Establishment of new treatment for chronic pulmonary aspergillosis with modulating microbiota of gut

• Project/Area Number: 16K09936
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Infectious disease medicine
• Research Institution: Nagasaki University
• Principal Investigator: IZUMIKAWA Koichi 長崎大学, 医歯薬学総合研究科(医学系), 教授 (20404212)
• Co-Investigator(Kenkyū-buntansha): 田代 将人 長崎大学, 医歯薬学総合研究科(医学系), 助教 (20713457)
• Research Collaborator: NAKANO Yuichiro
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: アスペルギルス / マイクロバイオーム

Outline of Final Research Achievements

The aim of this study is to reveal the relation between the pathogenesis of chronic pulmonary aspergillosis and microbiota of gut and/or respiratory system. Chronic aspergillus infection with anti-aspergillus antibody production mouse model was established in first two years. The microbiota of this mouse model was modified with cefoperazone/sulbactam (C/S) contained drinking water and explore the influences to anti-aspergillus antibody production in C/S treated mice. The microbiota of mice treated with C/S was dramatically changed into only kind of enterobacteriaceae family, though varieties of enterobacteriaceae bacteria were proved in C/S un-treated mice group. The production of anti-aspergillus antibody was reduced in C/S treated mice with aspergillus challenged compared to those of C/S un-treated mice group. This result indicated that microbiota of gut influences the immunological effect against Aspergillus infection.

Academic Significance and Societal Importance of the Research Achievements

慢性肺アスペルギルス症は、難治性で予後不良な真菌症であり、おもに結核の治療後に罹患する。先進国でも結核の中蔓延国である我が国においては、潜在的に多くの患者が存在している。抗真菌薬が奏功しない例も多く、抗真菌薬に依存しない治療法の開発がもとめられる。腸内細菌叢はヒトの免疫能に影響を及ぼすと言われているが、今回のマウスを用いた動物実験結果から、アスペルギルス症において腸内細菌叢が、アスペルギルスに対する感染防御能を変化させるために重要な役割をしている可能性があることが証明された。腸内細菌叢をコントロールし、アスペルギルス症に対する免疫能を賦活化させる新しい治療につながる可能性を示した。

Research Products

• [Journal Article] Evaluation of Aspergillus-Specific Lateral-Flow Device Test Using Serum and Bronchoalveolar Lavage Fluid for Diagnosis of Chronic Pulmonary Aspergillosis (2019)
  • Author(s): Takazono Takahiro、Ito Yuya、Tashiro Masato、Nishimura Keitaro、Saijo Tomomi、Yamamoto Kazuko、Imamura Yoshifumi、Miyazaki Taiga、Yanagihara Katsunori、Mukae Hiroshi、Izumikawa Koichi
  • Journal Title: Journal of Clinical Microbiology Volume: 57 Issue: 5
  • DOI: 10.1128/jcm.00095-19
  • Peer Reviewed
• [Journal Article] Clinical features and cause analysis of false positive results of Aspergillus galactomannan assay in pulmonary cryptococcosis patients (2019)
  • Author(s): Takazono Takahiro、Saijo Tomomi、Ashizawa Nobuyuki、Oshima Kazuhiro、Nishimura Keitaro、Tashiro Masato、Yamamoto Kazuko、Imamura Yoshifumi、Miyazaki Taiga、Yanagihara Katsunori、Mukae Hiroshi、Izumikawa Koichi、Sheppard Donald C.
