今日の臨床サポート

肺非結核性抗酸菌症

著者: 森本耕三1) 公益財団法人結核予防会複十字病院呼吸器センター / 臨床医学研究科・特定非営利活動法人非結核抗酸菌症研究コンソーシアム(NTM-JRC)

著者: 長谷川直樹2) 慶應義塾大学医学部 感染症学教室・特定非営利活動法人非結核抗酸菌症研究コンソーシアム(NTM-JRC)

監修: 藤田次郎 琉球大学医学部

著者校正済:2021/11/10
現在監修レビュー中
参考ガイドライン:
  1. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases.
  1. Treatment of Nontuberculous Mycobacterial Pulmonary Disease: An Official ATS/ERS/ESCMID/IDSA Clinical Practice Guideline.
  1. 日本結核・非結核性抗酸菌症学会:肺非結核性抗酸菌症に対する外科治療の指針、結核 83巻7号、p.527-528、2008
  1. 日本結核・非結核性抗酸菌症学会:肺非結核性抗酸菌症化学療法に関する見解-2012改訂、結核 87巻2号、p.83-86、2012年
  1. The Nontuberculous Mycobacteriosis Control Committee of the Japanese Society for Tuberculosis The Scientific Assembly for Infection and Tuberculosis of the Japanese Respiratory SocietyGUIDELINES FOR CHEMOTHERAPY OF PULMONARY NONTUBERCULOUS MYCOBACTERIAL DISEASE ─2012 Revised Version, Kekkaku 88(1): p.29-32, 2013
  1. 日本結核・非結核性抗酸菌症学会:肺非結核性抗酸菌症診断に関する指針-2008年、結核 83巻7号、 p.525-526、2008年
患者向け説明資料

概要・推奨   

  1. 塗抹陽性、有空洞例では、積極的な治療開始を行うことが推奨される。
  1. 肺MAC症では、有空洞例を含む重症例では、治療初期からアミノグリコシドの併用を行うことが推奨される。
  1. 肺MAC症では、6カ月間培養陽性が持続する症例では吸入リポソーマルアミカシン混濁液の吸入またはアミノグリコシド薬の追加を検討することが推奨される。
  1. 難治例、クラリスロマイシン耐性例、M. abscessus症例の治療は専門医へコンサルトを行うことが推奨される。
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
森本耕三 : 特に申告事項無し[2021年]
長谷川直樹 : 研究費・助成金など(医学生物学研究所)[2021年]
監修:藤田次郎 : 講演料(塩野義製薬(株),杏林製薬(株),第一三共(株))[2021年]

改訂のポイント:
  1. 2020年に発行されたATS/ERS/ESCMID/IDSA NTMガイドラインに則って定期レビューを行った。
  1. リポソーマルアミカシン吸入液に関連する情報の追記を行った。
  1. 治療期間(菌陰性化15~18カ月が望ましい)とする知見の追記を行った。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 肺非結核性抗酸菌症(肺NTM症)の診断には2007年に米国胸部学会/米国感染症学会が発表したガイドライン[1]をもとに、2008年に日本呼吸器学会/日本結核病学会が定めた基準[2]が用いられている。本疾患を示唆する画像所見に加え、喀痰培養検査で複数回、菌を検出することがポイントである。
 
肺NTM症の診断基準:
  1. 下記臨床的基準と細菌学的基準をともに満たす場合に肺NTM症と診断する。
  1. 臨床的基準(以下の2項目を満たす):
  1. 肺部画像所見(HRCTを含む)で、
  1. 結節性陰影、小結節性陰影や分岐状陰影の散布
  1. 均等性陰影、空洞性陰影
  1. 気管支または細気管支拡張所見のいずれか(複数可)を示す。ただし、先行肺疾患による陰影がすでにある場合にはこの限りではない。
  1. 他の疾患を除外できる。
  1. 細菌学的基準(菌種の区別なく、以下のいずれか1項目を満たす):
  1. 2回以上の異なった喀痰検体での培養陽性(間隔を問わない)。
  1. 1回以上の気管支洗浄液での培養陽性。
  1. 経気管支肺生検または肺生検組織の場合には、抗酸菌症に合致する組織学的所見と同時に組織、または気管支洗浄液、または喀痰での1回以上の培養陽性。
  1. まれな菌種や環境から高頻度に分離される菌種の場合には、検体種類を問わず2回以上の培養陽性と菌種同定検査を原則とし、専門家の見解を必要とする。
  1. 解説:非結核性抗酸菌は結核菌と同じ抗酸菌に属するが、水系、土壌などの環境に生息している。ヒトからヒトへは感染しないとされるが、感染と発病の関係は結核のように明らかにされておらず、誰が感染し、感染者のうちどのくらいの者が、感染後どのくらいの時間を経て発病するのか明らかではない。通常、呼吸器感染症を惹起し、画像所見は多彩であるが比較的均一な臨床像を呈する。診断には症状の有無は問わず、胸部CTや胸部単純X線写真に陰影を認め、喀痰検査で複数回菌検出することが重要である。診断されても治療開始時期については個別に判断する。自然経過も十分に解明されていないが、自覚症状の明らかなもの、画像所見が進行性に増悪するもの、空洞を有するものには多剤併用による化学療法が考慮される。治療期間も明確にされていないが一般的には排菌陰性化が達成されてから1年とされるが、さらに長い治療期間が必要であるという報告もある。
 
NTMの感染源は?
  1. NTMは土壌や水系の常在菌であり、誰もが日常生活で曝露されているので、感染源は環境にあると考えることは妥当であろう。実際に水道管やシャワーヘッド・土壌などに存在する菌が感染源になるとの報告がある。過去の報告より炊事場、洗濯場や浴室の掃除を定期的に行うことは、日常生活において曝露機会を減少させるための一策として指導してもよいと考える。
  1. ヒトからヒトへの感染については呼吸器系の日和見感染を容易に起こす嚢胞性線維症(cystic fibrosis )患者間での感染が報告されている。しかし、それ以外ではHIV感染症、あるいは家族性に発症した肺MAC症の検討でもヒトからヒトへの感染は証明されていない[3][4][5]
  1. NTMの感染源が身近な環境であることが指摘されている。例えば、肺MAC症の患者より検出された菌と遺伝情報の相同性が高い菌が自宅の水道管、シャワーヘッド、土壌などから検出され、環境菌が感染源になる可能性が指摘されている。これは環境中に生存するNTMがエアロゾル化し経気道的に感染する可能性を示唆する。一方NTM は水道水1L中に107個存在することや、消毒薬への感受性が低く、酸性環境にも強いこと(肺MAC症の患者は高率(19.8%)に逆流性食道炎を合併すること)も指摘されている[6][7][8][9][10][11]
  1. これは、いったん飲料水として摂取された水に含まれるNTMが、胃食道の逆流を経て、気道系に誤飲されて感染する可能性を示唆する。一方、逆流性食道炎の合併頻度はアジアでは低く、手洗いや飲料水を沸騰させてから使用する、などの習慣がNTMのcolonizationの頻度の違いを生み出す可能性も指摘されている。以上より、患者の感染源は身近な環境である可能性は高く、自宅の炊事場、洗濯場、浴室などの乾燥しにくい部位の掃除と乾燥に留意することを患者に勧めることは生活指導として重要であろう[12][13]
  1. また今後これらの環境と人からの検出菌についての詳細な検討により、その臨床像がさらに明らかにされてゆくことが期待される。
 
毒力の強い菌がいるのか?
  1. 基本的にNTMは弱毒菌であり、ヒトへの病原性は低い。今のところMAC菌が産生する明らかな障害性因子は発見されていない。また感染しやすい菌や、病原性の強い株の特徴についても研究が進められているが詳細は不明である。
  1. 現在、病状や病勢と関連する菌側の因子について研究が進められているが、最近は、菌の細胞への侵入に関与する菌体成分も報告されている。一方、MAC症の持続感染にはMAC菌がホストの免疫反応の活性化と抑制のバランスを保ちながら、免疫機構から逃れてホストの中で持続的に生存することが重要である。現在、MAC菌においては明らかな組織障害因子は発見されていないが、このような視点からは、ホスト細胞を傷害するのではなく、ホスト細胞と共存し続けることがNTMの病原性とも考えられる[14][15]
  1. 菊池らは、診断確定した肺MAC症患者を一定期間経過観察し、病状が進行した例と進行しなかった例から採取された菌株のクラスター解析を行った。臨床経過によりクラスター形成を認め、感染症の増悪と関連する菌側因子の存在が示唆されたが、その後、韓国の追試では同様の結果は得られなかった。また従来 M. aviumM. intracellulareはMACと総称されてきたが、M. avium感染症よりもM. intracellulare感染症のほうが重症化しやすいことを示唆する報告もある[16][17][18]。現在、進行性や重症化を規定する菌側の特定因子は不明である。
 
肺非結核性抗酸菌症の疫学
  1. 肺NTM症はヒトからヒトに感染しないため公衆衛生学的に注目度が低く、報告義務が課されている国、地域はほとんどない。またかつて固形培地が用いられていた時代の診断基準は環境常在菌であるために、複数回の菌検出を要するだけでなく、菌量要件が付帯し、さらにその基準が菌種や病態により異なるというきわめて複雑なものであったために疫学調査にも不適であった。その後結核を含む抗酸菌検査に液体培地が使用されるようになったが本培養法ではコロニーの目視ができないために定量が不可能であり、それを踏まえて2007年にATS/IDSAから細菌学的基準が簡素化された診断基準が発表された。
  1. 新たな基準では肺NTM症については、相当する病変を胸部画像検査で認め、喀痰から2回培養陽性になることが条件とされた。また気管支鏡検査で得られた検体については洗浄液で培養陽性であれば一回で診断確定とされた。その後は本診断基準が国際的に共通の診断基準として普及した。一方、診断基準の簡素化により複数の培養陽性をよりどころに疫学的解析が可能になった。この手法を用いた疫学調査がオレゴン州で実施され、その妥当性が知られるようになった[19][20]
  1. 肺NTM症は結核のような届出(報告)制がないこと、診断基準は臨床(画像)や菌の基準を満たす必要があることなどから正確な疫学情報を得ることは困難である。しかし、わが国では1970年代から束村らが中心となり国療研究班による疫学調査が行われてきた歴史がある。罹患率は、一定期間に診断されたNTM/結核比と結核の統計で得られる活動性結核罹患率の積から求められた。しかし、2008年に診断基準が更新されたのち、疫学調査は行われなかった。2014年に同様の手法を用いて日本呼吸器学会認定施設などを対象に行われた[21]。この結果、罹患率は14.7/10万人と菌陽性結核の罹患率をはじめて上回ったことが明らかにされた。この報告は、40年以上に渡る推移を示したものとして海外でも注目された。また、これは世界的にもきわめて高い罹患率といえる[22]
  1. さらに、肺NTM症の疫学解析として、主要検査会社の11万件を超える抗酸菌データ(2012~2013年)の解析が行われ、期間有病率は西日本で高いこと、菌種ごとの地域差が明らかであること(MACのうちM. intracellulareは西日本に高く、M. aviumは東日本で高い。M. kansasiiは近畿地方で高く、M. abscessus speciesは九州沖縄地方で高い)、菌種構成は、MACが約90%を占め、M. kansasiiM. abscessus speciesが数パーセントで続いており、希少菌種とされていたM. abscessus speciesがM. kansasiiに迫る数であることなどが示された[23]
問診・診察のポイント  
  1. 肺NTM症は健診などで画像により偶然に発見され、自覚症状を認めない例もあるが、喀痰、咳嗽、息切れ、または普段は自覚症状を認めなくても血痰を自覚する場合がある。経過の長い慢性疾患であるが、進行性に増悪し呼吸不全に至る例もあり、以下の点に留意する。

