveillance study of invasive MRSA1 0.74/100,000nEMERGEncy 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,requi

15、re 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 CAP1Klevens JAMA 2007;298:1763-1771;2Moran CID 2012;54:1126-33 Approach to Empiric Therapy:CAPEmpiric treatment for MRSA is recommended for

16、 severe CAP defined by:nICU admissionnNecrotizing or cavitary infiltratesnEmpyemaDiscontinue empiric Rx if cultures do not grow MRSALiu CID 2011;52;285-322中国社区MRSA流行病学？我们怎么办？Valentini Ann of Clin Micro 2008Prediction of MRSA in Patients with Non-Nosocomial pneumoniaBMC Infectious Diseases 2013,13:37

17、0 doi:10.1186/1471-2334-13-370Retrospective study from January 2008 to December 2011.943 culture-positive MRSA and non-MRSA pneumonia outside the hospitalIdentified risk factors associated with MRSA pneumonia.开始开始抗感染治疗的判定标准抗感染治疗的判定标准建议仅使用临床标准判定临床标准+PCT临床标准+sTERM-1临床标准+CRP临床标准+CPIS专家组均采用精度研究分析发现:-PCT

18、诊断HAP/VAP敏感度为67%、特异度为83%，可能导致的误诊率并不优于单纯临床判断。-PCT指导抗生素治疗方案并不能提高生存率,且可能延迟抗生素起始，从而导致较差的临床结局。-sTERM-1/CRP/CPIS的推荐理由与PCT相似。推荐理由 强推荐，中等质量证据 强推荐，中等质量证据 强推荐，中等质量证据 弱推荐，低质量证据 弱推荐，低质量证据VAP患者经气管插管48h后发生的肺炎HAP指患者入院时不存在，也不处于感染潜伏期，而于入院48h后发生的肺炎The Microbiology of HAP-ATS/IDSAGram-negative=48%uPseudomonas spp.uAci

19、netobacter spp.uKlebsiella spp.uE.coliGram-positive=43%uS.aureusuS.pneumoniaeOthers=9%(viruses 1%)Adapted from Am J Respir Crit Care Med.2005;171:388416.Epidemiology,Etiology and Diagnosis of HAP and VAP in Asian CountriesChawla R,et al.Am J Infect Control 2008;36:s93-100Stratification of HAP/VAP Pa

20、tients at Risk for MDR OrganismsThe 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自主通气(HAP)VS 机械通气(VAP)1/Ewig S,Torres A,

21、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 159:1881982/Rello J,Torres A(1996)Microbial causes of VAP.Semin Respir Infect 11:2431Pujol M et al.EJ CMID.

22、1998;17:622-628.Mechanical Ventilation Is Associated With a Significantly Increased Incidence of Respiratory Tract MRSA Infection 早发性及晚发性VAPp区分早发性与晚发性VAP的意义n上呼吸道定植为随后支气管定植的独立预测因子n上下呼吸道的定植类型在初始3-4天内从社区菌谱转换为医院菌谱天内从社区菌谱转换为医院菌谱n早发性肺炎菌群分布更类似社区菌谱，而晚发性肺炎菌群分布更类似医院菌谱n给予1-2剂量头孢菌素的预防性治疗，可降低社区病原菌的定植 但随之发生的早发性VA

23、P为典型医院病原菌2016年指南中仅推荐VAP的治疗方案需考虑早发与晚发的意义，认为VAP发生之前已住院5天MDR发生风险提高抗生素暴露-医院获得性肺炎细菌学演变及治疗方向抗MRSA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 舒巴坦复合制剂 左氧 莫西 环丙 替加环素/多粘菌素 MRSA HAP中国流行病学刘又宁,等.中华结核和呼吸杂志.2012;35(10):739-47 2008年-2010年在国内13家教学医院进行HAP多中心、前瞻性调查研究金葡菌中MRSA占87.8%For patients being treated empirically for HAP,w

24、e recommend prescribing an antibiotic with activity against S.aureus(葡萄球菌葡萄球菌)(strong recommendation,very low-quality evidence).(See below for recommendations regarding empiric coverage of MRSA vs MSSA.)MRSA coverage:Risk factor for MRSA infection(ie,prior IV antibiotic use within 90 days,hospitaliz

25、ation in a unit where MRSA prevalence 20%,or unknown MRSA prevlance，or High risk for mortality(need for ventilatory support due to HAP and septic shock).)MSSA coverage:No risk factors for MRSA infection and not high risk of mortalityFor patients with HAP who are being treated empirically,we recommen

26、d prescribing antibiotics with activity against P.aeruginosa(铜绿铜绿)and other gram-negative bacilli(strong recommendation,very low-quality evidence).PA coverage:-2 antibiotics against PA from 2 different classes(weak recommendation,very low-quality evidence)Risk factors for PA and G-negatives(ie,prior

27、 IV antibiotic use within 90 days or High risk for mortality(need for ventilatory support due to HAP and septic shock)-1antibiotic against PA for other patients -not using an AGs as the sole antipseudomonal agent (strong recommendation,very low-quality evidence).HAP-初始经验抗生素治疗推荐(2016 IDSA HAPHAP/VAP指