  • Journal Title: European Journal of Clinical Microbiology & Infectious Diseases Volume: 38 Issue: 4 Pages: 735-741
  • DOI: 10.1007/s10096-019-03469-3
  • Peer Reviewed
• [Journal Article] Recent Advances in Diagnosing Chronic Pulmonary Aspergillosis (2018)
  • Author(s): Takazono Takahiro、Izumikawa Koichi
  • Journal Title: Frontiers in Microbiology Volume: 9 Pages: 1810-1810
  • DOI: 10.3389/fmicb.2018.01810
  • Peer Reviewed / Open Access
• [Journal Article] Case Definition of Chronic Pulmonary Aspergillosis in Resource-Constrained Settings (2018)
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• [Journal Article] Comparison of Efficacy of Antimicrobial Agents Among Hospitalized Patients With Mycoplasma pneumoniae Pneumonia in Japan During Large Epidemics of Macrolide-Resistant M. pneumoniae Infections: A Nationwide Observational Study (2017)
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  • Journal Title: Clin Infect Dis Volume: 65 Issue: 11 Pages: 1837-1842
  • DOI: 10.1093/cid/cix695
  • NAID: 120006988062
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• [Journal Article] In vitro and In vivo antifungal activities of T-2307, a novel arylamidine, against Cryptococcus gatiii: an emerging fungal pathogen. (2017)
  • Author(s): Nishikawa H, Fukuda Y, Mitsuyama J, Tashiro M, Tanaka A, Takazono T, Saijo T, Yamamoto K, Nakamura S, Imamura Y, Miyazaki T, Kakeya H, Yamamoto Y, Yanagihara K, Mukae H, Kohno S, Izumikawa K.
  • Journal Title: Journal of Antimicrobial Chemotherapy Volume: 72 Issue: 6 Pages: 1709-1713
  • DOI: 10.1093/jac/dkx020
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• [Journal Article] Efficacy and pharmacokinetics of ME1100, a novel optimized formulation of arbekacin for inhalation, compared with amikacin in a murine model of ventilator-associated pneumonia caused byPseudomonas aeruginosa (2017)
  • Author(s): Kaku Norihito、Morinaga Yoshitomo、Takeda Kazuaki、Kosai Kosuke、Uno Naoki、Hasegawa Hiroo、Miyazaki Taiga、Izumikawa Koichi、Mukae Hiroshi、Yanagihara Katsunori
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• [Journal Article] Efficacy and pharmacokinetics of the combination of OP0595 and cefepime in a mouse model of pneumonia caused by Extended-Spectrum-Beta-Lactamase-Producing Klebsiella pneumoniae (2017)
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  • NAID: 120006987457
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• [Journal Article] Risk Factors for Acquisition of Fluoroquinolone or Aminoglycoside Resistance in Addition to Carbapenem Resistance in (2017)
  • Author(s): Kosai Kosuke、Kaku Norihito、Uno Naoki、Saijo Tomomi、Morinaga Yoshitomo、Imamura Yoshifumi、Hasegawa Hiroo、Miyazaki Taiga、Izumikawa Koichi、Mukae Hiroshi、Yanagihara Katsunori
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• [Journal Article] Unexpected effects of azole transporter inhibitors on antifungal susceptibility in Candida glabrata and other pathogenic Candida species (2017)
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• [Journal Article] Adjunctive corticosteroid therapy for inpatients with Mycoplasma pneumoniae pneumonia (2017)
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  • Journal Title: BMC Pulm Med Volume: 17 Issue: 1 Pages: 219-219
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• [Journal Article] Examination of cryptococcal glucuronoxylomannan antigen in bronchoalveolar lavage fluid for diagnosing pulmonary cryptococcosis in HIV-negative patients (2017)