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11月30日(火)までにお申込みいただくと、
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文献 

著者: David E Griffith, Timothy Aksamit, Barbara A Brown-Elliott, Antonino Catanzaro, Charles Daley, Fred Gordin, Steven M Holland, Robert Horsburgh, Gwen Huitt, Michael F Iademarco, Michael Iseman, Kenneth Olivier, Stephen Ruoss, C Fordham von Reyn, Richard J Wallace, Kevin Winthrop, ATS Mycobacterial Diseases Subcommittee, American Thoracic Society, Infectious Disease Society of America
雑誌名: Am J Respir Crit Care Med. 2007 Feb 15;175(4):367-416. doi: 10.1164/rccm.200604-571ST.
Abstract/Text
PMID 17277290  Am J Respir Crit Care Med. 2007 Feb 15;175(4):367-416. ・・・
著者: E Tanaka, T Kimoto, H Matsumoto, K Tsuyuguchi, K Suzuki, S Nagai, M Shimadzu, H Ishibatake, T Murayama, R Amitani
雑誌名: Am J Respir Crit Care Med. 2000 May;161(5):1643-7. doi: 10.1164/ajrccm.161.5.9907144.
Abstract/Text We report two Japanese families affected by pulmonary Mycobacterium avium complex (MAC) disease, involving an older brother and younger sister in one family and two brothers in the second family. We investigated whether defects in the natural resistance-associated macrophage protein gene (NRAMP1) underlay susceptibility to MAC in these cases. All of the patients had computed tomographic findings of peripheral nodules and bronchiectasis. Pulse-field gel electrophoresis patterns of mycobacterial genomic DNA restriction fragments revealed that none of the MAC strains isolated from the patients was epidemiologically related to any of the others. Direct sequencing of the complementary DNA of the patients' NRAMP1 revealed a nonconservative missense mutation at codon 419 in one patient, which was heterozygous and was not seen in his affected sibling. No variations similar to those found in mice that show susceptibility to MAC were found. The results suggest an underlying genetic defect in host defense rather than exposure to an unusually virulent strain of MAC as the pathogenetic factor in MAC disease; however, alterations in the coding region of NRAMP1 do not appear to explain the susceptibility to MAC.

PMID 10806169  Am J Respir Crit Care Med. 2000 May;161(5):1643-7. doi:・・・
著者: C F von Reyn, R D Arbeit, C R Horsburgh, M A Ristola, R D Waddell, S M Tvaroha, M Samore, L R Hirschhorn, J Lumio, A D Lein, M R Grove, A N A Tosteson
雑誌名: J Infect. 2002 Apr;44(3):166-70. doi: 10.1053/jinf.2001.0950.
Abstract/Text OBJECTIVES: To identify the sources of disseminated Mycobacterium avium complex (MAC) infection in AIDS.
METHODS: HIV positive subjects with CD4 counts <100/mm(3) in Atlanta, Boston, New Hampshire and Finland were entered in a prospective cohort study. Subjects were interviewed about potential MAC exposures, had phlebotomy performed for determination of antibody to mycobacterial lipoarabinomannin and for culture. Patient-directed water samples were collected from places of residence, work and recreation. Patients were followed for the development of disseminated MAC. Univariate and multivariate risk factors for MAC were analyzed.
RESULTS: Disseminated MAC was identified in 31 (9%) subjects. Significant risks in univariate analysis included prior Pneumocystis carinii pneumonia (PCP) (hazard ratio 1.821), consumption of spring water (4.909), consumption of raw seafood (34.3), gastrointestinal endoscopy (2.894), and showering outside the home (0.388). PCP, showering and endoscopy remained significant in a Cox proportional hazards model. There was no association between M. avium colonization of home water and risk of MAC. In patients with CD4<25, median OD antibody levels to lipoarabinomannin at baseline were 0.054 among patients who did not develop MAC and 0.021 among patients who did develop MAC (P=0.077).
CONCLUSIONS: MAC infection results from diverse and likely undetectable environmental and nosocomial exposures. Mycobacterial infection before HIV infection may confer protection against disseminated MAC in advanced AIDS.

Copyright 2002 The British Infection Society.
PMID 12099743  J Infect. 2002 Apr;44(3):166-70. doi: 10.1053/jinf.2001・・・
著者: Josephine M Bryant, Dorothy M Grogono, Daniela Rodriguez-Rincon, Isobel Everall, Karen P Brown, Pablo Moreno, Deepshikha Verma, Emily Hill, Judith Drijkoningen, Peter Gilligan, Charles R Esther, Peadar G Noone, Olivia Giddings, Scott C Bell, Rachel Thomson, Claire E Wainwright, Chris Coulter, Sushil Pandey, Michelle E Wood, Rebecca E Stockwell, Kay A Ramsay, Laura J Sherrard, Timothy J Kidd, Nassib Jabbour, Graham R Johnson, Luke D Knibbs, Lidia Morawska, Peter D Sly, Andrew Jones, Diana Bilton, Ian Laurenson, Michael Ruddy, Stephen Bourke, Ian Cjw Bowler, Stephen J Chapman, Andrew Clayton, Mairi Cullen, Thomas Daniels, Owen Dempsey, Miles Denton, Maya Desai, Richard J Drew, Frank Edenborough, Jason Evans, Jonathan Folb, Helen Humphrey, Barbara Isalska, Søren Jensen-Fangel, Bodil Jönsson, Andrew M Jones, Terese L Katzenstein, Troels Lillebaek, Gordon MacGregor, Sarah Mayell, Michael Millar, Deborah Modha, Edward F Nash, Christopher O'Brien, Deirdre O'Brien, Chandra Ohri, Caroline S Pao, Daniel Peckham, Felicity Perrin, Audrey Perry, Tania Pressler, Laura Prtak, Tavs Qvist, Ali Robb, Helen Rodgers, Kirsten Schaffer, Nadia Shafi, Jakko van Ingen, Martin Walshaw, Danie Watson, Noreen West, Joanna Whitehouse, Charles S Haworth, Simon R Harris, Diane Ordway, Julian Parkhill, R Andres Floto
雑誌名: Science. 2016 Nov 11;354(6313):751-757. doi: 10.1126/science.aaf8156.
Abstract/Text Lung infections with Mycobacterium abscessus, a species of multidrug-resistant nontuberculous mycobacteria, are emerging as an important global threat to individuals with cystic fibrosis (CF), in whom M. abscessus accelerates inflammatory lung damage, leading to increased morbidity and mortality. Previously, M. abscessus was thought to be independently acquired by susceptible individuals from the environment. However, using whole-genome analysis of a global collection of clinical isolates, we show that the majority of M. abscessus infections are acquired through transmission, potentially via fomites and aerosols, of recently emerged dominant circulating clones that have spread globally. We demonstrate that these clones are associated with worse clinical outcomes, show increased virulence in cell-based and mouse infection models, and thus represent an urgent international infection challenge.

Copyright © 2016, American Association for the Advancement of Science.
PMID 27846606  Science. 2016 Nov 11;354(6313):751-757. doi: 10.1126/sc・・・
著者: Leah M Feazel, Laura K Baumgartner, Kristen L Peterson, Daniel N Frank, J Kirk Harris, Norman R Pace
雑誌名: Proc Natl Acad Sci U S A. 2009 Sep 22;106(38):16393-9. doi: 10.1073/pnas.0908446106. Epub 2009 Sep 14.
Abstract/Text The environments we humans encounter daily are sources of exposure to diverse microbial communities, some of potential concern to human health. In this study, we used culture-independent technology to investigate the microbial composition of biofilms inside showerheads as ecological assemblages in the human indoor environment. Showers are an important interface for human interaction with microbes through inhalation of aerosols, and showerhead waters have been implicated in disease. Although opportunistic pathogens commonly are cultured from shower facilities, there is little knowledge of either their prevalence or the nature of other microorganisms that may be delivered during shower usage. To determine the composition of showerhead biofilms and waters, we analyzed rRNA gene sequences from 45 showerhead sites around the United States. We find that variable and complex, but specific, microbial assemblages occur inside showerheads. Particularly striking was the finding that sequences representative of non-tuberculous mycobacteria (NTM) and other opportunistic human pathogens are enriched to high levels in many showerhead biofilms, >100-fold above background water contents. We conclude that showerheads may present a significant potential exposure to aerosolized microbes, including documented opportunistic pathogens. The health risk associated with showerhead microbiota needs investigation in persons with compromised immune or pulmonary systems.

PMID 19805310  Proc Natl Acad Sci U S A. 2009 Sep 22;106(38):16393-9. ・・・
著者: Joseph O Falkinham
雑誌名: Emerg Infect Dis. 2011 Mar;17(3):419-24. doi: 10.3201/eid1703.101510.
Abstract/Text To determine whether plumbing could be a source of nontuberculous mycobacteria (NTM) infection, during 2007-2009 I isolated NTM from samples from household water systems of NTM patients. Samples from 22/37 (59%) households and 109/394 (28%) total samples yielded NTM. Seventeen (46%) of the 37 households yielded ≥1 Mycobacterium spp. isolate of the same species as that found in the patient; in 7 of those households, the patient isolate and 1 plumbing isolate exhibited the same repetitive sequence-based PCR DNA fingerprint. Households with water heater temperatures ≤125 degrees C (≤50 degrees C) were significantly more likely to harbor NTM compared with households with hot water temperatures ≥130 degrees F (≥55 degrees C) (p = 0.0107). Although households with water from public or private water systems serving multiple households were more likely to have NTM (19/27, 70%) compared with households with a well providing water to only 1 household (5/12, 42%), that difference was not significant (p = 0.1532).

PMID 21392432  Emerg Infect Dis. 2011 Mar;17(3):419-24. doi: 10.3201/e・・・
著者: Yukiko Nishiuchi, Aki Tamura, Seigo Kitada, Takahiro Taguri, Sohkichi Matsumoto, Yoshitaka Tateishi, Mamiko Yoshimura, Yuriko Ozeki, Narumi Matsumura, Hisashi Ogura, Ryoji Maekura
雑誌名: Jpn J Infect Dis. 2009 May;62(3):182-6.
Abstract/Text Medical treatment of pulmonary Mycobacterium avium complex (MAC) disease does not always provide curative effects and is frequently hampered by recurrence. This suggests the presence of a reservoir for MAC in the environment surrounding patients. We previously reported the recovery of MAC isolates from the residential bathrooms of outpatients. In the present study, to ascertain the colonizing sites and the possibility of an MAC reservoir in the bathrooms of patients, we tested the recovery and the genetic diversity of MAC isolates from 6 sites of specimens, including 2 additional sampling sites, inside the showerhead and the bathtub inlet, in the residential bathrooms of patients with pulmonary MAC disease. MAC isolates were recovered from 15 out of the 29 bathrooms (52%), including specimens from 14 bathtub inlets and 3 showerheads. Nearly half of these bathrooms (7/15) contained MAC strains that were identical or similar to their respective clinical isolates Additionally, in 5 out of 15 bathrooms, polyclonal colonization was revealed by pulsed-field gel electrophoresis. The results imply that colonization of MAC organisms in the bathrooms of MAC patients occurs predominantly in the bathtub inlets, and there is thus a risk of infection and/or reinfection for patients via use of the bathtub and other sites in the bathroom.

