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慢性下気道感染症(DPB以外)

著者: 石井寛 福岡大学筑紫病院 呼吸器内科

監修: 藤田次郎 琉球大学医学部

著者校正/監修レビュー済:2020/03/26
参考ガイドライン:
  1. 日本呼吸器学会「呼吸器感染症に関するガイドライン」成人気道感染症診療の基本的考え方.2003;7.
患者向け説明資料

概要・推奨   

  1. 慢性の湿性咳嗽を呈する患者、すなわち慢性下気道感染症と考えられる患者には、マクロライド少量長期療法が勧められる(SBS/DPB/気管支拡張症の場合)(推奨度1)。
  1. 慢性の湿性咳嗽を呈する患者、すなわち慢性下気道感染症と考えられる患者には、マクロライド少量長期療法が勧められる(COPDの場合)(推奨度2)。
  1. すべての慢性下気道感染症患者にインフルエンザワクチンの接種が勧められる(推奨度1)。
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧
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:
石井寛 : 特に申告事項無し[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. 定期レビューを行い、加筆修正した。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 慢性下気道感染症とは、気管分岐部以下の気道に基礎疾患を有するために局所的な感染防御能が低下し、持続する細菌感染を認める状態である。
  1. 慢性気道感染症は、健常者にも起こり得る急性気道感染症が単に遷延した病態とは異なる。
  1. 代表的疾患として、びまん性汎細気管支炎(diffuse panbronchiolitis、DPB)や気管支拡張症、慢性閉塞性肺疾患(chronic obstructive pulmonary disease、COPD)のうち末梢気道病変優位型のものなどがある。
  1. 欧米における慢性気道感染症の代表である常染色体劣性遺伝の嚢胞性線維症(cystic fibrosis、CF)や、原発性線毛機能不全症(primary ciliary dyskinesia)などもあり、これらはDPBと同様に慢性副鼻腔炎を合併する[1]
  1. DPBは近年減少し、わが国ではCOPDが重要となってきている。
問診・診察のポイント  
  1. 気道における細菌の定着が刺激となって粘液産生の亢進がみられる。疾患により程度の差はあるものの、慢性的に存在する痰を喀出するため、生理的な現象として慢性の湿性咳嗽を呈することが多い。

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文献 

著者: S D Greenberg, J Z Ainsworth
雑誌名: South Med J. 1966 Jan;59(1):64-74.
Abstract/Text
PMID 5902758  South Med J. 1966 Jan;59(1):64-74.
著者: Katsunori Yanagihara, Kazunori Tomono, Yoshifumi Imamura, Yukihiro Kaneko, Misuzu Kuroki, Toyomitsu Sawai, Yoshitsugu Miyazaki, Yoichi Hirakata, Hiroshi Mukae, Jun-Ichi Kadota, Shigeru Kohno
雑誌名: J Antimicrob Chemother. 2002 May;49(5):867-70.
Abstract/Text Fourteen-membered macrolides (e.g. clarithromycin and erythromycin), but not 16-membered macrolides (e.g. josamycin), are effective in diffuse panbronchiolitis. However, there are no studies that have compared the effects of 14- and 16-membered macrolide antibiotics on biofilm formation. Treatment with high-dose clarithromycin (100 mg/kg) resulted in a significant decrease in the number of viable bacteria in an experimental murine model. Josamycin at a dose of up to 100 mg/kg had no effect on the number of viable bacteria in the lung. Our results may explain, at least in part, the clinical efficacy of 14-membered macrolide antibiotics in patients with chronic pneumonia caused by Pseudomonas aeruginosa.

