真菌性脓毒症诊治进展

1、安徽省立医院安徽省立医院 重症医学科重症医学科周树生周树生The Epidemiology of Sepsis in the United States from 1979 through 2000N Engl J Med 2003; 348:1546-1554 Long-term mortality and medical care charges in patients with severe sepsis.Crit Care Med. 2003 Sep;31(9):2316-23. Cumulative mortality rate among patients with severe

2、sepsisDistribution of various microorganisms and sites of infection in severe sepsis patients and the outcome according to the microorganisms and sites of infection in severe sepsis patientsCrit Care Med 2007; 35: 2538-2546 Epidemiology of severe sepsis in critically ill surgical patients in ten uni

3、versity hospitals in China Characteristics of critically ill patients in ICUs in mainland China Crit Care Med. 2013 Jan;41(1):84-92 Patient Outcome and Risk Factors There were 1,034 survivors: 986 (76.0%) were discharged home, and 48 (3.7%) were still in the hospital on November 30, 2009. There were

4、 263 nonsurvivors(20.3%): 211 died in the ICU, and the other 52 died in the general wards. Bin Du, MD; Youzhong An, MD; Yan Kang, MD et al;20042004年，年，1111个国际医学组织的个国际医学组织的感染和脓毒症诊治方面的专家，感染和脓毒症诊治方面的专家，出版了第一个改进重症脓毒症出版了第一个改进重症脓毒症和脓毒症休克预后的指南。这和脓毒症休克预后的指南。这个工作组联合其他工作组在个工作组联合其他工作组在20062006年和年和20072007年再次举行

5、会议，年再次举行会议，用新的循证方法论系统来评估用新的循证方法论系统来评估证据的质量和推荐力度，以更证据的质量和推荐力度，以更新该指南文件。这些建议的目新该指南文件。这些建议的目的是用来指导临床医生治疗重的是用来指导临床医生治疗重症脓毒症和脓毒症性休克的病症脓毒症和脓毒症性休克的病人。人。需要指出的是，当医生面需要指出的是，当医生面对具体病人独特的临床指标时，对具体病人独特的临床指标时，这些指南中的建议不能取代临这些指南中的建议不能取代临床医生的决策。床医生的决策。2004 2008 201211个国际组织 15个国际组织 29个国际组织44位委员 55位委员 69位委员135篇参考文献 34

6、1篇参考文献 636篇参考文献Chest.1992 Jun;101(6):1644-55 不足之处：不足之处：标准存在的敏感性高但特异性差的问题标准存在的敏感性高但特异性差的问题 ACCP/SCCM 1992ACCP/SCCM 1992Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsisNew diagnostic Criteria for Sepsis:2012Crit Care Med. 2013 Feb;41(2):580-637.New

7、diagnostic Criteria for Sepsis:2012Crit Care Med. 2013 Feb;41(2):580-637.One case:女性，女性，85岁，住院号：岁，住院号：2260073 主诉：患者系“反复咳嗽、咳痰三年，加重一周”入院入院时间：2013年3月26日转入时间：2013年4月05日诊疗过程：入我院干部病房后出现发热现象，同时伴有胸闷、气喘加重，痰培养示细菌（嗜麦芽窄食假单胞菌及热带念珠菌）；2012年5月行肺CT检查示“间质性肺炎” One case:女性，女性，85岁，住院号：岁，住院号：2260073 2013年4月5日出现呼吸困难加重，氧饱和

8、度下降至82%，予以积极的对症处理后，症状不能改善，故转入我科加强治疗。 转入后检查急诊生化 K5.05mmol/L,Na141.1mmol/L,CL113.0mmol/L,Ca1.46mmol/L,CREA248.4umol/LCO2 15.8 mmol/L,AG 17.30,GLU 3.01mmol/L,ALB 16.3g/L 入科诊断：入科诊断：重症医院获得性肺炎(吸入性)；感染性休克？；呼吸衰竭(型)；间质性肺疾病(IPF/IIP)；3级高血压，极高危；老年性痴呆；慢性肾衰竭。诊疗计划：诊疗计划：1、一般治疗，纠正休克；2、气管插管、机械通气（轻度镇痛镇静）；3、抗感染治疗（头孢哌酮舒

