修改稿难治性曲霉感染的诊疗策略附病例报道

安徽省立医院重症医学科 副主任医师、副教授安徽医科大学 硕士研究生导师周树生,Series PPT of Intensive care unit（20140607）,Dr.Ignaz Semmelweis 匈牙利医生伊格纳兹.塞麦尔维斯,Ignaz Philipp Semmelweis (1818-1865)Med Welt. 1981 Dec 25;32(51-52):1962-3.,公元1847年他要求医生用漂白粉洗手，产褥热病人大幅减少,Nobel prize forGerhardDomagkin 1939 for discovery of the antibacterial activity ofprontosil.,Wiad Lek.1968 Jun 15;21(12):1089,百浪多息,格哈德多马克,One case:女性，76岁，住院号：06551801,主 诉：“呼吸困难进行性加重7日，伴发热3天”入院入院时间：2014年4月2日12:10现病史：患者一周前在无明显诱因下开始出现运动后呼吸急促现象，呈进行性加重，在当地医院予以抗感染治疗后效果欠佳，3天前该患者开始出现发热现象，约39，并出现咯血及意识模糊现象，拟诊肺部感染，感染性休克收住急诊内科，入科后患者出现血氧饱和度进行性下降，最低达70%，故予以气管插管后转入我科进一步治疗。既往史：糖尿病，高血压病史20余年。,2014年4月2日肺部CT检查（大结节状）,急诊生化 K4.05mmol/L,Na141.1mmol/L,CL113.0mmol/L,Ca1.46mmol/L,CREA148.4umol/LCO2 15.8 mmol/L,AG 17.30,GLU 5.81mmol/L,ALB 26.3g/L,2014年4月02日血常规检查结果,血气分析+乳酸: PH 7.272,PCO2 38.6mmHg,PO247.2mmHg,SBE -5.0mmol/L,Lac 5.5mmol/L；BP：85/56mmHg,痰及血培养及药敏实验，痰真菌培养（口腔+肺纤维支气管镜取痰）； 抗核抗体全套滴度检查； ANCA检查； 1,3-D-葡聚糖检查（G实验）； T细胞亚群检测。,进一步完善相关检查：,诊断问题：重症肺炎？感染性休克？肺部CT大结节状阴影的解读？病原微生物判断？经验性抗生素的选择？,存在问题：,必要条件：影像学资料出现新的浸润影同时满足下列两项或两项以上：发热白细胞升高或降低脓性痰敏感性为69%，特异性为75%,Am J Respir Crit Care Med.2005;171(4):388-416(IF=12.041),ATS/IDSA.Guidelines for the management of adults with hospital-acquired,ventilator associated, and healthcare-associated pneumonia.,肺部炎症诊断标准：,临床肺部感染评分(clinical pulmonary infection score，CPIS),指标：体温、血白细胞计数、痰液性状、X线胸片、氧合指数和半定量培养总分12分，一般以CPIS大于6分作为诊断标准敏感性为72%，特异性为85% ，加上培养结果特异性为95%。,Am Rev Respir Dis.1991May;143(5 Pt 1):1121-9,CPIS=6分,General variables(一般指标),Diagnostic Criteria for Sepsis（脓毒症诊断标准）,Intensive Care Med.2013 Feb;39(2):165-228(IF=5.258),WBC = white blood cell; SBP = systolic blood pressure; MAP = mean arterial pressure; INR =international normalized ratio; aPTT = activated partial thromboplastin time.,Hemodynamic variables(血流动力学指标),Tissue perfusion variables(组织灌注指标),Inflammatory variables(炎症指标),Diagnostic Criteria for Sepsis（脓毒症诊断标准）,Intensive Care Med.2013 Feb;39(2):165-228(IF=5.258),Organ dysfunction variables(脏器功能不全指标),Diagnostic Criteria for Sepsis（脓毒症诊断标准）,WBC = white blood cell; SBP = systolic blood pressure; MAP = mean arterial pressure; INR =international normalized ratio; aPTT = activated partial thromboplastin time.,Intensive Care Med.2013 Feb;39(2):165-228(IF=5.258),入科诊断：重症社区获得性肺炎；感染性休克；呼吸衰竭(型)影像学及微生物学判断：1、细菌（社区获得性相关？）2、结核？3、卡氏肺孢子虫？4、转移性肿瘤？5、其他,病例一：住院号：6741099，男性，45岁，诊断：肺结核(抗酸杆菌阳性),病例二：住院号：6362670，男性，22岁，诊断：卡氏肺孢子虫（六胺银染色法）,初始病原学判断：社区获得性细菌感染，真菌待排？,病例三：门诊号：4117296，女性，55岁，诊断：肝癌肺转移（肝穿刺活检病理）,2014年4月03日T细胞亚群检查结果,2014年4月04日抗核抗体滴度及ANCA检查结果,1、一般治疗；2、纠正休克（留置CVP导管）；3、有创机械通气；4、镇痛镇静(Ramsay3-4)；5、抗感染治疗（亚胺培南西司他丁钠1.0g,q8h;替考拉宁注射液 0.4g 静脉滴注 bid）。