PMID 19468176  Jpn J Infect Dis. 2009 May;62(3):182-6.
著者: Yukiko Nishiuchi, Ryoji Maekura, Seigo Kitada, Aki Tamaru, Takahiro Taguri, Yukimi Kira, Toru Hiraga, Atsushi Hirotani, Kenji Yoshimura, Mari Miki, Masami Ito
雑誌名: Clin Infect Dis. 2007 Aug 1;45(3):347-51. doi: 10.1086/519383. Epub 2007 Jun 15.
Abstract/Text The distribution of Mycobacterium avium-intracellulare complex (MAC) in residences was examined. MAC was only recovered from bathrooms but not from other sites of residences. The appearance ratio in the bathrooms of patients with pulmonary MAC was significantly higher than that in healthy volunteers' bathrooms (P=.01). For 2 patients, the genotypes of environmental isolates were identical to their respective clinical isolates.

PMID 17599313  Clin Infect Dis. 2007 Aug 1;45(3):347-51. doi: 10.1086/・・・
著者: K Fujita, Y Ito, T Hirai, K Maekawa, S Imai, S Tatsumi, A Niimi, Y Iinuma, S Ichiyama, M Mishima
雑誌名: Clin Microbiol Infect. 2013 Jun;19(6):537-41. doi: 10.1111/j.1469-0691.2012.03929.x. Epub 2012 Jun 19.
Abstract/Text Mycobacterium avium-intracellulare complex (MAC) strains were recovered from 48.9% of residential soil samples (agricultural farms (n = 7), residential yards (n = 79), and planting pots (n = 49)) of 100 pulmonary MAC patients and 35 non-infected control patients. The frequency of MAC recovery did not differ among soil types or among patients regardless of the presence of pulmonary MAC disease, infecting MAC species or period of soil exposure. Variable numbers of tandem repeats (VNTR) analysis for MAC clinical and soil isolates revealed 78 different patterns in 47 M. avium clinical isolates and 41 soil isolates, and 53 different patterns in 18 M. intracellulare clinical isolates and 37 soil isolates. Six clinical and corresponding soil isolate pairs with an identical VNTR genotype were from case patients with high soil exposure (≥2 h per week, 37.5% (6/16) with high exposure compared with 0.0% (0/19) with low or no exposure, p <0.01), suggesting that residential soils are a likely source of pulmonary MAC infection.

© 2012 The Authors. Clinical Microbiology and Infection © 2012 European Society of Clinical Microbiology and Infectious Diseases.
PMID 22712883  Clin Microbiol Infect. 2013 Jun;19(6):537-41. doi: 10.1・・・
著者: Won-Jung Koh, Jun Haeng Lee, Yong Soo Kwon, Kyung Soo Lee, Gee Young Suh, Man Pyo Chung, Hojoong Kim, O Jung Kwon
雑誌名: Chest. 2007 Jun;131(6):1825-30. doi: 10.1378/chest.06-2280. Epub 2007 Mar 30.
Abstract/Text BACKGROUND: Knowledge of the relationship between respiratory disorders and gastroesophageal reflux disease (GERD) is increasing. However, the association between GERD and pulmonary disease caused by nontuberculous mycobacteria (NTM) has not been studied in detail. We investigated the prevalence of GERD in patients with the nodular bronchiectatic form of NTM lung disease.
METHODS: Fifty-eight patients with the nodular bronchiectatic form of NTM lung disease underwent ambulatory 24-h esophageal pH monitoring. Of the 58 patients, 27 patients were identified as having Mycobacterium avium complex infection (15 with Mycobacterium intracellulare and 12 with M avium), and 31 patients had Mycobacterium abscessus pulmonary infection.
RESULTS: The prevalence of GERD in patients with the nodular bronchiectatic form of NTM lung disease was 26% (15 of 58 patients). Only 27% (4 of 15 patients) had typical GERD symptoms. No statistically significant differences were found between patients with GERD and those without GERD with regard to age, sex, body mass index, or pulmonary function test results. However, patients with GERD were more likely to have a sputum smear that was positive for acid-fast bacilli (12 of 15 patients, 80%), compared with patients without GERD (19 of 43 patients, 44%) [p = 0.033]. In addition, bronchiectasis and bronchiolitis were observed in more lobes in patients with GERD than in patients without GERD (p = 0.008 and p = 0.005, respectively).
CONCLUSIONS: Patients with the nodular bronchiectatic form of NTM lung disease have a high prevalence of increased esophageal acid exposure, usually without typical GERD symptoms.

PMID 17400680  Chest. 2007 Jun;131(6):1825-30. doi: 10.1378/chest.06-2・・・
著者: Benjamin C Y Wong, Yoshikazu Kinoshita
雑誌名: Clin Gastroenterol Hepatol. 2006 Apr;4(4):398-407. doi: 10.1016/j.cgh.2005.10.011.
Abstract/Text BACKGROUND & AIMS: The epidemiology of gastroesophageal reflux disease (GERD) has been a subject of much interest in recent years. This review ascertains the prevalence of GERD in eastern and southeastern Asia, and reports on complications and risk factors.
METHODS: This qualitative systematic review of the epidemiology of GERD in eastern and southeastern Asia identified studies in adults reported in English in the Medline database (searched through April 2005), relevant reviews, and our own bibliographic databases.
RESULTS: Thirteen studies were included. The reported population prevalence of GERD in eastern Asia ranged from 2.5% to 6.7% for at least weekly symptoms of heartburn and/or acid regurgitation and may be increasing. No reliable data are available on the prevalence of esophagitis in the general population. In case studies, the prevalence of reflux esophagitis ranged from 3.4% to 16.3%. Well-established risk factors for GERD in Asian populations included hiatus hernia and obesity. Age and male sex also may be risk factors. Chest pain is the predominant extraesophageal manifestation of GERD in China, whereas in Japan, a link with asthma has been implicated in patients with severe esophagitis.
CONCLUSIONS: There is a paucity of studies reporting the prevalence of GERD in eastern and southeastern Asia. These results highlight the need for further epidemiologic studies using representative study populations and a standardized methodology. Recognition and awareness of GERD need to increase concomitantly to ensure appropriate diagnosis and treatment of the disease.

PMID 16616342  Clin Gastroenterol Hepatol. 2006 Apr;4(4):398-407. doi:・・・
著者: Tomasz Jagielski, Alina Minias, Jakko van Ingen, Nalin Rastogi, Anna Brzostek, Anna Żaczek, Jarosław Dziadek
雑誌名: Clin Microbiol Rev. 2016 Apr;29(2):239-90. doi: 10.1128/CMR.00055-15.
Abstract/Text Molecular typing has revolutionized epidemiological studies of infectious diseases, including those of a mycobacterial etiology. With the advent of fingerprinting techniques, many traditional concepts regarding transmission, infectivity, or pathogenicity of mycobacterial bacilli have been revisited, and their conventional interpretations have been challenged. Since the mid-1990s, when the first typing methods were introduced, a plethora of other modalities have been proposed. So-called molecular epidemiology has become an essential subdiscipline of modern mycobacteriology. It serves as a resource for understanding the key issues in the epidemiology of tuberculosis and other mycobacterial diseases. Among these issues are disclosing sources of infection, quantifying recent transmission, identifying transmission links, discerning reinfection from relapse, tracking the geographic distribution and clonal expansion of specific strains, and exploring the genetic mechanisms underlying specific phenotypic traits, including virulence, organ tropism, transmissibility, or drug resistance. Since genotyping continues to unravel the biology of mycobacteria, it offers enormous promise in the fight against and prevention of the diseases caused by these pathogens. In this review, molecular typing methods for Mycobacterium tuberculosis and nontuberculous mycobacteria elaborated over the last 2 decades are summarized. The relevance of these methods to the epidemiological investigation, diagnosis, evolution, and control of mycobacterial diseases is discussed.

Copyright © 2016, American Society for Microbiology. All Rights Reserved.
PMID 26912567  Clin Microbiol Rev. 2016 Apr;29(2):239-90. doi: 10.1128・・・
著者: J M Rocco, V R Irani
雑誌名: Int J Tuberc Lung Dis. 2011 Apr;15(4):447-52. doi: 10.5588/ijtld.09.0695.
Abstract/Text Pathogenesis by mycobacteria requires the exploitation of host-cell signaling pathways to enhance intracellular survival and persistence of the pathogen. Among patients with end-stage acquired immune-deficiency syndrome, disseminated infection with Mycobacterium avium, a member of the M. avium complex (MAC), is the most common bacterial infection. The virulence and intrinsic multidrug resistance of this pathogen has been attributed in part to its unique cell wall, which is a complex array of hydrocarbon chains containing the arabinogalactan-peptidoglycan mycolic acid core found in all mycobacteria, surrounded by a second electron-dense layer made up, in part, of serovar-specific glycopeptidolipids (GPLs) found only in MAC. Via cell-surface receptors, M. avium, an intra-macrophage (mφ) pathogen, can modulate various host signaling pathways such as the mitogen-activated protein kinase and nuclear factor κB pathways. The modulation of specific mφ signaling cascades can result in the regulation of pro- and anti-inflammatory cytokine production, and the process of phagolysosome fusion. The outcome of this M. avium-host mφ interaction could result in host disease or death of the invading pathogen. This review will focus on the immunomodulation aspects of M. avium pathogenesis as well as the role of GPLs as virulence factors.

PMID 21396201  Int J Tuberc Lung Dis. 2011 Apr;15(4):447-52. doi: 10.5・・・
著者: Lindsay Sweet, Jeffrey S Schorey
雑誌名: J Leukoc Biol. 2006 Aug;80(2):415-23. doi: 10.1189/jlb.1205702. Epub 2006 Jun 7.
Abstract/Text The Toll-like receptors (TLRs) are key components in the immune response against numerous pathogens. Previous studies have indicated that TLR2 plays an essential role in promoting immune responses against mycobacterial infections. Prior work has also shown that mice deficient in TLR2 are more susceptible to infection by Mycobacterium tuberculosis, Mycobacterium bovis bacillus Calmette-Guerin, and Mycobacterium avium. Therefore, it is important to define the molecules expressed by pathogenic mycobacteria, which bind the various TLRs. Although a number of TLR agonists have been characterized for M. tuberculosis, no specific TLR ligand has been identified in M. avium. We have found that glycopeptidolipids (GPLs), which are highly expressed surface molecules on M. avium, can stimulate the nuclear factor-kappaB pathway as well as mitogen-activated protein kinase p38 and Jun N-terminal kinase activation and production of proinflammatory cytokines when added to murine bone marrow-derived macrophages. This stimulation was dependent on TLR2 and myeloid differentiation primary-response protein 88 (MyD88) but not TLR4. M. avium express apolar and serovar-specific (ss)GPLs, and it is the expression of the latter that determines the serotype of a particular M. avium strain. It is interesting that the ssGPLs activated macrophages in a TLR2- and MyD88-dependent manner, and no macrophage activation was observed when using apolar GPLs. ssGPLs also differed in their ability to activate macrophages with Serovars 1 and 2 stimulating inhibitor of kappaB p38 and phosphorylation and tumor necrosis factor alpha (TNF-alpha) secretion, while Serovar 4 failed to stimulate p38 activation and TNF-alpha production. Our studies indicate that ssGPLs can function as TLR2 agonists and promote macrophage activation in a MyD88-dependent pathway.