  • Author(s): Oshima Kazuhiro、Takazono Takahiro、Saijo Tomomi、Tashiro Masato、Kurihara Shintaro、Yamamoto Kazuko、Imamura Yoshifumi、Miyazaki Taiga、Tsukamoto Misuzu、Yanagihara Katsunori、Mukae Hiroshi、Kohno Shigeru、Izumikawa Koichi
  • Journal Title: Med Mycol Volume: 56 Issue: 1 Pages: 88-94
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• [Journal Article] Performance evaluation of the Verigene®Clostridium difficile nucleic acid test, an automated multiplex molecular testing system for detection of C. difficile toxin. (2017)
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• [Journal Article] Comparative efficacies of daptomycin, vancomycin, and linezolid in experimental enterococcal peritonitis (2017)
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• [Journal Article] A case series of histoplasmosis patients with elevated serum soluble interleukin-2 receptor levels (2017)
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  • Journal Title: J Infect Chemother. Volume: 23 Issue: 9 Pages: 642-647
  • DOI: 10.1016/j.jiac.2017.03.006
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• [Journal Article] Tedizolid inhibits MUC5AC production induced by methicillin-resistant Staphylococcus aureus in human airway epithelial cells (2017)
  • Author(s): Takeda Kazuaki、Kaku Norihito、Morinaga Yoshitomo、Kosai Kosuke、Uno Naoki、Imamura Yoshifumi、Hasegawa Hiroo、Miyazaki Taiga、Izumikawa Koichi、Mukae Hiroshi、Yanagihara Katsunori
  • Journal Title: Journal of Infection and Chemotherapy Volume: 23 Issue: 9 Pages: 598-603
  • DOI: 10.1016/j.jiac.2017.04.015
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• [Journal Article] Quantitative detection of periodontopathic bacteria in lower respiratory tract specimens by real-time PCR (2017)
  • Author(s): Nagaoka Kentaro、Yanagihara Katsunori、Harada Yosuke、Yamada Koichi、Migiyama Yohei、Morinaga Yoshitomo、Izumikawa Koichi、Kohno Shigeru
  • Journal Title: J Infect Chemother. Volume: 23 Issue: 2 Pages: 69-73
  • DOI: 10.1016/j.jiac.2016.09.013
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• [Journal Article] Interstitial Lung Disease Induced by Pazopanib Treatment (2017)
  • Author(s): Ide Shotaro、Sakamoto Noriho、Hara Shintaro、Hara Atsuko、Kakugawa Tomoyuki、Nakamura Yoichi、Futsuki Yoji、Izumikawa Koichi、Ishimatsu Yuji、Yanagihara Katsunori、Mukae Hiroshi
  • Journal Title: Internal Medicine Volume: 56 Issue: 1 Pages: 79-83
  • DOI: 10.2169/internalmedicine.56.7380
  • NAID: 130005239489
  • ISSN: 0918-2918, 1349-7235
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• [Journal Article] Pulmonary Actinomycosis Mimicking Pulmonary Aspergilloma and a Brief Review of the Literature (2017)
  • Author(s): Higashi Yoshitsugu、Nakamura Shigeki、Ashizawa Nobuyuki、Oshima Kazuhiro、Tanaka Akitaka、Miyazaki Taiga、Izumikawa Koichi、Yanagihara Katsunori、Yamamoto Yoshihiro、Miyazaki Yoshitsugu、Mukae Hiroshi、Kohno Shigeru
  • Journal Title: Internal Medicine Volume: 56 Issue: 4 Pages: 449-453
  • DOI: 10.2169/internalmedicine.56.7620
  • NAID: 130005345660
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• [Journal Article] Efficacy and Safety of Intravenous Peramivir Compared With Oseltamivir in High-Risk Patients Infected With Influenza A and B Viruses: A Multicenter Randomized Controlled Study (2017)
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  • Journal Title: Open Forum Infectious Diseases Volume: 4 Issue: 3
