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1、肿瘤合并粒细胞减少病人抗生素使用临床实践指南,2007 UPDATE进行中Alison Freifeld,MDIDSA 粒减伴发热治疗专家组主席,2008-01-24,一、此处添加标题,CLINICAL PRACTICE GUIDELINEFOR THE USE OF ANTIMICROBIALAGENTS IN NEUTROPENICPATIENTS WITH CANCER:2007 UPDATEIn ProgressAlison Freifeld,MDChair,IDSA Expert Panel onManagement of Fever andNeutropenia,Disclosur
2、es,Research support:Enzon,Astellas,VicalConsuling:Schering-PloughScientific Advisory Board:EnzonSpeakers bureaus:none currently(9/06-9/07),Panel Members,Alison Freifeld,MD,ChairMichael Boeckh,MDEric J.Bow,MD,MScJames I.Ito,MDCraig Mullen,MD,PhDIssam I.Raad,MD,Kenneth V.Rolston,MDKent A.Sepkowitz,MDJ
3、o-Anne van Burik,MDJohn R.Wingard,MDStuart Cohen,MD,SPGC Liaison,专家组成员,Alison Freifeld,MD,Chair Michael Boeckh,MDEric J.Bow,MD,MScJames I,Ito,MDCraig Mullen,MD,PHDIssam I.Raad,MD,Kenneth V.Rolston,MDKent A.Sepkowitz,MDJo-Anne van Burik,MDJohn R.Wingard,MDStuart Cohen,MD,SPGC Liaison,Guideline Compar
4、ison,2002 Guidelines Clinical features of theneutropenic patient Evaluation of thepatient Initial antibiotic therapy,2007 Update Clinical features Risk assessment:definitions of high andlow risk Evaluation of the patient Initial antibiotic therapy High risk Low risk,指南对比,2002 指南粒减病人 的临床特征病人的评估初始抗生素治
5、疗,2007 更新临床特征风险评估；高危和低危的定义病人的评估初始抗生素治疗高危低危,Guideline Comparison cont.(2),2002 Guidelines Management during thefirst week Afebrile day 3-5 Persistent fever day 3-5 Duration of antibiotics Afebrile by day 3 Persistent feveron day 3,2007 Update Management during thefirst week Documented infections Feve
6、r of unknownetiology Duration of antibiotics Documented infections Fever of unknownetiology:high risk or lowrisk patients,指南对比（2）,2002 指南第一周的治疗无发热天数 35持续发热天数35抗生素持续时间无发热天数3持续发热天数3,2007 更新第一周的治疗证实的感染不明病因的发热抗生素持续时间证实的感染不明病因的发热：高危和低危,Guideline Comparison cont.(3),2002 Guidelines Use of antiviral drugs
7、Granulocyte transfusions Antibiotic prophylaxis Economic issues2007 Update Antibacterial prophylaxis Antifungal prophylaxis,empiric and pre-emptivetherapy Antiviral prophylaxis andtreatment Colony-stimulating factors Catheter infections InfeEcntniovuisr Doinsemaseesn Stoacli e ptyr oefc Aamuetriioca
8、ns,指南对比（3）,2002 指南抗病毒药物的使用粒细胞输入抗生素预防经济问题,2007 更新抗生素预防抗真菌预防，经验性及先发性治疗抗病毒预防及治疗细胞集落刺激因子导管感染环境警戒,IDSA Ranking of Recommendations,Strength of Recommendation A Good evidence to support use BModerate evidence to support use C Poor evidence to support use D Moderate evidence against use EGood evidence again
9、st use Quality of Evidence I 1 properly randomized,controlled trial II1 trial,non-randomized,cohort or case-control,from multiple time-series or dramatic results III Opinions of respected authorities,based on clinicalexperience,descriptive studies or expert committee reports,IDSA 推荐序列,推荐强度 A 良好的证据支持
10、使用 B 中等证据支持使用 C 差的证据支持使用 D 中等证据反对使用 E 良好证据反对使用证据质量 I 1严格的随机、控制良好的试验 II 1试验，非随机，同期组群或病例对照，来源于多重时间序列或引人注目的结果 III 权威专家的意见，基于临床经验，描述性试验或专家委员会报告,Who requiresempiric antibiotic therapy?,Patients who meet the standard definitions for fever(T 38.3 or 38.0 over 1 hour)and neutropenia(ANC 500/mm3 or whose ANC