9、巴坦 2.0 静脉滴注 q12h ;灭滴灵注射液 0.5g 静脉滴注 bid;）；）；4、补液、营养支持及维持水电解质平衡等对症支持处理；血气分析血气分析+乳酸乳酸: PH 7.072,PCO2 32.6mmHg,PO2 47.2mmHg,ABE -19.1mmol/LSBE -19.0mmol/L，Lac 5.5mmol/L。 CURB-65评分:4分同时，进一步完善病原学诊断（血培养，痰培养等）同时，进一步完善病原学诊断（血培养，痰培养等）Because invasion of the lung parenchyma by Candida species with resulting Ca

10、ndida 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 Jan 1;183(1):96-128.An official American Thoracic Society statement: Treatment of fungal

11、 infections in adult pulmonary and critical care patients.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

12、 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):4

13、00-3. Epub 2001 Dec 17.ANCA：C-ANCA（-）及P-ANCA（-）尿常规：阴性4月07日4月08日4月09日4月10日4月11日4月12日4月13日升压药物去甲肾难以撤除，尿量逐渐减少调整抗生素（替考拉宁）?转入后检查复查床边胸片无明显进展性改变。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)

14、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）（无反应性肺炎）Curr Opin Pulm Med. 2005 May;11(3):247-52. Progressive and nonresol

15、ving pneumonia.Nonresolving pneumonia definitions（无反应性肺炎）（无反应性肺炎）after at least72h of antimicrobial treatment. Antimicrobial treatment failures in patients with community-acquired pneumonia: causes and prognostic implications.Am J Respir Crit Care Med. 2000 Jul;162(1):154-60. 444 patients, 49 patien

16、ts (11%) had a repeated investigation because of antimicrobial treatment failure.Considerations when a patient with community-acquired pneumonia is not improving1、女性，85岁；2、“反复咳嗽、咳痰三年，加重一周伴胸闷、气喘”，长期服用抗生素及激素；3、抗生素治疗效果差（无反应）；4、CD4/CD8=1.1总结分析病史特点：总结分析病史特点：诊断：无反应性肺炎诊断：无反应性肺炎Results: Treatment failure oc

17、curred in 215 patients (15.1%): 134 early failure (62.3%) and81 late failure (37.7%).The causes were infectious in 86 patients (40%),non-infectious in 34 (15.8%).Thorax. 2009 Nov;59(11):960-5. Risk factors of treatment failure in community acquired pneumonia.The main causes of early failure were pro

18、gressive pneumonia (n=54), pleural empyema (n=18) lack of response (n = 13), and uncontrolled sepsis (n = 9). Arch Intern Med. 2010 Mar 8;164(5):502-8. Causes and factors associated with early failure in hospitalized patients with CAPResults ：The following showed the prevalence rates of the causes:

19、infection 41.7%,unknown causes 50.0%,non-infectious causes 8.3%Diagnosis and Treatment of Nonresponding Pneumonia PatientsPJCCPVD January 2012,Vol,20 No.1（顾靖华）进一步完善相关检查进一步完善相关检查 重症患者侵袭性真菌感染诊断和治疗指南重症患者侵袭性真菌感染诊断和治疗指南中华医学会重症医学分会中华医学会重症医学分会N Engl J Med 2003; 348:1546-1554 The Epidemiology of Sepsis in t

20、he United States from 1979 through 2000Int J Antimicrob Agents.2008;32:S87-91Epidemiology of candidemia in intensive care units外周静脉外周静脉CVC血培养检查结果（微生物室电话提前报，血培养检查结果（微生物室电话提前报，5月月9日下午）日下午）BDG=102 pg/mlThe University of Virginia risk factors scoring system：36 Nosocomial Bloodstream Infections in US Hos

21、pitals:Analysis of 24,179 Cases from a Prospective Nationwide Surveillance Study.Clin Infect Dis. 2004 Aug 1;39(3):309-17. n107 (39.5%) patients with isolated candidemia, n 77 (28.4%) with invasive candidiasis. nIn 37% of the cases, candidemia occurred within the first 5 days after ICU admission.Cri

22、t Care Med. 2009 May;37(5):1612-8 One hundred eighty ICUs in FranceAnn Surg. 2001 Apr;233(4):542-8. Pelz RK, Hendrix CW, Swoboda SM, Int J Antimicrob Agents. 2009 Sep;34(3):205-9 Consensus statement on the management of invasive candidiasis in ICU in the Asia-Pacific RegionCHINA SCAN teamNon albican

