Classification of Medical Fungi Introduction of Fungus Yeasts unicellular, budding cells Molds multicellular, filamentous (細絲狀的), hyphae(菌絲), mycelium

Outlines Mycology (真菌學) 黴菌感染之治療策略 Invasive fungal infection (侵襲性) 蔡哲安 醫師 台中榮總 感染科 Treatment 真菌? Introduction of Fungus Prokaryotes 原核生物 Eukaryotes 真核生物 Three Domain Systems Bacetria Eukaryota 真核域 Archaea古細菌 Five Kingdoms 界 Protista 原生生物界 Monera 原核界 Plantae Fungi Animalia Plantae Fungi Animalia Six Kingdoms Eubacteria Archaebacteria Protista ( Campbell 1996:P.495) Five Kingdoms (五個生物界) 真菌界 Introduction of Fungus 植物界 Eukaryotic (真核生物), heterotrophic (異養生物) microorganisms Chitin cell wall (Galactomannoprotein, glucan) Cell membrane (sterol ergosterol) Cytoplasm (細胞質), organelles (細胞器) and nucleus 原生生物界 這和之後藥物治療有關 原核生物界 Life Science 2010 5 ~87~

Classification of Medical Fungi Introduction of Fungus Yeasts unicellular, budding cells Molds multicellular, filamentous (細絲狀的), hyphae(菌絲), mycelium(菌絲團) Dimorphic two forms (yeast or mold) Yeast Candida, Cryptococcus, Trichosporon, Rhodotorula Septated hyphae (1) Hyaline Opportunists: Aspergillus, Fusarium, Scedosporium, Mold Paecilomyces Dermatophytes: Trichophyton, Microsporon (2) Dematiaceous: Curvularia, Exophiala Aseptate hyphae Zygomycetes, Rhizopus, Mucor Dimorphic Histoplasma, Penicillium, Coccidioides,, Paracoccidioides, Sporothrix Others Pneumocystis jiroveci Candida : Disease Spectrum Diseases Caused by Fungi Superficial Mycoses the skin, the hair, and the nails. Cutaneous Mucous membrane Diaper Oral thrush Deep organ Bloodstream & Disseminated Subcutaneous Mycoses Brain abscess the dermis, subcutaneous tissue or adjacent structures Systemic Mycoses Endocarditis Primary Pathogenic Fungi healthy Opportunistic Fungi immunocompromised Osteoarticular Intertrigo Esophagitis 今日的主題 TOP 5 Endogenous Infective thrombosis 常造成感染的念珠菌 種類 GI mucositis Invasion Candidemia Dissemination Hepatosplenic microabscess UTI Pathophysiology of Invasive Candidiasis Intravascular cath Candidiemia Empyema deep infections of the internal organs. Exogenous Ocular 敘 述 白色念珠菌 Candida albicans 正常菌叢存於胃腸道 念珠菌感染的第1大病原 Candida glabrata 全世界發生率提高且抗黴菌劑敏感性降低 已為重要病原菌 Candida parapsilosis 念珠菌菌血症的第4大病原 新生兒加護病房念珠菌菌血症的病原 之一 與導管和其他醫療器材有關 最常由加護病房醫護人員雙手上分離出 致命性較他種念珠菌低 Candida tropicalis 白血病 長期嗜中性白血球減少症和長期待在加護病房為主要風 險因子 癌症病患發生率提高 由於GI道損傷且內生常在菌(microflora)受 抗生素抑制 以致生物體侵入機會增加 Candida krusei 雖較少見 但對fluconazole的抗藥性 仍具臨床重要性 Eggimann P et al. Lancet Infect Dis 2003 ~88~

Morphology of Colonies C. parapsilosis C. albicans Candida albicans C. tropicalis C. krusei C. glabrata J Clin Microbiology 1994;32:1923-1929 Aspergillosis Aspergillus Flavus 念珠菌感染和麴菌感染的臨床表現 Outlines 今日的主題 念珠菌感染 Candida 麴菌感染 Aspergillosis 多關節疼痛(polyarthralgia) 無 氮血症(azotemia) 無 皮膚損傷 + 肝臟損傷 罕見 鼻竇的徵象和症狀 無 呼吸的徵象和/或症狀 無 + 腦部的徵象和/或症狀 少見 臨床表現 發燒 Mycology (真菌學) Invasive fungal infection (侵襲性) Treatment ~89~

醫學中心加護病房不分部位 常見之醫療照護相關感染菌種排名 醫學中心加護病房不分部位 常見之醫療照護相關感染菌種排名 Source: 2014 TNIS data 2015 Asia candidaemia survey (20102011 period) Nonalbicans is increasing 20102011 Species distribution of 1910 nonduplicate Candida blood isolates identified to the species level (number denotes %). 彰基 20092012 (N=209) 20012006 (N=91) 1.4% 4.1% 1.1% 2.2% 1.1% Risk Factors for IC in ICU Patients NonAlbicans is Increasing 7.3% 11.0% C. albicans C. tropicalis C. glabrata 19.8% 43.6% 21.6% C. parapsilosis 64.8% C. Krusei Others 22.0% Journal of Microbiology, Immunology and infection 2013 OstroskyZeichner et al. Crit Care Med. 2006;34:857863 ~90~