28、南)Not at High Risk of Mortality and no Factors Increasing the Likelihood of MRSAOne of the following:Pip-tazo 4.5 g IV q6h OR Cefepime 2 g IV q8h OR Levo 750 mg IV daily Cipro 400 mg IV q8h OR Imipenem 500 mg IV q6h Meropenem 1 g IV q8h Recommended Initial Empiric Antibiotic Therapy for Hospital-Acq

29、uired Pneumonia(Non-Ventilator-Associated Pneumonia)Not at High Risk of Mortality but With FactorsIncreasing the Likelihood of MRSAOne of the following:Pip-tazo 4.5 g IV q6h OR Cefepime 2 g IV q8h or ceftazidime 2 g IV q8h OR Levo 750 mg IV daily Cipro 400 mg IV q8h OR Imipenem 500 mg IV q6h Meropen

30、em 1 g IV q8h OR Aztreonam 2 g IV q8hPlus:Vanco 15 mg/kg IV q812h with goal to target1520 mg/mL trough level(consider a loadingdose of 2530 mg/kg 1 for severe illness)ORLinezolid 600 mg IV q12h High Risk of Mortality or Receipt of IntravenousAntibiotics During the Prior 90dOne of the following:avoid

31、 2-lactams:Pip-tazo 4.5 g IV q6h OR Cefepime 2 g IV q8h or ceftazidime 2 g IV q8h OR Levo 750 mg IV dailyCipro 400 mg IV q8h OR Imipenem 500 mg IV q6hMeropenem 1 g IV q8h OR Amikacin 1520 mg/kg IV dailyGentamicin 57 mg/kg IV dailyTobramycin 57 mg/kg IV daily ORAztreonam 2 g IV q8hPlus:Vanco 15 mg/kg

32、 IV q812h with goal to target1520 mg/mL trough level(consider a loadingdose of 2530 mg/kg 1 for severe illness)ORLinezolid 600 mg IV q12h 2016IDSA指南指南-非机械通气非机械通气HAP覆盖覆盖MRSA指征指征 -过去90天IV抗生素2周 -所在病区MRSA分离率不清 -MRSA分离率20%.-先期培养或非培养筛查检出MRSA 选择20%阈值是基于有效初始治疗和过度 用药之间的平衡，各医院可以依其价值观 和偏好自行选择In patients with s

33、uspected VAP,covere S.aureus,Pseudomonas aeruginosa,and other gram-negative bacilli in all empiric regimens(strong recommendation,low-quality evidence).MRSA coverage in patients with any of the following:a risk factor for antimicrobial resistance，MRSA prevalence 10-20%，MRSA prevalence known(weak rec

34、ommendation,very low-quality evidence).2 antipseudomonal antibiotics from different classes only in patients with any of the following:a risk factor for antimicrobial resistance,patients in units where 10%of gram-negative isolates are resistant to an agent being considered for monotherapy,and patien

35、ts in an ICU where local antimicrobial susceptibility rates are not available(weak recommendation,low-quality evidence).1 antipseudomonal antibiotic for the empiric treatment of suspected VAP in patients without risk factors for antimicrobial resistance who are being treated in ICUs where 10%of gram

36、-negative isolates are resistant to the agent being considered for monotherapy(weak recommendation,low-quality evidence)Avoid aminoglycosides if alternative agents with adequate gram-negative activity are available(weak recommendation,low-quality evidence).Avoiding colistin if alternative agents wit

37、h adequate gram-negative activity are available(weak recommendation,very low-quality evidence).VAP-初始经验抗生素治疗推荐(2016 IDSA HAP/VAPVAP指南)MDRMDR VAP VAP风险因子风险因子-近90天内使用过静脉抗感染治疗-VAP期间发生脓毒性休克-VAP之前发生过ARDS-VAP发生之前已住院5天-VAP发生之前使用过急性肾脏替代治疗MRSA VAP MRSA VAP 风险因子风险因子-近90天内使用过静脉抗感染治疗MDRMDR假单胞菌假单胞菌 VAP VAP 风险因子风

38、险因子-近90天内使用过静脉抗感染治疗单药联合VAP初始经验抗生素治疗推荐(2016 IDSA HAP/VAP指南)A.具有抗MRSA活性的革兰阳性菌抗生素B.具有抗铜绿假单胞菌活性的革兰阴性菌抗 生素：-内酰胺类药物C.具有抗铜绿假单胞菌活性的革兰阴性菌抗生素：非-内酰胺类药物糖肽类a：万古霉素 15mg/kg IV q8-12h(严重疾病时可考虑给予首剂负荷浓度25-30mg/kg)抗铜绿假单胞菌类青霉素b：哌拉西林他唑巴坦 4.5g IV q6h喹诺酮类：环丙沙星环丙沙星 400mg IV q8h左氧氟沙星左氧氟沙星 750mg IV q24h 或者或者或者恶唑烷酮类：利奈唑胺 600m