PMID 12003986  J Antimicrob Chemother. 2002 May;49(5):867-70.
著者: Masanori Asada, Motoki Yoshida, Yukimasa Hatachi, Takahiko Sasaki, Hiroyasu Yasuda, Xue Deng, Hidekazu Nishimura, Hiroshi Kubo, Ryoichi Nagatomi, Mutsuo Yamaya
雑誌名: Respir Physiol Neurobiol. 2012 Jan 15;180(1):112-8. doi: 10.1016/j.resp.2011.10.017. Epub 2011 Nov 7.
Abstract/Text To examine the effects of l-carbocisteine on airway infection with respiratory syncytial (RS) virus, human tracheal epithelial cells were pretreated with l-carbocisteine and infected with RS virus. Viral titer, virus RNA, and pro-inflammatory cytokine secretion, including interleukin (IL)-1 and IL-6, increased with time after infection. l-carbocisteine reduced the viral titer in the supernatant fluids, the amount of RS virus RNA, RS virus infection susceptibility, and the concentration of pro-inflammatory cytokines induced by virus infection. l-carbocisteine reduced the expression of intercellular adhesion molecule (ICAM)-1, an RS virus receptor, on the cells. However, l-carbocisteine had no effects on the expression of heparan sulfate, a glycosaminoglycan that binds to the RS virus attachment protein, or on the amount of intracellular activated-RhoA, isoform A of the Ras-homologous family, that binds to the RS virus fusion protein. These findings suggest that l-carbocisteine may inhibit RS virus infection by reducing the expression of ICAM-1. It may also modulate airway inflammation during RS virus infection.

Copyright © 2011 Elsevier B.V. All rights reserved.
PMID 22080978  Respir Physiol Neurobiol. 2012 Jan 15;180(1):112-8. doi・・・
著者: Mutsuo Yamaya, Hidekazu Nishimura, Kyoko Shinya, Yukimasa Hatachi, Takahiko Sasaki, Hiroyasu Yasuda, Motoki Yoshida, Masanori Asada, Naoya Fujino, Takaya Suzuki, Xue Deng, Hiroshi Kubo, Ryoichi Nagatomi
雑誌名: Am J Physiol Lung Cell Mol Physiol. 2010 Aug;299(2):L160-8. doi: 10.1152/ajplung.00376.2009. Epub 2010 Jun 11.
Abstract/Text Type A human seasonal influenza (FluA) virus infection causes exacerbations of bronchial asthma and chronic obstructive pulmonary disease (COPD). l-carbocisteine, a mucolytic agent, reduces the frequency of common colds and exacerbations in COPD. However, the inhibitory effects of l-carbocisteine on FluA virus infection are uncertain. We studied the effects of l-carbocisteine on FluA virus infection in airway epithelial cells. Human tracheal epithelial cells were pretreated with l-carbocisteine and infected with FluA virus (H(3)N(2)). Viral titers in supernatant fluids, RNA of FluA virus in the cells, and concentrations of proinflammatory cytokines in supernatant fluids, including IL-6, increased with time after infection. l-carbocisteine reduced viral titers in supernatant fluids, RNA of FluA virus in the cells, the susceptibility to FluA virus infection, and concentrations of cytokines induced by virus infection. The epithelial cells expressed sialic acid with an alpha2,6-linkage (SAalpha2,6Gal), a receptor for human influenza virus on the cells, and l-carbocisteine reduced the expression of SAalpha2,6Gal. l-carbocisteine reduced the number of acidic endosomes from which FluA viral RNA enters into the cytoplasm and reduced the fluorescence intensity from acidic endosomes. Furthermore, l-carbocisteine reduced NF-kappaB proteins including p50 and p65 in the nuclear extracts of the cells. These findings suggest that l-carbocisteine may inhibit FluA virus infection, partly through the reduced expression of the receptor for human influenza virus in the human airway epithelial cells via the inhibition of NF-kappaB and through increasing pH in endosomes. l-carbocisteine may reduce airway inflammation in influenza virus infection.

PMID 20543005  Am J Physiol Lung Cell Mol Physiol. 2010 Aug;299(2):L16・・・
著者: H Yasuda, M Yamaya, T Sasaki, D Inoue, K Nakayama, M Yamada, M Asada, M Yoshida, T Suzuki, H Nishimura, H Sasaki
雑誌名: Eur Respir J. 2006 Jul;28(1):51-8. doi: 10.1183/09031936.06.00058505. Epub 2006 Mar 1.
Abstract/Text The aim of the study was to examine the effects of a mucolytic drug, carbocisteine, on rhinovirus (RV) infection in the airways. Human tracheal epithelial cells were infected with a major-group RV, RV14. RV14 infection increased virus titres and the cytokine content of supernatants. Carbocisteine reduced supernatant virus titres, the amount of RV14 RNA in cells, cell susceptibility to RV infection and supernatant cytokine concentrations, including interleukin (IL)-6 and IL-8, after RV14 infection. Carbocisteine reduced the expression of mRNA encoding intercellular adhesion molecule (ICAM)-1, the receptor for the major group of RVs. It also reduced the supernatant concentration of a soluble form of ICAM-1, the number and fluorescence intensity of acidic endosomes in the cells before RV infection, and nuclear factor-kappaB activation by RV14. Carbocisteine also reduced the supernatant virus titres of the minor group RV, RV2, although carbocisteine did not reduce the expression of mRNA encoding a low density lipoprotein receptor, the receptor for RV2. These results suggest that carbocisteine inhibits rhinovirus 2 infection by blocking rhinovirus RNA entry into the endosomes, and inhibits rhinovirus 14 infection by the same mechanism as well as by reducing intercellular adhesion molecule-1 levels. Carbocisteine may modulate airway inflammation by reducing the production of cytokines in rhinovirus infection.