PMID 16760377  J Leukoc Biol. 2006 Aug;80(2):415-23. doi: 10.1189/jlb.・・・
著者: T Kikuchi, A Watanabe, K Gomi, T Sakakibara, K Nishimori, H Daito, S Fujimura, R Tazawa, A Inoue, M Ebina, Y Tokue, M Kaku, T Nukiwa
雑誌名: Thorax. 2009 Oct;64(10):901-7. doi: 10.1136/thx.2009.114603. Epub 2009 Jun 23.
Abstract/Text BACKGROUND: Non-tuberculous mycobacterial lung disease, most commonly caused by Mycobacterium avium infection, tends to show variable disease progression, and significant disease predictors have not been adequately established.
METHODS: Variable numbers of tandem repeats (VNTR) were evaluated in 16 mycobacterial interspersed repetitive unit (MIRU) loci from M avium isolates cultured from respiratory specimens obtained from 2005 to 2007. Specifically, the association between VNTR profiles and disease progression was assessed.
RESULTS: Among the 37 subjects who provided positive respiratory cultures for M avium during the 2005-6 period, 15 subjects were treated within 10 months following a microbiological diagnosis of progressive M avium lung disease. Nine subjects underwent long-term follow-up (>24 months) without treatment for stable M avium lung disease. Based on a neighbour-joining cluster analysis used to classify M avium-positive subjects according to the VNTR profile, subjects with progressive versus stable lung disease were found to be grouped together in distinct clusters. Further analysis using logistic regression modelling showed that disease progression was significantly associated with the genetic distance of the M avium isolate from an appropriately selected reference (age-adjusted odds ratio 1.95; 95% confidence interval 1.16 to 3.30; p = 0.01 for the most significant model). A best-fit model could be used to predict the progression of M avium lung disease when subjects from the 2005-6 period were combined with those from 2007 (p = 0.003).
CONCLUSION: Progressive lung disease due to M avium infection is associated with specific VNTR genotypes of M avium.

PMID 19553234  Thorax. 2009 Oct;64(10):901-7. doi: 10.1136/thx.2009.11・・・
著者: S-Y Kim, S-T Lee, B-H Jeong, K Jeon, J-W Kim, S J Shin, W-J Koh
雑誌名: Int J Tuberc Lung Dis. 2012 Oct;16(10):1393-9. doi: 10.5588/ijtld.12.0147.
Abstract/Text SETTING: A recent study in Japan found that mycobacterial genotyping was associated with disease progression and susceptibility to certain drugs in Mycobacterium avium lung disease. However, it is not known whether this association is true in other populations.
OBJECTIVE: To investigate the association between mycobacterial genotype, clinical characteristics and the progression of M. avium lung disease in Korean patients.
DESIGN: A total of 102 M. avium clinical isolates were genotyped using M. avium tandem repeats-variable number of tandem repeats (MATR-VNTR).
RESULTS: MATR-VNTR typing demonstrated a high discriminatory power and genetic diversity for molecular epidemiological studies of M. avium. In the phylogenetic tree, the M. avium clinical isolates were divided into three major clusters: A, B and C. Cluster A was observed most frequently (64/102, 63%), whereas cluster C was found in a minor proportion of the isolates (8/102, 8%). However, there was no association between the clinical characteristics, disease progression and drug susceptibility and the phylogenetic tree based on VNTR genotyping.
CONCLUSIONS: MATR-VNTR genotyping may be useful for epidemiological studies of M. avium lung disease; however, no association was found between the specific VNTR genotypes of M. avium and the clinical characteristics of Korean patients.

PMID 23107637  Int J Tuberc Lung Dis. 2012 Oct;16(10):1393-9. doi: 10.・・・
著者: Won-Jung Koh, Byeong-Ho Jeong, Kyeongman Jeon, Nam Yong Lee, Kyung Soo Lee, Sook Young Woo, Sung Jae Shin, O Jung Kwon
雑誌名: Chest. 2012 Dec;142(6):1482-8. doi: 10.1378/chest.12-0494.
Abstract/Text BACKGROUND: Mycobacterium avium and Mycobacterium intracellulare are grouped together as the M avium complex; however, little is known about the clinical impact of this species differentiation. This study compared the clinical features and prognoses of patients with M avium and M intracellulare lung disease.
METHODS: From 2000 to 2009, 590 patients were given a new diagnosis of M avium complex lung disease; 323 (55%) had M avium lung disease, and 267 (45%) had M intracellulare lung disease.
RESULTS: Compared with the patients with M avium lung disease, the patients with M intracellulare lung disease were more likely to have the following characteristics: older age (64 vs 59 years, P = .002), a lower BMI (19.5 kg/m² vs 20.6 kg/m², P < .001), respiratory symptoms such as cough (84% vs 74%, P = .005), a history of previous treatment for TB (51% vs 31%, P < .001), the fibrocavitary form of the disease (26% vs 13%, P < .001), smear-positive sputum (56% vs 38%, P < .001), antibiotic therapy during the 24 months of follow-up (58% vs 42%, P < .001), and an unfavorable microbiologic response after combination antibiotic treatment (56% vs 74%, P = .001).
CONCLUSIONS: Patients with M intracellulare lung disease exhibited a more severe presentation and had a worse prognosis than patients with M avium lung disease in terms of disease progression and treatment response. Therefore, species differentiation between M avium and M intracellulare may have prognostic and therapeutic implications.

PMID 22628488  Chest. 2012 Dec;142(6):1482-8. doi: 10.1378/chest.12-04・・・
著者: P Maureen Cassidy, Katrina Hedberg, Ashlen Saulson, Erin McNelly, Kevin L Winthrop
雑誌名: Clin Infect Dis. 2009 Dec 15;49(12):e124-9. doi: 10.1086/648443.
Abstract/Text BACKGROUND: Nontuberculous mycobacteria (NTM) are important human pathogens, yet little is known about disease prevalence in the United States. Reports suggest prevalence has increased, particularly in women, but population-based data to substantiate this are lacking. We sought to estimate NTM disease prevalence in Oregon, and describe disease by site, species, and patient demographic characteristics.
METHODS: We contacted laboratories that performed mycobacterial cultures on Oregon residents in 2005-2006. For each isolate, we obtained source, collection date, species, and patient demographics. We used the microbiologic component of the American Thoracic Society/Infectious Diseases Society of America's pulmonary NTM disease criteria to define cases of pulmonary NTM, and patients with isolates from a normally sterile site were classified as having extrapulmonary disease.
RESULTS: We identified 933 patients with > or =1 NTM isolate. Of these, 527 (56%) met the case definition (annualized prevalence, 7.2 cases per 100,000 persons). Pulmonary cases predominated (5.6 cases per 100,000 persons), followed by skin/soft-tissue cases (0.9 cases per 100,000 persons). Mycobacterium avium complex was the most common species identified in pulmonary cases (4.7 cases per 100,000 persons). Pulmonary disease prevalence was significantly higher in women (6.4 cases per 100,000 persons) than men (4.7 cases per 100,000 persons) and was highest in persons aged >50 years (15.5 cases per 100,000 persons).
CONCLUSIONS: NTM are frequently isolated from Oregon residents; more than one-half of all isolates likely represent true disease. Pulmonary NTM is most common among elderly women, and M. avium causes most disease. Future efforts to monitor disease trends should be undertaken, and efforts made to validate the use of the ATS/IDSA microbiologic criteria alone to predict pulmonary NTM disease.

PMID 19911942  Clin Infect Dis. 2009 Dec 15;49(12):e124-9. doi: 10.108・・・
著者: Kevin L Winthrop, Erin McNelley, Brian Kendall, Allison Marshall-Olson, Christy Morris, Maureen Cassidy, Ashlen Saulson, Katrina Hedberg
雑誌名: Am J Respir Crit Care Med. 2010 Oct 1;182(7):977-82. doi: 10.1164/rccm.201003-0503OC. Epub 2010 May 27.
Abstract/Text RATIONALE: Respiratory specimens with nontuberculous mycobacteria (NTM) are increasingly common; however, pulmonary disease prevalence is unknown.
OBJECTIVES: To determine the disease prevalence, clinical features, and risk factors for NTM disease, and to examine the predictive value of the microbiologic criteria of the American Thoracic Society (ATS)/Infectious Diseases Society of America (IDSA) pulmonary NTM case definition for true NTM disease.
METHODS: We identified all Oregon residents during 2005-2006 with at least one respiratory mycobacterial isolate. From a population-based subset of these patients, we collected clinical and radiologic information and used the ATS/IDSA pulmonary NTM disease criteria to define disease.
MEASUREMENTS AND MAIN RESULTS: In the 2-year time period, 807 Oregonians had one or more respiratory NTM isolates. Four hundred and seven (50%) resided within the Portland metropolitan region, among which 283 (70%) had evaluable clinical records. For those with records, 134 (47%) met ATS/IDSA pulmonary NTM disease criteria for a minimum overall 2-year period prevalence of 8.6/100,000 persons, and 20.4/100,000 in those at least 50 years of age within the Portland region. Case subjects were 66 years of age (median; range, 12-92 yr), frequently female (59%), and most with disease caused by Mycobacterium avium complex (88%). Cavitation (24.5%), bronchiectasis (16%), chronic obstructive pulmonary disease (28%), and immunosuppressive therapy (25.5%) were common. Eighty-six percent of patients meeting the ATS/IDSA microbiologic criteria for disease also met the full ATS/IDSA disease criteria.
CONCLUSIONS: Respiratory NTM isolates frequently represent disease. Pulmonary NTM disease is not uncommon, particularly among elderly females. The ATS/IDSA microbiologic criteria are highly predictive of disease and could be useful for laboratory-based NTM disease surveillance.

PMID 20508209  Am J Respir Crit Care Med. 2010 Oct 1;182(7):977-82. do・・・
著者: Ho Namkoong, Atsuyuki Kurashima, Kozo Morimoto, Yoshihiko Hoshino, Naoki Hasegawa, Manabu Ato, Satoshi Mitarai
雑誌名: Emerg Infect Dis. 2016 Jun;22(6):1116-7. doi: 10.3201/eid2206.151086.
Abstract/Text
PMID 27191735  Emerg Infect Dis. 2016 Jun;22(6):1116-7. doi: 10.3201/e・・・
著者: D Rebecca Prevots, Theodore K Marras
雑誌名: Clin Chest Med. 2015 Mar;36(1):13-34. doi: 10.1016/j.ccm.2014.10.002. Epub 2014 Nov 6.
Abstract/Text Population-based data have documented a worldwide increase in the prevalence of human nontuberculous mycobacterial (NTM) infections since 2000. Mycobacterium avium complex is predominant in North America and East Asia, whereas in regions within Europe, M kansasii, M xenopi, and M malmoense are more common. Host factors important to the current epidemiology of NTM pulmonary disease include thoracic skeletal abnormalities, rheumatoid arthritis, and use of immunomodulatory drugs. Clustering of disease within families suggests a heritable genetic predisposition to disease susceptibility. Warm, humid environments with high atmospheric vapor pressure contribute to population risk.

