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1 Jpn. J. Med. Mycol. Vol. 45, , 2004 ISSN ,, 3 proven fungal infection, clinically documented fungal infection, CT halo sign, possible fungal infection, B empiric therapy targeted therapy, 400 mg/ B mg/kg/, B mg/kg/ Key words: guideline, candidiasis, aspergillosis, prophylaxis, empiric therapy, targeted therapy I., ,,, II. 3 proven fungal infection,,, clinically documented fungal infection ,,, Table 1, possible fungal infection,,,, III. 1. Fig. 1 1, 10, , Candida albicans, C. tropicalis, C. parapsilosis, C. glabrata, C. krusei, non-albicans Candida 3.,,

2 Table 1. Serological/molecular diagnosis for invasive fungal infection Fungi Substance Method Candida Heat labile glycoprotein Cand-Tec LA Mannan Pastorex Candida LA Uni-medi Candida ELISA Platelia Candida ELISA D-arabinitol Arabinitec auto Enzyme colorimetric assay Candida DNA Geni Q Candida Real-time PCR Pathologic fungal gene diagnosis PCR Aspergillus Galactomannan Pastorex Aspergillus LA Platelia Aspergillus ELISA Aspergillus DNA Geni Q Aspergillus Real-time PCR Pathologic fungal gene diagnosis PCR Cryptococcus Glucuronoxylomannan Serodirect Eiken Cryptococcus LA Pastorex Cryptoplus LA Fungi D glucan Fungitec G test Colorimetric kinetic assay -glucan test Wako Turbidimetric assay LA: Latex agglutination, ELISA: Enzyme-linked immunosorbent assay, PCR: Polymerase chain reaction A. High risk group Neutropenia: PMN<500/mm 3 for more than 10 days Prolonged neutropenia (>10 days) in the previous 60 days Use of significant immunosuppressive agents in the previous 30 days Invasive fungal infection in a previous episode Signs and symptoms indicating GVHD Prolonged use of corticosteroids (>3 weeks) Prophylaxis FLCZ p.o.: mg/day AMPH p.o.:600 2,400mg/day AMPH div: mg/kg/day ITCZ p.o.: 200mg/day B. Clinical symptom and Laboratory data Clinical symptom: Persistent fever for >96 hrs refractory to appropriate broad spectrum antibacterial treatment (, ) Papular or nodular skin lesions ( ) Right hypochondralgia ( ) Laboratory data : CRP, Al-P ( ), WBC ( ) Empiric therapy AMPH div: mg/kg/day FLCZ div: mg/day MCFG div: mg/day C. Diagnostic approach Diagnostic methods for Proven FI: Histology: liver biopsy ( ) Microbiological culture: blood (, ), liver aspirate ( ) Additional diagnostic methods for clinically documented/s: Intraocular findings suggestive of hematogenous fungal chorioretinitis or endophthalmitis ( ) Small, peripheral, target-like abscesses (Bull's eye) in liver and/or spleen demonstrated by CT, MRI or USG ( ) -D-glucan, Candida antigen, D-arabinitol (, ) Candida DNA(, ) Proven FI Clinically documented FI Targeted therapy AMPH div: mg/kg/day FLCZ div: mg/day MCFG div: 150mg/day Fig. 1 Diagnosis and treatment of systemic candidiasis Fungemia, Chronic disseminated candidiasis - 4,, 5. -,,, -, DNA,, 2,, CT