Outlines Development of antifungal agents Mycology (真菌學) Invasive fungal infection (侵襲性) Treatment Classifications of Antifungal Agents Range of Activity for Antifungal Agents mannoproteins Fungi Yeasts 1,3 1,6 glucans PPL bilayer β1,3 glucan synthase chitin Echinocandins Ergosterol Micafungin - Caspofungin Polyene Anidulafungin Amphotericin B, LipidAMB DNA Synthesis Azole - Fluctyosine Ketoconazole Voriconazole Posaconazole Molds Yeast AMB FCZ ITZ VZ PS CF Mica AF Candida albicans C. tropicalis C. parapsilosis C. krusei C. glabrata Cryptococcus neoformans Aspergillus fumigatus Zygomycetes Fusarium spp Polyene; AMB=amphotericin B, AmBisome, Amphotec, Abelcet Azole; FCZ = fluconazole; ITZ = itraconazole; VZ = voriconazole; PS = posaconazole Echinocandin; CF = caspofungin; MF = micafungin; AF = anidulafungin Adapted from JP Donnelly by Malcolm Richardson. Presented at: New Challenges and New Options in the Treatment of Invasive Fungal Infections in Stem Cell Transplant Patients, a Satellite Symposium at the 20th Annual Meeting of the EBMT; March 24, 2002; Montreux, Switzerland. Relationship between hospital mortality and the timing of antifungal treatment 死亡率達>50% ~91~

Clinical Practice Guideline for the Management of Candidiasis: 2016 IDSA Nonneutropenia patients Strength of recommendation Quality of the evidence Treatment for candidemia An echinocandin Strong (caspofungin, micafungin, anidulafungin) is recommended as initial therapy Weak strong recommendation; highquality evidence). High is an acceptable alternative to an echinocandin Moderateas initial therapy in selected patients, including Lowthose who are not critically ill and who are considered Very lowunlikely to have a fluconazoleresistant Candida species strong recommendation; highquality evidence What Is the Role of Empiric Treatment for Suspected Invasive Candidiasis in Nonneutropenic Patients in the ICU? Recommendations Severe Candida Sepsis Time for a new approach? Patient with systemic Candida infection Empiric antifungal therapy should be considered in critically ill patients with risk factors for invasive candidiasis and no other known cause of fever and should be based on clinical assessment of risk factors, surrogate markers for invasive candidiasis,and/or culture data from nonsterile sites Strong recommendation; moderatequality evidence <Timing>Empiric antifungal therapy should be started as soon as possible in patients who have the above risk factors and who have clinical signs of septic shock Start fluconazole treatment Blood culture Susceptibility test sensitive insensitive Continue Escalate to fluconazole echinocandin Start echinocandin treatment Blood culture Susceptibility test sensitive insensitive Deescalate to Continue fluconazole echinocandin Escalation approach Deescalation approach 100 MIC Distribution of Blood Candida Isolates N= 476, NTUH, 2009-2010- Echinocandins ESCMID Candida Guideline Treatment of invasive candidiasis/candidaemia in adults Cumulated % of Isolates 80 60 40 20 Caspofungin Micafungin Anidulafungin 00 0.008 0.015 0.03 0.06 0.12 0.25 0.5 1 2 4 8 MIC ( g/ml) ~92~

Micafungin 重度肝腎功能不全 不需調整劑量 Clinically relevant interactions of antifungals and immunosuppressors Ciclosporin A Tacrolimus Mycophenolate mofetil Sirolimus Ambisome Potential nephrotoxicity Potential nephrotoxicity Ciclo AUC (1.8fold) Oral tacro conc (up to 5fold) Sirol conc Voriconazole Ciclo Cmax & AUC (13%, 70%) Tacro Cmax & AUC (117%, 221%) Sirol Cmax conc (6.6fold, 11fold) Posaconazoel Ciclo conc Tacro Cmax & AUC (121%, 358%) Siro Cmax & AUC (6.7fold, 8.9fold) Caspofungin Caspofungin AUC (35%) Tacrolimus Cmin (26%) Micafungin Siro AUC (21%) Anidulafungin Anidulafungin AUC (22%) 2013年 Mycamine Package insert No specific recommendation No dose adjustment Can be coadministered, but required monitor/dose adjustment required Contraindicated Micafungin 適應症 & 劑量 全民健康保險藥品給付規定 caspofungin (Cancidas) 1.限用於其他黴菌藥物治療無效或有嚴重副作用之侵入性麴菌症 侵 入性念珠菌感染症之第二線用藥 適應症 建議劑量(mg) 一天一次 2.符合衛生署之適應症範圍且經感染症專科醫師認定需使用者 惟治 療食道念珠菌感染限用於fluconazole無效或有嚴重副作用者 預防接受造血幹細胞移植術病患 的念珠菌感染 50 治療念珠菌血症與其他念珠菌感 染 100 治療16歲以上成人的食道念珠菌 感染 150 micafungin(mycamine) 1.治療16歲以上成人的食道念珠菌感染 2.預防接受造血幹細胞移植病患的念珠菌感染 3.治療念珠菌血症與其他侵襲性之念珠菌感染 Anidulafungin (Eraxis) 限用於治療非白血球低下之成人念珠菌血症 念珠菌腹膜炎及念 珠菌腹腔內膿瘍 MYCAMINE Package Insert. Taiwan ~93~

不用 loading dose, 使用方便 Thank you! ~94~