Molecular epidemiology and characteristics of carbapenemase-producing Escherichia coli and Klebsiella pneumoniae

• Project/Area Number: 16K09940
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Infectious disease medicine
• Research Institution: Nara Medical University
• Principal Investigator: Yano Hisakazu 奈良県立医科大学, 医学部, 教授 (20374944)
• Co-Investigator(Kenkyū-buntansha): 遠藤 史郎 東北大学, 医学系研究科, 大学院非常勤講師 (40614491) ; 笠原 敬 奈良県立医科大学, 医学部, 准教授 (50405403) ; 中野 竜一 奈良県立医科大学, 医学部, 講師 (80433712)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); 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: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 薬剤耐性菌 / カルバペネマーゼ / 大腸菌 / 肺炎桿菌 / 病原性 / IMP-6産生大腸菌 / CTX-M型β-ラクタマーゼ / カルバペネム耐性大腸菌 / IMP-6 / IncN / カルバペネム系薬

Outline of Final Research Achievements

Between 2014 and 2017, 136 carbapenemase-producing E. coli and 104 carbapenemase-producing Klebsiella pneumoniae were obtained throughout Japan. All were positive for IMP, and 130 E. coli and 83 K. pneumoniae carried IMP-6 gene.　Of these IMP-6 producers, 99 E. coli and 73 K. pneumoniae were positive for the CTX-M enzyme. In this study, we found the high frequency of IMP-6 among E. coli and K. pneumoniae in Japan.

Academic Significance and Societal Importance of the Research Achievements

今回の解析で、本邦におけるカルバペネマーゼはIMP-6産生菌が優位であった。IMP-6産生菌はカルバペネム系薬であるイミペネムのMIC値が低いことから、IMP型酵素産生菌と認識できない可能性が示唆され、医療関連感染対策の遅れや、不適切な治療に繋がる可能性が危惧される。また、多くがIncNに属したが、IncNプラスミドは大腸菌、肺炎桿菌を中心に広く腸内細菌科細菌をホストとすることができ、さらに伝達頻度も非常に高いことから、今後、各種腸内細菌科細菌に伝播拡散していく可能性が示唆された。

Research Products

• [Int'l Joint Research] Research Institute for Tropical Medicine(フィリピン)
• [Int'l Joint Research] Research Institute for Tropical Medicine(フィリピン)
• [Journal Article] Indication of Minimum Inhibitory Concentration of β-Lactam Antimicrobials for the Primary Extraction of IMP-Producing <i>Enterobacteriaceae</i> (2019)
  • Author(s): Saito Kyoichi、Nakamura Kiwamu、Harada Rie、Nakano Ryuichi、Yano Hisakazu、Kanemitsu Keiji
  • Journal Title: Japanese Journal of Infectious Diseases Volume: 72 Issue: 1 Pages: 68-70
  • DOI: 10.7883/yoken.JJID.2018.297
  • NAID: 130007577804
  • ISSN: 1344-6304, 1884-2836
  • Year and Date: 2019-01-31
  • Peer Reviewed
• [Journal Article] Prevalence and mechanism of fluoroquinolone resistance in clinical isolates of Proteus mirabilis in Japan (2019)
  • Author(s): Nakano Ryuichi、Nakano Akiyo、Abe Michiko、Nagano Noriyuki、Asahara Miwa、Furukawa Taiji、Ono Yasuo、Yano Hisakazu、Okamoto Ryoichi
  • Journal Title: Heliyon Volume: 5 Issue: 3 Pages: e01291-e01291
  • DOI: 10.1016/j.heliyon.2019.e01291
  • Peer Reviewed / Open Access
• [Journal Article] Emergence of IMP-34 and OXA-58-producing carbapenem-resistant Acinetobacter colistiniresistens (2019)
  • Author(s): Suzuki Y, Endo S, Nakano R, Nakano A, Saito K, Kakuta R, Kakuta N, Horiuchi S, Yano H, and Kaku M
