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Semin Respir Crit Care Med 2003; 24(6): 737-748
DOI: 10.1055/s-2004-815669
Copyright © 2003 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Macrolides as Biological Response Modifiers in Cystic Fibrosis and Bronchiectasis

Andrew Bush1,2 , Bruce K. Rubin3,4
  • 1Department of Pediatric Respirology, Imperial School of Medicine at National Heart and Lung Institute
  • 2Royal Brompton Hospital, London, United Kingdom
  • 3Department of Pediatrics, Wake Forest University Health Sciences, Winston-Salem, North Carolina
  • 4Department Biomedical Engineering, Physiology and Pharmacology, Wake Forest University Health Sciences, Winston-Salem, North Carolina
Further Information

Publication History

Publication Date:
15 January 2004 (online)

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ABSTRACT

For 50 years, macrolide antibiotics have been used to treat community acquired pneumonia and atypical infections such as Chlamydia pneumonia and Mycoplasma. In the late 1960s it was noted that when the 14-member ring macrolide antibiotic troleandomycin was given to asthma patients who required large doses of systemic corticosteroids, they could often reduce their steroid dose or even stop steroids completely without exacerbation of their asthma. Because of this experience, Prof. S. Kodoh and colleagues first used erythromycin as an immunomodulatory agent to treat diffuse panbronchiolitis (DPB). DPB is a cystic fibrosis (CF)-like condition seen predominantly in young, nonsmoking adults in Japan and Korea. The introduction of erythromycin profoundly improved survival, and in many of these very ill patients the illness disappeared. Since then, research has focused attention on many nonantibacterial, disease modifying effects of this class of compounds. These include downregulation of proinflammatory cytokines via an effect on nuclear transcription factors, reduction in adhesion molecule expression, suppression of inducible nitric oxide synthase (iNOS), reduced neutrophil chemotaxis and degranulation, inhibition of neutrophil elastase, cytoprotection against bioactive phospholipids, improvement in the rheological properties of mucus, reduction in bronchial hyperreactivity, and, perhaps, modulation of neutrophil death by apoptosis pathways, and in the end, airway remodeling. Additionally, they have unconventional effects on microorganisms, including inhibiting Pseudomonas aeruginosa twitching motility and thus biofilm formation. There are small case series and three large randomized controlled trials that have established unequivocal evidence of benefit in CF. There is less evidence for an immunomodulatory effect in bronchiectasis. Future work is likely to focus on the development of macrolides with disease-specific modes of action.

KEYWORDS

Cystic fibrosis - bronchiectasis - macrolide - cytokine - adhesion molecule - diffuse panbronchiolitis - neutrophils

REFERENCES

  • 1 Eigen H, Rosenstein B, Fitzsimmons S, Schidlow D. A multi-center study of alternate day prednisolone therapy in patients with cystic fibrosis.  J Pediatr . 1995;  126 515-523
    CrossrefPubMedGoogle Scholar
  • 2 Balfour-Lynn I M, Klein N J, Dinwiddie R. Randomised controlled trial of inhaled corticosteroids (fluticasone propionate) in cystic fibrosis.  Arch Dis Child . 1997;  77 124-130
    PubMedGoogle Scholar
  • 3 Bisgaard H, Pedersen S S, Nielsen K G. et al . Controlled trial of inhaled budesonide in patients with cystic fibrosis and chronic bronchopulmonary Pseudomonas aeruginosa infection.  Am J Respir Crit Care Med . 1997;  156 1190-1196