11、 is expected to fallbelow 500/mm3 over the next 48 hours)requireempiric antibiotic therapy.Afebrile patients who are neutropenic and have newonset of abdominal pain,mental status changes,respiratory symptoms or other signs or symptomscompatible with possible infection should beevaluated and consider
12、ed high risk candidates forempiric antibiotics.,谁需要经验性抗生素治疗？,符合标准发热（T38.3或38.0超过1小时）及粒减（ANC500/mm3或预计48小时后ANC降低至500/mm3以下）定义的病人需要经验性抗生素治疗未发热病人有粒减且有新的腹部疼痛发作，精神状态改变，呼吸症状或其他与感染可能相关的体征或症状，则应被评估且作为高危候选人进行经验治疗,Risk Assessment,2002:MASCC scoring systemCharacteristic ScoreBurden of illnessno/mild sx 5modera
13、te sx 3No hypotension 5No COPD 4Solid tumor or no fungal infxn 4No dehydration 3Outpatient at onset fever 3Age 60 yrs 2,2007:MASCC scoring system now validated:95%of pts categorized as lowrisk could be successfully treated orally.(AII)High vs Low risk factors better elucidated byclinical trials 42:5
14、33,Innes SuppCare Cancer Sept 25,2007 epub.,风险评估,2002 MASCC评分系统 特征 分数 疾病负荷 无/轻度体征 5 中度体征 3无低血压 5无COPD 4实体肿瘤或无真菌感染 4无脱水 3门诊病人发热发作 3年龄60岁 2,2007MASCC评分系统已被确认：95的被分类为低危的病人口服给药治疗成功高危因素比低危因素更好的被临床试验和经验所阐明,风险评分21分指示病人发生并发症及死亡率的风险可能较低,IDSA Risk Criteria forFever&Neutropenia,High Risk Neutropenia anticipate
15、d to extendbeyond 7 days Medical Co-morbiditiesHemodynamic instabilityOral or GI mucositis-dysphagia/diarrheaAbdominal or peri-rectal painNausea/vomitingDiarrhea(6 loose stools daily)Neurologic/mental-status changesIntravascular-catheter infectionNew pulmonary infiltrate,hypoxemia,orunderlying COPDH
16、epatic insufficiency(aminotransferase values 5x normal)Renal insufficiency(creatinine clearance 30 ml/min).,Low Risk Neutropenia expected toresolve within()7 days Absence of any medicalco-morbidity listed inhigh risk criteria Adequate hepatic andrenal function,IDSA粒减伴发热风险标准,高危预期粒减持续时间超过7天医学共病 血液动力学不
17、稳定 口腔或胃肠道粘膜炎吞咽困难/腹泻 腹部的或直肠周痛 恶心/呕吐 腹泻（6 次每天）神经系统/精神状态改变 血管内导管感染 新的肺浸润，低氧血症，或潜在COPD 肝功能不足（转氨酶5倍正常值）肾功能不足（肌酐清除率30 ml/min),低危粒减预期7天内恢复没有任何高危标准中所列的医学共病足够的肝及肾功能,Response to Empiric Antibioticsaccording to Duration of Neutropenia,Kern WV CID 2006;42:533,粒减持续时间与经验性抗生素治疗有效率,经验性抗生素治疗有效率45%,Initial Evaluation
18、 of the Patient,Blood cultures x 2 sets Peripheral plus catheter:importance of timing Both peripheral if no catheter in place Both catheter-not standard of care CXR Respiratory signs/symptoms;consider in all high risk R/O infiltrate before considering outpatient treatment Culture other sites-depends
19、 on signs/symptoms CBC+differential,BUN/Creatinine q 3 days;monitor LFTs in high risk patients IL-6,IL-8,CRP and procalcitonin are not currentlyrecommendedDesJardin Ann Intern Med 1999;13:641;Oude Nijuis JCO 2005;23:7437,病人初始评估,血液标本2 部位外周血加导管标本：重在时效性两个外周血标本，如果没有导管两个导管标本：不作为标准考虑肺部X光检查呼吸症状/体征；所有高危病人都需
20、考虑门诊病人如有R/O浸润其他部位标本视体征/症状而定CBC微分，BUN/肌氨酸 每3天;对高危病人监测LFTIL-6,IL-8,CRP及原降钙素检测目前未被推荐DesJardin Ann Intern Med 1999;13:641;Oude Nijuis JCO 2005;23:7437,Initial Empiric Antibiotics:High Risk Patients,Monotherapy with an IV anti-pseudomonal-lactam:cefepime,ceftazidime,meropenem,imipenem,or piperacillin-taz