,初始诊疗计划,4月03日,4月04日,4月05,5月06日,5月07日,5月08日,5月09日,2014年4月03日普通痰培养+药敏检查结果,痰培养检查结果（口腔）（微生物室电话报，4月04日下午3时）,4月03日,4月04日,4月05,5月06日,5月07日,5月08日,5月09日,卡泊芬净+伊曲康唑,Am J Respir Crit Care Med.2011;183(1):96-128(IF=11.041),It is a clinical syndrome in which focal infiltrates begin with some clinical association of acute pulmonary infection(i.e.fever,expectoration,malaise,or dyspnea)and despite a minimum of 10 days of antibiotic therapy patients either do not improve or worsen clinically or radiographic opacities fail to resolve within 12 weeks of the onset of the pneumonia.,Nonresolving pneumonia（无反应性肺炎）,Curr Opin Pulm Med.2005 May;11(3):247-52(IF=3.119),Failure to respond to antimicrobial treatment was classified as nonresponding or progressive pneumonia.Nonresponding pneumonia was defined as persisting fever38and/or clinical symptoms (cough,expectoration,dyspnea)after at least72h of antimicrobial treatment.,Antimicrobial treatment failures in patients with community-acquired pneumonia:causes and prognostic implications,重新考虑诊断-是另一种疾病表现为肺炎？血管炎？ 你错误处理了病原体？例如按照常规菌进行治疗，但结核分枝杆菌，真菌，或卡氏肺孢子虫？ 错误的药物治疗正确的病原体？例如，MRSA而没有接受万古霉素或利奈唑胺。 诱因无法去除，如肺癌引起支气管的阻塞？ 忽略了一个未引流或转移性化脓性病灶，如脓胸，脑脓肿，感染性心内膜炎，或骨髓炎吗？ 药物热,Progressive and nonresolving pneumonia,Considerations when a patient with community-acquired pneumonia is not improving,Curr Opin Pulm Med.2005 May;11(3):247-52(IF=3.119),Because invasion of the lung parenchyma by Candida species with resulting Candida pneumonia is a rare event, controversy surrounds this entity. In fact, the isolation of candidal species from respiratory secretions is most often not clinically significant.,Am J Respir Crit Care Med.2011;183(1):96-128(IF=11.041),At Memorial Hospital and New York Hospital, 30 patients.The Candida pulmonary disease appeared to be significant clinical factor in only three cases.Pulmonary disease caused by Candida species.Am J Med. 1977 Dec;63(6):914-25.,To date, few data are available on the Candida species that cause PC, It is of note that in our series, the various non-albicans species of Candida did not appear to be more likely to cause PC than is Candida albicans.,Pulmonary candidiasis in patients with cancer: an autopsy study.Clin Infect Dis. 2002 Feb 1;34(3):400-3. Epub 2001 Dec 17.,An official American Thoracic Society statement:Treatment of fungal infections in adult pulmonary and critical care patients.,痰培养检查结果（纤维支气管镜，微生物室电话报，4月06日下午5时）,院微生物室：土曲霉,Imaging findings in patients with invasive pulmonary aspergillosis,Most patients presented with a macronodule and/or halo sign a in this study of IPA.大多数IPA影像学表现为大结节或和晕轮征。