    CrossrefPubMedGoogle Scholar
  • 4 Konstan M W, Byard P J, Hoppel C L, Davis P B. Effect of high-dose ibuprofen in patients with cystic fibrosis.  N Engl J Med . 1995;  322 848-854
    PubMedGoogle Scholar
  • 5 Birrer P, McElvaney N G, Rudeberg C. et al . Protease-antiprotease imbalance in the lungs of children with cystic fibrosis.  Am J Respir Crit Care Med . 1994;  150 207-213
    PubMedGoogle Scholar
  • 6 Bonfield T L, Konstan M, Burfeind P, Panuska J R, Hilliard J B, Berger M. Normal bronchial epithelial cells constitutively produce the anti-inflammatory cytokine interleukin-10, which is down-regulated in cystic fibrosis.  Am J Respir Cell Mol Biol . 1995;  13 257-261
    PubMedGoogle Scholar
  • 7 Khan T Z, Wagener J S, Boat T, Martinez J, Accurso F J, Riches D W. Early pulmonary inflammation in patients with cystic fibrosis.  Am J Respir Crit Care Med . 1995;  151 1075-1082
    PubMedGoogle Scholar
  • 8 Konstan M W, Berger M. Current understanding of the inflammatory process in cystic fibrosis: onset and aetiology.  Pediatr Pulmonol . 1997;  24 137-142
    CrossrefPubMedGoogle Scholar
  • 9 Armstrong D S, Grimwood K, Carlin J B. et al . Lower airway inflammation in infants and young children with cystic fibrosis.  Am J Respir Crit Care Med . 1997;  156 1197-1204
    PubMedGoogle Scholar
  • 10 Muhlebach M S, Stewart P W, Leigh M W, Noah T L. Quantitation of inflammatory responses to bacteria in young cystic fibrosis and control patients.  Am J Respir Crit Care Med . 1999;  160 186-191
    CrossrefPubMedGoogle Scholar
  • 11 Scheid P, Kempster L, Griesenbach U. et al . Inflammation in cystic fibrosis airways: relationship to increased bacterial adherence.  Eur Respir J . 2001;  17 27-35
    CrossrefPubMedGoogle Scholar
  • 12 Nagai H, Shishido H, Yoneda R, Yamaguchi E, Tamura A, Kurashima A. Long-term, low-dose administration of erythromycin to patients with diffuse panbronchiolitis.  Respiration . 1991;  58 145-149
    PubMedGoogle Scholar
  • 13 Fujii T, Kadota J, Kawakami K. et al . Long-term effects of erythromycin therapy in patients with chronic Pseudomonas aeruginosa infection.  Thorax . 1995;  50 1246-1252
    PubMedGoogle Scholar
  • 14 Kudoh S, Azuma A, Yamamoto M, Izumi T, Ando M. Improvement in survival of patients with diffuse panbronchiolitis treated with low dose erythromycin.  Am J Respir Crit Care Med . 1998;  157 1829-1832
    CrossrefPubMedGoogle Scholar
  • 15 Høiby N. Diffuse panbronchiolitis and cystic fibrosis: East meets West.  Thorax . 1994;  49 531-532
    PubMedGoogle Scholar
  • 16 Oda H, Kadota J, Kohno S, Hara K. Erythromycin inhibits neutrophil chemotaxis in bronchoalveolar lavage in diffuse panbronchiolitis.  Chest . 1994;  106 1116-1123
    PubMedGoogle Scholar
  • 17 Rubin B K, Tamaoki J. Macrolide antibiotics as biological response modifiers.  Curr Opin Invest Drugs . 2000;  1 169-172
    PubMedGoogle Scholar
  • 18 Jaffe A, Bush A. Anti-inflammatory effects of macrolides in lung disease.  Pediatr Pulmonol . 2001;  31 464-473
    CrossrefPubMedGoogle Scholar
  • 19 Culic O, Erakovic V, Parnham M J. Anti-inflammatory effects of macrolide antibiotics.  Eur J Pharmacol . 2001;  429 209-229
    CrossrefPubMedGoogle Scholar
  • 20 Dumont F J. FK506, an immunosuppressant targeting calcineurin function.  Curr Med Chem . 2000;  7 731-748
    PubMedGoogle Scholar
  • 21 Mazzei T, Mini E, Novelli A, Perti P. Chemistry and mode of action of macrolides.  J Antimicrob Chemother . 1993;  31 (suppl C) S1-S9
    PubMedGoogle Scholar
  • 22 Wu Y J. Highlights of semi-synthetic developments from erythromycin A.  Curr Pharm Des . 2000;  6 181-223