39、g IV q12h头孢菌素类b：头孢匹肟或头孢他啶 2g IV q8h氨基糖苷类a,c：阿米卡星 15-20mg/kg/天 IV 庆大霉素 5-7mg/kg/天 IV 妥布霉素 5-7mg/kg/天 IV 或者或者碳青霉烯类b：亚胺培南 500mg IV q6h d美罗培南 1g IV q8h多粘菌素a,e：粘菌素 5mg/kg IV*1(负荷剂量)接着给予2.5mg*（1.5*CrCl+30）IV q12h（维持剂量）多粘菌素B 2.5-3.0mg/kg/d分成每天2次静脉给药或者单环内酰胺类f：氨曲南 2g IV q8ha.需要监测药物浓度及调整相应剂量和/或给药间隔时间b.可能需要延长输

40、注c.Meta分析结果提示，氨基糖苷类可能临床有效率较低但死亡率无明显差异d.体重.05Median duration of bacteremia7 days(5-11)9 days(6-13).05Median duration of fever7 days(3-8)7 days(3-10).05联合庆大霉素或利福平导致毒性增加Addition of gentamicin or rifampin to vancomycin is associated with toxicity risk of nephrotoxicity with initial low-dose gentamicin3

41、risk of elevated transaminases(5X baseline),drug interactions with rifampin,resistance concerns21Fowler NEJM 2006;355:653-65;2Riedel D AAC 2008;52:2463-7 3Cosgrove S CID 2009;48:713-21;+gentamicin*Gentamicin was an independent predictor of clinically significant in CrClDuration of therapyLower succe

42、ss rates in pts receiving 14 days of therapy have been observed.Fowler NEJM 2006;355:653-65;Cosgrove CID 2008;46:S386-93Cosgrove CID 2008;46:S386-93 DurationIndication14 daysUncomplicated bacteremia:-No evidence of endocarditis-No implanted prosthetic devices (e.g.cardiac devices,arthroplasties,valv

43、es)-Negative follow-up blood cultures at 2-4d-Fever resolves by day 3-No metastatic sites of infection 4-6 weeks(at least)Complicated bacteremia:Failure to meet one or more of the above criteria Liu CID 2011;52:285-322如何认定万古霉素治疗失败:血培养MRSA持续阳性时的考量Defining Vancomycin Treatment Failure:Approach to Pers

44、istent MRSA Bacteremia Presence of and ability to remove other foci of infection -感染灶的处理至关重要 source control is criticalPatients overall clinical response-一般状态/体温趋势 -菌血症清除的时间 median time to clearance of bacteremia1,2,3Results of susceptibility testing(e.g.vanco MIC)-MIC多少考虑转换治疗方案 which MIC to switch

45、therapy?Vancomycin optimal dosing 优化万古霉素应用 -which AUIC and trough concentrations1Korzeniowski Ann Intern Med 1982;4:496-50;2Levine Ann Intern Med 1991;115:674-80;3Fowler NEJM 2006;355:653-65Septic EmbolusSeptic ArthritisOsteomyelitisSeptic(cannonball)EmboliCavitationPsoas AbscessMyocardial AbscessSo

46、urce Control Is Critical细菌清除的中位数时间 Median time to clearance of bacteremia1,2,3:MSSA with-lactam abx3-4 daysMRSA with vancomycin,daptomycin7-9 days1Korzeniowski Ann Intern Med 1982;4:496-50;2Levine Ann Intern Med 1991;115:674-80;3Fowler NEJM 2006;355:653-65至少等待7天 Wait at least 7 days如何认定万古霉素治疗失败:血培养M

47、RSA持续阳性时的考量Defining Vancomycin Treatment Failure:Approach to Persistent MRSA Bacteremia Presence of and ability to remove other foci of infection -感染灶的处理至关重要 source control is criticalPatients overall clinical response-一般状态/体温趋势 -菌血症清除的时间 median time to clearance of bacteremia1,2,3Results of suscept

48、ibility testing(e.g.vanco MIC)-MIC多少考虑转换治疗方案 which MIC to switch therapy?Vancomycin optimal dosing 优化万古霉素应用 -which AUIC and trough concentrations1Korzeniowski Ann Intern Med 1982;4:496-50;2Levine Ann Intern Med 1991;115:674-80;3Fowler NEJM 2006;355:653-65如何认定万古霉素治疗失败:血培养MRSA持续阳性时的考量Defining Vancomyc

49、in Treatment Failure:Approach to Persistent MRSA Bacteremia High Vanco MICs are Associated with Worse Outcomes Should We Switch Therapy?Causal relationship between vancomycin exposure and high vanco MIC remains unclear 万古霉素治疗失败与高MIC因果关系尚不清楚Limitations in vancomycin susceptibility testing 万古霉素药敏实验局限性

50、Lack of clearly superior alternative 缺乏有明确优势备选药物 高万古霉素MIC与临床结果的关系 -3项meta-analysis的结果High vancomycin MIC（2ug/ml by E-test）was associated with a higher mortality rate in MRSA BSIHigh MIC(MIC 1 mg/l by BMD or 1.5 mg/l by Etest)is associated with increased mortality and treatment failureNo statisticall