,Clin Infect Dis.2007 Feb 1;44(3):373-9(IF=9.374),Invasiveaspergillosisin the ICU: an emerging disease,Intensive Care Med.2007 Oct;33(10):1679-81(IF=5.258),曲霉的发生率0.3-15% 死亡率为59-95%之间,JAMA.2009 Dec 2;302(21):2323-9(IF=29.978),International study of the prevalence and outcomes of infection inICU,EPIC II：全球各地在ICU感染类型分布,Prevalence of the ve most common invasive fungal infections identied at autopsy in patients with haematological malignancies over a 20 year period,Mycoses.2013Nov;56(6):638-45(IF=1.278),Epidemiology and sites of involvement of invasive fungal infections in patients with haematological malignancies: a 20-year autopsy study,Trends in microbiologically or histologically documented aspergillosis,Epidemiology and sites of involvement of invasive fungal infections in patients with haematological malignancies: a 20-year autopsy study,Aspergillus fumigatus=烟曲霉；A.terreus=土曲霉；A.flavus=黄曲霉；Fusarium=镰刀菌；Mucorales=毛霉菌,Mycoses.2013Nov;56(6):638-45(IF=1.278),Epidemiology,diagnosis and treatment of fungal respiratory infections in critically ill patient,Rev Esp Quimioter.2013 Jun;26(2):173-88(IF=0.836),Aspergillus fumigatus is the most frequent species isolated in invasive aspergillosis (8090%)烟曲霉是最常见的侵袭性曲霉病（8090%）。while there has been a trend over the last few years for an increasing incidence of nonfumigatus species,especially Aspergillus flavus and Aspergillus terreus.在过去几年，黄曲霉和土曲霉的发病率越来越高。,Am J Respir Crit Care Med.2004;170:621-625(IF=11.041),Invasive Aspergillosis in Critically Ill Patients without Malignancy,约半数患者没有恶性肿瘤等基础病，COPD成为主要危险因素；ICU气道分离出曲霉菌无论定植或感染，均为不良预后的指标。,1850名ICU患者有127(6.7%)名感染曲霉菌,Clin Infect Dis.2002 Jan 1;34(1):7-14(IF=9.374),补充诊断：重症社区获得性肺炎（侵袭性肺曲霉病）；感染性休克；呼吸衰竭(型),IA一线治疗失败的患者需行挽救治疗，挽救治疗指南建议：首日静脉卡泊芬净70mg,后50mg/d静脉用药,或静脉米卡芬净100-150mg/d直至病情改善，序贯口服伏立康唑或口服伊曲康唑直至疾病治愈。初始口服泊沙康唑200mg,每日4次,疾病稳定后400mg,每日2次口服。,Am J Respir Crit Care Med.2011;183(1):96-128(IF=11.041),ATS statement:Treatment of fungal infections in adult pulmonary and critical care patients 2011年美国胸科学会成人呼吸与重症监护患者真菌感染治疗指南,全球首例病例报道治疗方案：两性霉素 B(累计剂量1200mg)和外科清创治疗无效后,改用泊沙康唑每次200mg,一日4次, 治疗一周后效果显著。,Mucormycosis (Zygomycosis) in a Heart-Kidney Transplant Recipient:Recovery after Posaconazole Therapy,治疗前,治疗后,Clin Infect Dis.2003 Jun 1;36(11):1488-91(IF=9.374),Drugs.2007;67(11):1567-601(IF=4.633),Invasive aspergillosis: epidemiology, diagnosis and management in immunocompromised patients,Posaconazole is an effective alternative for patients with invasive aspergillosis refractory to conventional therapy.泊沙康唑对传统药物难治的侵袭性曲霉菌病有效，可作为一种治疗选择。Survival rates at 30days(74%)and at the end of therapy (38%) were significantly higher amongposaconazole-treated patients than among controls (49% and 22%,respectively).研究人员报道，泊沙康唑治疗的患者30天内生存率（74%）及治疗终点生存率（38%）均显著高于对照组30天内生存率（49%）及治疗终点生存率（22%）。