    CrossrefPubMedGoogle Scholar
  • 23 Omura S. Macrolide Antibiotics: Chemistry, Biology, and Practice. San Diego: Elsevier Science 2002
    Google Scholar
  • 24 Bearden D T, Rodvold K A. Penetration of macrolides into pulmonary sites of infection.  Infect Med . 1999;  16 480-484
    PubMedGoogle Scholar
  • 25 Miossec-Bartoli C, Pilatre L, Peyron P. et al . The new ketolide HMR3647 accumulates in the azurophil granule of human polymorhonuclear cells.  Antimicrob Agents Chemother . 1999;  43 2457-2462
    PubMedGoogle Scholar
  • 26 Vazifeh D, Abdelghaffar H, Labro M T. Cellular accumulation of the new ketolides RU64004 by human neutrophils: comparison with that of azithromycin and roxithromycin.  Antimicrob Agents Chemother . 1997;  41 2099-2107
    PubMedGoogle Scholar
  • 27 McDonald P J, Pruul H. Phagocyte uptake and transport of azithromycin.  Eur J Clin Microbiol Infect Dis . 1991;  10 828-833
    PubMedGoogle Scholar
  • 28 Sakito O, Kadota J, Kohno S. et al . Interleukin-1, tumor necrosis factor-alpha, and interleukin-8 in bronchoalveolar lavage fluid of patients with diffuse panbronchiolitis: a potential mechanism for macrolide therapy.  Respiration . 1996;  63 42-48
    PubMedGoogle Scholar
  • 29 Khair O A, Devalia J L, Abdelaziz M M, Sapsford R J, Davies R J. Effect of erythromycin on Haemophilus influenzae endotoxin-induced release of IL-6, IL-8 and sICAM-1 by cultured human bronchial epithelial cells in vitro.  Eur Respir J . 1995;  8 1451-1457
    PubMedGoogle Scholar
  • 30 Kawasaki S, Takizawa H, Ohtushi T. et al . Roxithromycin inhibits cytokine production by and neutrophil attachment to human bronchial epithelial cells in vitro.  Antimicrob Agents Chemother . 1998;  42 1499-1502
    PubMedGoogle Scholar
  • 31 Ashitani J, Mukae H, Nakazato M. et al . Elevated concentrations of defensins in bronchoalveolar lavage fluid in serum of patients with diffuse panbronchiolitis.  Eur Respir J . 1998;  11 104-111
    CrossrefPubMedGoogle Scholar
  • 32 Mukae H, Kadota J, Ashitani J. et al . Elevated levels of soluble adhesion molecules in serum of patients with diffuse panbronchiolitis.  Chest . 1997;  112 1615-1621
    PubMedGoogle Scholar
  • 33 Takizawa H, Desaki M, Ohtoshi T. et al . Erythromycin modulates IL-8 expression in normal and inflamed human bronchial epithelial cells.  Am J Respir Crit Care Med . 1997;  156 266-271
    PubMedGoogle Scholar
  • 34 Desaki M, Takizawa H, Ohtoshi T. et al . Erythromycin suppresses nuclear factor-κβ and activator protein-1 in human bronchial epiuthelial cells.  Biochem Biophys Res Commun . 2000;  267 124-128
    CrossrefPubMedGoogle Scholar
  • 35 Aoki Y, Kao P N. Erythromycin inhibits transcriptional activation of NF-κB, but not NFAT, through calcineurin-independent signalling in T-cells.  Antimicrob Agents Chemother . 1999;  43 2678-2684
    PubMedGoogle Scholar
  • 36 Abe S, Nakamura H, Inoue S. et al . Interleukin-8 gene repression by clarithromycin is mediated by activator protein-1 binding site in human bronchial epithelial cells.  Am J Respir Cell Mol Biol . 2000;  22 51-60
    PubMedGoogle Scholar
  • 37 Iino T, Toriyama M, Kudo K, Natori Y, You A. Erythromycin inhibition of lipopolysaccharide-stimulated tumor necrosis factor alpha production by human monocytes in vitro.  Ann Otol Rhinol Laryngol . 1992;  157(suppl) 16-20
    PubMedGoogle Scholar
  • 38 Schultz M J, Speelman P, Zaat S, van Deventer J S, van der Poll T. Erythromycin inhibits tumor necrosis alpha and interleukin-6 production induced by heat-killed Streptococcus pneumoniae in whole blood.  Antimicrob Agents Chemother . 1998;  42 1605-1609