Published by Elsevier Inc.
PMID 25676516  Clin Chest Med. 2015 Mar;36(1):13-34. doi: 10.1016/j.cc・・・
著者: Kozo Morimoto, Naoki Hasegawa, Kiyohiko Izumi, Ho Namkoong, Kazuhiro Uchimura, Takashi Yoshiyama, Yoshihiko Hoshino, Atsuyuki Kurashima, Jun Sokunaga, Shunsuke Shibuya, Masahiro Shimojima, Manabu Ato, Satoshi Mitarai
雑誌名: Ann Am Thorac Soc. 2016 Oct 27;. doi: 10.1513/AnnalsATS.201607-573OC. Epub 2016 Oct 27.
Abstract/Text RATIONALE: Since 2010, studies that utilize mycobacterial examination results have been widely used to survey nontuberculous mycobacterial (NTM) lung disease.
OBJECTIVES: Our study aims to reveal the clinical and epidemiological status of NTM lung disease in Japan.
METHODS: All data on the isolation and identification of mycobacteria in 2012 and 2013 were obtained from three dominant commercial laboratories in Japan. Pulmonary disease were defined based on the bacteriological diagnostic criteria issued by the American Thoracic Society and the Infectious Diseases Society of America (ATS/IDSA). The coverage population was estimated using the ratio between national tuberculosis registration data and laboratory results for each of the eight regions.
MEASUREMENTS AND MAIN RESULTS: A total of 113,313 mycobacterial specimens from 4,710 institutes were collected, of which specimens from 26,059 patients tested positive for NTM cultures at least once. Among these positive patients, 7,167 (27.5%) satisfied the ATS/IDSA criteria for NTM lung disease, resulting in a 2-year prevalence rate of 24.0 per 100,000. Mycobacterium avium complex (MAC) was the most commonly isolated species (93.3%), and 29.0% of the patients in which MAC was isolated satisfied the criteria for NTM lung disease. Individuals older than 70 years of age accounted for the majority of cases, and 65.5% of cases involved females. After MAC, M. kansasii and M. abscessus exhibited the highest (43.6%) and second-highest (37.1%) incidences per isolation, respectively. The prevalence of M. kansasii was highest in the Kinki region (p < 0.05), and M. abscessus had the greatest prevalence in the Kyushu-Okinawa region (p < 0.005). The proportion of M. intracellulare in MAC cases was higher in the southwestern part of Japan than in other regions. The period prevalence was highest in the southwestern part of Japan, and the standardized prevalence ratio was highest in central regions. Evaluations of clarithromycin susceptibility revealed a clear binomial distribution.
CONCLUSIONS: This investigation is the first laboratory-based study that assessed a large number of mycobacterial cases in Japan. Although the calculated prevalence might be underestimated, the approach used here could be a useful and relatively timely method for monitoring relative epidemiological data for NTM lung disease.

PMID 27788025  Ann Am Thorac Soc. 2016 Oct 27;. doi: 10.1513/AnnalsATS・・・
著者: Makoto Hayashi, Noboru Takayanagi, Tetsu Kanauchi, Yousuke Miyahara, Tsutomu Yanagisawa, Yutaka Sugita
雑誌名: Am J Respir Crit Care Med. 2012 Mar 1;185(5):575-83. doi: 10.1164/rccm.201107-1203OC. Epub 2011 Dec 28.
Abstract/Text RATIONALE: The prognostic factors of Mycobacterium avium complex lung disease (MAC-LD) are not clearly defined.
OBJECTIVES: To assess the prognostic factors of all-cause and MAC-specific mortality in patients with MAC-LD, especially in accordance with radiographic features, first-line treatment, and host predisposition.
METHODS: Medical records of 634 HIV-negative patients with MAC-LD treated at our institution in Saitama, Japan were retrospectively analyzed.
MEASUREMENTS AND MAIN RESULTS: Patients' mean age was 68.9 years, and median follow-up period was 4.7 years. Radiographic features included nodular/bronchiectatic (NB) disease: 482 patients (76.0%); fibrocavitary (FC) disease: 105 patients (16.6%); FC+NB disease: 30 patients (4.7%); and other types: 17 patients (3.0%). First-line treatments were observation or one drug: 479 patients (75.6%); 2 to 5 drugs: 131 patients (20.7%); and unknown: 24 patients (3.8%). A multivariate Cox proportional hazard model showed male sex, older age, presence of systemic and/or respiratory comorbidity, non-NB radiographic features, body mass index (BMI) less than 18.5 kg/m(2), anemia, hypoalbuminemia, and erythrocyte sedimentation rate greater than or equal to 50 mm/h to be negative prognostic factors for all-cause mortality, and FC or FC+NB radiographic features, BMI less than 18.5 kg/m(2), anemia, and C-reactive protein greater than or equal to 1.0 mg/dl to be negative prognostic factors for MAC-specific mortality.
CONCLUSIONS: The first-line treatment regimen was not associated with all-cause mortality. FC or FC+NB disease, BMI less than 18.5 kg/m(2), and anemia were negative prognostic factors for both all-cause and MAC-specific mortality.

PMID 22199005  Am J Respir Crit Care Med. 2012 Mar 1;185(5):575-83. do・・・
著者: Kozo Morimoto, Kazuro Iwai, Kazuhiro Uchimura, Masao Okumura, Takashi Yoshiyama, Kozo Yoshimori, Hideo Ogata, Atsuyuki Kurashima, Akihiko Gemma, Shoji Kudoh
雑誌名: Ann Am Thorac Soc. 2014 Jan;11(1):1-8. doi: 10.1513/AnnalsATS.201303-067OC.
Abstract/Text RATIONALE: Pulmonary disease caused by nontuberculous mycobacteria is generally reported to have a good prognosis. However, the actual mortality rate over time has not been reported in a large-scale survey.
OBJECTIVES: To determine the annual trend in mortality from nontuberculous mycobacteriosis, based on nearly four decades of patient data, and to estimate the prevalence of these cases in 2005.
METHODS: The annual mortality rate and regional distribution of nontuberculous mycobacteriosis-related deaths in Japan were obtained from Vital Statistics of Japan, which is published annually. The crude and age-adjusted mortality rates and associated regional differences were calculated from the Japanese census data. A 5-year follow-up study including 309 patients with pulmonary nontuberculous mycobacteriosis who visited and registered at our institute from 2004 to 2006 was conducted to determine the 5-year prognosis and the annual mortality rate.
MEASUREMENTS AND MAIN RESULTS: The crude mortality rates for both sexes have increased since 1970, and the mortality rate from pulmonary disease was greater in women after 2005. The age-adjusted rates of disease also showed a gradual increase until 2010 in women. Geographically, higher standardized mortality ratios were observed in middle and western Japan, particularly in the southern coastal regions along the Pacific Ocean. In a clinical follow-up study, the mortality rate was approximately 1-2% annually. The prevalence of pulmonary nontuberculous mycobacteriosis was estimated to be 6- to 10-fold higher than the annual incidence.
CONCLUSIONS: There was a constant and steady increase of nontuberculous mycobacteriosis-related mortality in Japan, and this mortality rate showed significant geographical variation. The prevalence of environmental mycobacterial disease in Japan is higher than reported in most other countries.

PMID 24102151  Ann Am Thorac Soc. 2014 Jan;11(1):1-8. doi: 10.1513/Ann・・・
著者: R E Chaisson, C A Benson, M P Dube, L B Heifets, J A Korvick, S Elkin, T Smith, J C Craft, F R Sattler
雑誌名: Ann Intern Med. 1994 Dec 15;121(12):905-11.
Abstract/Text OBJECTIVE: To determine the antimicrobial activity and tolerability of clarithromycin for treating bacteremic Mycobacterium avium complex disease in patients with the acquired immunodeficiency syndrome (AIDS).
DESIGN: A randomized, double-blind, dose-ranging study.
SETTING: Outpatient clinics.
PATIENTS: 154 patients with human immunodeficiency virus (HIV) infection and blood cultures positive for M. avium complex who had symptomatic disease.
INTERVENTIONS: Random assignment to clarithromycin at dosages of 500 mg, 1000 mg, or 2000 mg twice daily for 12 weeks.
MAIN OUTCOME MEASURE: Median number of colony-forming units of M. avium complex per milliliter of blood.
RESULTS: Clarithromycin decreased mycobacterial CFUs from 2.7 to 2.8 log 10/mL of blood at baseline to less than 0 log 10/mL during follow-up (P < 0.0001). After 2 weeks, patients receiving 500 mg twice daily were less likely to be culture negative than were patients receiving 1000 or 2000 mg twice daily (11% compared with 33% or 29%; P = 0.08). At 6 weeks, the median number of CFUs of M. avium complex/mL of blood was 0 or 1 for all three groups. Clarithromycin-resistant isolates of M. avium complex developed in 46% of patients at a median of 16 weeks. Median survival was longer in patients assigned to 500 mg twice daily (median, 249 days) than in patients assigned to 1000 mg or 2000 mg. Death in the first 12 weeks was lowest in the 500-mg group (P = 0.007).
CONCLUSIONS: Clarithromycin therapy acutely decreased M. avium complex bacteremia in patients with HIV infection by more than 99%. Clarithromycin, 500 mg twice daily, was well tolerated and associated with better survival. Emergence of clarithromycin-resistant organisms was an important problem.

PMID 7978715  Ann Intern Med. 1994 Dec 15;121(12):905-11.
著者: L Heifets, N Mor, J Vanderkolk
雑誌名: Antimicrob Agents Chemother. 1993 Nov;37(11):2364-70.
Abstract/Text Mycobacterium avium strains susceptible to clarithromycin and azithromycin contain mutants resistant to these macrolides with a frequency of 1.1 x 10(-10) to 1.2 x 10(-6). Cross-resistance between clarithromycin and azithromycin was demonstrated with mutants selected in the laboratory as well as with resistant strains isolated from patients. The susceptibility-resistance patterns of the macrolide-resistant strains with drugs other than macrolides were the same as those of the original susceptible strains. The emergence of clarithromycin resistance in patients was a result of multiplication of the preexisting resistant mutants that survived the elimination of bacteria during the initial period of treatment and was an exclusive cause of the relapse of bacteremia.

PMID 8031351  Antimicrob Agents Chemother. 1993 Nov;37(11):2364-70.
著者: R J Wallace, B A Brown, D E Griffith, W M Girard, D T Murphy, G O Onyi, V A Steingrube, G H Mazurek
雑誌名: Am J Respir Crit Care Med. 1994 May;149(5):1335-41. doi: 10.1164/ajrccm.149.5.8173775.
Abstract/Text Sputum conversion rates in Mycobacterium avium-intracellulare (MAI) complex lung disease have ranged from only 50 to 80% despite the use of three to five antituberculosis agents. We initiated a prospective, open, noncomparative trial of initial clarithromycin monotherapy at 500 mg twice a day for 4 months in HIV-negative patients with MAI lung disease. The primary study end point was microbiologic improvement. Of 30 patients enrolled, 20 completed therapy. This latter group was predominantly male (60%), smokers (70%), older than 45 yr of age (90%), infected with Mycobacterium intracellulare (70%) and with bilateral disease (85%). Of 19 patients with pretreatment minimum inhibitory concentrations (MIC) for clarithromycin < 16 micrograms/ml, 58% became sputum-negative, and 21% showed significant reductions in sputum positivity. Heavily positive sputum cultures (> 200 colonies) were reduced from 30 to 47 samples pretherapy (64%) to three of 54 (6%) post-therapy (p < 0.0001); 18 of 19 patients (95%) showed an improvement in sputum cultures, chest radiographs, or both. Only two patients (7%) discontinued the drug because of adverse events. Only three (16%) of 19 isolates developed clarithromycin resistance (MIC > 32 micrograms/ml). Clarithromycin-susceptible and -resistant MAI isolates from the same patient had identical DNA large-restriction fragment patterns. Clarithromycin is the first single agent to be shown efficacious in the treatment of MAI lung disease.