  • DOI: 10.1093/ofid/ofx129
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• [Journal Article] Efficacy of high-dose Meropenem (six grams per day) in treatment of experimental murine pneumonia induced by meropenem-resistant Pseudomonas aeruginosa (2016)
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  • Journal Title: Antimicrob Agents Chemother Volume: 61 Issue: 1
  • DOI: 10.1128/aac.02056-16
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• [Journal Article] Executive summary of Japanese domestic guidelines for management of deep-seated mycosis 2014. (2016)
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  • Journal Title: Med Mycol J Volume: 57
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• [Journal Article] Effect of long-term treatment with corticosteroids on skeletal muscle strength, functional exercise capacity and health status in patients with interstitial lung disease (2016)
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  • Journal Title: Respirology Volume: 21 Issue: 6 Pages: 1088-1093
  • DOI: 10.1111/resp.12807
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• [Journal Article] Successful Treatment of <i>Aspergillus</i> Empyema Using Open Window Thoracostomy Salvage Treatment and the Local Administration of an Antifungal Agent (2016)
  • Author(s): Ashizawa N, Nakamura S, Ide S, Tashiro M, Takazono T, Imamura Y, Miyazaki T, Izumikawa K, Yamamoto Y, Yanagihara K, Miyazaki Y, Kohno S
  • Journal Title: Internal Medicine Volume: 55 Issue: 15 Pages: 2093-2099
  • DOI: 10.2169/internalmedicine.55.6250
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• [Journal Article] Premedication with clarithromycin is effective against secondary bacterial pneumonia during influenza virus infection in a pulmonary emphysema mouse model. (2016)
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  • Journal Title: J Pharmacol Exp Ther Volume: 358 Issue: 3 Pages: 457-463
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• [Journal Article] Pharmacokinetic parameters of gefitinib predict efficacy and toxicity in patients with advanced non-small cell lung cancer harboring EGFR mutations (2016)
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  • Journal Title: Cancer Chemother Pharmacol Volume: 72 Issue: 2 Pages: 377-382
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• [Journal Article] A mortality prediction rule for non-elderly patients with community-acquired pneumonia. (2016)
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  • Journal Title: BMC Pulm Med Volume: 16 Issue: 1 Pages: 39-39
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• [Journal Article] The world first two cases of severe fever with thrombocytopenia. syndrome: An epidemiological study in Nagasaki, Japan (2016)
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  • Author(s): Hirayama T, Takazono T, Horai Y, Tashiro M, Saijo T, Kosai K, Morinaga Y, Kurihara S, Nakamura S, Imamura Y, Miyazaki T, Tsukamoto M, Izumikawa K, Yanagihara K, Kawakami A, Kohno S
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  • Author(s): Takazono T, Sawai T, Tashiro M, Saijo T, Yamamoto K, Imamura Y, Miyazaki T, Suyama N, Izumikawa K, Kakeya H, Yanagihara K, Mukae H, Kohno S
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• [Journal Article] Recurrent Streptococcus agalactiae toxic shock syndrome triggered by a tumor necrosis factor-α inhibitor (2016)