21、obactam(A-I).Ceftazidime may be less reliable monotherapy.PCN-allergic pts:ciprofloxacin or aztreonam+clindamycin or vancomycin.(C-II)Aminoglycoside,fluorquinolone and/or vancomycinmay be added for management of complicated cases(i.ehypotension,pneumonia)or if antimicrobial resistance issuspected/pr
22、oven(A-II).Paul Cochrane Database 2003;2:CD003038;Furno Lancet ID 2002;2:231;Bow CID 2006;43:447,Glasmacher Clin Micro Infect 2005;11(S5):17,初始经验性抗生素治疗：高危病人,一个静脉抗铜绿假单胞菌内酰胺类抗生素的单药治疗：头孢吡肟，头孢他啶，美罗培南，亚胺培南或哌拉西林-他唑巴坦（A-I)头孢他啶作为单药治疗可能不可靠青霉素过敏病人：环丙沙星或氨曲南克林霉素或万古霉素。(C-II)对于治疗有并发症的病例（如低血压，肺炎）或怀疑/证实抗生素耐药，氨基糖苷类，
23、氟奎诺酮类及/或万古霉素可以被添加（A-II）。Paul Cochrane Database 2003;2:CD003038;Funo Lancet ID 2002;2:231Bow CID 2006;43:447,Glasmacher Clin Micro Infect 2005;11(S5);17,Antibiotic Monotherapy(AI),Monotherapy for F&N meta-analyses:fewer adverse events,less morbidity but similar rates of survival withmonotherapy compa
24、red to aminoglycoside-containing regimenPaul BMJ 2003,Furno Lancet ID 2002 Piperacillin-tazobactam Non-inferiority of piperacillin/tazobactam vs cefepime(n=528 high risk FN pts)Bow CID 2006 Ceftazidime Weaker Gram positive coverage Fritsche Diag Micro ID 2003 Weaker coverage resistant Gram-negatives
25、 Paterson J Clin Micro 2001 Lower responses in FN,in preliminary meta-analysisGlasmacher Clin Micro Infect 2005,抗生素单药治疗（A I）,单药治疗FN荟萃分析：单药治疗与联用氨基糖苷类药物相比具有较低的副反应，低的发病率，但存活率相似。Paul BMJ 2003,Furno Lancet ID 2002哌拉西林他唑巴坦哌拉西林/他唑巴坦和头孢吡肟相比没有差异。（n=528 高危FN病人）Bow CID 2006头孢他啶覆盖革兰氏阳性菌弱。Fritsche Diag Micro ID
26、2003覆盖耐药革兰氏阴形菌弱。Pater J Clin Micro 2001在初步的荟萃分析中，对FN治疗有效率低。Glasmacher Clin Micro Infect 2005,Cefepime(AI),Higher 30 day all-cause mortality rate than ceftazidime in largemeta-analysis(RR 1.26)Yahav Lancet ID 2007 All-cause mortality not uniformly reported No difference in infection-related mortality
27、 Trials employing variable dosing strategies of cefepime used“This finding is not supported by broad experience andcontrolled trials using cefepime as initial management for feverand neutropenia.In the absence of a plausible explanation for this finding,thepanel continues to consider cefepime a reli
28、able and safe firstlineagent for empiric antibiotic coverage for fever andneutropenia.”Ramphal et al Am J Med 1996;100:83S;Chuang et al Pediatr Infect Dis J.2002;21:203-9.,头孢吡肟（A I）,在大型荟萃分析中30天全部原因死亡率高于头孢他啶（RR 1.26)Yahav Lancet ID 2007所有原因的死亡率没有被一律报告。与感染相关的死亡率没有差异这些试验中对使用马斯平的剂量策略变换不定。“此文章的发现不被使用头孢吡肟
29、初始治疗粒减伴发热的广泛经验及控制良好的临床试验结果所支持。此文章的发现缺乏一个看似合理的解释，专家小组仍然认为头孢吡肟是一个对粒减伴发热进行经验性抗生素覆盖的可靠的、安全的一线药物”Ramphal et al Am J Med 1996;100:83S;Chuang et al Pediatr Infect Dis J.2002;21:203-9,The use of Gram-positive active agents:changing epidemiology,Vancomycin or other Gram-positive active agent should not beadd
30、ed routinely to the initial regimen(daptomycin,linezolid,quinupristin-dalfopristin).(E-I).These agents should bereserved for specific clinical indications:Documented catheter-related infection Skin/soft tissue infection Pneumonia*Hemodynamic instability Known colonization with MRSA*Daptomycin is not