    PubMedGoogle Scholar
  • 39 Kohyama T, Takizawa H, Kawasaki S. et al . Fourteen-membered macrolides inhibit interleukin-8 release by human eosinophils from atopic donors.  Antimicrob Agents Chemother . 1999;  43 907-911
    PubMedGoogle Scholar
  • 40 Sato E, Nelson D K, Koyama S, Hoyt J C, Robbins R A. Erythromycin modulates eosinophil chemotactic cytokine production by human lung fibroblasts in vitro.  Antimicrob Agents Chemother . 2001;  45 401-406
    CrossrefPubMedGoogle Scholar
  • 41 Shimane T, Asano K, Suzuki M, Hisamitsu T, Suzaki H. Influence of a macrolide antibiotic, roxithromycin, on mast cell growth and activation in vitro.  Mediators Inflamm . 2001;  10 323-332
    CrossrefPubMedGoogle Scholar
  • 42 Khan A A, Silfer T R, Araujo G, Remington J S. Effects of clarithromycin and azithromycin on production of cytokines by human monoocytes.  Int J Antimicrob Agents . 1999;  11 121-132
    PubMedGoogle Scholar
  • 43 Schultz M J, Speelman P, Hack C E. et al . Intravenous infusion of erythromycin inhibits CXC chemokine production, but augments neutrophil degranulation in whole blood stimulated with Streptococcus pneumoniae J Antimicrob Chemother .  2000;  46 235-240
    PubMedGoogle Scholar
  • 44 Lin H C, Wang C H, Liu C Y, Yu C T, Kuo H P. Erythromycin inhibits beta2 integrins (CD11b/CD18) expression, interleukin-8 release and intracellular oxidative metabolism in neutrophils.  Respir Med . 2000;  94 654-660
    PubMedGoogle Scholar
  • 45 Matsuoka N, Eguchi K, Kawakami A. et al . Inhibitory effect of clarithromycin on costimulatory molecule expression and cytokine production by synovial fibroblast-like cells.  Clin Exp Immunol . 1996;  104 501-508
    CrossrefPubMedGoogle Scholar
  • 46 Mitsuyama T, Hidaka K, Furono T, Hara N. Neutrophil-induced endothelial cell damage: inhibition by a 14-membered ring macrolide through the action of nitric oxide.  Int Arch Allergy Immunol . 1997;  114 111-115
    PubMedGoogle Scholar
  • 47 Tamaoki J, Kondo M, Kohri K. et al . Macrolide antibiotics protect against immune complex-induced lung injury in rats: role of nitric oxide from alveolar macrophages.  J Immunol . 1999;  163 2909-2915
    PubMedGoogle Scholar
  • 48 Witko-Sarsat V, Rieu P, Descamps-Latscha B, Lesavre P, Halbachs-Mecarelli L. Neutrophils: molecules, functions, and pathophysiological aspects.  Lab Invest . 2000;  80 617-653
    CrossrefPubMedGoogle Scholar
  • 49 Hojo M, Fujita I, Mamasaki M, Miyazaki S. Erythromycin does not affect neutrophil functions.  Chest . 1994;  106 1116-1123
    PubMedGoogle Scholar
  • 50 Torre D, Broggini M, Botta V. et al . In vitro and ex vivo effects of recent and new macrolide antibiotics on chemotaxis of human polymorphonuclear leukocytes.  J Chemother . 1991;  3 236-239
    PubMedGoogle Scholar
  • 51 Labro M T, el Benna J, Babin-Chevaye C. Comparison of the in vitro effect of several macrolides on the oxidative burst of human neutrophils.  J Antimicrob Chemother . 1989;  24 561-572
    PubMedGoogle Scholar
  • 52 Villagrasa V, Berto L, Cortijo J. et al . Effects of erythromycin on chemoattractant-activated human polymorphonuclear leukocytes.  Gen Pharmacol . 1997;  29 605-609
    CrossrefPubMedGoogle Scholar
  • 53 Hand W L, Hand D L, King-Thompson N L. Antibiotic inhibition of the respiratory burst in human polymorphonuclear leucocytes.  Antimicrob Agents Chemother . 1990;  34 863-870
    PubMedGoogle Scholar
  • 54 Aoshiba K, Nagai A, Konno K. Erythromycin shortens neutrophil survival by accelerating apoptosis.  Antimicrob Agents Chemother . 1995;  39 872-877