PMID 16510461  Eur Respir J. 2006 Jul;28(1):51-8. doi: 10.1183/0903193・・・
著者: Jin-Ping Zheng, Jian Kang, Shao-Guang Huang, Ping Chen, Wan-Zen Yao, Lan Yang, Chun-Xue Bai, Chang-Zheng Wang, Chen Wang, Bao-Yuan Chen, Yi Shi, Chun-Tao Liu, Ping Chen, Qiang Li, Zhen-Shan Wang, Yi-Jiang Huang, Zhi-Yang Luo, Fei-Peng Chen, Jian-Zhang Yuan, Ben-Tong Yuan, Hui-Ping Qian, Rong-Chang Zhi, Nan-Shan Zhong
雑誌名: Lancet. 2008 Jun 14;371(9629):2013-8. doi: 10.1016/S0140-6736(08)60869-7.
Abstract/Text BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterised by airflow limitation, and has many components including mucus hypersecretion, oxidative stress, and airway inflammation. We aimed to assess whether carbocisteine, a mucolytic agent with anti-inflammatory and antioxidation activities, could reduce the yearly exacerbation rate in patients with COPD.
METHODS: We did a randomised, double-blind, placebo-controlled study of 709 patients from 22 centres in China. Participants were eligible if they were diagnosed as having COPD with a postbronchodilator forced expiratory volume in 1 s (FEV(1)) to forced vital capacity (FVC) ratio (FEV(1)/FVC) of less than 0.7 and an FEV(1) between 25% and 79% of the predicted value, were aged between 40 and 80 years, had a history of at least two COPD exacerbations within the previous 2 years, and had remained clinically stable for over 4 weeks before the study. Patients were randomly assigned to receive 1500 mg carbocisteine or placebo per day for a year. The primary endpoint was exacerbation rate over 1 year, and analysis was by intention to treat. This trial is registered with the Japan Clinical Trials Registry (http://umin.ac.jp/ctr/index/htm) number UMIN-CRT C000000233.
FINDINGS: 354 patients were assigned to the carbocisteine group and 355 to the placebo group. Numbers of exacerbations per patient per year declined significantly in the carbocisteine group compared with the placebo group (1.01 [SE 0.06] vs 1.35 [SE 0.06]), risk ratio 0.75 (95% CI 0.62-0.92, p=0.004). Non-significant interactions were found between the preventive effects and COPD severity, smoking, as well as concomitant use of inhaled corticosteroids. Carbocisteine was well tolerated.
INTERPRETATION: Mucolytics, such as carbocisteine, should be recognised as a worthwhile treatment for prevention of exacerbations in Chinese patients with COPD.

