Optimization of antimicrobial therapy based on relation and interaction among drug, causative organism and host immunity

2017 Fiscal Year Annual Research Report

• Project/Area Number: 15K08590
• Research Institution: Hiroshima University
• Principal Investigator: 猪川 和朗 広島大学, 医歯薬保健学研究科(薬), 准教授 (40363048)
• Co-Investigator(Kenkyū-buntansha): 森川 則文 広島大学, 医歯薬保健学研究科(薬), 教授 (30346481) ; 大毛 宏喜 広島大学, 病院(医), 教授 (70379874)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: 臨床 / 感染症 / 薬物動態 / 薬力学

Outline of Annual Research Achievements

本研究では，感染症治療における薬物[抗菌薬・抗真菌薬・抗ウイルス薬]－病原体[細菌・真菌・ウイルス]－宿主[患者]免疫の３者が，相互に関連し合う関係性を解明し，薬物治療法を定量的に最適化することを目的とした。平成29年度には，下記のとおり実施した。
薬物動態・病原体耐性・宿主免疫データの収集に関しては，β-ラクタム系抗菌薬（cefepime，flomoxef，imipenem，piperacillin-tazobactam，sulbactam），キノロン系抗菌薬（levofloxacin，pazufloxacin，sitafloxacin），アミノグリコシド系抗菌薬（amikacin，arbekacin），抗耐性菌薬linezolid，teicoplanin，抗真菌薬voriconazoleの血漿中および組織体液（腹水・腹膜・前立腺・精巣上体）中の薬物濃度を測定した。微生物学的試験や殺菌時間曲線試験のデータ，また各種の臨床データを収集することができた。
定量的な解析・予測に関しては，薬物動態データおよび基礎・非臨床や治療データを定量的に評価し，母集団pharmacokinetic-pharmacodynamicモデリングおよびMonte Carloランダムシミュレーションなどの手法により，様々な関連性を説明し表現する関係式を構築することができた。
感染患者への臨床適用と修正に関しては，薬物，病原体，宿主の特性因子などから，個別最適療法を設計するツールを開発した。そして，患者への臨床適用し，医療現場から適用結果のフィードバックを得ることができた。