  • Journal Title: Antimicrob Agents Chemother Volume: in press Issue: 6
  • DOI: 10.1128/aac.02633-18
  • Peer Reviewed
• [Journal Article] Molecular epidemiology and clinical features of extended-spectrum β-lactamase- or carbapenemase-producing Escherichia coli bacteremia in JapanRisk factors for and outcomes of patients with extended-spectrum β-lactamase- or carbapenemase-producing Escherichia coli bacteremia in Japan (2018)
  • Author(s): Komatsu Y, Kasahara K, Inoue T, Muratani T, Yano H, Kirita T, Mikasa K
  • Journal Title: PLoS ONE Volume: 13 Issue: 8 Pages: e0202276-e0202276
  • DOI: 10.1371/journal.pone.0202276
  • Peer Reviewed / Open Access
• [Journal Article] Emergence of VIM-2-producing Citrobacter freundii in Japan (2018)
  • Author(s): Ando S, Nakano R, Kuchibiro T, Yamasaki K, Suzuki Y, Nakano A, Mizuno T, Kasahara K, Yano H
  • Journal Title: Infectious Diseases (Lond) Volume: 50 Issue: 11-12 Pages: 862-863
  • DOI: 10.1080/23744235.2018.1498592
  • Peer Reviewed
• [Journal Article] Rapid Identification of bla(IMP-1) and bla(IMP-6) by Multiplex Amplification Refractory Mutation System PCR (2018)
  • Author(s): Nakano A, Nakano R, Suzuki Y, Saito K, Kasahara K, Endo S, Yano H
  • Journal Title: Ann Lab Med Volume: 38 Issue: 4 Pages: 378-380
  • DOI: 10.3343/alm.2018.38.4.378
  • Peer Reviewed / Open Access
• [Journal Article] Role of AmpR in the High Expression of the Plasmid-Encoded AmpC β-Lactamase CFE-1. (2017)
  • Author(s): Nakano R, Nakano A, Yano H, Okamoto R
  • Journal Title: mSphere Volume: 2 Issue: 4
  • DOI: 10.1128/msphere.00192-17
  • Peer Reviewed / Open Access
• [Journal Article] Suitability of the Carbapenem Inactivation Method (CIM) to Detect IMP Metallo-β-lactamase-Producing Enterobacteriaceae. (2017)
  • Author(s): K Saito, R Nakano, Y Suzuki, A Nakano, Y Ogawa, S Yonekawa, S Endo, F Mizuno, K Kasahara, K Mikasa, M Kaku, H Yano
  • Journal Title: Journal of Clinical Microbiology Volume: 55 Issue: 4 Pages: 1220-1222
  • DOI: 10.1128/jcm.02275-16
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 薬剤感受性検査の読み方～ESBL, CREを中心に～ (2017)
  • Author(s): 矢野寿一、中野竜一、中野章代
  • Journal Title: medicina Volume: 54 Pages: 44-46
• [Presentation] 抗菌薬を大事に使おう～耐性菌の基礎知識からその対策まで～ (2019)
  • Author(s): 矢野寿一
  • Organizer: 日本集中治療医学会第3回中四国支部学術集会
  • Invited
• [Presentation] Molecular characteristics of CTX-M β-lactamase-producing Escherichia coli isolated from livestock and human patients in Japan (2018)
  • Author(s): Nakano R, Nakano A, Nishisouzu, Hikosaka K, Kasahara K, Ono Y, Yano H
  • Organizer: 28th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID)
  • Int'l Joint Research
• [Presentation] Analysis of NMC-A expression in Enterobacter ludwigii first isolated in Japan (2018)
