Discovery of drug-resistant mechanism and development of new treatment strategy by modulating virulence factors against drug-resistant Aspergillus infection

• Project/Area Number: 25461515
• 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): MIYAZAKI Taiga 長崎大学, 医歯薬学総合研究科(医学系), 講師 (60448496) ; 田代 将人 長崎大学, 医歯薬学総合研究科(医学系), 助教 (20713457) ; 高園 貴弘 長崎大学, 医歯薬学総合研究科(医学系), 助教 (30716569)
• Research Collaborator: HIRANO Katsuji ; YOSHIDA Masataka ; TAKEDA Kazuaki
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2013: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
• Keywords: アスペルギルス / 薬剤耐性 / 病原性 / 吸入治療 / MUC5AC / マクロライド / CYP51A / カルシニューリン

Outline of Final Research Achievements

Although increasing number of the patients and acquiring drug-resistance becomes emerging issues of aspergillosis addition to its high mortality and morbidity, the new antifungals have not been available yet. To improve the prognosis of aspergillosis, we proved that how Aspergillus acquires the drug-resistance, effectiveness of high-dose azole inhalation treatment and macrolides for modulating human host-defense system. These findings may lead to develop new treatment options for aspergillosis.

Research Products

• [Journal Article] Toll-like receptor 4 agonistic antibody promotes host defense against chronic Pseudomonas aeruginosa lung infection in mice (2016)
  • Author(s): Nakamura S, Iwanaga N, Seki M, Fukudome K, Oshima K, Miyazaki T, Izumikawa K, Yanagihara K, Miyazaki Y, Mukae H, Kohno S.
  • Journal Title: Infect Immun Volume: 印刷中
  • Peer Reviewed / Open Access
• [Journal Article] <i>Pseudomonas aeruginosa</i> Bacteremia among Immunocompetent and Immunocompromised Patients: Relation to Initial Antibiotic Therapy and Survival (2016)
  • Author(s): Migiyama Y, Yanagihara K, Kaku N, Harada Y, Yamada K, Nagaoka K, Morinaga Y, Akamatsu N, Matsuda J, Izumikawa K, Kohrogi H, Kohno S.
  • Journal Title: Japanese Journal of Infectious Diseases Volume: 69 Issue: 2 Pages: 91-96
  • DOI: 10.7883/yoken.JJID.2014.573
  • NAID: 130005138559
  • ISSN: 1344-6304, 1884-2836
  • Peer Reviewed / Open Access
• [Journal Article] A mortality prediction rule for non-elderly patients with community-acquired pneumonia. (2016)
  • Author(s): Tashiro M, Fushimi K, Takazono T, Kurihara S, Miyazaki T, Tsukamoto M, Yanagihara K, Mukae H, Tashiro T, Kohno S, Izumikawa K.
  • Journal Title: BMC Pulm Med Volume: 16 Issue: 1 Pages: 39-39
  • DOI: 10.1186/s12890-016-0199-z
  • Peer Reviewed / Open Access
• [Journal Article] A novel method for rapid detection of Streptococcus pneumoniae antigens in blood. (2016)
  • Author(s): Fukushima K, Kubo T, Ehara N, Nakano R, Matsutake T, Ishimatu Y, Tanaka Y, Akamatsu S, Izumikawa K, Kohno S.
  • Journal Title: J Infect Chemother. Volume: 22 Issue: 3 Pages: 143-148
  • DOI: 10.1016/j.jiac.2015.12.004
  • Peer Reviewed / Open Access
• [Journal Article] Recent advances in chronic pulmonary aspergillosis (2016)
  • Author(s): Izumikawa K
  • Journal Title: Respir Investig Volume: 54 Issue: 2 Pages: 85-91
  • DOI: 10.1016/j.resinv.2015.10.003
  • Peer Reviewed / Open Access
• [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)
  • Author(s): Takeda K, Imamura Y, Takazono T, Yoshida M, Ide S, Hirano K, Tashiro M, Saijo T, Kosai K, Morinaga Y, Nakamura S, Kurihara S, Tsukamoto M, Miyazaki T, Tashiro T, Kohno S, Yanagihara K, Izumikawa K.
  • Journal Title: Med Mycol. Volume: 54 Issue: 2 Pages: 120-127
  • DOI: 10.1093/mmy/myv093
  • Peer Reviewed
• [Journal Article] Post-operative infection of endoscopic submucosal dissection of early colorectal neoplasms: a case-controlled study using a Japanese database (2016)
  • Author(s): Muro T, Higuchi N, Imamura M, Nakagawa H, Honda M, Nakao K, Izumikawa K, Sasaki H, Kitahara T.