,Posaconazole: when and how? The clinicians view,Mycoses.2012 Mar;55(2):110-22(IF=1.278),Results of Phase III clinical trials and case/series reports indicate that posaconazole is effective in treating oesophageal candidiasis, including azole-refractory disease,and other IFI refractory to standard antifungal therapies.三期临床试验表明,泊沙康唑能够治疗包括唑类难治性疾病，以及其他难治性真菌感染,Significantly fewer patients in the posaconazole group had invasive aspergillosis,and survivalwas significantly longer among recipients of posaconazole than among recipients offluconazole or itraconazole.在泊沙康唑组，在治疗侵袭性曲霉病患者时，能够延长生存期，和伏立康唑或伊曲康唑相比较时。,An official American Thoracic Society statement:Treatment of fungal infections in adult pulmonary and critical care patients.,Am J Respir Crit Care Med.2011;183(1):96-128(IF=11.041),泊沙康唑临床主要用于顽固性侵袭性真菌感染(IFI)的挽救治疗,Rev Recent Clin Trials.2011 Sep;6(3):204-19,Posaconazole: a new antifungal weapon,-无活性;可能有活性;+有活性，作三线用药（至少临床有效）;+有活性，二线用药(临床作用稍差）;+有活性，一线用药（临床常常有效）,体外抗真菌活性曲霉菌和其它真菌,2013第43版热病-桑福德抗微生物治疗指南,Molecules. 2014 Jan 17;19(1):1085-119(IF=2.428),Invasivefungal infectionsin theICU：how to approach，how to treat,注：S=敏感，SDD=剂量依赖性敏感，R=耐药，I=中度敏感,For refractory disease,posaconazole,itraconazole,voriconazole,or AmB suspension is recommended.2009美国传染病学会:对于难治性真菌感染，推荐使用泊沙康唑、伊曲康唑、伏立康唑及二性霉素B脂质体。,Clin Infect Dis.2009 Mar 1;48(5):503-35(IF=9.374),Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America,下一步调整治疗方案：单用还是联合？,Liposomal amphotericin B has become the therapeutic agent of choice. 两性霉素B在治疗接合菌已成为首选的治疗药物。Posaconazole is a new orally administered triazole antifungal and the first member of this class to have comparable in vitro activity to amphotericin B against most zygomycetes. 泊沙康唑是一种新型口服给药的三唑类抗真菌药，在治疗接合菌方面有类似的体两性霉素B的作用。A further consideration is combination antifungal therapy, there are case reports that describe successful outcomes with combinations of liposomal amphotericin B with either caspofungin or posaconazole, where single agent therapy had failed.报告表明,脂质体两性霉素B联合卡泊芬净或泊沙康唑可成功治疗单药治疗失败的曲霉感染患者。,治疗曲霉病:两性霉素B、泊沙康唑或两者联合?,J Antimicrob Chemother.2008;61Suppl1:i35-40(IF=5.338),但唑类联合两性霉素B存在争议，因唑类可影响两性霉素B的结合位点而降低抗菌效能。,Clinicaloutcomesoflung-transplantrecipientstreatedby伏立康唑and卡泊芬净 combinationinaspergillosis.,We showed that a median of 12.3days was required for voriconazole to reach high enough blood levels卡泊芬净 combination with 伏立康唑 provides cover against Aspergillus infection during the periodwhen voriconazole may be at 亚治疗水平 with good tolerabilit。,12.3,14.9,8.3,J Clin Pharm Ther.2010 Feb;35(1):49-53(IF=2.104),卡泊芬净可增加细胞的通透性,因此有利于两性霉素B和唑类穿过细胞壁。,4月03日,4月04日,4月05,4月06日,4月07日,4月08日,4月09日,卡泊芬净+伊曲康唑,卡泊芬净+泊沙康唑,气管切开,4月10日,4月11日,4月12日,4月13日,4月14日,4月15日,4月16日,SBT/脱机,4月06日,4月16日,泊沙康唑临床治疗有效,2014年4月14日血常规检查结果,2014年4月19日痰真菌培养检查结果,2014年4月16日肺部CT检查（部分结节消失或变小淡化）,一点遗憾：未能得到进一步的影像学资料（经济原因17日回当地医院治疗）,J Antimicrob Chemother.2010 Aug;65(8):1765-70(IF=5.338)