  • Author(s): NakanoR, Yamada Y, Nakano A, Ando S, Mizuno T, Suzuki Y, Narita K, Suwabe A, Yano H
  • Organizer: 28th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID)
  • Int'l Joint Research
• [Presentation] Emergence of multidrug-resistant Escherichia coli strain harbouring blaCTX-M-55, rmtB, and fosA3-encoding plasmid isolated from a food poisoning patient in Japan (2018)
  • Author(s): Nakano A, Nakano R, Kasahara K, Suzuki Y, Ando S, Mizuno T, Mikasa K, Yano H
  • Organizer: 28th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID)
  • Int'l Joint Research
• [Presentation] Environmental dissemination of carbapenem-resistant Gram-negative bacteria in the Philippines (2018)
  • Author(s): Suzuki Y, Nakano R, Nakano A, Nakashima K, Yano H
  • Organizer: 28th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID)
  • Int'l Joint Research
• [Presentation] Diversity of CTX-M β-lactamase genotypes among IMP-6 β-lactamase-producing Escherichia coli in Japan (2018)
  • Author(s): Mizuno T, Nakano R, Ogawa M, Suzuki Y, Nakano A, Ando S, Tanouchi A, Kakuta N, Masui T, Saito K, Kasahara K, Yano H
  • Organizer: 28th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID)
  • Int'l Joint Research
• [Presentation] Emergence of Escherichia coli harbouring IMP-6, CTX-M-2, and CTX-M-1 group isolated in Japan (2018)
  • Author(s): Mizuno T, Nakano R, Ogawa M, Suzuki Y, Nakano A, Ando S, Tanouchi A, Kakuta N, Masui T, Yano H, Kasahara K
  • Organizer: 28th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID)
  • Int'l Joint Research
• [Presentation] First isolation of VIM-2 beta-lactamase-producing Citrobacter freundii in Japan &#8211; indications that plasmid suspected to be transferred from Pseudomonas aeruginosa (2018)
  • Author(s): Ando S, Nakano R, Kuchibiro T, Yamasaki K, Suzuki Y, Nakano A, Mizuno T, Tanouchi A, Kakuta N, Masui T, Yano H
  • Organizer: 28th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID)
  • Int'l Joint Research
• [Presentation] Emergence of IMP-6-producing Escherichia coli co-harbouring CTX-M-35 isolates from patients in Japan (2018)
  • Author(s): Ando S, Nakano R, Suzuki Y, Nakano A, Ogawa M, Mizuno T, Tanouchi A, Kakuta N, Masui T, Yano H
  • Organizer: 28th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID)
  • Int'l Joint Research
• [Presentation] Carbapenemase activity test (CAT), a rapid phenotypic screening method to detect carbapenemase production in Gram-negative bacilli (2018)
  • Author(s): Saito K, Endo S, Nakano R, Suzuki Y, Nakano A, Kasahara K, Yano H, Kaku M
  • Organizer: 28th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID)
  • Int'l Joint Research
• [Presentation] Multicenter clinical and molecular epidemiological analysis of carbapenem-resistant Enterobacteriaceae CRE in Japan. (2018)