PMID 18555912  Lancet. 2008 Jun 14;371(9629):2013-8. doi: 10.1016/S014・・・
著者: Patrick Waller, Samy Suissa
雑誌名: Lancet. 2008 Nov 8;372(9650):1630; author reply 1631-2. doi: 10.1016/S0140-6736(08)61681-5.
Abstract/Text
PMID 18994655  Lancet. 2008 Nov 8;372(9650):1630; author reply 1631-2.・・・
著者: Hiroyasu Yasuda, Mutsuo Yamaya, Takahiko Sasaki, Daisuke Inoue, Katsutoshi Nakayama, Naoki Tomita, Motoki Yoshida, Hidetada Sasaki
雑誌名: J Am Geriatr Soc. 2006 Feb;54(2):378-80. doi: 10.1111/j.1532-5415.2005.00592_9.x.
Abstract/Text
PMID 16460403  J Am Geriatr Soc. 2006 Feb;54(2):378-80. doi: 10.1111/j・・・
著者: Fumito Okada, Yumiko Ando, Sachie Yoshitake, Shinji Yotsumoto, Shunro Matsumoto, Masaki Wakisaka, Toru Maeda, Hiromu Mori
雑誌名: Radiology. 2006 Aug;240(2):559-64. doi: 10.1148/radiol.2402050886.
Abstract/Text PURPOSE: To retrospectively evaluate pulmonary computed tomographic (CT) findings in human T-lymphotropic virus type 1 (HTLV-1) carriers, who were characterized by means of polyclonal integration of proviral DNA.
MATERIALS AND METHODS: Institutional review board approval was obtained, and informed consent was waived. Chest CT scans obtained between January 1996 and October 2004 in 320 (154 men, 166 women; age range, 31-86 years; mean, 64 years) patients with HTLV-1 were retrospectively evaluated by three chest radiologists. Parenchymal abnormalities (ground-glass opacity, consolidation, centrilobular nodules, thickening of bronchovascular bundles, interlobular septal thickening, and bronchiectasis) were evaluated, along with enlarged lymph nodes and pleural effusion. In 58 patients who underwent surgical biopsy or transbronchial biopsy, comparison of CT images with the actual specimens was performed by a pathologist and three chest radiologists.
RESULTS: On CT scans, abnormal findings were seen in 98 (30.1%) patients and consisted of centrilobular nodules (n = 95), thickening of bronchovascular bundles (n = 55), ground-glass opacity (n = 51), bronchiectasis (n = 50), interlobular septal thickening (n = 28), and consolidation (n = 5). These abnormalities were predominantly seen in the peripheral lung parenchyma (n = 70). Pathologically, these findings corresponded to lymphocytic infiltration along respiratory bronchioles and bronchovascular bundles. Pleural effusion and enlarged lymph nodes were found in two and five patients, respectively.
CONCLUSION: CT findings in patients with HTLV-1 consisted mainly of centrilobular nodules, ground-glass opacity, and thickening of the bronchovascular bundles in the peripheral lung. These CT findings are considered suggestive of thoracic involvement in patients with HTLV-1.

RSNA, 2006
PMID 16864677  Radiology. 2006 Aug;240(2):559-64. doi: 10.1148/radiol.・・・
著者: Jun-ichi Kadota, Hiroshi Mukae, Takeshi Fujii, Masafumi Seki, Kazunori Tomono, Shigeru Kohno
雑誌名: Chest. 2004 Apr;125(4):1239-47.
Abstract/Text STUDY OBJECTIVES: Human T-cell lymphotropic virus type 1 (HTLV-1)-associated bronchiolitis and diffuse panbronchiolitis might overlap. We examined whether these conditions can be differentiated by comparing their clinical features and the effect of long-term macrolide treatment.
PATIENTS AND METHODS: Fifty-eight Japanese patients, including 15 with HTLV-1-associated bronchiolitis and 43 with diffuse panbronchiolitis. Both conditions were clinically compared using the clinical criteria for diffuse panbronchiolitis, including findings from CT scans and BAL fluid testing. Pulmonary function, blood gas levels, and cold hemagglutinin (CHA) levels were assessed before and after long-term treatment with macrolides. Interleukin-2 receptor (IL-2R) expression in T cells obtained from the BAL fluid of patients with HTLV-1-associated bronchiolitis or diffuse panbronchiolitis was analyzed by flow cytometry.
RESULTS: Clinical, laboratory, radiologic, and bacterial features were strikingly similar in both groups, except for the fact that patients with HTLV-1-associated bronchiolitis had a higher ratio of IL-2R-positive cells in the BAL fluid. The histopathologic features were also similar. Long-term treatment with macrolides improved PaO(2), FEV(1), and CHA in patients with HTLV-1-associated bronchiolitis to a lesser extent than in those with diffuse panbronchiolitis, and PaO(2) and FEV(1) in the group of patients with HTLV-1-associated bronchiolitis who had high IL-2R levels did not respond after therapy.
CONCLUSIONS: These findings showed that the clinicopathologic features of the two conditions are quite similar, suggesting that diffuse panbronchiolitis is a chronic pulmonary manifestation of HTLV-1 infection. However, HTLV-1-associated bronchiolitis might be associated with conditions that are distinct from those of diffuse panbronchiolitis based on the different responses to macrolide treatment and the difference in the number of activated T cells bearing IL-2R in the lungs.