    PubMedGoogle Scholar
  • 55 Brennan S, Cooper D, Sly P D. Directed neutrophil migration to IL-8 is increased in cystic fibrosis: a study of the effect of erythromycin.  Thorax . 2001;  56 62-64
    CrossrefPubMedGoogle Scholar
  • 56 Andersen R, Fernandes A C, Eftychis H E. Studies on the ingestion of a single 500 mg oral dose of erythromycin stearate on leucocyte motility and transformation and on release in vitro of prostaglandin E2 by stimulated leucocytes.  J Antimicrob Chemother . 1984;  14 41-50
    PubMedGoogle Scholar
  • 57 Andersen R. Erythromycin and roxithromycin potentiate human neutrophil locomotion in vitro by inhibition of leukoattractant-activated superoxide generation and autooxidation.  J Infect Dis . 1989;  159 966-973
    PubMedGoogle Scholar
  • 58 Gorrini M, Lupi A, Viglio S. et al . Inhibition of human neutrophil elastase by erythromycin and flurythromycin, two macrolide antibiotics.  Am J Respir Cell Mol Biol . 2001;  25 492-499
    PubMedGoogle Scholar
  • 59 Jones A, Elphick H, Pettitt E, Everard M L, Evans G S. Colistin stimulates the activity of neutrophil elastase and Pseudomonas aeruginosa elastase.  Eur Respir J . 2002;  19 1136-1141
    CrossrefPubMedGoogle Scholar
  • 60 Feldman C, Anderson R, Theron A J. et al . Roxithromycin, clarithromycin, and azithromycin attenuate the injurious effects of bioactive phospholipids on human respiratory epithelium in vitro.  Inflammation . 1997;  21 655-665
    CrossrefPubMedGoogle Scholar
  • 61 Feldman C, Anderson R, Theron A. et al . The effects of ketolides on bioactive phospholipid-induced injury to human respiratory epithelium in vitro.  Eur Respir J . 1999;  13 1022-1028
    CrossrefPubMedGoogle Scholar
  • 62 Okamoto K, Kishioka C, Kim J S. et al . Erythromycin inhibits mucin secretion in the inflamed trachea.  Am J Respir Crit Care Med . 1999;  159 A35
    PubMedGoogle Scholar
  • 63 Tamaoki J, Takeyama K, Tagaya E, Konno K. Effect of clarithromycin on sputum production and its rheological properties in chronic respiratory infections.  Antimicrob Agents Chemother . 1995;  39 1688-1690
    PubMedGoogle Scholar
  • 64 Rubin B K, Druce H, Ramirez O E, Palmer R. Effect of clarithromycin on nasal mucus properties in healthy subjects and in patients with purulent rhinitis.  Am J Respir Crit Care Med . 1997;  155 2018-2023
    PubMedGoogle Scholar
  • 65 Rubin B K. A superficial view of mucus and the cystic fibrosis defect.  Pediatr Pulmonol . 1992;  13 4-5
    PubMedGoogle Scholar
  • 66 Shibuya Y, Wills P J, Cole P J. The effect of erythromycin on mucociliary transportability and rheology of cystic fibrosis and bronchiectasis sputum.  Respiration . 2001;  68 615-619
    CrossrefPubMedGoogle Scholar
  • 67 Miyatake H, Taki F, Taniguchi H. et al . Erythromycin reduces the severity of bronchial hyperresponsiveness in asthma.  Chest . 1991;  99 670-673
    PubMedGoogle Scholar
  • 68 Takizawa H, Desaki M, Ohtoshi T. et al . Erythromycin and clarithromycin attenuate cytokine-induced endothelin-1 expression in human bronchial epithelial cells.  Eur Respir J . 1998;  12 57-63
    CrossrefPubMedGoogle Scholar
  • 69 Tamaoki J, Tagaya E, Sakai A, Konno K. Effect of macrolide antibiotics on neurally mediated contraction of human isolated bronchus.  J Allergy Clin Immunol . 1995;  95 853-859
    PubMedGoogle Scholar
  • 70 Yatsunami J, Fukuno Y, Nagata M. et al . Antiangiogenic and antitumor effects of 14-membered macrolides on mouse B16 melanoma cells.  Clin Exp Metastasis . 1999;  17 361-367
    PubMedGoogle Scholar