  • Author(s): Hayakawa K, Kato H, Hase R, Hasumi J, Nei T, Nakano R, Yano H, Nagashima M, Ohmagari N
  • Organizer: IDWeek
  • Int'l Joint Research
• [Presentation] ヒトにおける薬剤耐性菌の現状と問題点 (2018)
  • Author(s): 矢野寿一
  • Organizer: 第92回日本感染症学会学術講演会・第66回日本化学療法学会総会合同学会
• [Presentation] 薬剤耐性菌の脅威～抗菌薬を大事に使おう～ (2018)
  • Author(s): 矢野寿一
  • Organizer: 日本耳鼻咽喉科学会島根県地方部会総会・学術講演会
  • Invited
• [Presentation] β-ラクタマーゼの基礎 (2018)
  • Author(s): 矢野寿一
  • Organizer: 第88回日本感染症学会西日本・第61回日本感染症学会中日本・第66回日本化学療法学会西日本
  • Invited
• [Presentation] 薬剤耐性菌の基礎、AMR対策における薬剤耐性菌の知識 (2018)
  • Author(s): 矢野寿一
  • Organizer: 第58回日臨技近畿支部医学検査学会
  • Invited
• [Presentation] One Health的アプローチから薬剤耐性菌を考える (2018)
  • Author(s): 矢野寿一
  • Organizer: 日本耳鼻咽喉科学会宮城県地方部会第174回例会
  • Invited
• [Presentation] Analysis of Gram-negative antimicrobial resistant bacteria isolated from environmental samples (2018)
  • Author(s): Yano H
  • Organizer: RITM LabCon 2018
  • Int'l Joint Research / Invited
• [Presentation] 「環境・動物・食品に分布する耐性菌がヒトの感染症に与える影響を考える」ヒトにおける耐性菌の現状 (2018)
  • Author(s): 矢野寿一
  • Organizer: 第91回日本細菌学会総会
  • Invited
• [Presentation] Accuracy of carbapenem inactivation method (CIM) for detecting carbapenemase-producing Gram-negative bacteria corresponding to bacterial species and enzymes (2017)
  • Author(s): Saito K, Nakano R, Suzuki Y, Nakano A, Yonekawa S, Endo S, Mizuno F, Kasahara K, Mikasa K, Kaku M, Yano H
  • Organizer: 27th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID)
  • Place of Presentation: Vienna, Austria
  • Year and Date: 2017-04-22
  • Int'l Joint Research
• [Presentation] Molecular characteristics and epidemiology of clinical isolates of carbapenemase-producing Escherichia coli in Japan (2017)
  • Author(s): Mizuno T, Nakano R, Ogawa M, Suzuki Y, Nakano A, Saito K, Ando S, Mizuno F, Kasahara K, Yano H
  • Organizer: 27th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID)
  • Place of Presentation: Vienna, Austria
  • Year and Date: 2017-04-22
  • Int'l Joint Research
• [Presentation] 病院検査室で実施可能な濁度計を用いたカルバペネマーゼ産生菌迅速検査法の新規開発 (2017)
  • Author(s): 斎藤恭一、中野竜一、鈴木由希、中野章代、米川真輔、遠藤史郎、水野文子、笠原 敬、三笠桂一、賀来満夫、矢野寿一
  • Organizer: 第91回日本感染症学会・第65回日本化学療法学会
  • Place of Presentation: 東京
  • Year and Date: 2017-04-07
• [Presentation] 国内で分離された IMP-6, CTX-M-2, CTX-M-15 同時保有株に関する分子遺伝学的解析 (2017)
  • Author(s): 水野友貴、中野竜一、鈴木由希、中野章代、斎藤恭一、小川美保、水野文子、笠原 敬、三笠桂一、矢野寿一
  • Organizer: 第91回日本感染症学会・第65回日本化学療法学会
  • Place of Presentation: 東京
  • Year and Date: 2017-04-07
• [Presentation] 耐性菌 (2017)
  • Author(s): 矢野寿一
  • Organizer: 第91回日本感染症学会・第65回日本化学療法学会
  • Place of Presentation: 東京
  • Year and Date: 2017-04-07
  • Invited
• [Presentation] 本邦で分離されたカルバペネム耐性大腸菌の耐性機序の解析 (2017)
  • Author(s): 小川美保、市村禎宏、中野竜一、遠藤史郎、矢野寿一、賀来満夫
  • Organizer: 第28回日本臨床微生物学会総会・学術集会
  • Place of Presentation: 長崎
  • Year and Date: 2017-01-20