  • Journal Title: J Clin Pharm Ther Volume: 印刷中
  • NAID: 120006986918
  • Peer Reviewed
• [Journal Article] Clinical characteristics and risk factors of enterococcal infections in Nagasaki, Japan: a retrospective study. (2015)
  • Author(s): Kajihara T, Nakamura S, Iwanaga N, Oshima K, Takazono T, Miyazaki T, Izumikawa K, Yanagihara K, Kohno N, Kohno S.
  • Journal Title: BMC Infect Dis Volume: 15 Issue: 1 Pages: 426-426
  • DOI: 10.1186/s12879-015-1175-6
  • NAID: 120006986848
  • Peer Reviewed / Open Access
• [Journal Article] International expert opinion on the management of infection caused by azole-resistant Aspergillus fumigatus. (2015)
  • Author(s): Verweij PE, Ananda-Rajah M, Andes D, Arendrup MC, Bruggemann RJ, Chowdhary A, Cornely OA, Denning DW, Groll AH, Izumikawa K, Kullberg BJ, Lagrou K, Maertens J, Meis JF, Newton P, Page I, Seyedmousavi S, Sheppard DC, Viscoli C, Warris A, Donnelly JP
  • Journal Title: Drug Resist Updat Volume: 21-22 Pages: 30-40
  • DOI: 10.1016/j.drup.2015.08.001
  • NAID: 120006986920
  • Peer Reviewed / Open Access
• [Journal Article] Macrolides promote CCL2-mediated macrophage recruitment and clearance of nasopharyngeal pneumococcal colonies in mice. (2015)
  • Author(s): Naoki Iwanaga, Shigeki Nakamura, Kazuhiro Oshima, Toshiki Kajihara, Takahiro Takazono, Taiga Miyazaki, Koichi Izumikawa, Katsunori Yanagihara, Akihiro Sugawara, Toshiaki Sunazuka, Satoshi Omura and Shigeru Kohno
  • Journal Title: J. Infect. Dis. Volume: - Issue: 7 Pages: 1150-1159
  • DOI: 10.1093/infdis/jiv157
  • Peer Reviewed / Open Access
• [Journal Article] The effect of intravenous peramivir, compared with oral oseltamivir, on the outcome of post-influenza pneumococcal pneumonia in mice. (2015)
  • Author(s): Tanaka A, Nakamura S, Seki M, Iwanaga N, Kajihara T, Kitano M, Homma T, Kurihara S, Imamura Y, Miyazaki T, Izumikawa K, Kakeya H, Yanagihara K, Kohno S
  • Journal Title: Antivir Ther Volume: 20 Issue: 1 Pages: 11-19
  • DOI: 10.3851/imp2744
  • Peer Reviewed / Open Access
• [Journal Article] Clinical significance of methicillin-resistant coagulase-negative staphylococci obtained from sterile specimens. (2015)
  • Author(s): Tashiro M, Izumikawa K, Ashizawa N, Narukawa M, Yamamoto Y.
  • Journal Title: Diagn Microbiol Infect Dis Volume: 81 Issue: 1 Pages: 71-75
  • DOI: 10.1016/j.diagmicrobio.2014.09.019
  • NAID: 120006986317
  • Peer Reviewed / Open Access
• [Journal Article] Clinical features of pulmonary cryptococcosis in non-HIV patients in Japan (2015)
  • Author(s): Shigeru Kohno, Hiroshi Kakeya, et al.
  • Journal Title: Journal of Infections and Chemotherapy Volume: 21 Issue: 1 Pages: 23-30
  • DOI: 10.1016/j.jiac.2014.08.025
  • Peer Reviewed / Open Access
• [Journal Article] Utility of a Sputum Antigen Detection Test in Pneumococcal Pneumonia and Lower Respiratory Infectious Disease in Adults (2015)
  • Author(s): Fukushima K, Nakamura S, Inoue Y, Higashiyama Y, Ohmichi M, Ishida T, Yoshimura K, Sawai T, Takayanagi N, Nakahama C, Kakugawa T, Izumikawa K, Aoki N, Nishioka Y, Kosaka O, Kohno S.