PMID 8173775  Am J Respir Crit Care Med. 1994 May;149(5):1335-41. doi・・・
著者: B Dautzenberg, D Piperno, P Diot, C Truffot-Pernot, J P Chauvin
雑誌名: Chest. 1995 Apr;107(4):1035-40.
Abstract/Text Mycobacterium avium complex infections, common in patients with AIDS as either pulmonary or disseminated disease, are infrequent in patients without AIDS. Participants were 45 HIV-negative patients with lung disease and positive sputum cultures for M avium; 10 had documented immunocompromise, and 24 had preexisting lung disease. Clarithromycin dosage was 500 to 2,000 mg daily (mean +/- SD = 1,633 +/- 432 mg). The drug was administered either alone (n = 14) or in combination with rifampin (n = 8), aminoglycoside (n = 1), quinolone (n = 10), clofazimine (n = 18), isoniazid (n = 5), ethambutol (n = 9), pyrazinamide (n = 1), or minocycline (n = 6). At 3 months, 36 patients among 39 bacteriologically assessed had negative sputum cultures, 3 had positive culture, 3 were dead, and 3 discontinued treatment. At the end of treatment, 32 patients remained negative, 7 were positive. The success rate was 15 of 22 (64%) in patients previously treated with antimycobacterial drugs for M avium disease and 17 of 23 (74%) in new patients. Adverse effects included mild hearing loss (n = 4), increase in liver enzyme levels (n = 5), and gastrointestinal pain (n = 10, two of whom had to stop treatment). Patients stopped treatment after 300 +/- 186 days due to side effects (3), death (4), or the patient's (5) or physician's decision (33). During the follow-up, one patient suffered a relapse with peripheral lymph nodes. A daily dose of 30 mg/kg of clarithromycin in the treatment of M avium infections appears to be effective and safe. Concomitant drug therapy should be assessed for its ability to prevent relapse.

PMID 7705112  Chest. 1995 Apr;107(4):1035-40.
著者: R J Wallace, B A Brown, D E Griffith, W M Girard, D T Murphy
雑誌名: Am J Respir Crit Care Med. 1996 Jun;153(6 Pt 1):1766-72. doi: 10.1164/ajrccm.153.6.8665032.
Abstract/Text Intermediate results of the first 50 patients treated with clarithromycin (CLARI) regimens for Mycobacterium avium-intracellulare (MAI) lung disease were evaluated. Patients were HIV negative, and pretreatment isolates were susceptible to CLARI. Patients received CLARI 500 mg twice daily, ethambutol, rifampin (RMP), or rifabutin (RBT) and initial streptomycin, and they were treated until culture-negative 1 yr. Eleven of 50 patients (22%) were dropped in the first 3 mo. Of the remaining 39 patients, 36 (92%) converted their sputa to negative, and 32 (82%) remain culture negative to date. This includes 11 of 16 (69%) with prior drug therapy and 21 of 23 (91%) with no prior therapy. One or more companion drugs were discontinued in 16 of 39 (41%) of patients because of adverse events. Isolates from six of 39 patients (15%) became CLARI-resistant. Of 23 patients who are alive and were culture-negative a mean of 12.0 mo while receiving therapy, all remain culture-negative without therapy a mean of 19.1 mo. Despite reduced CLARI serum levels in patients also receiving RMP, 10 of 13 patients (77%) receiving this regimen were successfully treated. Although not directly compared with previous regimens, the success of this regimen strongly suggests it is superior to previous non-CLARI-containing regimens.

PMID 8665032  Am J Respir Crit Care Med. 1996 Jun;153(6 Pt 1):1766-72・・・
著者: Naoki Hasegawa, Tomoyasu Nishimura, Sumire Ohtani, Kei Takeshita, Koichi Fukunaga, Sadatomo Tasaka, Tetsuya Urano, Koudou Ishii, Mamoru Miyairi, Akitoshi Ishizaka
雑誌名: Chest. 2009 Dec;136(6):1569-75. doi: 10.1378/chest.08-2567. Epub 2009 Jun 19.
Abstract/Text BACKGROUND: The objective of this study was to find an optimal initial combination chemotherapy that includes clarithromycin (CAM) for treatment-naive patients with Mycobacterium avium complex (MAC) pulmonary disease, as assessed by microbiological conversion using a Mycobacterium growth indicator tube (MGIT).
METHODS: Thirty-four patients with treatment-naive MAC pulmonary disease (determined using 1997 American Thoracic Society criteria) were evaluated retrospectively. They demonstrated a nodular and bronchiectatic pattern without cavity on high-resolution CT (HRCT) scans. The following three regimens were administered: regimen A (n = 9) consisted of CAM (400 mg/d), ethambutol (EB) [750 mg/d], and rifampicin (RFP) [450 mg/d]; regimen B (n = 12) consisted of CAM (800 mg/d), EB (750 mg/d), and RFP (450 mg/d); and regimen C (n = 13) consisted of CAM (800 mg/d), EB (1,000 mg/d), and RFP (600 mg/d) during the first 2 months followed by a reduction of the dosage of EB from 1,000 to 750 mg/d. Gender, age, BMI, and HRCT scan finding scores were not significantly different among the three groups. Chemotherapy was continued for 18 months. Sputum culture was periodically assessed by MGIT.
RESULTS: Culture conversion at 18 months in regimen A (55.6%), which included a daily dosage of 400 mg of CAM (9.5 mg/kg), was significantly inferior to that in regimen B (91.7%), which included daily 800 mg of CAM (17.6 mg/kg; p < 0.05), but regimen B and C (92.3%) showed no between-group difference after > 18 months of chemotherapy.
CONCLUSIONS: The higher dose of CAM allowed for better culture conversion. Daily combination chemotherapy that includes CAM (800 mg) seems appropriate as an initial treatment against treatment-naive patients with nodular and bronchiectatic MAC pulmonary disease.

PMID 19542259  Chest. 2009 Dec;136(6):1569-75. doi: 10.1378/chest.08-2・・・
著者: Yoshihiro Kobashi, Masaaki Abe, Keiji Mouri, Yasushi Obase, Naoyuki Miyashita, Mikio Oka
雑誌名: J Infect. 2010 Nov 19;. doi: 10.1016/j.jinf.2010.11.011. Epub 2010 Nov 19.
Abstract/Text BACKGROUND: This study compared the clinical usefulness of combination chemotherapy including various doses of clarithromycin (CAM) for pulmonary Mycobacterium avium complex (MAC) disease. METHODS: The subjects were divided into three groups receiving combination chemotherapy at various dose levels of CAM. The analysis of microbiological effects was based on the sputum conversion rate and sputum relapsing rate and that of clinical effects was performed by clinical symptoms and radiological findings for patients with pulmonary MAC disease. RESULTS: There were no significant differences among the three groups with regard to patient characteristics. The sputum conversion rate significantly increased with the dose of CAM (CAM 400mg: 43%, CAM 600mg: 69%, CAM 800mg: 88%). The sputum relapsing rate did not significantly differ among the three groups (CAM 400mg: 47%, CAM 600mg: 35%, CAM 800mg: 33%). Along with the sputum conversion rate, the rate of clinical improvement was significantly increased with the dose of CAM (CAM 400mg: 27%, CAM 600mg: 40%, CAM 800mg: 54%). Adverse reactions, such as gastrointestinal symptoms, were most frequently recognized in the group receiving CAM 800mg (38%) compared to those in the other two groups (CAM 400mg: 23% and CAM 600mg: 25%). CONCLUSIONS: Although both the sputum conversion rate and clinical improvement significantly increased with the dose of CAM, the rate of adverse reactions, such as gastrointestinal symptoms, also increased. It is important to continue close monitoring of patients with pulmonary MAC disease treated with a regimen that includes CAM 800mg.

Copyright © 2010. Published by Elsevier Ltd.
PMID 21094662  J Infect. 2010 Nov 19;. doi: 10.1016/j.jinf.2010.11.011・・・
著者: Seiichi Miwa, Masahiro Shirai, Mikio Toyoshima, Toshihiro Shirai, Kazumasa Yasuda, Koshi Yokomura, Takashi Yamada, Masafumi Masuda, Naoki Inui, Kingo Chida, Takafumi Suda, Hiroshi Hayakawa
雑誌名: Ann Am Thorac Soc. 2014 Jan;11(1):23-9. doi: 10.1513/AnnalsATS.201308-266OC.
Abstract/Text RATIONALE: Patients with Mycobacterium avium complex pulmonary disease are frequently administered a combination of clarithromycin, ethambutol, and rifampicin. However, rifampicin is known to reduce the serum levels of clarithromycin. It remains unclear whether a reduction in clarithromycin serum levels influences the clinical outcome of the Mycobacterium avium complex pulmonary disease treatment regimen.
OBJECTIVES: To compare a three-drug regimen (clarithromycin, ethambutol, and rifampicin) to a two-drug regimen (clarithromycin and ethambutol) for the treatment of Mycobacterium avium lung disease.
METHODS: In a preliminary open-label study, we randomly assigned newly diagnosed, but as-yet untreated, patients with disease caused by Mycobacterium avium complex without HIV infection to either the three-drug or the two-drug regimen for 12 months. The primary endpoint was the conversion of sputum cultures to negative after 12 months of treatment. Patient data were analyzed using the intention-to-treat method.
MEASUREMENTS AND MAIN RESULTS: Of 119 eligible patients, 59 were assigned to the three-drug regimen and 60 to the two-drug regimen. The rate of sputum culture conversion was 40.6% with the three-drug regimen and 55.0% with the two-drug regimen (difference, -14.4% [95% confidence interval, -32.1 to 3.4]). The incidence of adverse events leading to the discontinuation of treatment was 37.2 and 26.6% for the three-drug and the two-drug regimens, respectively.
CONCLUSIONS: This preliminary study suggests that treatment with clarithromycin and ethambutol is not inferior to treatment with clarithromycin, ethambutol, and rifampicin for Mycobacterium avium complex lung disease. Our findings justify a larger clinical trial to compare long-term clinical outcomes for the two treatment regimens. Clinical trial registered with http://www.umin.ac.jp/english/ (UMIN000002819).