23、s54.7%C. albicans41.8%mixed infectionotherCandida speciesDiagnostic confirmation was basedsolely on at least one positiveblood culture in 290 (94.8%) casesDiagnosis was confirmed by histopathology in one patient (0.3%)Invasive candidiasis in intensive care units in China: a multicentre prospective o

24、bservational study.J Antimicrob Chemother.2013 Mar 29.1-9 Fengmei Guo1,Yi Yang1, Yan Kang,et al.Crit Care. 2008;12(1):R5 Impact of invasive fungal infection on outcomes of severe sepsis: a mul-ticenter matched cohort study in critically ill surgical patientsOutcomes of candidemic septic shock patien

25、ts compared with bacteremic septic shock patientsCrit Care Med. 2002 Aug;30(8):1808-14.International Guidelines for Management of Severe Sepsis and Septic Shock: 2012what actually changed about fungus?Use of the 1,3 beta-D-glucan assay (grade 2B), mannan and anti-mannan antibody assays (2C).Change 1

26、:DiagnosisIntern Med. 2011;50(22):2783-91 Diagnosis of invasive fungal disease using serum (13)-D-glucan: a bivariate meta-analysis.NOTE. AUC, the area under the summary receiver operating characteristic curve; CI, confidence interval; galactomannan ,GM; IA, invasive aspergillosis; IFD, invasive fun

27、gal disease; NLR, negative likelihood ratio; PLR, positive likelihood ratio; SEN, sensitivity; SPE, specificity.Pooled Test Performance of the Included Studies in the Meta-AnalysisInternal control detection was positive for all samples that were negative by PCR. The median time from diagnostic cultu

28、res for Candida to collection of samples for PCR and BDG was 4 days (interquartile range: 1-6 days).Abbreviations: BDG, 1,3-b-D-glucan; PCR, polymerase chain reaction.a Candidemia and deep-seated candidiasis groups included 5 patients who had both conditions.b Deep-seated candidiasis included patien

29、ts with intra-abdominal infections and infections of other sites (bone and devitalized surrounding tissue, n=2; lumbar spine device, n=1; cranial abscess, n=1).c PCR was positive if positive result was obtained on plasma and/or sera.d P values are for sensitivities of the respective assays, as deter

30、mined by McNemar test.Performance of Polymerase Chain Reaction and 1,3-D-Glucan AssaysClin Infect Dis. 2012 May;54(9):1240-8. Change 2:DiagnosisUse of low procalcitonin levels or similar biomarkers to assist the clinician in the discontinuation of empiric antibiotics in patientswho initially appeare

31、d septic, but have no subsequent evidence of infection (grade 2C).Diagn Microbiol Infect Dis. 2012 Jul;73(3):221-7 Am J Respir Crit Care Med.2001 Aug 1;164(3):396-402 Areas under the ROC were: PCT, 0.92; IL-6, 0.75; IL-8, 0.71clinical model with PCT, 0.94, and clinical model without PCT, 0.77Baselin

32、e Plasma Levels of PCT, IL-6, and IL-8Clinical experiences with a new semi-quantitative solid phase immunoassay for rapid measurement of procalcitonin.Clin Chem Lab Med. 2000 Oct;38(10):989-95. Crit Care Med. 2006 Jul;34(7):1996-2003. Global diagnostic accuracy odds ratios for procalcitoninProcalcit

33、onin as a diagnostic test for sepsis in critically ill adults and after surgery or trauma: a systematic review and meta-analysisReview ArticleA PCTcut-off value of 2ng/mL separated Candida sepsis from bacterial sepsis with a sensitivity of 92%, a specificity of 93%,and positive and negative predicti

34、ve values of 94%. The best cut-off value for CRP to separate bacterial sepsis from Candida sepsis was 100mg/L,with a sensitivity of 82% and a specificity of 53%The combination of CRP(with a cut-off value of 100mg/L) and PCT(with acut-off of 2ng/mL)did not increase sensitivity or specificity for a di