  • Author(s): Yoshida M, Takazono T, Tashiro M, Saijo T, Morinaga Y, Yamamoto K, Nakamura S, Imamura Y, Miyazaki T, Sawai T, Nishino T, Izumikawa K, Yanagihara K, Mukae H, Kohno S
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• [Journal Article] The risk factors for developing of chronic pulmonary aspergillosis in nontuberculous mycobacteria patients and clinical characteristics and outcomes in chronic pulmonary aspergillosis patients coinfected with nontuberculous mycobacteria. (2016)
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  • Journal Title: Med Mycol. Volume: 54 Issue: 2 Pages: 120-127
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• [Journal Article] Clinical features of severe or fatal Mycoplasma pneumoniae pneumonia (2016)
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• [Journal Article] Recent advances in chronic pulmonary aspergillosis (2016)
  • Author(s): Izumikawa K
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• [Journal Article] 長崎県島原半島における肺結核の疫学的、臨床的検討 (2016)
  • Author(s): 泉川欣一, 長谷川麻衣子, 峰松明日香, 泉川公一
  • Journal Title: 長崎医学会雑誌 Volume: 91 Pages: 102-109
  • NAID: 40020965737
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• [Journal Article] 成人肺炎マイコプラズマ感染症に対するクラリスロマイシンの有効性の検討 (2016)
  • Author(s): 河野 茂, 門田淳一, 田中裕士, 宮下修行, 松瀬厚人, 泉川公一, 尾内一信
  • Journal Title: 日本呼吸器学会誌 Volume: 2016 Pages: 64-70
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• [Journal Article] キャピリアMAC抗体検査の精度評価と患者背景の臨床的検討 (2016)
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  • Journal Title: 結核 Volume: 91 Pages: 27-32
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• [Journal Article] 帯状疱疹ウイルスによる急性咽頭炎に対して術前治療を行った後に生体肝移植を施行し良好な経過を得た1例 (2016)
  • Author(s): 山口 峻, 曽山 明彦, 日高 匡章, 夏田 孔史, 釘山 統太, 原 貴信, 今村 一歩, 岡田 怜美, 大野 慎一郎, 北里 周, 藤田 文彦, 田代 将人, 黒木 保, 泉川公一, 江口 晋
  • Journal Title: 移植 Volume: 51 Pages: 218-221
  • NAID: 130005260515
  • Peer Reviewed
• [Journal Article] 当院における血液培養検査推進キャンペーンとその効果 (2016)
  • Author(s): 塚本千絵, 小佐井康介, 志岐直美, 寺坂陽子, 今村政信, 賀来敬仁, 田代将人, 塚本美鈴, 栗原慎太郎, 泉川公一, 迎 寛, 栁原克紀
  • Journal Title: 環境感染誌 Volume: 31 Pages: 241-246
  • NAID: 130005249269
  • Peer Reviewed
• [Presentation] Implementation of antifungal stewardship in critically ill patients (2018)
  • Author(s): Koichi Izumikawa
  • Organizer: 20th Congress of Asia Paciific Association of Critical Care Medicine and Annual Scientific Meeting
  • Int'l Joint Research / Invited
• [Presentation] AMR、AST、BSL、AFSなど、キーワードから読み解く感染症の現状と課題 (2018)
  • Author(s): 泉川公一
  • Organizer: 第92回日本感染症学会・第66回日本化学療法学会合同学会
• [Presentation] 避難施設における感染制御と支援のありかた ～熊本地震での支援経験を踏まえて、今後を考察する～ (2018)
  • Author(s): 泉川公一
  • Organizer: 第33回日本環境感染学会総会
• [Presentation] Advances in Diagnosis of Respiratory Infectious Diseases (2017)
  • Author(s): 泉川公一
  • Organizer: Union APRC2017
  • Int'l Joint Research
• [Presentation] 抗菌薬使用の現状と課題（大学病院の立場） (2017)
  • Author(s): 泉川公一
  • Organizer: 第91回日本感染症学会・第65回日本化学療法学会合同学会
• [Presentation] いま、そこにある感染症の危機 ～院内感染症アウトブレイクから自然災害、グローバル感染症まで～ (2017)
  • Author(s): 泉川公一
  • Organizer: 第91回日本感染症学会・第65回日本化学療法学会合同学会
• [Presentation] 呼吸器領域における深在性真菌症の診療マネジメント～診断・予防・治療～ (2017)
  • Author(s): 泉川公一
  • Organizer: 第57回日本呼吸器学会
• [Presentation] Outbreak of carbapenem-resistant enterobacteriaceae in neonatal intensive care unit and growing care unit in Nagasaki University Hospital (2017)
  • Author(s): 泉川公一
  • Organizer: The 13th NUS Nagasaki Joint Symposium