PMID 24298907  Ann Am Thorac Soc. 2014 Jan;11(1):23-9. doi: 10.1513/An・・・
著者: David E Griffith, Barbara A Brown-Elliott, Brett Langsjoen, Yansheng Zhang, Xi Pan, William Girard, Kenwyn Nelson, James Caccitolo, Julio Alvarez, Sara Shepherd, Rebecca Wilson, Edward A Graviss, Richard J Wallace
雑誌名: Am J Respir Crit Care Med. 2006 Oct 15;174(8):928-34. doi: 10.1164/rccm.200603-450OC. Epub 2006 Jul 20.
Abstract/Text RATIONALE: The clinical features and outcome of macrolide-resistant Mycobacterium avium complex (MAC) lung disease are not known.
OBJECTIVES: Characterize patients, treatment, and isolates in macrolide-resistant MAC lung disease.
METHODS: Retrospective chart review, susceptibility testing, molecular fingerprinting, and DNA sequence analyses of resistant MAC isolates.
MEASUREMENTS AND MAIN RESULTS: We identified 51 patients over a 15-yr period with clarithromycin-resistant MAC (minimum inhibitory concentration (MIC)>or=32 microg/ml) lung disease at a single referral center. Twenty-four (47%) patients had nodular disease with bronchiectasis and 27 (53%) had upper lobe cavitary disease. Most patients (77%) had M. intracellulare. Sequencing of the 23S r-RNA gene showed 49 of 51 isolates (96%) with the expected mutation in adenine 2058 or 2059. Risk factors for resistance included macrolide monotherapy or combination with a quinolone only (39/51 or 76%). Macrolide resistance developed in 12 of 303 (4.0%) patients started on the American Thoracic Society-recommended two companion drugs, with no risk difference in clarithromycin versus azithromycin and daily versus intermittent therapy. Sputum conversion with macrolide-resistant MAC occurred in 11 of 14 (79%) patients who received more than 6 mo of injectable aminoglycoside therapy and lung resection, compared with 2 of 37 (5%) who did not. The 1-yr mortality in patients who remained culture positive was 34% (13/38) compared with 0% (0/13) of patients who became culture negative (converted).
CONCLUSIONS: Macrolide resistance rarely occurs in patients also receiving ethambutol and a rifamycin. Macrolide-resistant MAC lung disease requires aggressive drug and surgical therapy for cure.

PMID 16858014  Am J Respir Crit Care Med. 2006 Oct 15;174(8):928-34. d・・・
著者: Kozo Morimoto, Ho Namkoong, Naoki Hasegawa, Taku Nakagawa, Eriko Morino, Yuji Shiraishi, Kenji Ogawa, Kiyohiko Izumi, Jin Takasaki, Takashi Yoshiyama, Yoshihiko Hoshino, Shuichi Matsuda, Yuta Hayashi, Yuka Sasaki, Makoto Ishii, Atsuyuki Kurashima, Tomoyasu Nishimura, Tomoko Betsuyaku, Hajime Goto, Nontuberculous Mycobacteriosis Japan Research Consortium
雑誌名: Ann Am Thorac Soc. 2016 Nov;13(11):1904-1911. doi: 10.1513/AnnalsATS.201604-246OC.
Abstract/Text RATIONALE: The management of macrolide-resistant Mycobacterium avium complex (MR-MAC) pulmonary disease is difficult and is thought to be analogous to that of multidrug-resistant tuberculosis (MDR-TB).
OBJECTIVES: This study aimed to clarify the cause of MR-MAC, to see how its management affected outcome, and to compare its prognosis with that of MDR-TB.
METHODS: The medical records of 102 consecutive cases with MR-MAC pulmonary disease at three tertiary hospitals for mycobacteriosis in metropolitan Tokyo and one in Aichi prefecture from 2005 to 2014 were reviewed. The data of 311 consecutive cases with MDR-TB were extracted from the medical data at Fukujuji Hospital.
MEASUREMENTS AND MAIN RESULTS: Of the 90 patients who met the criteria, 53 (58.9%) received inappropriate first-line treatment, and 28 (31.1%) deviated from the standard treatment because of the adverse effects of ethambutol. The survival rates for MR-MAC disease and MDR-TB were not significantly different (P = 0.6). Multivariate analysis showed that the combination of aminoglycoside and surgery resulted in the best treatment outcome (P = 0.02), although neither of the two factors reached significance by themselves. The continuation of clarithromycin and the addition of fluoroquinolones did not improve the outcome for the treatment of disease caused by MR-MAC.
CONCLUSIONS: Inappropriate prescription patterns and deviations from the standard treatment because of adverse drug reactions appeared to be the main causes of macrolide resistance in this patient series. Drug sensitivity testing should be performed at diagnosis to identify macrolide resistance and patients who may benefit from other therapy.

PMID 27513168  Ann Am Thorac Soc. 2016 Nov;13(11):1904-1911. doi: 10.1・・・
著者: M P Dubé, F R Sattler, F J Torriani, D See, D V Havlir, C A Kemper, M G Dezfuli, S A Bozzette, A E Bartok, J M Leedom, J G Tilles, J A McCutchan
雑誌名: J Infect Dis. 1997 Nov;176(5):1225-32.
Abstract/Text Patients with AIDS and Mycobacterium avium complex (MAC) bacteremia are at high risk for relapse and emergence of resistant isolates during monotherapy with clarithromycin. Ninety-five AIDS patients with MAC bacteremia received clarithromycin plus clofazimine, with or without ethambutol, in a prospective, multicenter, randomized open-label trial. Of 80 patients with positive baseline cultures, sterilization or a 2 log10 reduction in colony-forming units of MAC in two consecutive blood cultures occurred in 69% of both groups. There were nine relapses in the two-drug arm and three in the three-drug arm. Kaplan-Meier estimates of risk of relapse at 36 weeks were 68% and 12%, respectively (P = .004). All relapse isolates were resistant to clarithromycin. Median time to clarithromycin resistance was 16 weeks with two drugs and 40 weeks with three drugs (P = .004). Ethambutol reduced relapses and emergence of clarithromycin resistance and should be considered an essential component of clarithromycin-based therapies for MAC bacteremia.

PMID 9359722  J Infect Dis. 1997 Nov;176(5):1225-32.
著者: E Tanaka, T Kimoto, K Tsuyuguchi, I Watanabe, H Matsumoto, A Niimi, K Suzuki, T Murayama, R Amitani, F Kuze
雑誌名: Am J Respir Crit Care Med. 1999 Sep;160(3):866-72. doi: 10.1164/ajrccm.160.3.9811086.
Abstract/Text We have investigated the efficacy of a clarithromycin-containing four-drug regimen for Mycobacterium avium complex (MAC) pulmonary disease in 46 patients without acquired immunodeficiency syndrome (AIDS). The patients were 14 males and 32 females with a mean age of 60.9 +/- 11.5 yr. Patients received 10 mg/kg/d of clarithromycin plus ethambutol, rifampin, and initial kanamycin and subsequent quinolone for 24 mo. Seven patients (15.2%) were dropped in the first 6 mo. Among 39 patients who received more than 6 mo of therapy, 28 patients (71.8%) converted their sputa to negative: 26 of 31 patients (83.9%) infected with clarithromycin-susceptible strains and two of eight patients (25.0%) with resistant or intermediate strains. The timing of sputum conversion was 3.6 +/- 1.9 mo, with a range of 2 to 9 mo. The conversion rate was significantly lower in patients who were infected with clarithromycin-resistant or intermediate strains, who had had prior therapy (55.0% versus 89.5%), or who were acid-fast bacilli (AFB) smear-positive at entry (60.7% versus 100%). The age and sex of patients, the species of pathogen (M. avium or M. intracellulare), type and extent of the disease, and the use of kanamycin did not significantly affect the conversion rate. Although the regimen was efficacious for newly treated patients, frequent adverse reactions and a low conversion rate of sputum in retreated patients are problems that remain to be solved.

PMID 10471610  Am J Respir Crit Care Med. 1999 Sep;160(3):866-72. doi:・・・
著者: Yoshihiro Kobashi, Masaaki Abe, Keiji Mouri, Yasushi Obase, Shigeki Kato, Mikio Oka
雑誌名: J Infect Chemother. 2012 Aug;18(4):436-43. doi: 10.1007/s10156-011-0351-x. Epub 2011 Dec 17.
Abstract/Text There are a few recent reports about the relationship between the clinical effect and drug-sensitivity test. We investigated the relationship between the clinical efficacy of treatment for pulmonary Mycobacterium avium complex (MAC) and drug-sensitivity test for isolated MAC by comparison between data from 2005 to 2007 and from 2008 to 2010. We studied 60 patients who satisfied diagnostic criteria of nontuberculous mycobacterial infection established by the American Thoracic Society in 2007 and who received combination therapy using rifampicin (RFP), ethambutol (EB), streptomycin (SM), and clarithromycin (CAM). Average CAM dosage was increased from the early (517 mg/day) to the later (800 mg/day) period. Sputum conversion rate increased from 63% in the early period to 83% in the later period. Clinical improvement also increased from 38% in the early period to 53% in the later period. The causative microorganisms isolated were M. avium in 35 patients and M. intracellulare in 25. In both periods, isolated MAC strains showed excellent minimum inhibitory concentration (MIC) for CAM. Regarding the relationship between clinical efficacy and MICs of RFP, EB, CAM, and SM, most patients with good clinical effects showed low MIC for CAM in both periods. Good clinical efficacy, including the sputum conversion rate, was obtained with an increased dose of CAM in the later period. We speculate that the increased dose of CAM influenced the good clinical effect in both periods.

PMID 22205543  J Infect Chemother. 2012 Aug;18(4):436-43. doi: 10.1007・・・
著者: Koji Furuuchi, Kozo Morimoto, Atsuyuki Kurashima, Keiji Fujiwara, Keitaro Nakamoto, Yoshiaki Tanaka, Hiromasa Tachibana, Kozo Yoshimori, Yuka Sasaki, Ken Ohta
雑誌名: Chest. 2020 Jun;157(6):1442-1445. doi: 10.1016/j.chest.2019.12.016. Epub 2020 Jan 16.
Abstract/Text
PMID 31954692  Chest. 2020 Jun;157(6):1442-1445. doi: 10.1016/j.chest.・・・
著者: Yoshihiro Kobashi, Toshiharu Matsushima, Mikio Oka
雑誌名: Respir Med. 2007 Jan;101(1):130-8. doi: 10.1016/j.rmed.2006.04.002. Epub 2006 Jun 5.
Abstract/Text A prospective study of the clinical efficacy of an aminoglycoside antibiotic (streptomycin, SM) for the treatment of pulmonary Mycobacterium avium complex (MAC) disease was carried out. In a multicenter trial, patients with pulmonary MAC disease received protocol-guided combined chemotherapy with or without SM. SM was given to the patients intramuscularly 15 mg/kg three times per week for the initial 3 months and three other antibiotics (rifampicin, ethambutol, and clarithromycin) were added and administered for over 24 months after the conversion of MAC strains. From April 1998 to December 2004, 160 HIV-negative patients were enrolled in this trial. Fourteen patients were found to be ineligible because they could not continue the treatment, and they were excluded from the analysis after randomization. Seventy-three patients were assigned to receive combined chemotherapy with SM (group A) and 73 were assigned to receive combined chemotherapy without SM (group B). The median durations of treatment were 27.6 months in group A and 28.4 months in group B. The difference in the backgrounds of the groups was not statistically significant. There were no differences in microbiological and radiological findings between the groups, but the sputum conversion rate for pulmonary MAC disease at the completion of treatment was significantly higher in group A than that in group B. Although, there were no significant differences in the sputum relapse rate and clinical improvement including both clinical symptoms and radiological findings, group A showed better initial microbiological response than group B. As for adverse reactions and abnormal laboratory findings, there were no significant differences between the groups. Based on the results of this double-blind randomized study, we support treatment including SM according to both the American Thoracic Society (ATS) and the Japanese Society for Tuberculosis (JST) guidelines for patients with pulmonary MAC disease without HIV infection.