  • Journal Title: Internal Medicine Volume: 54 Issue: 22 Pages: 2843-2850
  • DOI: 10.2169/internalmedicine.54.4082
  • NAID: 130005108826
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed / Open Access
• [Journal Article] artial lung resection of supernumerary tracheal bronchus combined with pulmonary artery sling in an adult: report of a case (2015)
  • Author(s): Miyazaki T, Yamasaki N, Tsuchiya T, Matsumoto K, Hayashi H, Izumikawa K, Izumikawa K, Nagayasu T
  • Journal Title: Gen Thorac Cardiovasc Surg Volume: 63 Issue: 3 Pages: 173-176
  • DOI: 10.1007/s11748-013-0287-4
  • Peer Reviewed / Open Access
• [Journal Article] Clinical features, risk factors and treatment of fulminant Mycoplasma pneumoniae pneumonia: a review of the Japanese literature. (2014)
  • Author(s): Izumikawa K et al.
  • Journal Title: J Infect Chemother. Volume: 20 Issue: 3 Pages: 181-185
  • DOI: 10.1016/j.jiac.2013.09.009
  • NAID: 120006986332
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy and safety of garenoxacin tablets on bacterial pneumonia: Postmarketing surveillance in Japan. (2014)
  • Author(s): Izumikawa K et al.
  • Journal Title: J Infect Chemother. Volume: 20 Issue: 9 Pages: 549-557
  • DOI: 10.1016/j.jiac.2014.05.003
  • NAID: 120006986418
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy and safety of garenoxacin tablets on clinically diagnosed atypical pneumonia: Postmarketing surveillance in Japan (2014)
  • Author(s): Izumikawa K et al.
  • Journal Title: J Infect Chemother. Volume: 20 Issue: 9 Pages: 541-548
  • DOI: 10.1016/j.jiac.2014.05.002
  • NAID: 120006986417
  • Peer Reviewed / Open Access
• [Journal Article] Pathogenesis and clinical features of chronic pulmonary aspergillosis - Is it possible to distinguish CNPA and CCPA clinically? (2014)
  • Author(s): Izumikawa K et al.
  • Journal Title: J Infect Chemother. Volume: 20 Issue: 3 Pages: 208-212
  • DOI: 10.1016/j.jiac.2013.10.016
  • NAID: 120006986333
  • Peer Reviewed
• [Journal Article] Cavitary pulmonary metastases and aspergillosis: an autopsy case. (2013)
  • Author(s): Takazono T, Izumikawa K et al.
  • Journal Title: Intern Med Volume: 52 Pages: 1751-1752
  • NAID: 130003365739
  • Peer Reviewed
• [Journal Article] A case series of chronic necrotizing pulmonary aspergillosis and a new proposal (2013)
  • Author(s): Tashiro T, Izumikawa K et al.
  • Journal Title: Jpn J Infect Dis Volume: 66 Pages: 312-316
  • NAID: 130003381694
  • Peer Reviewed
• [Presentation] Chronic Cavitary Pulmonary Aspergillosis (2016)
  • Author(s): Izumikawa K
  • Organizer: 26th ECCMID
  • Place of Presentation: アムステルダム(オランダ）
  • Year and Date: 2016-04-09
  • Int'l Joint Research / Invited
• [Presentation] The burden of serious fungal diseases in Japan (2016)
  • Author(s): Izumikawa K, Tashiro M, Takazono T, Kurihara S, Saijo T, Yamamoto K, Imamura Y, Miyazaki T, Tsukamoto M, Yanagihara K, Mukae H, Kohno S, Denning DW.
  • Organizer: 7th Advances in Aspergillus and Aspergillosis
  • Place of Presentation: マンチェスター(英国）
  • Year and Date: 2016-02-23
  • Int'l Joint Research
• [Presentation] Selection of antifungals for initial maintenance therapy of chronic pulmonary aspergillosis: a longitudinal analysis (2016)
  • Author(s): Tashiro M, Takazono T, Saijo T, Yamamoto K, Imamura Y, Miyazaki T, Kakeya H, Ando T, Ogawa K, Kishi K, Tokimatsu I, Hayashi Y, Fujiuchi S, Yanagihara K, Ichihara K, Kohno S, Izumikawa K.