3 Jpn. J. Med. Mycol. Vol. 45 No. 4, ,,,, -, DNA,, 3,,,,,,,, 2. Fig. 2, Aspergillus fumigatus, A. flavus, A. niger, A. nidulans 7.,,, X,,,,,,,,, 8. CT halo sign 9. Air crescent sign,,,,,,,,, A. High risk group Neutropenia: PMN<500/mm 3 for more than 10 days Prolonged neutropenia (>10 days) in the previous 60 days Use of significant immunosuppressive agents in the previous 30 days Invasive fungal infection in a previous episode Signs and symptoms indicating GVHD Prolonged use of corticosteroids (>3 weeks) Prophylaxis AMPH p.o: 600 2,400mg/day ITCZ p.o: 200mg/ day AMPH div: mg/kg/day AMPH inhalation: 10 15mg/day B. Clinical symptom and Laboratory data Clinical symptom Persistent fever for >96 hrs refractory to appropriate broad spectrum antibiotics Cough, chest pain, hemoptysis, dyspnea ), nasal discharge, stuffiness, epistaxis, periorbital pain and swelling, maxillary tenderness etc ), seizures, hemiparesis, cranial nerve palsies, mental changes etc Laboratory data CRP Empiric therapy AMPH div: 0.7 1mg/kg/day MCFG div: 150mg/day ITCZ p.o.: mg/day C. Diagnostic approach Diagnostic methods for Proven FI: Histology/Cytology: sputum, BAL, lung biopsy Microbiological culture: sputum, BAL, blood Additional diagnostic methods for clinically documented/s: Typical pulmonary infiltrate on chest X-P: wedge-shaped Any of the following new infiltrates on CT imaging: halo sign, air-crescent sign, cavity within an area of consolidation, or other new infiltrate -D-glucan, Aspergillus antigen Aspergillus DNA Proven FI Clinically documented FI Targeted therapy AMPH div: mg/kg/day If not effective ITCZ p.o mg/day 5-FC p.o. 100mg/kg/day MCFG div: mg/day The use of high-efficacy particulate air (HEPA) filters is recommended for prophylaxis of aspergillosis Fig. 2 Diagnosis and treatment of invasive aspergillosis Lung, Sinus, CNS

4 Platelia Aspergillus 10, 11, 12. PCR 13. -, - Fusarium Pseudoallescheria,, IV., targeted therapy, empiric therapy, prophylaxis 1. Fig. 1 1 FLCZ 14, , 17. FLCZ B AMPH ITCZ 2 febrile neutropenia, 1 AMPH 18,, FLCZ micafungin MCFG 3 C. albicans C. tropicalis, C. parapsilosis AMPH, FLCZ Table Japan Adult Leukemia Study Group JALSG 17. C. albicans FLCZ,, AMPH AMPH flucytosine ITCZ FLCZ AMPH, MCFG C. glabrata C. krusei FLCZ, AMPH MCFG C. parapsilosis MCFG AMPH,, AMPH FLCZ 19. MCFG AMPH 2. Fig. 2 1 HEPA 7. AMPH ITCZ 17. AMPH, ITCZ oral solution 20. 2,,, AMPH mg/kg/, MCFG 3 AMPH, mg/kg/ 21.,,, Table 2 JALSG 1.0 mg/kg/ 41%,, AMPH, MCFG CT, ,, ITCZ,,,

5 Jpn. J. Med. Mycol. Vol. 45 No. 4, Table 2. Targeted therapy for proven fungal infection Fungemia due to Invasive pulmonary Candida albicans Antifungal agent Stable disease a Unstable disease b aspergillosis Am-B 0.5 mg/kg div Am-B 0.7 mg/kg div Am-B 1 mg/kg div Am-B 1.5 mg/kg div 2 FLCZ 200 mg div 14 3 FLCZ 400 mg div ITCZ 200 mg po MCZ 1200 mg div 3 3 Am-B 0.7 mg/kg div FLCZ 400 mg div 11 Am-B 0.7 mg/kg div 5-FC 100 mg/kg po 1 1 Am-B 0.7 mg/kg div ITCZ 200 mg po 1 10 Am-B 0.7 mg/kg div MCZ 1200 mg div 0 Am-B 1 mg/kg div 5-FC 100 mg/kg po 1 Am-B 1 mg/kg div ITCZ 200 mg po 6 Others From the fact-finding questionnaire developed by the Japan Adult Leukemia Study Group Yoshida M et al. Reference No. 17 n 125, a stable vital signs, b unstable vital signs, pneumonia or hepatosplenic candidiasis, Agent not indicated in the question Am-B, amphotericin B; FLCZ, fluconazole; ITCZ, itraconazole; MCZ, miconazole; 5-FC, flucytosine V., 1,,, 1 47, Viscoli C, Girmenia C, Marinus A, Collette L, Martino P, Vandercam B, Doyen C, Lebeau B, Spence D, Kremery V, De Pauw B, Meunier F, Invasive fungal infection group of the EORTC: Candidemia in cancer patients: a prospective, multicenter surveillance study by the invasive fungal