35、agnosis of Candida sepsis.Markers ofsepsisandorgandysfunctionattimeofbloodculture.Dataareexpressedasmedian. Procalcitoninlevelsinsurgicalpatientsatriskof candidemia J Infect. 2010 Jun;60(6):425-30. Serum levels of C-reactive protein (CRP) and procalcitonin (PCT) on the studied days according to the

36、presence of invasive fungal infection (IFI) or bacterial infection (BI).Eur J Clin Microbiol Infect Dis. 2005 Apr;24(4):272-5. Value of measuring serum procalcitonin, C-reactive protein, and mannan antigens to distinguish fungal from bacterial infectionsSerum levels of C-reactive protein (CRP) and p

37、rocalcitonin (PCT) on the studied days according to the presence of invasive fungal infection (IFI) or bacterial infection (BI).Eur J Clin Microbiol Infect Dis. 2005 Apr;24(4):272-5. Value of measuring serum procalcitonin, C-reactive protein, and mannan antigens to distinguish fungal from bacterial

38、infections成也萧何，败也萧何 Eur J Clin Invest.2008 Oct;38(10):784-5Acute influence of aerobic physical exercise on procalcitonin马拉松也能升高马拉松也能升高PCTPCTChange 2:DiagnosisUse of low procalcitonin levels or similar biomarkers to assist the clinician in the discontinuation of empiric antibiotics in patientswho ini

39、tially appeared septic, but have no subsequent evidence of infection (grade 2C).Diagn Microbiol Infect Dis. 2012 Jul;73(3):221-7 Patients randomized to the PCT group had a significantly shorter median ICU length of stay than control subjects (3 d;range, 118 d, vs. 5 d; range, 130 d, respectively; P=

40、0.03), and a tendency to stay for a shorter period in the hospital (14 d; range, 564 d, vs. 21 d; range, 589 d;P=0.16)Am J Respir Crit Care Med. 2008 Mar 1;177(5):498-505 Use of procalcitonin to shorten antibiotic treatment duration in septic patients: a randomized trial.Lancet. 2010 Feb 6;375(9713)

41、:463-74 Change 3: DiagnosisTime to positivity of blood culture (TTP) can predict different Candida species instead of pathogen concentration in candidemiaJ Clin Microbiol. 2008 Jul;46(7):2222-6 Time to blood culture positivity as a marker for catheter-related candidemiaTime to blood culture positivi

42、ty as a marker for catheter-related candidemiaAccuracy of a TTP cutoff of 30 h for the diagnosis of CRC in 50 patients with indwelling CVCsJ Clin Microbiol. 2008 Jul;46(7):2222-6 In patients with an indwelling CVC,definite CRC group exhibited significantly shorter TTP than cultures from the non-CRC

43、group (17.32 h versus 37.75 h; P 0.009).Time to blood culture positivity as a marker for catheter-related candidemiap The time to detection of C. glabrata was significantly longer than for other Candida species.pIn conclusion, our results suggest that the TTP may be a useful tool in the evaluation o

44、f patients with candidemia who have an indwelling CVC, and in selected cases, it may support a decision to retain the catheter.DISCUSSIONTime to positivity of blood cultures of different Candida species causing fungaemia pThe mean TTP for all isolates causing candidaemia was25.924.9 h.The TTP for C.

45、 glabrata was significantly longer than the TTP of the other species.pIn contrast, the TTP of C. tropicalis was significantly shorter than that of the other three species.J Med Microbiol. 2012 May;61(Pt 5):701-4 No.of vials with positive culturesTTP(hr)means+_ SDCandida albicans8334.2+25.1Candida tr

46、opicalis4116.9+7.7Candida glabrata3356.5+25.5Candida parapsilosis1438.9+17.1Time to positivity of different Candida speciesEur J Clin Microbiol Infect Dis. 2013 Feb 1. Department of Clinical Laboratory, Peking University First Hospital, Beijing, China1996-2005,The appropriateness of initial antimicr

47、obial therapy, the clinical infection site, and relevant pathogens were retrospectively determined for 5,715 patients with septic shock in three countries.Inappropriate initial antimicrobial therapy for septic shock occurs in about 20% of p a t i e n t s a n d i s a s s o c i a t e d w i t h a f i v e f o l d r e d u c t i o n i n s u r v i v a lChest. 2009 Nov;136(5):1237-48. ESCMID* guide