  • Organizer: 7th Advances in Aspergillus and Aspergillosis
  • Place of Presentation: マンチェスター(英国）
  • Year and Date: 2016-02-23
  • Int'l Joint Research
• [Presentation] 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対応の実際 (2016)
  • Author(s): 泉川公一
  • Organizer: 第31回日本環境感染学会
  • Place of Presentation: 京都国際会議場(京都府・京都市）
  • Year and Date: 2016-02-19
• [Presentation] カルバペネム耐性菌感染症のアウトブレイクを経験して (2015)
  • Author(s): 泉川公一
  • Organizer: 耐性菌シンポジウム2015
  • Place of Presentation: 東京国際フォーラム（東京都・千代田区）
  • Year and Date: 2015-12-19
• [Presentation] 術後肺炎予防・診断・治療の最前線 「原因菌診断」 (2015)
  • Author(s): 泉川公一
  • Organizer: 第28回日本外科感染症学会
  • Place of Presentation: 名古屋東急ホテル(愛知県・名古屋市）
  • Year and Date: 2015-12-02
• [Presentation] 肺真菌症 Up to date ～アスペルギルス～ (2015)
  • Author(s): 泉川公一
  • Organizer: 第64回日本感染症学会東日本地方会学術集会・第62回日本化学療法学会東日本支部総会
  • Place of Presentation: ロイトン札幌（北海道・札幌市）
  • Year and Date: 2015-10-22
• [Presentation] 多様化する感染症とその対策 ～長崎大学病院の事例より見えてくるもの～ (2015)
  • Author(s): 泉川公一
  • Organizer: 第58回日本感染症学会中日本地方会学術集会・第85回日本感染症学会西日本地方会学術集会・第63回日本化学療法学会西日本支部総会
  • Place of Presentation: 奈良県新公会堂(奈良県・奈良市）
  • Year and Date: 2015-10-16
• [Presentation] 真菌感染症における感染制御の役割 (2015)
  • Author(s): 泉川公一
  • Organizer: 第59回 日本医真菌学会
  • Place of Presentation: ホテルさっぽろ芸文館(北海道・札幌市）
  • Year and Date: 2015-10-09
• [Presentation] 慢性肺アスペルギルス症を対象とした予後調査後ろ向き研究 (2015)
  • Author(s): 泉川公一
  • Organizer: 第9回アスペルギルス研究会
  • Place of Presentation: 日本赤十字社医療センター福祉総合センター（東京都・渋谷区）
  • Year and Date: 2015-10-09
• [Presentation] 名古屋 (2015)
  • Author(s): 泉川公一
  • Organizer: 第125回日本結核病学会東海地方会・第107回日本呼吸器学会東海地方会・第10回日本サルコイドーシス肉芽腫性疾患学会中部支部会
  • Place of Presentation: 名古屋市中小企業振興会館(愛知県・名古屋市）
  • Year and Date: 2015-06-14
  • Invited
• [Presentation] The Pathogenesis of Chronic Pulmonary Aspergillosis and Azole Resistance (2015)
  • Author(s): Izumikawa K
  • Organizer: The 12th NUS Nagasaki Joint Symposium
  • Place of Presentation: シンガポール（シンガポール）
  • Year and Date: 2015-06-11
  • Int'l Joint Research
• [Presentation] 2013年度 Mycoplasma pneumoniaeによる15歳以上 急性呼吸器感染症に対するクラリスロマイシンの有効性検討 (2015)
  • Author(s): 泉川公一、門田淳一、田中裕士、松瀬厚人、宮下修行、尾内一信、河野 茂
  • Organizer: 第42回日本マイコプラズマ学会
  • Place of Presentation: 慶應義塾大学薬学部（東京都・港区）
  • Year and Date: 2015-05-22
• [Presentation] 明日から役立つ呼吸器感染症治療戦略 マイコプラズマ感染症の第一選択薬は？ (2015)
  • Author(s): 泉川公一
  • Organizer: 第55回日本呼吸器学会総会
  • Place of Presentation: 東京国際フォーラム（東京都・千代田区）
  • Year and Date: 2015-04-19
• [Presentation] 移植医療における感染症マネジメント (2015)
  • Author(s): 泉川公一
  • Organizer: 第89回日本感染症学会
  • Place of Presentation: 京都国際会議場(京都府・京都市）
  • Year and Date: 2015-04-16
• [Presentation] 肺抗酸菌症と肺真菌症 ～新しい話題～ (2015)
  • Author(s): 泉川公一
  • Organizer: 第90回日本結核病学会
  • Place of Presentation: ブリックホール（長崎県）
  • Year and Date: 2015-03-30
• [Presentation] アゾール耐性アスペルギルスの治療（欧州のコンセンサス） (2014)
  • Author(s): 泉川公一
  • Organizer: 第58回日本医真菌学会
  • Place of Presentation: ワークピア横浜（神奈川県）
  • Year and Date: 2014-11-01
• [Presentation] 感染症を取り巻く現状 ～深在性真菌症領域における課題～ (2014)
  • Author(s): 泉川公一
  • Organizer: 第58回日本医真菌学会
  • Place of Presentation: ワークピア横浜（神奈川県）
  • Year and Date: 2014-11-01
• [Presentation] アスペルギルス症研究の今 (2014)