infection group IFIG of the European Organization for Research and Treatment of Cancer EORTC Clin Infect Dis 28: , Abi-Said D, Anaissie E, Uzun O, Raad I, Pinzcowski H, Vartivarian S: The epidemiology of hematogenous candidiasis caused by different Candida species. Clin Infect Dis 24: , Obayashi T, Yoshida M, Mori T, Goto H, Yasuoka A, Iwasaki H, Teshima H, Kohno S, Horiuchi A, Ito A, Yamaguchi H, Shimada K, Kawai T: Plasma D-glucan determination in the diagnosis of invasive deep mycosis and fungal febrile episodes. Lancet 345: 17 20, Iwama A, Yoshida M, Miwa A, Obayashi T, Sakamoto S, Miura Y: Improved survival from fungaemia in patients with haematological malignancies: Analiysis of risk factors for death and usefulness of early antifungal therapy. Eur J Haematol 51: , Thaler M, Pastakia B, Shawker TH, O leary T, Pizzo PA: Hepatic candidiasis in cancer patients: The evolving picture of the syndrome. Ann Intern Med 108: , Denning DW: Invasive aspergillosis. Clin Infect Dis 26: , Hori A, Kami M, Kishi Y, Machida U, Matsumura T, Kashima T: Clinical significance of extra-pulmonary involvement of invasive aspergillosis: a retrospective autopsy-based study of 107 patients. J Hosp Infect 50: , Caillot D, Casasnovas O, Bernard A, Couaillier JF, Durand C, Cuisenier B, Solary E, Piard F, Petrella T, Bonnin A, Couillault G, Dumas M, Guy H: Improved management of invasive pulmonary aspergillosis in neutropenic patients using early thoracic computed tomographic scan and surgery. J Clin Oncol 15: , Verweji PE, Stynen D, Rijs AJMM, DePauw BE, Hoogkamp-Korstanje JAA, Meis JFGM: Sandwich enzyme-linked immunosorbent assay compared with Pastorex latex agglutination test for diagnosing invasive aspergillosis in immunocompromised patients. J Clin Microbiol 33: , Maertens J, Verhaegen J, Lagrou K, Eldere JV, Boogaerts M: Screening for circulating galactomannan as a noninvasive diagnostic tool for invasive aspergil-

6 losis in prolonged neutropenic patients and stem cell transplantation recipients: a prospective validation. Blood 97: , Herbrecht R, Letscher-Bru V, Oprea C, Lioure B, Waller J, Campos F, Villard O, Liu KL, Natarajan- Ame S, Lutz P, Dufour P, Bergerat JP, Candolfi E: Aspergillus galactomannan detection in the diagnosis of invasive aspergillosis in cancer patients. J Clin Oncol 20: , Kami M, Fukui T, Ogawa S, Kazuyama Y, Machida U, Tanaka Y, Kanda Y, Kashima T, Yamazaki Y, Hamaki T, Mori S, Akiyama H, Mutou Y, Sakamaki H, Osumi K, Kimura S, Hirai H: Real-time polymerase chain reaction using blood samples for diagnosis of invasive aspergillosis. Clin Infect Dis 33: , Goodman JL, Winston DJ, Greenfield RA, Chandrasekar PH, Fox P, Kaiser H, Shadduck RK, Shea TC, Stiff P, Friedman DJ, Powderly WG, Silber JL, Horowitz H, Lichtin A, Wolff SN, Mangan KF, Silver SM, Weisdorf D, Ho WG, Gilbert G, Buell D: A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation. N Engl J Med 326: , Slavin MA, Osborne B, Adams R, Levenstein MJ, Schoch HG, Feldman AR, Meyers JD, Bowden RA: Efficacy and safety of fluconazole prophylaxis for fungal infection after marrow transplantation -a prospective, randomized, double-blind study. J Infect Dis 171: , Kanda Y, Yamamoto R, Chizuka A, Hamaki T, Suguro M, Arai C, Matsuyama T, Takezato N, Miwa A, Kern W, Kami M, Akiyama