  • 71 Yatsunami J, Tsuruta N, Hara N, Hayashi S. Inhibition of tumour angiogenesis by roxithromycin, a 14-membered ring macrolide antibiotic.  Cancer Lett . 1998;  131 137-143
    CrossrefPubMedGoogle Scholar
  • 72 Oyama T, Sakuta T, Matsushita K. et al . Effects of roxithromycin on tumor necrosis factor-alpha-induced vascular endothelial growth factor expression in human periodontal ligament cells in culture.  J Periodontol . 2000;  71 1546-1553
    CrossrefPubMedGoogle Scholar
  • 73 Kitadai Y, Takahashi Y, Haruma K. et al . Transfection of interleukin-8 increases angiogenesis and tumorigenesis of human gastric carcinoma cells in nude mice.  Br J Cancer . 1999;  81 647-653
    CrossrefPubMedGoogle Scholar
  • 74 Yatsunami J, Tsuruta N, Ogata K. et al . Interleukin-8 participates in angiogenesis in non-small cell but not small cell carcinoma of the lung.  Cancer Lett . 1998;  120 101-108
    PubMedGoogle Scholar
  • 75 Nonaka M, Pawankar R, Tomiyama S, Yagi T. A macrolide antibiotic, roxithromycin, inhibits the growth of nasal polyp fibroblasts.  Am J Rhinol . 1999;  13 267-272
    PubMedGoogle Scholar
  • 76 Davies J, Stern M, Dewar A. et al . CFTR gene transfer reduces the binding of Pseudomonas aeruginosa to cystic fibrosis respiratory epithelium.  Am J Respir Cell Mol Biol . 1997;  16 657-663
    PubMedGoogle Scholar
  • 77 Pier G B, Grout M, Zaidi T S. et al . Role of mutant CFTR in hypersusceptibility of cystic fibrosis patients to lung infections.  Science . 1996;  271 64-67
    CrossrefPubMedGoogle Scholar
  • 78 Smith J J, Travis S M, Greenberg E P, Welsh M J. Cystic fibrosis airway epithelia fail to kill bacteria because of abnormal airway surface fluid.  Cell . 1996;  85 229-236
    CrossrefPubMedGoogle Scholar
  • 79 Baumann U, Fischer J J, Gudowius P. et al . Buccal adherence of Pseudomonas aeruginosa in patients with cystic fibrosis under long-term therapy with azithromycin.  Infection . 2001;  29 7-11
    CrossrefPubMedGoogle Scholar
  • 80 Tsang K W, Ng P, Ho P L. et al . Effects of erythromycin on Pseudomonas aeruginosa adherence to collagen and morphology in vitro Eur Respir J .  2003;  21 401-406
    PubMedGoogle Scholar
  • 81 Yamasaki T. Adherence of Pseudomonas aeruginosa to mouse tracheal epithelium: the effect of antimicrobial agents.  J Jpn Assoc Infect Dis . 1990;  64 575-583
    PubMedGoogle Scholar
  • 82 Kawamura-Sato K, Iinuma Y, Hasegagwa T. et al . Effect of subinhibitory concentrations of macrolides on the expression of flagellin in Pseudomonas aeruginosa and Proteus mirabilis Antimicrob Agents Chemother .  2000;  44 2869-2872
    PubMedGoogle Scholar
  • 83 Kawamura-Sato K, Iinuma Y, Hasegagwa T, Yamashino T, Ohta M. Postantibiotic suppression effect of macrolides on the expression of flagellin in Pseudomonas aeruginosa and Proteus mirabilis J Infect Chemother .  2001;  7 51-54
    PubMedGoogle Scholar
  • 84 Tateda K, Ishii Y, Matsumoto T. et al . Direct evidence for antipseudomonal activity of macrolides: exposure-dependant bactericidal activity and inhibition of protein synthesis by erythromycin, clarithromycin, and azithromycin.  Antimicrob Agents Chemother . 1996;  40 2271-2275
    PubMedGoogle Scholar
  • 85 Kishioka C, Okamoto K, Hassett D J, de Mello D, Rubin B K. Pseudomonas aeruginosa alginate is a potent secretagogue in the isolated ferret trachea.  Pediatr Pulmonol . 1999;  27 174-179
    CrossrefPubMedGoogle Scholar
  • 86 Kobayashi H. Biofilm disease: its clinical manifestation and therapeutic possibilities of macrolides.  Am J Med . 1995;  99 265-305
    PubMedGoogle Scholar