PMID 16750618  Respir Med. 2007 Jan;101(1):130-8. doi: 10.1016/j.rmed.・・・
著者: David E Griffith, Gina Eagle, Rachel Thomson, Timothy R Aksamit, Naoki Hasegawa, Kozo Morimoto, Doreen J Addrizzo-Harris, Anne E O'Donnell, Theodore K Marras, Patrick A Flume, Michael R Loebinger, Lucy Morgan, Luigi R Codecasa, Adam T Hill, Stephen J Ruoss, Jae-Joon Yim, Felix C Ringshausen, Stephen K Field, Julie V Philley, Richard J Wallace, Jakko van Ingen, Chris Coulter, James Nezamis, Kevin L Winthrop, CONVERT Study Group
雑誌名: Am J Respir Crit Care Med. 2018 Dec 15;198(12):1559-1569. doi: 10.1164/rccm.201807-1318OC.
Abstract/Text Rationale: Improved therapeutic options are needed for patients with treatment-refractory nontuberculous mycobacterial lung disease caused by Mycobacterium avium complex (MAC). Objectives: To evaluate the efficacy and safety of daily amikacin liposome inhalation suspension (ALIS) added to standard guideline-based therapy (GBT) in patients with refractory MAC lung disease. Methods: Adults with amikacin-susceptible MAC lung disease and MAC-positive sputum cultures despite at least 6 months of stable GBT were randomly assigned (2:1) to receive ALIS with GBT (ALIS + GBT) or GBT alone. Once-daily ALIS was supplied in single-use vials delivering 590 mg amikacin to the nebulizer. The primary endpoint was culture conversion, defined as three consecutive monthly MAC-negative sputum cultures by Month 6. Measurements and Main Results: Enrolled patients (ALIS + GBT, n = 224; GBT-alone, n = 112) were a mean 64.7 years old and 69.3% female. Most had underlying bronchiectasis (62.5%), chronic obstructive pulmonary disease (14.3%), or both (11.9%). Culture conversion was achieved by 65 of 224 patients (29.0%) with ALIS + GBT and 10 of 112 (8.9%) with GBT alone (odds ratio, 4.22; 95% confidence interval, 2.08-8.57; P < 0.001). Patients in the ALIS + GBT arm versus GBT alone were more likely to achieve conversion (hazard ratio, 3.90; 95% confidence interval, 2.00-7.60). Respiratory adverse events (primarily dysphonia, cough, and dyspnea) were reported in 87.4% of patients receiving ALIS + GBT and 50.0% receiving GBT alone; serious treatment-emergent adverse events occurred in 20.2% and 17.9% of patients, respectively. Conclusions: Addition of ALIS to GBT for treatment-refractory MAC lung disease achieved significantly greater culture conversion by Month 6 than GBT alone, with comparable rates of serious adverse events. Clinical trial registered with www.clinicaltrials.gov (NCT02344004).

PMID 30216086  Am J Respir Crit Care Med. 2018 Dec 15;198(12):1559-156・・・
著者: Kevin L Winthrop, Patrick A Flume, Rachel Thomson, Kevin C Mange, Dayton W Yuen, Monika Ciesielska, Kozo Morimoto, Stephen J Ruoss, Luigi R Codecasa, Jae-Joon Yim, Theodore K Marras, Jakko van Ingen, Richard J Wallace, Barbara A Brown-Elliott, Chris Coulter, David E Griffith
雑誌名: Ann Am Thorac Soc. 2021 Jul;18(7):1147-1157. doi: 10.1513/AnnalsATS.202008-925OC.
Abstract/Text Rationale: Patients with refractory Mycobacterium avium complex (MAC) lung disease have limited treatment options. In the CONVERT study, amikacin liposome inhalation suspension (ALIS) added to guideline-based therapy (GBT) increased culture conversion rates versus GBT alone by Month 6. Limited data are available regarding >6-month treatment in a refractory population.Objectives: Evaluate 12-month safety, tolerability, and efficacy of ALIS+GBT.Methods: Adults with refractory MAC lung disease not achieving culture conversion by CONVERT Month 6 could enroll in this open-label extension (INS-312) to receive 590 mg once-daily ALIS+GBT for 12 months. Two cohorts enrolled: the "ALIS-naive" cohort included patients randomized to GBT alone in CONVERT, and the "prior-ALIS" cohort included those randomized to ALIS+GBT in CONVERT. Safety and tolerability of ALIS over 12 months (primary endpoint) and culture conversion by Months 6 and 12 were assessed.Results: In the ALIS-naive cohort, 83.3% of patients (n = 75/90) experienced respiratory treatment-emergent adverse events (TEAEs), and 35.6% (n = 32) had serious TEAEs; 26.7% (n = 24) achieved culture conversion by Month 6 and 33.3% (n = 30) by Month 12. In the prior-ALIS cohort, 46.6% of patients (n = 34/73) experienced respiratory TEAEs, and 27.4% (n = 20) had serious TEAEs; 9.6% (n = 7) achieved culture conversion by Month 6 (≤14 mo ALIS exposure) and 13.7% (n = 10) by Month 12 (≤20 mo ALIS exposure). Nephrotoxicity-related TEAEs and measured hearing decline were infrequent in both cohorts.Conclusions: In up to 20 months of ALIS use, respiratory TEAEs were common, nephrotoxicity and hearing decline were infrequent, and culture conversion continued beyond 6 months of therapy.Clinical trial registered with www.clinicaltrials.gov (NCT02628600).

PMID 33326356  Ann Am Thorac Soc. 2021 Jul;18(7):1147-1157. doi: 10.15・・・
著者: Sheridan M Hoy
雑誌名: Clin Drug Investig. 2021 Apr;41(4):405-412. doi: 10.1007/s40261-021-01010-z. Epub 2021 Mar 16.
Abstract/Text Amikacin liposome inhalation suspension (ALIS) [Arikayce® Liposomal (EU); Arikayce® (USA)], a liposomal suspension of the aminoglycoside amikacin (590 mg) for nebulization via the Lamira® Nebulizer System, is available as add-on therapy for treatment-refractory Mycobacterium avium complex (MAC) lung disease in adults who have little or no alternative treatment options. Its addition to guideline-based therapy (GBT) significantly improved the likelihood of achieving sputum culture conversion (defined as three consecutive monthly MAC-negative sputum cultures) by month 6 relative to GBT alone in adults with treatment-refractory MAC lung disease, with the conversion response maintained over up to 12 months' therapy and at 3 months' post treatment in significantly higher proportions of ALIS plus GBT than GBT alone recipients. ALIS as an add-on therapy to GBT was associated with an increased risk of respiratory adverse reactions compared with GBT alone, but treatment-emergent adverse events associated with systemic amikacin exposure were uncommon.

PMID 33723805  Clin Drug Investig. 2021 Apr;41(4):405-412. doi: 10.100・・・
著者: R E CARR, P HENKIND
雑誌名: Arch Ophthalmol. 1962 May;67:566-71.
Abstract/Text
PMID 13876814  Arch Ophthalmol. 1962 May;67:566-71.
著者: R K Tsai, Y H Lee
雑誌名: J Ocul Pharmacol Ther. 1997 Oct;13(5):473-7.
Abstract/Text Ethambutol hydrochloride is one of the routinely used drugs as the first line of antitubercular agents. The delayed onset of ocular toxicity is usually thought to be reversible following rapid withdrawal of the drug. We collected ten consecutive patients with severe visual defects due to ethambutol toxicity, and these patients had received presumably safe ethambutol dosages. Although ethambutol was stopped immediately in all cases, only five patients (50%) experienced visual improvement after a period of 12 months to 3 years follow-up. The other five patients (50%) had permanent visual impairment without recovery. There were no predisposing or risk factors to contribute to poor visual outcome. In the group over 60 years old, only 20% (1/5) experienced visual improvement; in the group less than 60 years old, 80% (4/5) had some visual recovery, the difference between these two age groups being statistically significant. We need more patient collections to answer whether the older patients with ethambutol optic neuropathy have poor prognoses. Ethambutol optic neuropathy, in our follow-up study, is not always reversible, especially in the older population. It may cause permanent visual disability. There is no so-called "safe-dosage". We suggest reconsideration regarding the use of ethambutol as one of the first-line antitubercular drugs, especially in older patients.

PMID 9326729  J Ocul Pharmacol Ther. 1997 Oct;13(5):473-7.
著者: David E Griffith, Barbara A Brown-Elliott, Sara Shepherd, Jerry McLarty, Lee Griffith, Richard J Wallace
雑誌名: Am J Respir Crit Care Med. 2005 Jul 15;172(2):250-3. doi: 10.1164/rccm.200407-863OC. Epub 2005 Apr 28.
Abstract/Text Ethambutol (EMB) is an important component of multidrug treatment regimens for Mycobacterium avium complex lung disease. Ocular toxicity is the most important potential EMB toxicity, especially in the elderly population with M. avium complex lung disease. Two hundred twenty-nine patients with M. avium complex lung disease, 55% women and 53% with nodular/bronchiectatic disease, received a mean of 16.1 +/- 10.8 months of multidrug therapy that included EMB. Fifty patients (22%) were known to have preexisting ocular disease. While on EMB, 97 (42%) patients consulted an opthalmologist and 24 (10%) stopped EMB at least temporarily. Eight of 139 patients (6%) on daily therapy were diagnosed with EMB ocular toxicity, whereas 0 of 90 patients on intermittent therapy had EMB ocular toxicity (p = 0.05). All patients with EMB ocular toxicity developed symptoms between outpatient clinic appointments; none were diagnosed with routine visual acuity and color vision testing. All patients with EMB ocular disease returned to baseline ocular status after discontinuation of EMB. Intermittent EBM administration was associated with less ocular toxicity than daily EMB administration in this patient population.

PMID 15860751  Am J Respir Crit Care Med. 2005 Jul 15;172(2):250-3. do・・・
著者: Katherine Anne Talbert Estlin, Alfredo A Sadun
雑誌名: Int Ophthalmol. 2010 Feb;30(1):63-72. doi: 10.1007/s10792-009-9293-z. Epub 2009 Feb 11.
Abstract/Text CONTEXT: Optic neuropathy is a well-known complication of ethambutol therapy and usually manifests as a decrease in visual acuity, cecocentral scotomas, and deficits in color vision.
OBJECTIVE: To support or disprove the hypothesis that a significant majority of patients who develop ocular toxicity while undergoing treatment for a mycobacterium infection do so after experiencing either a prolonged course or unusually high serum levels of ethambutol.
DESIGN: Retrospective chart review (16 cases) and literature meta-analysis (54 cases).
RESULTS: Many cases lacked important data, but none countered the hypothesis. Age, duration of ethambutol, and dose of ethambutol were positively correlated with risk of toxicity.
CONCLUSIONS: Given an understanding of the risk factors for ethambutol optic toxicity, there exists a rationale for an optimization of ethambutol dosing protocols that can maximize the therapeutic effect while minimizing the incidence of optic toxicity.

PMID 19205626  Int Ophthalmol. 2010 Feb;30(1):63-72. doi: 10.1007/s107・・・
著者: Howard L Geyer, Steven Herskovitz, Thomas L Slamovits, Herbert H Schaumburg
雑誌名: J Neuroophthalmol. 2014 Sep;34(3):257-8. doi: 10.1097/WNO.0000000000000141.
Abstract/Text Ethambutol is known to cause optic neuropathy and, more rarely, axonal polyneuropathy. We characterize the clinical, neurophysiological, and neuroimaging findings in a 72-year-old man who developed visual loss and paresthesias after 11 weeks of exposure to a supratherapeutic dose of ethambutol. This case demonstrates the selective vulnerability of the anterior visual pathways and peripheral nerves to ethambutol toxicity.

PMID 24897009  J Neuroophthalmol. 2014 Sep;34(3):257-8. doi: 10.1097/W・・・

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