Long‐Term Azithromycin Therapy in Cystic Fibrosis Patients: A Study on Drug Levels and Sputum Properties

Baumann, Ulrich; King, Malcolm; App, Ernst M.; Tai, Shusheng; König, Armin; Fischer, J.J.; Zimmermann, Till; Sextro, Wolfgang; Hardt, H. von der

doi:10.1155/2004/747841

Cited by 45 publications

(26 citation statements)

References 24 publications

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“…The 0.125-g/ml concentration of azithromycin used in these studies is approximately that found in serum (28). More importantly, azithromycin concentrates in human tissues, attaining 3 g/ml in airway surface liquid (28) and 9 g/ml in CF sputum (1). This study showed that even the most azithromycin resistant of over 6,000 clinical NTHi isolates were susceptible to biofilm inhibition at sub-MIC azithromycin concentrations (Fig.…”

Section: Discussionmentioning

confidence: 81%

Subinhibitory Concentrations of Azithromycin Decrease Nontypeable Haemophilus influenzae Biofilm Formation and Diminish Established Biofilms

Starner

Shrout

Parsek

et al. 2008

Antimicrob Agents Chemother

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Nontypeable Haemophilus influenzae (NTHi) commonly causes otitis media, chronic bronchitis in emphysema, and early airway infections in cystic fibrosis. Long-term, low-dose azithromycin has been shown to improve clinical outcomes in chronic lung diseases, although the mechanism of action remains unclear. The inhibition of bacterial biofilms by azithromycin has been postulated to be one mechanism mediating these effects. We hypothesized that subinhibitory concentrations of azithromycin would affect NTHi biofilm formation. Laboratory strains of NTHi expressing green fluorescent protein and azithromycin-resistant clinical isolates were grown in flow-cell and static-culture biofilm models. Using a range of concentrations of azithromycin and gentamicin, we measured the degree to which these antibiotics inhibited biofilm formation and persistence. Large biofilms formed over 2 to 4 days in a flow cell, displaying complex structures, including towers and channels. Subinhibitory concentrations of azithromycin significantly decreased biomass and maximal thickness in both forming and established NTHi biofilms. In contrast, subinhibitory concentrations of gentamicin had no effect on biofilm formation. Furthermore, established NTHi biofilms became resistant to gentamicin at concentrations far above the MIC. Biofilm formation of highly resistant clinical NTHi isolates (azithromycin MIC of >64 g/ml) was similarly decreased at subinhibitory azithromycin concentrations. Clinically obtainable azithromycin concentrations inhibited biofilms in all but the most highly resistant isolates. These data show that subinhibitory concentrations of azithromycin have antibiofilm properties, provide mechanistic insights, and supply an additional rationale for the use of azithromycin in chronic biofilm infections involving H. influenzae.

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Section: Discussionmentioning

confidence: 81%

Subinhibitory Concentrations of Azithromycin Decrease Nontypeable Haemophilus influenzae Biofilm Formation and Diminish Established Biofilms

Starner

Shrout

Parsek

et al. 2008

Antimicrob Agents Chemother

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“…Importantly, there have been many reports of the anti-inflammatory properties of azithromycin [24,25]. As a result, low-dose azithromycin has already been used for clinical trials in various disease states, including cystic fibrosis [26], panbronchiolitis [27] and bronchiolitis obliterans [22]. In addition, an in vivo study of human volunteers treated with 500 mg?day -1 azithromycin for 3 days demonstrated an increase in neutrophil apoptosis up to 28 days after the last azithromycin dose, and a continuous fall in chemokine and IL-6 concentrations in serum [28].…”

Section: Discussionmentioning

confidence: 99%

Azithromycin increases phagocytosis of apoptotic bronchial epithelial cells by alveolar macrophages

Hodge¹,

Hodge²,

Brozyna³

et al. 2006

European Respiratory Journal

176

152

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Chronic obstructive pulmonary disease (COPD) is associated with increased apoptosis and defective phagocytosis in the airway. As uncleared cells can undergo secondary necrosis and perpetuate inflammation, strategies to improve clearance would have therapeutic significance. There is evidence that the 15-member macrolide antibiotic azithromycin has antiinflammatory properties. Its effects may be increased in the lung due to its ability to reach high concentrations in alveolar macrophages (AMs).The present study investigated the effects of low-dose (500 ng?mL -1 ) azithromycin on the phagocytosis of apoptotic bronchial epithelial cells and neutrophils by AMs. Flow cytometry was applied to measure phagocytosis and receptors involved in AM recognition of apoptotic cells. Cytokines were investigated using cytometric bead array. Baseline phagocytosis was reduced in COPD subjects compared with controls. Azithromycin significantly improved the phagocytosis of epithelial cells or neutrophils by AMs from COPD subjects by 68 and 38%, respectively, often up to levels comparable with controls.The increase in phagocytosis was partially inhibited by phosphatidylserine, implicating the phosphatidylserine pathway in the pro-phagocytic effects of azithromycin. Azithromycin had no effect on other recognition molecules (granulocyte-macrophage colony-stimulating factor, CD44, CD31, CD36, CD91, avb3 integrin). At higher doses, azithromycin decreased levels of proinflammatory cytokines. Thus, low-dose azithromycin therapy could provide an adjunct therapeutic option in chronic obstructive pulmonary disease.

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“…Consequently, administration of azithromycin to COPD patients for 12 weeks significantly improved AM phagocytosis [37]. Low doses of azithromycin were reported to have not only a beneficial anti-inflammatory effect in COPD, CF and panbronchiolitis [93,94], but also to improve phagocytosis when given for 12 weeks, possibly by increasing the surface expression of MR [37].…”

Section: Possible Strategies For Improvement Of Apoptotic Cell Clearancementioning

confidence: 99%

Impairment of phagocytosis of apoptotic cells and its role in chronic airway diseases

et al. 2010

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Phagocytosis of dying cells is a complex and dynamic process coordinated by the interaction of many surface molecules, adaptors, and chemotactic molecules, and it is controlled at multiple levels. This well regulated clearance process is of utmost importance for the development and homeostasis of organisms because defective or inefficient phagocytosis may contribute to human pathologies. In this review we discuss recent advances in the knowledge of the molecular interactions involved in recognition and clearance of apoptotic cells and how derangement of these processes can contribute to the pathogenesis of chronic airway diseases such as chronic obstructive pulmonary disease, cystic fibrosis and asthma. We will briefly consider how different types of macrophages are implicated in chronic airway diseases. Finally, we will address possible therapeutic strategies, such as the use of macrolide antibiotics and statins, for modulating apoptotic cell clearance.

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Long‐Term Azithromycin Therapy in Cystic Fibrosis Patients: A Study on Drug Levels and Sputum Properties

Abstract: The findings suggest that antipseudomonal activity has to be considered among the potential mechanisms of macrolide therapy. Further, viscoelasticity may be a valuable parameter in future clinical trials.

Cited by 45 publications

References 24 publications

Subinhibitory Concentrations of Azithromycin Decrease Nontypeable Haemophilus influenzae Biofilm Formation and Diminish Established Biofilms

Subinhibitory Concentrations of Azithromycin Decrease Nontypeable Haemophilus influenzae Biofilm Formation and Diminish Established Biofilms

Azithromycin increases phagocytosis of apoptotic bronchial epithelial cells by alveolar macrophages

Impairment of phagocytosis of apoptotic cells and its role in chronic airway diseases

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