  • 87 Mizukane R, Hirataka Y, Kaku M. et al . Comparative in vitro exoenzyme-suppressing activities of azithromycin and other macrolide antibiotics against Pseudomonas aeruginosa Antimicrob Agents Chemother .  1994;  38 528-533
    PubMedGoogle Scholar
  • 88 Saiman L, Chen Y, Gabriel P S, Knirsch C. Synergistic activities of macrolide antibiotics against Pseudomonas aeruginosa, Burkholderia cepacia, Stenotrophomonas maltophilia, and Alcaligenes xylosidans isolated from patients with cystic fibrosis.  Antimicrob Agents Chemother . 2002;  46 1105-1107
    CrossrefPubMedGoogle Scholar
  • 89 Torrens T K, Dawkins P, Conway S P, Moya E. Non-tuberculous mycobacteria in cystic fibrosis.  Thorax . 1998;  53 182-185
    CrossrefPubMedGoogle Scholar
  • 90 Wallace Jr J R, Zhang Y, Brown-Elliot B A. et al . Repeat positive cultures in Mycobacterium intracellulare lung disease after macrolide therapy represent new infections in patients with nodular bronchiectasis.  J Infect Dis . 2002;  186 266-273
    CrossrefPubMedGoogle Scholar
  • 91 McKlendin K, Stark P. Mycobacterium avium intracellulare complex as a cause of bronchiectasis.  Semin Respir Infect . 2001;  16 85-87
    PubMedGoogle Scholar
  • 92 Piedmonte G, Wolford E T, Fordham L A, Leigh M W, Wood R E. Mediastinal lymphadenopathy caused by Mycobacterium avium-intracellulare complex in a child with normal immunity.  Pediatr Pulmonol . 1997;  24 287-291
    CrossrefPubMedGoogle Scholar
  • 93 Tsang K W, Lam S-K, Lam W-K. et al . High seroprevalence of Helicobacter pylori in active bronchiectasis.  Am J Respir Crit Care Med . 1998;  158 1047-1051
    PubMedGoogle Scholar
  • 94 Lallemand J Y, Stoven V, Annereau J P. et al . Induction by antitumoral drugs of proteins that functionally complement CFTR: a novel therapy for cystic fibrosis [abstract].  Lancet . 1997;  350 711-712
    PubMedGoogle Scholar
  • 95 Sermet-Gaudelus I, Kessler R, Stoven V. et al . Dramatic improvement of cystic fibrosis during and after antitumurous chemotherapy: a report of three cases.  Pediatr Pulmonol . 1998;  17(suppl) 219-220
    PubMedGoogle Scholar
  • 96 Gant T W, O'Connor C K, Corbitt R, Thorgeirsson U, Thorgeirsson S S. In vivo induction of liver p-glycoprotein expression by xenobiotics in monkeys.  Toxicol Appl Pharmacol . 1995;  133 269-276
    CrossrefPubMedGoogle Scholar
  • 97 Altschuler E L. Azithromycin, the multidrug resistant protein, and cystic fibrosis [letter].  Lancet . 1998;  351 1286
    PubMedGoogle Scholar
  • 98 Kanoh S, Kondo M, Tamaoki J. et al . Effect of FK506 on ATP-induced intracellular calcium oscillations in cow tracheal epithelium.  Am J Physiol (Lung Cell Molec Physiol) . 1999;  276 L891-L899
    PubMedGoogle Scholar
  • 99 Zhao D-M, Xue H-H, Chida K. et al . Effect of erythromycin on ATP-induced intracellular calcium response in A549 cells.  Am J Physiol . 2000;  278 L276-L336
    PubMedGoogle Scholar
  • 100 Tamaoki J, Isono K, Sakai N, Kanemura T, Konno K. Erythromycin inhibits Cl secretion across canine epithelial cells.  Eur Respir J . 1992;  5 234-238
    PubMedGoogle Scholar
  • 101 Nakanishi N, Ueda N, Kitade M, Moritaka T. A case of cystic fibrosis in a Japanese student.  Jpn J Thoracic Dis . 1995;  33 771-774
    PubMedGoogle Scholar
  • 102 Ordonez C L, Stulbarg M, Grundland H. et al . Effect of clarithromycin on airway obstruction and sputum neutrophilia in patients with cystic fibrosis.  Am J Respir Crit Care Med . 1999;  159 A680
    PubMedGoogle Scholar
  • 103 Jaffe A, Francis J, Rosenthal M, Bush A. Long-term azithromycin may improve lung function in children with cystic fibrosis [research letter].  Lancet . 1998;  351 420
    CrossrefPubMedGoogle Scholar