• [Presentation] Carbapenem Inactivation Method (CIM) によるカルバペネマーゼ産生腸内細菌科の検出感度の評価 (2017)
  • Author(s): 水野友貴、中野竜一、斎藤恭一、鈴木由希、中野章代、安藤冴佳、遠藤史郎、水野文子、中村ふくみ、笠原敬、三笠桂一、賀来満夫、矢野寿一
  • Organizer: 第28回日本臨床微生物学会総会・学術集会
  • Place of Presentation: 長崎
  • Year and Date: 2017-01-20
• [Presentation] CTX-M-35を保有するIMP-6産生大腸菌について (2017)
  • Author(s): 安藤冴佳、中野竜一、中野章代、斎藤恭一、鈴木由希、水野友貴、水野文子、小川美保、矢野寿一
  • Organizer: 第28回日本臨床微生物学会総会・学術集会
  • Place of Presentation: 長崎
  • Year and Date: 2017-01-20
• [Presentation] Multiplex ARMS PCR法によるIMP-1とIMP-6の迅速識別法の開発 (2017)
  • Author(s): 中野章代、中野竜一、鈴木由希、斎藤恭一、安藤冴佳、水野友貴、水野文子、笠原敬、三笠桂一、矢野寿一
  • Organizer: 第28回日本臨床微生物学会総会・学術集会
  • Place of Presentation: 長崎
  • Year and Date: 2017-01-20
• [Presentation] Prevalence and characterization of extended spectrum β-Lactamase-producing Escherichia coli in faecal samples of healthy bovine and farmers (2017)
  • Author(s): Nakano R, Nakano A, Nishisouzu R, Ono Y, Yano H
  • Organizer: 27th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID)
  • Int'l Joint Research
• [Presentation] Molecular epidemiology and mechanisms of carbapenem-resistant Acientoabcter spp. clinical isolates from sputum specimen in Japan (2017)
  • Author(s): Suzuki Y, Endo S, Nakano R, Saito K, Nakano A, Mizuno F, Yano H, Kaku M
  • Organizer: 27th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID)
  • Int'l Joint Research
• [Presentation] Molecular characteristics of extended spectrum β-lactamase-producing Escherichia coli in clinical isolates from outpatients in Japan (2017)
  • Author(s): Fujikawa Y, Endo S, Yano H, Kaku M
  • Organizer: ASM Microbe 2017
  • Int'l Joint Research
• [Presentation] 我が国における薬剤耐性グラム陰性桿菌の現状 (2017)
  • Author(s): 矢野寿一
  • Organizer: 第65回化療西日本・第60回感染症中日本・第87回感染症西日本
  • Invited
• [Presentation] 世界で広がるカルバペネム耐性腸内細菌科細菌（CRE）に関する最近の話題 (2017)
  • Author(s): 矢野寿一
  • Organizer: 東北小児感染症懇話会2017
  • Place of Presentation: 仙台
  • Invited
• [Presentation] 世界で広がるカルバペネム耐性腸内細菌科細菌（CRE）に関する最近の話題、 (2017)
  • Author(s): 矢野寿一
  • Organizer: 第1回島根大学耐性菌セミナー
  • Place of Presentation: 出雲
  • Invited
• [Presentation] Carbapenem Inactivation Method (CIM)を用いたカルバぺネマーゼ産生腸内細菌科（CPE）検出精度の評価 (2016)
  • Author(s): 斎藤恭一、中野竜一、鈴木由希、中野章代、遠藤史郎、水野文子、笠原敬、三笠桂一、賀来満夫、矢野寿一
  • Organizer: 第86回感染症西日本・第59回感染症中日本・第64回化療西日本
  • Place of Presentation: 沖縄
  • Year and Date: 2016-11-25
• [Presentation] Multiplex ARMS PCR法によるIMP-1とIMP-6の簡易識別法の開発 (2016)
  • Author(s): 中野章代、中野竜一、鈴木由希、斎藤恭一、水野文子、笠原敬、三笠桂一、矢野寿一
  • Organizer: 第86回感染症西日本・第59回感染症中日本・第64回化療西日本
  • Place of Presentation: 沖縄
  • Year and Date: 2016-11-25
• [Presentation] LAMP法によるカルバぺネマーゼ産生アシネトバクター迅速検出法の開発 (2016)
  • Author(s): 中野竜一、Xiaoqin Mu、中野章代、鴨志田剛、祖母井庸之、永川茂、上田たかね、遠藤史郎、矢野寿一、斧康雄
  • Organizer: 第86回感染症西日本・第59回感染症中日本・第64回化療西日本
  • Place of Presentation: 沖縄
  • Year and Date: 2016-11-25