  • Int'l Joint Research
• [Presentation] Chronic Respiratory Infection of Aspergillus (2017)
  • Author(s): 泉川公一
  • Organizer: 2017 Peking University Fungal Infection Summit and the Workshop on Medical Mycology
  • Invited
• [Presentation] “AMR対策アクションプランが求める感染症診療における新展開” 大学病院における課題と取り組み (2017)
  • Author(s): 泉川公一
  • Organizer: 第60回日本感染症学会中日本地方会学術集会・第87回日本感染症学会西日本地方会学術集会・第65回日本化学療法学会西日本支部総会共同開催
• [Presentation] AMR時代における感染症の現状・対策・課題～薬剤耐性菌は減らすことが可能か？～ (2017)
  • Author(s): 泉川公一
  • Organizer: 第203回日本小児科学会長崎地方会
• [Presentation] カルバペネム耐性腸内細菌の危機管理、CREのアウトブレイク対応 (2016)
  • Author(s): 泉川公一
  • Organizer: 第59回日本感染症学会中日本地方会学術集会・第86回日本感染症学会西日本地方会学術集会・第64回日本化学療法学会西日本支部総会共同開催
  • Place of Presentation: 沖縄コンベンションセンター(沖縄県・宜野湾市）
• [Presentation] 熊本地震災害時の感染症と感染対策 被災地における感染症アウトブレイクに対する対応の実際 ～DICT制度の必要性～ (2016)
  • Author(s): 泉川公一
  • Organizer: 第59回日本感染症学会中日本地方会学術集会・第86回日本感染症学会西日本地方会学術集会・第64回日本化学療法学会西日本支部総会共同開催
  • Place of Presentation: 沖縄コンベンションセンター(沖縄県・宜野湾市）
• [Presentation] Chronic pulmonary aspergillosis and azole resistance (2016)
  • Author(s): 泉川公一
  • Organizer: 6th Asia Pacific Society of Medical Mycology
  • Place of Presentation: Bali, Indonesia
  • Int'l Joint Research
• [Presentation] 薬剤耐性時代における呼吸器真菌症 (2016)
  • Author(s): 泉川公一
  • Organizer: 第77回日本呼吸器学会・日本結核病学会・日本サルコイドーシス／肉芽腫性疾患学会 九州支部 夏季学術講演会
  • Place of Presentation: 翠香園ホテル（福岡県・久留米市）
• [Presentation] 長崎大学病院におけるカルバペネム耐性腸内細菌科細菌によるアウトブレイクと散発例への対応 (2016)
  • Author(s): 泉川公一
  • Organizer: 第64回日本化学療法学会総会
  • Place of Presentation: 神戸国際会議場（兵庫県・神戸市）
• [Presentation] ガイドラインup to date -深在性真菌症の診断・治療GL2014 発刊から2年たった今- 呼吸器内科の立場から (2016)
  • Author(s): 泉川公一
  • Organizer: 第22回 真菌症フォーラム
  • Place of Presentation: TFTビル（東京都、江東区）
• [Presentation] グローバル時代の感染症とその対策 ～長崎大学病院における自験例と取り組み～ (2016)
  • Author(s): 泉川公一
  • Organizer: 第15回日本旅行医学会大会
  • Place of Presentation: 国立オリンピック記念青少年総合センター（東京都、渋谷区）
• [Presentation] Chronic Cavitary Pulmonary Aspergillosis (2016)
  • Author(s): 泉川公一
  • Organizer: 26th European Congress of Clinical Microbiology and Infectious Diseases
  • Place of Presentation: Amsterdam, The Netherland
  • Int'l Joint Research
• [Book] ～臨床・画像・病理を通して理解できる！～呼吸器疾患：Clinical-Radiological-Pathologicalアプローチ (2017)
  • Author(s): 田代将人、泉川公一
  • Total Pages: 280
  • Publisher: 南江堂
  • ISBN: 9784524259649
• [Book] 呼吸器疾患診断治療アプローチ (2017)
  • Author(s): 田代将人、泉川公一
  • Total Pages: 368
  • Publisher: 中山書店
  • ISBN: 9784521745268
• [Book] 今日の処方 (2017)
  • Author(s): 田代将人、泉川公一
  • Total Pages: 1220
  • Publisher: 南江堂
  • ISBN: 9784524268115
• [Book] NiCE 病態・治療論 (2017)
  • Author(s): 河野圭、泉川公一
  • Total Pages: 366
  • Publisher: 南江堂
  • ISBN: 9784524253234
• [Book] 1336専門家による私の治療 (2017)
  • Author(s): 河野圭、泉川公一
  • Total Pages: 1734
  • Publisher: 日本医事新報社
  • ISBN: 9784784946501
• [Book] 肺真菌症に対する新しい治療は？. EBM呼吸器疾患の治療2016－2017 (2016)
  • Author(s): 髙園貴弘, 泉川公一
  • Total Pages: 496
  • Publisher: 中外医学社
• [Book] 抗菌薬パーフェクトガイド～基礎から臨床まで～ (2016)
  • Author(s): 田代将人、泉川公一
  • Total Pages: 359
  • Publisher: ヴァンメディカル
• [Book] 感染症 最新の治療2016-2018 (2016)
  • Author(s): 田代将人、泉川公一
  • Total Pages: 364
  • Publisher: 南江堂
• [Book] 診療ガイドラインUP-TO-DATE 2016-2017 (2016)
  • Author(s): 田代将人、泉川公一
  • Total Pages: 968
  • Publisher: メディカルレビュー社
• [Book] 呼吸器疾患ー最新の薬物療法ー (2016)
  • Author(s): 田代将人、泉川公一
  • Total Pages: 172
  • Publisher: 克誠堂出版
• [Book] 病気を持った患者の歯科治療 第4版 (2016)
  • Author(s): 田代将人、泉川公一
  • Total Pages: 408
  • Publisher: 長崎県保険医協会