31、 indicated In local settings where high rates of MRSA infection arefound,consideration should be given to early addition oflinezolid or vancomycin,particularly in an unstable patient.(B-III)MMWR 1999;44(RR-12):1,抗革兰氏阳性菌药物的使用：流行病学的改变,万古霉素或其他抗革兰氏阳性菌药物不应被常规的加入初始治疗（达托霉素，利奈唑胺，奎奴普丁-达福普汀），（E-I）。这些药物应被保留，用于
32、特定的临床感染：证实的导管相关感染皮肤/软组织感染肺炎*血液动力学不足已知MRSA定值*不包括达托霉素在MRSA感染发生率高的地区，应考虑早期添加利奈唑胺或万古霉素，尤其对于不稳定的病人。（B-III）MMWR 1999;44(RR-12):1,Initial Empiric Antibiotics:Low Risk Patients,Inpatient Oral or IV antibiotics IV regimens as for high risk patients(A-I)or-Oral regimen:ciprofloxacin+amoxicillin/clavulanate.(A
33、-I)Oral regimen for PCN allergic pts:levofloxacin,moxifloxacin,ciprofloxacin+azithromycin,ciprofloxacin+clindamycin.(C-III)Freifeld et al NEJM 1999;341:305.Kern et al NEJM 1999;341:312.Rolston CID 1999;29:512.Chamilos et al Cancer 2005;103:2629.Cornely et al IntJ Hematol 2004:79:74;Innes Supp Care C
34、ancer Sept 25,2007 epub.,初始经验抗生素治疗：低危病人,住院病人口服或静脉抗生素治疗静脉药物与高危病人相同（A-I）口服药物：环丙沙星阿莫西林/克拉维酸。（A-I）青霉素过敏病人口服药物：左氧氟沙星，莫西沙星，环丙沙星阿奇霉素，环丙沙星克林霉素。（C-III）,Freifeld et al NEJM 1999;341:305.Kern et al NEJM 1999;341:312Rolston CID 1999;29:512.Chamilos et al Cancer 2005;103:2629.Comely et al IntJ Hematol 2004;79:74
35、;Inne Supp Care Cancer Sept 25,2007 epub,Initial Empiric Antibiotics:Low Risk Patients,Outpatient oral antibiotics,after a period ofclinic or inpatient observation,for carefullyselected patients(A-II).Appropriate duration of inpatient observation?24hrs?Combination ciprofloxacin+amoxicillin/clavulana
36、te isrecommended(A-I)Ciprofloxacin monotherapy is effective in low risk pediatricpatients in small studies(B-II);not well studied in FN adults Levofloxacin has not been rigorously studied.Vidal Cochrane 2004;18:3992;Kern CID 2006;42:533;Escalante Supp CareCancer 2004;12:657;Innes Supp Care Cancer Se
37、pt 25,2007 epub.;Cornely Int J Haem 2004;79:74;Paganini Cancer 2003;97:1775,初始经验抗生素治疗：低危病人,门诊病人口服抗生素，经过一段时间的临床或住院观察，小心选择过的病人（A-II）适当的住院观察时间？24小时？联合环丙沙星阿莫西林/克拉维酸被推荐（A-I）在小型的试验中环丙沙星单药治疗低危儿科病人是有效的（B-II）；对成人FN没有好的研究。左氧氟沙星没有被严格的研究过,Vidal Cochrane 2004;18:3992.Kern CID 2006;42:533;Escalante Supp CareCance
38、r 2004;12:657;Innes Supp Care Cancer Sept 25,2007 epubComely Int J Haem 2004;79-74;Paganini Cancer 2003;97:1775,Outpatient Oral Initial Empiric Therapy:General Rules,No signs of severe infection or co-morbidity(e.g.,hypotension,pneumonia,catheter infection,SSTI,or organ failure).Best in setting of r
39、ecovering neutrophil counts than when countsdecreasing or there is no indication of imminent marrow recovery Prompt access to appropriate medical care Institutional infrastructure Patient distance from the hospital Availability of a home caregiver Transportation/Telephone Fluoroquinolone prophylaxis
40、 strictly precludesthe subsequent use of fluoroquinolones for initial empiric therapyin low risk patients,门诊口服初始经验性治疗：普遍性原则,没有严重感染或并发疾病的症状（如：低血压，肺炎，导管感染，SSTI，或初始治疗失败）口服给药在中性粒细胞计数恢复期远好于计数下降或无骨髓快速恢复指征。提倡适当的医学关怀公共机构基础设施病人和医院的距离家庭护理者的可用性交通/电话氟奎诺酮类预防严重妨碍了氟奎诺酮类药物在随后的初始经验治疗中的使用,Modifications to Initial The