Research Products

• [Journal Article] Population pharmacokinetics/pharmacodynamics of linezolid in sepsis patients with and without continuous renal replacement therapy. (2018)
  • Author(s): Ide Takeshi, Takesue Yoshio, Ikawa Kazuro, Morikawa Norifumi, Ueda Takashi, Takahashi Yoshiko, Nakajima Kazuhiko, Takeda Kenta, Nishi Shinichi.
  • Journal Title: Int J Antimicrob Agents. Volume: in press Pages: in press
  • DOI: 10.1016/j.ijantimicag.2018.01.021
  • Peer Reviewed
• [Journal Article] Pharmacokinetics and outcome of tazobactam/piperacillin in Japanese patients undergoing low-flow continuous renal replacement therapy: dosage considerations. (2017)
  • Author(s): Kohama Hanako, Ide Takeshi, Ikawa Kazuro, Morikawa Norifumi, Nishi Shinichi.
  • Journal Title: Clin Pharmacol. Volume: Volume 9 Pages: 39～44
  • DOI: 10.2147/CPAA.S127502
  • Peer Reviewed
• [Journal Article] Clinical pharmacokinetics of oral levofloxacin and sitafloxacin in epididymal tissue. (2017)
  • Author(s): Sadahira Takuya, Wada Koichiro, Ikawa Kazuro, Morikawa Norifumi, Kurahashi Hiroaki, Yoshioka Takashi, Ariyoshi Yuichi, Kobayashi Yasuyuki, Araki Motoo, Ishii Ayano, Watanabe Masami, Uehara Shinya, Watanabe Toyohiko, Nasu Yasutomo.
  • Journal Title: J Infect Chemother. Volume: 23 Pages: 214～217
  • DOI: 10.1016/j.jiac.2016.12.010
  • Peer Reviewed
• [Journal Article] Pharmacokinetics of piperacillin-tazobactam in plasma, peritoneal fluid and peritoneum of surgery patients, and dosing considerations based on site-specific pharmacodynamic target attainment. (2017)
  • Author(s): Murao Naoki, Ohge Hiroki, Ikawa Kazuro, Watadani Yusuke, Uegami Shinnosuke, Shigemoto Norifumi, Shimada Norimitsu, Yano Raita, Kajihara Toshiki, Uemura Kenichiro, Murakami Yoshiaki, Morikawa Norifumi, Sueda Taijiro.
  • Journal Title: Int J Antimicrob Agents. Volume: 50 Pages: 393～398
  • DOI: 10.1016/j.ijantimicag.2017.03.025
  • Peer Reviewed
• [Journal Article] Clinical pharmacokinetics and pharmacodynamic target attainment of pazufloxacin in prostate tissue: Dosing considerations for prostatitis. (2017)
  • Author(s): Nakamura Kogenta, Ikawa Kazuro, Nishikawa Genya, Kobayashi Ikuo, Narushima Masahiro, Muramatsu Hiroyuki, Morinaga Shingo, Kajikawa Keishi, Kato Yoshiharu, Watanabe Masahito, Zennami Kenji, Kanao Kent, Morikawa Norifumi, Sumitomo Makoto.
  • Journal Title: J Infect Chemother. Volume: 23 Pages: 809～813
  • DOI: 10.1016/j.jiac.2017.08.005
  • Peer Reviewed
• [Presentation] Population pharmacokinetic-pharmacodynamic modeling and simulation of imipenem for dosing optimization in pediatric patients. (2017)
  • Author(s): Ikawa K, Morikawa N.
  • Organizer: 15th International Congress of Therapeutic Drug Monitoring and Clinical Toxicology
  • Int'l Joint Research
• [Presentation] Prediction of thrombocytopenia associated with linezolid based on pharmacokinetic-pharmacodynamic simulation. (2017)
  • Author(s): Onita T, Ishihara N, Nishimura N, Tamaki H, Ikawa K, Morikawa N, Naora K.
  • Organizer: 15th International Congress of Therapeutic Drug Monitoring and Clinical Toxicology
  • Int'l Joint Research
• [Presentation] Population pharmacokinetic analysis of piperacillin and tazobactam by using their blood and urine level data in Japanese pediatric patients. (2017)
  • Author(s): Ishihara N, Nishimura N, Ikawa K, Tamaki H, Morikawa N, Naora K.
  • Organizer: 15th International Congress of Therapeutic Drug Monitoring and Clinical Toxicology
  • Int'l Joint Research
• [Presentation] Voriconazole TDM based on both unchanged drug and metabolite concentrations in Japanese patients. (2017)
  • Author(s): Shigemi A, Watanabe E, Umezaki Y, Ikeda R, Matsumoto K, Yokoyama Y, Ikawa K, Morikawa N, Takeda Y.
  • Organizer: 15th International Congress of Therapeutic Drug Monitoring and Clinical Toxicology
  • Int'l Joint Research
• [Presentation] External evaluation of amikacin population pharmacokinetic models in Japanese adult patients. (2017)
  • Author(s): Sako K, Yoshikawa N, Hashimoto N, Matsuki Y, Arai K, Ikawa K, Morikawa N, Matsuda Y.
  • Organizer: 15th International Congress of Therapeutic Drug Monitoring and Clinical Toxicology
  • Int'l Joint Research
• [Presentation] Estimation of the duration to reach peak arbekacin concentration by Monte Carlo simulation. (2017)
  • Author(s): Yamaguchi K, Abe T, Takeuchi T, Watanabe M, Tsuchiya K, Ikawa K, Fukuoka N, Kaji M, Tanaka H, Asakura M, Kosaka S, Houchi H.
  • Organizer: 15th International Congress of Therapeutic Drug Monitoring and Clinical Toxicology
  • Int'l Joint Research
• [Presentation] Pharmacokinetic and pharmacodynamic characterization of piperacillin-tazobactam, flomoxef and pazufloxacin in prostate tissue and plasma of prostatic hypertrophy patients. (2017)
  • Author(s): Kuroda A, Ikawa K, Ugawa H, Tanaka K, Odagawa S, Matsuyama Y, Nakamura K, Nishikawa G, Kobayashi I, Sumitomo M, Morikawa N.
  • Organizer: 15th International Congress of Therapeutic Drug Monitoring and Clinical Toxicology
  • Int'l Joint Research
• [Presentation] Pharmacokinetic/pharmacodynamic evaluation of teicoplanin against Staphylococcus aureus in murine thigh infection model. (2017)
  • Author(s): Takeda Y, Watanabe E, Shigemi A, Umezaki Y, Nakamura K, Ueno K, Ikeda R, Yokoyama Y, Matsumoto K, Ikawa K, Morikawa N.
  • Organizer: 15th International Congress of Therapeutic Drug Monitoring and Clinical Toxicology
  • Int'l Joint Research
• [Presentation] Semi-mechanistic pharmacokinetic/pharmacodynamic modeling and simulation for time-kill curve profile of sulbactam against Acinetobacter baumannii. (2017)
  • Author(s): Yokoyama Y, Ikawa K, Matsumoto K, Nakamura T, Morikawa N.
  • Organizer: 第11回次世代を担う若手医療薬科学シンポジウム
• [Presentation] セフェピム投与後に代謝性脳症を発現し薬物血中濃度を測定した1例. (2017)
  • Author(s): 眞継賢一, 猪川和朗, 森川則文, 濱口良彦.
  • Organizer: 第65回日本化学療法学会学術集会・第91回日本感染症学会学術講演会