PMID 15078730  Chest. 2004 Apr;125(4):1239-47.
著者: Kristin L Nichol, James D Nordin, David B Nelson, John P Mullooly, Eelko Hak
雑誌名: N Engl J Med. 2007 Oct 4;357(14):1373-81. doi: 10.1056/NEJMoa070844.
Abstract/Text BACKGROUND: Reliable estimates of the effectiveness of influenza vaccine among persons 65 years of age and older are important for informed vaccination policies and programs. Short-term studies may provide misleading pictures of long-term benefits, and residual confounding may have biased past results. This study examined the effectiveness of influenza vaccine in seniors over the long term while addressing potential bias and residual confounding in the results.
METHODS: Data were pooled from 18 cohorts of community-dwelling elderly members of one U.S. health maintenance organization (HMO) for 1990-1991 through 1999-2000 and of two other HMOs for 1996-1997 through 1999-2000. Logistic regression was used to estimate the effectiveness of the vaccine for the prevention of hospitalization for pneumonia or influenza and death after adjustment for important covariates. Additional analyses explored for evidence of bias and the potential effect of residual confounding.
RESULTS: There were 713,872 person-seasons of observation. Most high-risk medical conditions that were measured were more prevalent among vaccinated than among unvaccinated persons. Vaccination was associated with a 27% reduction in the risk of hospitalization for pneumonia or influenza (adjusted odds ratio, 0.73; 95% confidence interval [CI], 0.68 to 0.77) and a 48% reduction in the risk of death (adjusted odds ratio, 0.52; 95% CI, 0.50 to 0.55). Estimates were generally stable across age and risk subgroups. In the sensitivity analyses, we modeled the effect of a hypothetical unmeasured confounder that would have caused overestimation of vaccine effectiveness in the main analysis; vaccination was still associated with statistically significant--though lower--reductions in the risks of both hospitalization and death.
CONCLUSIONS: During 10 seasons, influenza vaccination was associated with significant reductions in the risk of hospitalization for pneumonia or influenza and in the risk of death among community-dwelling elderly persons. Vaccine delivery to this high-priority group should be improved.

Copyright 2007 Massachusetts Medical Society.
PMID 17914038  N Engl J Med. 2007 Oct 4;357(14):1373-81. doi: 10.1056/・・・
著者: I Alfageme, R Vazquez, N Reyes, J Muñoz, A Fernández, M Hernandez, M Merino, J Perez, J Lima
雑誌名: Thorax. 2006 Mar;61(3):189-95. doi: 10.1136/thx.2005.043323. Epub 2005 Oct 14.
Abstract/Text BACKGROUND: A study was undertaken to evaluate the clinical efficacy of the 23-valent pneumococcal polysaccharide vaccine (PPV) in immunocompetent patients with chronic obstructive pulmonary disease (COPD).
METHODS: A randomised controlled trial was carried out in 596 patients with COPD of mean (SD) age 65.8 (9.7) years, 298 of whom received PPV. The main outcome was radiographically proven community acquired pneumonia (CAP) of pneumococcal or unknown aetiology after a mean period of 979 days (range 20-1454).
RESULTS: There were 58 first episodes of CAP caused by pneumococcus or of unknown aetiology, 25 in the intervention group and 33 in the non-intervention group. Kaplan-Meier survival curves for CAP did not show significant differences between the intervention and non-intervention arms (log rank test = 1.15, p = 0.28) in the whole group of patients. The efficacy of PPV in all patients was 24% (95% CI -24 to 54; p = 0.333). In the subgroup aged <65 years the efficacy of PPV was 76% (95% CI 20 to 93; p = 0.013), while in those with severe functional obstruction (forced expiratory volume in 1 second <40%) it was 48% (95% CI -7 to 80; p = 0.076). In younger patients with severe airflow obstruction the efficacy was 91% (95% CI 35 to 99; p = 0.002). There were only five cases of non-bacteraemic pneumococcal CAP, all in the non-intervention group (log rank test = 5.03; p = 0.025). Multivariate analysis gave a hazard ratio for unknown and pneumococcal CAP in the vaccinated group, adjusted for age, of 0.20 (95% CI 0.06 to 0.68; p = 0.01).
CONCLUSIONS: PPV is effective in preventing CAP in patients with COPD aged less than 65 years and in those with severe airflow obstruction. No differences were found among the other groups of patients with COPD.