  • Author(s): 泉川公一
  • Organizer: 第97回細菌学会関東支部会
  • Place of Presentation: 東京ドームホテル（東京都）
  • Year and Date: 2014-10-29
  • Invited
• [Presentation] 深在性真菌症の変貌 ~最近10年間と今後~ 慢性肺アスペルギルス症と薬剤耐性 (2014)
  • Author(s): 泉川公一
  • Organizer: 第57回日本感染症学会中日本地方会学術集会・第84回日本感染症学会西日本地方会学術集会・第62回日本化学療法学会西日本支部総会共同開催
  • Place of Presentation: ヒルトン福岡シーホーク（福岡県）
  • Year and Date: 2014-06-22
• [Presentation] Aspergillosis, from bench to bedside Chronic pulmonary aspergillosis and azole resistance (2014)
  • Author(s): Koichi IZUMIKAWA
  • Organizer: 第54回日本呼吸器学会学術講演会
  • Place of Presentation: 大阪国際会議場（大阪府）
  • Year and Date: 2014-04-25
• [Presentation] Induction of MUC5AC expression to Aspergillus fumigatus in airway epithelial cells and suppressive effects brought about macrolide antibacterial agents (2014)
  • Author(s): Hirano K, Izumikawa K et al.
  • Organizer: 6th Advances against Aspergillosis
  • Place of Presentation: Madrid, Spain
• [Presentation] Efficacy of antifungal therapy with inhaled itraconazole against murine invasive pulmonary aspergillosis with azole low susceptible Aspergillus fumigatus (2014)
  • Author(s): Yoshida M, Izumikawa K et al.
  • Organizer: 6th Advances against Aspergillosis
  • Place of Presentation: Madrid, Spain
• [Presentation] Effect of ghrelin for prevention in murine invasive pulmonary aspergillosis model (2014)
  • Author(s): Takeda K, Izumikawa K et al.
  • Organizer: 6th Advances against Aspergillosis
  • Place of Presentation: Madrid, Spain
• [Presentation] α-glucanase inhibits conidial agglutination of Aspergillus fumigatus and promote inflammation cytokine production from THP-1 (2014)
  • Author(s): Ide S, Izumikawa K et al.
  • Organizer: 6th Advances against Aspergillosis
  • Place of Presentation: Madrid, Spain
• [Presentation] 呼吸器真菌症の病態生理と免疫応答 (2013)
  • Author(s): 泉川公一
  • Organizer: 第53回日本呼吸器学会学術講演会
  • Place of Presentation: 東京フォーラム（東京都中央区）
• [Presentation] The management of chronic pulmonary aspergillosis and azole resistance (2013)
  • Author(s): Izumikawa K
  • Organizer: 28th International Congress of Chemotherapy and Infection
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
• [Presentation] Pathological and clinical analysis of chronic pulmonary aspergillosis (2013)
  • Author(s): Izumikawa K
  • Organizer: 28th International Congress of Chemotherapy and Infection
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
• [Presentation] Topics of pulmonary aspergillosis (2013)
  • Author(s): Izumikawa K
  • Organizer: 28th International Congress of Chemotherapy and Infection
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
• [Book] 呼吸器領域における深在性真菌症 (2015)
  • Author(s): 田代将人, 泉川公一
  • Total Pages: 4
  • Publisher: 先端医療技術研究所
• [Book] 今日の治療指針2014 (2014)
  • Author(s): 泉川公一
  • Total Pages: 890
  • Publisher: 医学書院
• [Book] 感染症関連ガイドラインと使用上の注意 真菌症（神経感染症を究める） (2014)
  • Author(s): 髙園貴弘, 泉川公一, 河野 茂
  • Total Pages: 250
  • Publisher: 中山書店
• [Book] 肺アスペルギルス症（臨床雑誌内科 内科疾患最新の治療 明日への指針 (2014)
  • Author(s): 髙園貴弘, 泉川公一, 河野 茂
  • Total Pages: 1010
  • Publisher: 南江堂
• [Book] 分子呼吸器病 (2014)
  • Author(s): 高園隆弘、泉川公一
  • Total Pages: 176
  • Publisher: 先端医学社