41、rapyduring the First Week,Modifications should be made according toclinical,microbiologic or radiologic evidence ofa new/previously untreated infection.(A-I)Persistent fever alone is not an indicationto change the antibiotic regimen.Median time to defervescence in low risk=2 days,in high risk=5 days
42、 Adjust antibiotics to cover isolated pathogen(s)Stop vancomycin or other Gram+coverage after 2 days,ifinitially started,and there is no evidence for a Gram+infection.(B-III),第一周内初始治疗的调整,调整必须依据临床、微生物或放射学的证实有新的/先前未治疗的感染的证据。（A-I）单独的持续发热不是一个改变抗生素药物的指征。退热的中线时间 低危2天 高危5天调整抗生素以覆盖分离出的病菌如果没有革兰氏阳性菌感染的证据，则2天以
43、后停止万古霉素或其他抗革兰氏阳性菌药物。（B-III）,Documented Infections:Modifications forincreasingly resistant organisms,Gram-negative bloodstream infections-lactam or carbapenem+aminoglycosides or antipseudomonalfluoroquinolone,to ensure early coverage of multi-drug resistantpathogens(B-III)Discontinue second agent if
44、responding/susceptibility OK(B-III)Pneumonia Considered“healthcare-acquired“in neutropenic cancer pts-lactam or carbapenem+aminoglycosides or antipseudomonalfluoroquinolone+vancomycin or linezolid(B-III)Gram-positive infections(bloodstream,respiratory tract or SSTI-)-early addition of vancomycinor l
45、inezolid is recomCompeynridgehdt 2t0o0 c7o Ivnefer cMtioRuSsA D i(sBe-aIsIeI),证实的感染：对越来越多的耐药菌的调整,革兰氏阴性菌血液系统感染内酰胺类或碳青霉烯类氨基糖苷类或抗铜绿假单胞菌氟奎诺酮类。确保对多重耐药菌的早期覆盖。（B-III）如果有效性及敏感性OK，停止第二药物。（B-III）肺炎对粒缺肿瘤病人，应考虑“健康护理获得性肺炎（HCAP）”内酰胺类或碳青霉烯类氨基糖苷类或抗铜绿假单胞菌氟奎诺酮类万古霉素或利奈唑胺（B-III）革兰氏阳性菌感染（血液系统，呼吸道或SSTI）推荐早期添加万古霉素或利奈唑胺以覆盖
46、MRSA。（B-III）,Fever of Unknown Etiology:Modifications toInitial Therapy,High Risk patients:Tailor IV to oral agents if patient is afebrile,stable,and absorption is felt adequate(B-III)Consider early discharge on oral agents(C-III)Low risk patients:Consider discharge to the outpatient setting ifinitia
47、lly hospitalized(A-II)If outpatient,readmit&treat IV for:o New symptoms c/w high risko New or persiCsotepnyrti gfhetv 2e0r,不明病因的发热：初始治疗的调整,高危病人：如果病人无发热，稳定且吸收率足够，可用口服药物续贯静脉治疗（B-III）考虑尽早给予口服药物（C-III）低危病人：如初始医院治疗，考虑出院作为门诊治疗（A-II）如果门诊病人有以下情况，再入院&静脉治疗：新的症状符合高危标准新的或持续发热,Empiric Antifungal Therapy,After 4-
48、7 days of broadspectrum antibiotics,high riskpatients with continuing or recrudescent fever,shouldreceive empiric antifungal therapy(overall A-II)Amphotericin B desoxycholate used historically Caspofungin,liposomal ampho B(A-I);itraconazole(B-I),and voriconazole(B-I)are all acceptable.If already on
49、antifungal prophylaxis:inadequate data todirect empirical antifungal therapy.?broader spectrum and/or different class agentWinston Am J Med 2000;108:282.Walsh et al NEJM 2004 351:1391;NEJM2002;346:225.Booegarts etal Ann Intern Med 135:412 Maertens et al CID2005;41:1242,经验性抗真菌治疗,广谱抗生素治疗47天后，高危病人伴有持续或
50、复发的发热，应进行经验性抗真菌治疗（overall A-II）两性霉素B去氧胆酸盐根据历史方法使用卡泊芬净,两性霉素B脂质体(A-I);伊曲康唑(B-I),及伏立康唑(B-I)都可使用如果已经抗真菌预防：经验抗真菌治疗数据不充分？更广谱和/或其他类药物,Winston Am J Med 2000;108:282.Waish et al NEJM 2004 351:1391;NEJM2002;346:225.Booegarts et al Ann Interm Med135:412 Maertens et al CID 2005;41:1242,Fever after 4-7 days of B