PMID 16227328  Thorax. 2006 Mar;61(3):189-95. doi: 10.1136/thx.2005.04・・・
著者: Lisa Saiman, Bruce C Marshall, Nicole Mayer-Hamblett, Jane L Burns, Alexandra L Quittner, Debra A Cibene, Sarah Coquillette, Ann Yunker Fieberg, Frank J Accurso, Preston W Campbell, Macrolide Study Group
雑誌名: JAMA. 2003 Oct 1;290(13):1749-56. doi: 10.1001/jama.290.13.1749.
Abstract/Text CONTEXT: Treatment strategies for cystic fibrosis (CF) lung disease include antibiotics, mucolytics, and anti-inflammatory therapies. Increasing evidence suggests that macrolide antibiotics might be beneficial in patients with CF.
OBJECTIVE: To determine if an association between azithromycin use and pulmonary function exists in patients with CF.
DESIGN AND SETTING: A multicenter, randomized, double-blind, placebo-controlled trial conducted from December 15, 2000, to May 2, 2002, at 23 CF care centers in the United States.
PARTICIPANTS: Of the 251 screened participants with a diagnosis of CF, 185 (74%) were randomized. Eligibility criteria included age 6 years or older, infection with Pseudomonas aeruginosa for 1 or more years, and a forced expiratory volume in 1 second (FEV1) of 30% or more. Participants were stratified by FEV1 (> or =60% predicted vs <60% predicted), weight of less than 40 kg vs 40 kg or more, and CF center.
INTERVENTION: The active group (n = 87) received 250 mg (weight <40 kg) or 500 mg (weight > or =40 kg) of oral azithromycin 3 days a week for 168 days; placebo group (n = 98) received identically packaged tablets.
MAIN OUTCOME MEASURES: Change in FEV1 from day 0 to completion of therapy at day 168 and determination of safety. Secondary outcomes included pulmonary exacerbations and weight gain.
RESULTS: The azithromycin group had a mean 0.097-L (SD, 0.26) increase in FEV1 at day 168 compared with 0.003 L (SD, 0.23) in the placebo group (mean difference, 0.094 L; 95% confidence interval [CI], 0.023-0.165; P =.009). Nausea occurred in 17% more participants in the azithromycin group (P =.01), diarrhea in 15% more (P =.009), and wheezing in 13% more (P =.007). Participants in the azithromycin group had less risk of experiencing an exacerbation than participants in the placebo group (hazard ratio, 0.65; 95% CI, 0.44-0.95; P =.03) and weighed at the end of the study an average 0.7 kg more than participants receiving placebo (95% CI, 0.1-1.4 kg; P =.02).
CONCLUSION: Azithromycin treatment was associated with improvement in clinically relevant end points and should be considered for patients with CF who are 6 years or older and chronically infected with P aeruginosa.

PMID 14519709  JAMA. 2003 Oct 1;290(13):1749-56. doi: 10.1001/jama.290・・・
著者: Yoshihiro Yamamoto, Koichi Izumikawa, Naoki Hosogaya, Yoshitomo Morinaga, Shigeki Nakamura, Yoshifumi Imamura, Taiga Miyazaki, Noriho Sakamoto, Yuji Ishimatu, Hiroshi Kakeya, Katsunori Yanagihara, Akira Yasuoka, Shigeru Kohno
雑誌名: Intern Med. 2012;51(11):1383-6. Epub 2012 Jun 1.
Abstract/Text The prognosis of patients with chronic respiratory tract infections, especially diffuse panbronchiolitis, is remarkably improved by long-term administration of low-dose macrolides. However, in some cases, patients are refractory to macrolide treatment and show a low or no response; therefore, new treatment strategies are required. Here we present a patient refractory to either single low-dose clarithromycin or azithromycin but responded remarkably to the combination usage of both macrolides.