  • 104 Wolter J, Seeney S, Bell S. et al . Effect of long-term treatment with azithromycin on disease parameters in cystic fibrosis: a randomised controlled trial.  Thorax . 2002;  57 212-216
    CrossrefPubMedGoogle Scholar
  • 105 Equi A, Balfour-Lynn I, Bush A, Rosenthal M. Long-term azithromycin in children with cystic fibrosis: a randomized, placebo-controlled crossover trial.  Lancet . 2002;  360 978-984
    CrossrefPubMedGoogle Scholar
  • 106 Ripoll L, Reinert P, Pepin L F, Lagrange P H. Interaction of macrolides with alpha dornase during DNA hydrolysis.  J Antimicrob Chemother . 1996;  37 987-991
    PubMedGoogle Scholar
  • 107 Saiman L, Marshall B C, Mayer-Hamblett N. Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial.  JAMA . 2003;  290 1749-1756
    CrossrefPubMedGoogle Scholar
  • 108 Ordonez C L, Stulbarg M, Grundland H, Liu J T, Boushet H A. Effect of clarithromycin on airway obstruction and inflammatory markers in induced sputum in cystic fibrosis: a pilot study.  Pediatr Pulmonol . 2001;  32 29-37
    CrossrefPubMedGoogle Scholar
  • 109 Southern K W, Barker P M, Solis A. Macrolide antibiotics for cystic fibrosis.  Cochrane Database Syst Rev . 2000;  (3) CD002203
    PubMedGoogle Scholar
  • 110 Seppala H, Klauka T, Vuopio-Varkila J. et al . The effect of changes in the consumption of macrolide antibiotics on erythromycin resistance in group A streptococci in Finland. Finnish Study Group for Antimicrobial Resistance.  N Engl J Med . 1997;  337 441-446
    CrossrefPubMedGoogle Scholar
  • 111 Tagaya E, Tamaoki J, Kondo M, Nagai A. Effect of a short course of clarithromycin therapy on sputum production in patients with chronic airway hypersecretion.  Chest . 2002;  122 213-218
    CrossrefPubMedGoogle Scholar
  • 112 Tsang K W, Ho P I, Chan K N. et al . A pilot study of low-dose erythromycin in children with bronchiectasis: a double-blind, placebo-controlled study.  Eur Respir J . 1997;  10 994-999
    CrossrefPubMedGoogle Scholar
  • 113 Koh Y Y, Lee M H, Sun Y H, Sung K W, Chae J H. Effect of roxithromycin on airway responsiveness in children with bronchiectasis: a double-blind, placebo-controlled study.  Eur Respir J . 1997;  10 994-999
    CrossrefPubMedGoogle Scholar
  • 114 de Benedictis M F, Bush A. Hypothesis paper: rhinosinusitis and asthma-epiphenomenon or causal association?.  Chest . 1999;  115 550-556
    CrossrefPubMedGoogle Scholar
  • 115 Rhee C-S, Majima Y, Arima S. et al . Effects of clarithromycin on rheological properties of nasal mucus in patients with chronic sinusitis.  Ann Otol Rhinol Laryngol . 2000;  109 484-487
    PubMedGoogle Scholar
  • 116 MacLeod C M, Hamid Q A, Cameron L, Tremblay C, Brisco W. Anti-inflammatory activity of clarithromycin in adults with chronically inflamed sinus mucosa.  Adv Ther . 2001;  18 75-82
    PubMedGoogle Scholar
  • 117 Yamada T, Fujieda S, Mori S, Yamamoto H, Saito H. Macrolide treatment decreased the size of nasal polyps and IL-8 levels in nasal lavage.  Am J Rhinol . 2000;  14 143-148
    PubMedGoogle Scholar
  • 118 Suzuki H, Shimomura A, Ikeda K. et al . Inhibitory effect of macrolides on interleukin-8 secretion from cultured nasal epithelial cells.  Laryngoscope . 1997;  107 1661-1666
    PubMedGoogle Scholar
  • 119 Katz L, Doniado S. Polyketide synthesis: prospects for hybrid antibiotics.  Annu Rev Microbiol . 1993;  47 875-912
    CrossrefPubMedGoogle Scholar
  • 120 Tsoi C J, Khosla C. Combinatorial biosynthesis of “unnatural” natural products: the polyketide example.  Chem Biol . 1995;  2 355-362
    CrossrefPubMedGoogle Scholar
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