重癥患者真菌感染聚焦念珠菌及氟康唑的地位 201376 廣西北海m1

1、重癥患者侵襲性真菌感染 聚焦念珠菌感染及氟康唑的地位唐 建 國(guó) Trauma-Emergency-Critical Care Medicine Center (T-E-CCMC)1提 要ICU與感染危重病人侵襲性真菌感染念珠菌來(lái)源抗真菌藥物及選擇關(guān)于氟康唑2提 要ICU與感染危重病人侵襲性真菌感染念珠菌來(lái)源抗真菌藥物及選擇關(guān)于氟康唑3ICU 感染患者感染性疾病診治感染的預(yù)防與控制重癥感染入住ICUICU獲得感染 （ICU-acquired infections）ICU內(nèi)獲得性感染的預(yù)防與控制感染相關(guān)問(wèn)題是ICU永恒主題ICU 工作要點(diǎn)之一是感染475 countries1265 ICUS13

2、796 patients7087 (51.4%) infected patients9084 (71%) receiving antibioticsICU mortality rate 25% (infected) & 11% (non-infected) (p 165 species)C.Albican 白念Non C.Albicans 非白念32Candida ColonizationPulmonary treeBowelVaginaEsophageal / GI33Candida: Infection sitesC. parapsilosisC. tropicalisC. albican

3、sC. kruseiC. glabrata34The Source of CandidemiaClinical Infectious Diseases.2001,33:1959-67353637GI tractGI tractModel for Invasive CandidiasisBlijlevens, Donnelly, De Pauw. Brit J Haematol 2002;117:259-64insultinjurytranslocationinfectionantibioticsselectionNormal commensal floraDiseaseCentral veno

4、us catheterCandida speciesGI tract38Lancet Infect Dis. 2003. 3: 685-702394041Nat Rev Microbiol. 2013. 10(2):112-12242Nat Rev Microbiol. 2013. 10(2):112-1224344念珠菌來(lái)源外源性：導(dǎo)管位置、導(dǎo)管護(hù)理內(nèi)源性：胃腸粘膜保護(hù)、腸內(nèi)營(yíng)養(yǎng)定植 & 高負(fù)荷定植 & 感染45提 要ICU與感染危重病人侵襲性真菌感染念珠菌來(lái)源抗真菌藥物及選擇關(guān)于氟康唑46系統(tǒng)性抗真菌藥：全球isavuconazoleravuconazolefluconazoleitrac

5、onazoleposaconazoleL-AMBABCDABLCvoriconazolecaspofunginmicafunginanidulafunginAmphotericin BAzolesCandinsAMB47Phospholipid bilayerof the fungal cellmembraneFungalcell wallb-(1,3)-glucanb-(1,6)-glucanb-(1,3)-glucan synthaseGlucan Synthesis InhibitorEchinocadinCaspofunginMicafungin (FK463)Anidulafungi

6、n (LY303,306)ErgosterolPolyenes (AmB, LFAB)Azoles Fluconazole,ItraconazoleVoriconazolePosaconazoleRavuconazole (BMS-207,147)Antifungal Mechanisms of Action:“Newer” Antifungal AgentsnucleusNucleoside Analogs Flucytosine48Mayo Clin Proc. 2011; 86(8):805-81749General patterns of susceptibility of Candi

7、da Spp.IDSA Guidelines. CID 2009,48:503355051CHIF-NET 201052Journal of clinical microbiology. 2010, 48 (4):13661377 53In vitro susceptibilities of Candida spp. to uconazole and voriconazoleJournal of clinical microbiology. 2010, 48 (4):13661377 54555657 IDSA：Candidiasis Guideline 20095859Intensive C

8、are Med.2009, 35:20621460Carmeli like score61Antifungal systemic therapy according to Carmeli-like score62Carmeli-like score extended antifungal therapy algorithm 63抗真菌藥物及選擇抗真菌藥物選擇唑類(lèi)、多烯類(lèi)、棘白菌素類(lèi)機(jī)制抗真菌譜嚴(yán)重程度粒細(xì)胞三唑類(lèi)暴露局部的流行病學(xué)Carmeli Score64提 要ICU與感染危重病人侵襲性真菌感染念珠菌來(lái)源抗真菌藥物及選擇關(guān)于氟康唑65The Dosage of FluconazoleAAC

9、. 1998,42 (5):1105-1109T MICCmax / MICAUC / MIC66抗真菌藥物按PK/PD分類(lèi)Int J Antimicrob Agents. 2012 Jan;39(1):1-10.67Fluconazole dose & Cmax and AUC68Fungal densities in kidneys of mice treated with various Fluconazole69Pharmacodynamic variables for five total doses of FluconazoleED16ED37ED49ED60ED7570Dose-

10、response curve71p=0.00972AAC.2007,51(10):3599-360473Correlation of MIC data with Fluconazole treatment success74Correlation of Dose/MIC and AUC/MICversus outcomes 75氟康唑劑量/MIC50時(shí)臨床有效率可達(dá)86%以上氟康唑不同給藥劑量/MIC比值治療粘膜/侵襲性念珠菌病總體臨床治愈率Pfaller MA. Clinical Microbiology Reviews. 2006;19(2):435-47.三項(xiàng)侵入性念珠菌病的研究及一項(xiàng)粘

11、膜感染的研究的匯總結(jié)果劑量/MIC有效率(%)68%86%95%98%55%0204060801006.2550-75100-30040036/6552/7753/62135/142123/1256.25-12.576PK/PD of FluconazoleDose Dependent AgentAUC/MIC 45-90Dose/MIC 50-100S 8mg/l 6mg/kg/dSDD 16-32mg/l 12mg/kg/dR 64mg/l 20mg/kg/dAndesD.Pharmacokinetics and Pharmacodynamics of Antifungals.Infect

12、 Dis Clin North Am.2006, 20:679-697 IDSA Guidelines. CID 2009,48:50335775mg/kg/d10mg/kg/dCases3030Clinical response rate 60%83%Eradication of C. albicans from the blood 28/3030/30Death related to fungal infection 8/301/30Eradication of other sites of infection 9/2511/23Fluconazole at a dose of 10 mg/kg/day would seem to be an effective and safe drug for the management of C. albicans fungaemia Graninger W et al . J Infect. 1993;26:133-146 78Current Medi