PMID 22687847  Intern Med. 2012;51(11):1383-6. Epub 2012 Jun 1.
著者: Conroy Wong, Lata Jayaram, Noel Karalus, Tam Eaton, Cecilia Tong, Hans Hockey, David Milne, Wendy Fergusson, Christine Tuffery, Paul Sexton, Louanne Storey, Toni Ashton
雑誌名: Lancet. 2012 Aug 18;380(9842):660-7. doi: 10.1016/S0140-6736(12)60953-2.
Abstract/Text BACKGROUND: Azithromycin is a macrolide antibiotic with anti-inflammatory and immunomodulatory properties. We tested the hypothesis that azithromycin would decrease the frequency of exacerbations, increase lung function, and improve health-related quality of life in patients with non-cystic fibrosis bronchiectasis.
METHODS: We undertook a randomised, double-blind, placebo-controlled trial at three centres in New Zealand. Between Feb 12, 2008, and Oct 15, 2009, we enrolled patients who were 18 years or older, had had at least one pulmonary exacerbation requiring antibiotic treatment in the past year, and had a diagnosis of bronchiectasis defined by high-resolution CT scan. We randomly assigned patients to receive 500 mg azithromycin or placebo three times a week for 6 months in a 1:1 ratio, with a permuted block size of six and sequential assignment stratified by centre. Participants, research assistants, and investigators were masked to treatment allocation. The coprimary endpoints were rate of event-based exacerbations in the 6-month treatment period, change in forced expiratory volume in 1 s (FEV(1)) before bronchodilation, and change in total score on St George's respiratory questionnaire (SGRQ). Analyses were by intention to treat. This study is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12607000641493.
FINDINGS: 71 patients were in the azithromycin group and 70 in the placebo group. The rate of event-based exacerbations was 0·59 per patient in the azithromycin group and 1·57 per patient in the placebo group in the 6-month treatment period (rate ratio 0·38, 95% CI 0·26-0·54; p<0·0001). Prebronchodilator FEV(1) did not change from baseline in the azithromycin group and decreased by 0·04 L in the placebo group, but the difference was not significant (0·04 L, 95% CI -0·03 to 0·12; p=0·251). Additionally, change in SGRQ total score did not differ between the azithromycin (-5·17 units) and placebo groups (-1·92 units; difference -3·25, 95% CI -7·21 to 0·72; p=0·108).
INTERPRETATION: Azithromycin is a new option for prevention of exacerbations in patients with non-cystic fibrosis bronchiectasis with a history of at least one exacerbation in the past year.
FUNDING: Health Research Council of New Zealand and Auckland District Health Board Charitable Trust.

Copyright © 2012 Elsevier Ltd. All rights reserved.
PMID 22901887  Lancet. 2012 Aug 18;380(9842):660-7. doi: 10.1016/S0140・・・
著者: B W Ramsey, M S Pepe, J M Quan, K L Otto, A B Montgomery, J Williams-Warren, M Vasiljev-K, D Borowitz, C M Bowman, B C Marshall, S Marshall, A L Smith
雑誌名: N Engl J Med. 1999 Jan 7;340(1):23-30. doi: 10.1056/NEJM199901073400104.
Abstract/Text BACKGROUND AND METHODS: We conducted two multicenter, double-blind, placebo-controlled trials of intermittent administration of inhaled tobramycin in patients with cystic fibrosis and Pseudomonas aeruginosa infection. A total of 520 patients (mean age, 21 years) were randomly assigned to receive either 300 mg of inhaled tobramycin or placebo twice daily for four weeks, followed by four weeks with no study drug. Patients received treatment or placebo in three on-off cycles for a total of 24 weeks. The end points included pulmonary function, the density of P. aeruginosa in sputum, and hospitalization.
RESULTS: The patients treated with inhaled tobramycin had an average increase in forced expiratory volume in one second (FEV1) of 10 percent at week 20 as compared with week 0, whereas the patients receiving placebo had a 2 percent decline in FEV1 (P<0.001). In the tobramycin group, the density of P. aeruginosa decreased by an average of 0.8 log10 colony-forming units (CFU) per gram of expectorated sputum from week 0 to week 20, as compared with an increase of 0.3 log10 CFU per gram in the placebo group (P<0.001). The patients in the tobramycin group were 26 percent (95 percent confidence interval, 2 to 43 percent) less likely to be hospitalized than those in the placebo group. Inhaled tobramycin was not associated with detectable ototoxic or nephrotoxic effects or with accumulation of the drug in serum. The proportion of patients with P. aeruginosa isolates for which the minimal inhibitory concentration of tobramycin was 8 microg per milliliter or higher increased from 25 percent at week 0 to 32 percent at week 24 in the tobramycin group, as compared with a decrease from 20 percent at week 0 to 17 percent at week 24 in the placebo group.
CONCLUSIONS: In a 24-week study of patients with cystic fibrosis, intermittent administration of inhaled tobramycin was well tolerated and improved pulmonary function, decreased the density of P. aeruginosa in sputum, and decreased the risk of hospitalization.