H, Hirai H, Togawa A: Prophylactic action of oral fluconazole against fungal infection in neutropenic patients. A meta-analysis of 16 randomized, controlled trials. Cancer 89: , ,,,,,,,, Japan Adult Leukemia Study Group 51: , Hughes WT, Armstrong D, Bodey GP, Brown AE, Edwards JE, Feld R, Pizzo P, Rolston KVI, Shenep JL, Young LS: 1997 guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever. Clin Infect Dis 25: , Rex JH, Walsh TJ, Sobel JD, Filler SG, Pappas PG, Dismukes WE, Edwards JE: Practive guidelines for the treatment of candidiasis. Clin Infect Dis 30: , Morgenstern GR, Prentice AG, Prentice HG, Ropner JE, Schey SA, Warnock DW: A randomized controlled trial of itraconazole versus fluconazole for the prevention of fungal infections in patients with haematological malignancies. Brit J Haematol 105: , Stevens DA, Kan VL, Judson MA, Morrison VA, Dummer S, Denning DW, Bennett JE, Walsh TJ, Patterson TF, Pankey GA: Practice guidelines for diseases caused by Aspergillus. Clin Infect Dis 30: , Caillot D, Couaillier JF, Bernard A, Casasnovas O, Denning DW, Mannone L, Lopez J, Couillault G, Piard F, Vagner O, Guy H: Increasing volume and changing characteristics of invasive pulmonary aspergillosis on sequential thoracic computed tomography scans in patients with neutropenia. J Clin Oncol 19: , 2001.

7 Jpn. J. Med. Mycol. Vol. 45 No. 4, Guidelines for the Management of Deep Mycosis in Neutropenic Patients Minoru Yoshida Fourth Department of Internal Medicine, Teikyo University School of Medicine, Mizonokuchi, Takatsu-ku, Kawasaki City, Kanagawa , Japan Invasive fungal infections (IFIs) are a major cause of morbidity and mortality in neutropenic patients with leukemia and those undergoing hematopoietic stem cell transplant (HSCT). Two major IFIs are systemic candidiasis (including candidemia, chronic disseminated candidiasis and pneumonia) and invasive pulmonary aspergillosis. Recently, the incidence of the latter has been increasing. Three levels of diagnosis are specified in the Japanese guidelines for the diagnosis and treatment of IFIs. Proven fungal infections are diagnosed by histological/microbiological evidence of fungi at the site of infection or positive blood culture (fungemia). Clinically documented fungal infections are diagnosed by typical radiological findings such as halo sign on chest CT plus positive serological/molecular evidence of fungi such as Aspergillus galactomannan, -glucan or fungal DNA. Possible fungal infections are diagnosed by typical radiological findings or positive serological/molecular evidence of fungi. For patients with high risk such as those undergoing HSCT, antifungal prophylaxis using oral antifungal agents is recommended. For possible fungal infections, empiric therapy with fluconazole (FLCZ) or amphotericin B (AMPH) is recommended. For patients with proven fungal infections or clinically documented fungal infections, targeted therapy is warranted. In case of candidemia, the best choice is FLCZ (400 mg/day) or AMPH ( mg/kg/day), and for invasive pulmonary aspergillosis, a higher dose of AMPH ( mg/kg/day) is indicated. Micafungin (MCFG), recently licensed in Japan, is an active agent for both Candida and Aspergillus. This drug seems useful for empiric and targeted therapy of IFIs., 47 3