PMID 9878641  N Engl J Med. 1999 Jan 7;340(1):23-30. doi: 10.1056/NEJ・・・
著者: J Kadota, H Mukae, H Ishii, T Nagata, H Kaida, K Tomono, S Kohno
雑誌名: Respir Med. 2003 Jul;97(7):844-50.
Abstract/Text Diffuse panbronchiolitis (DPB) can now be cured with long-term erythromycin treatment. Our group conducted a prospective open trial of long-term treatment with a macrolide antibiotic, clarithromycin. We studied ten patients who were treated for 4 years with oral clarithromycin (200 mg once a day). Pulmonary function test, blood gas analysis, comprehensive improvement score, and bacterial culture of sputum were examined at 3, 6, 12 months, and at 2, 3, 4 years after the initiation of the therapy. Pulmonary function improved in most of the patients within 6 months: the forced expiratory volume in one second showed a maximal increase from a mean (SE) value of 1.74 (0.12) l at baseline to 2.31 (0.22) l at 6 months (P < 0.01) and the volume (l) of forced vital capacity also showed a maximal increase within 6 months. The partial pressure of arterial oxygen at rest significantly increased at 3-6 months. The comprehensive improvement score also reached maximum within 6 months in nine of the patients. The majority of patients have developed sputum culture in which bacteria were negative within 6 months after the therapy. All of the patients maintained a stable condition with continued therapy, and no side effects of clarithromycin were observed during the study. This prospective study demonstrated that 6-month treatment with clarithromycin might be necessary to improve the clinical conditions of patients with DPB and the drug could be safely used for a long term.

PMID 12854636  Respir Med. 2003 Jul;97(7):844-50.
著者: Jun-ichi Kadota, Hiroshi Mukae, Syunji Mizunoe, Kenji Kishi, Issei Tokimatsu, Hiroyuki Nagai, Kazunori Tomono, Shigeru Kohno, Masaru Nasu
雑誌名: Intern Med. 2005 Mar;44(3):200-6.
Abstract/Text OBJECTIVE: In the current studies, we investigated the clinical effects of long-term macrolide antibiotic therapy for patients with chronic small airway disease (CAD) that clinically and radiologically mimics but is pathologically distinct from diffuse panbronchiolitis (DPB).
PATIENTS AND METHODS: Twenty-one Japanese patients were selected on the basis of clinical criteria for DPB and were categorized as DPB or CAD following histological evaluation of surgical lung biopsies. All patients received long-term macrolide therapy, and therapeutic results were compared for the DPB and CAD groups.
RESULTS: Clinical, laboratory, radiological, and bacterial features, as well as neutrophilia in bronchoalveolar lavage fluid were strikingly similar in both groups. Long-term treatment with macrolides improved the clinical symptoms and PaO(2) in both groups. There was a significant improvement in forced expiratory volume in one second (FEV(1)), vital capacity (VC), and %VC in patients with DPB but not in patients with CAD. Neutrophilia in bronchoalveolar lavage fluid was also reduced following therapy in DPB patients but was refractory in CAD patients.
CONCLUSION: Based on the different responses to macrolides, CAD might be associated with conditions distinct from those of DPB. Nevertheless, low-dose macrolide therapy may be applied in CAD to achieve clinical improvement, such as in respiratory symptoms and PaO(2).

PMID 15805707  Intern Med. 2005 Mar;44(3):200-6.

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