Azithromycin in Patients With Cystic Fibrosis Chronically Infected With Pseudomonas aeruginosa

Saiman, Lisa; Marshall, Bruce C.; Mayer-Hamblett, Nicole; Burns, Jane L.; Quittner, Alexandra L.; Cibene, Debra A.; Coquillette, Sarah J.; Fieberg, Ann Yunker; Accurso, Frank J.; Campbell, Preston W.; Group, for the Macrolide Study

doi:10.1001/jama.290.13.1749

Cited by 904 publications

(676 citation statements)

References 28 publications

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“…The observed anti-virulence activity is likely to be involved in the clinical benefits associated with AZM treatment in the first year of therapy while the reduced efﬁcacy associated with longer treatment duration might be due to development of bacterial resistance to AZM anti-virulence activity. Thereby, evaluation of molecules with similar antibacterial mechanisms is important to find alternative treatments for patients not responding to AZM or for whom the treatment lost efficacy during time [18,29]. …”

Section: Discussionmentioning

confidence: 99%

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Inhibition of Pseudomonas aeruginosa secreted virulence factors reduces lung inflammation in CF mice

et al. 2018

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Background: Cystic fibrosis (CF) lung infection is a complex condition where opportunistic pathogens and defective immune system cooperate in developing a constant cycle of infection and inflammation. The major pathogen, Pseudomonas aeruginosa, secretes a multitude of virulence factors involved in host immune response and lung tissue damage. In this study, we examined the possible anti-inflammatory effects of molecules inhibiting P. aeruginosa virulence factors.Methods: Pyocyanin, pyoverdine and proteases were measured in bacterial culture supernatant from different P. aeruginosa strains. Inhibition of virulence factors by sub-inhibitory concentrations of clarithromycin and by protease inhibitors was evaluated. Lung inflammatory response was monitored by in vivo bioluminescence imaging in wild-type and CFTR-knockout mice expressing a luciferase gene under the control of a bovine IL-8 promoter.Results: The amount of proteases, pyocyanin and pyoverdine secreted by P. aeruginosa strains was reduced after growth in the presence of a sub-inhibitory dose of clarithromycin. Intratracheal challenge with culture supernatant containing bacteria-released products induced a strong IL-8-mediated response in mouse lungs while lack of virulence factors corresponded to a reduction in bioluminescence emission. Particularly, sole inactivation of proteases by inhibitors Ilomastat and Marimastat also resulted in decreased lung inflammation.Conclusions: Our data support the assumption that virulence factors are involved in P. aeruginosa pro-inflammatory action in CF lungs; particularly, proteases seem to play an important role. Inhibition of virulence factors production and activity resulted in decreased lung inflammation; thus, clarithromycin and protease inhibitors potentially represent additional therapeutic therapies for P. aeruginosa-infected patients.

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Section: Discussionmentioning

confidence: 99%

“…Unfortunately, there is a number of patients that do not benefit from AZM therapy or that show adverse effects to the drug [18]. Especially for these patients, it is important to find alternative treatments.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Pseudomonas aeruginosa secreted virulence factors reduces lung inflammation in CF mice

et al. 2018

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“…Subinhibitory concentrations of macrolides have been shown to be effective in inhibiting quorum-sensingdependent virulence both in vivo and in vitro (Imamura et al, 2004;Molinari et al, 1993;Sofer et al, 1999;Tateda et al, 2001). Furthermore, CF patients showed significant improvement in pulmonary function with the use of macrolides without any effect on the total Pseudomonas population (Fujii et al, 1995;Saiman et al, 2003). Despite its success in decreasing P. aeruginosa virulence, macrolides are not ideal because, like any other antibiotic, excessive usage is associated with bacterial resistance.…”

Section: C M Antunes and Othersmentioning

confidence: 99%

Quorum sensing in bacterial virulence

et al. 2010

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Bacteria communicate through the production of diffusible signal molecules termed autoinducers. The molecules are produced at basal levels and accumulate during growth. Once a critical concentration has been reached, autoinducers can activate or repress a number of target genes. Because the control of gene expression by autoinducers is cell-density-dependent, this phenomenon has been called quorum sensing. Quorum sensing controls virulence gene expression in numerous micro-organisms. In some cases, this phenomenon has proven relevant for bacterial virulence in vivo. In this article, we provide a few examples to illustrate how quorum sensing can act to control bacterial virulence in a multitude of ways. Several classes of autoinducers have been described to date and we present examples of how each of the major types of autoinducer can be involved in bacterial virulence. As quorum sensing controls virulence, it has been considered an attractive target for the development of new therapeutic strategies. We discuss some of the new strategies to combat bacterial virulence based on the inhibition of bacterial quorum sensing systems.

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“…The possibility that macrolides might modify the neutrophilic inflammatory response in CF was first investigated in the early 2000s. Since then, a number of clinical trials have confirmed their beneficial effects both in adults and children [31][32][33][34][35][36][37]. Recently, in a multicentre, randomised, double-blind, placebo-controlled trial, 260 CF patients, not infected with P. aeruginosa, were randomised in a 1:1 ratio to azithromycin 250 mg or 500 mg (based on body weight) 3 days per week, or placebo, for a period of 24 weeks.…”

Section: Cystic Fibrosismentioning

confidence: 99%

Long-term macrolide treatment for chronic respiratory disease

2012

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Long-term macrolide treatment was first shown to alter the natural history of diffuse panbronchiolitis (DPB) in the late 1980s. Since then, macrolides have been demonstrated to exert antiinflammatory and immunomodulatory activity in addition to being antimicrobial. Indeed, their spectrum of action extends to the regulation of leukocyte function and production of inflammatory mediators, control of mucus hypersecretion, resolution of inflammation and modulation of host defence mechanisms. As such, the potential benefit of macrolide antibiotics has been evaluated in a variety of chronic respiratory diseases. The best studied condition is cystic fibrosis, of which there have been six randomised controlled trials showing evidence of benefit. However, most of the studies were limited by small numbers of patients and short follow-up. More recently, landmark studies have demonstrated the efficacy of azithromycin in reducing the risk of acute exacerbations in patients with chronic obstructive pulmonary disease, but the optimal duration and dosing of macrolide treatment remain uncertain.With the exception of patients with DPB and cystic fibrosis, until clear evidence of efficacy is available, the long-term use of macrolides should be limited to highly selected patients after careful evaluation of benefit and harm, or in the context of randomised controlled clinical trials. @ERSpublications Several studies evaluating macrolide antibiotics for the treatment of chronic respiratory diseases are underway

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Azithromycin in Patients With Cystic Fibrosis Chronically Infected With Pseudomonas aeruginosa

Cited by 904 publications

References 28 publications

Inhibition of Pseudomonas aeruginosa secreted virulence factors reduces lung inflammation in CF mice

Inhibition of Pseudomonas aeruginosa secreted virulence factors reduces lung inflammation in CF mice

Quorum sensing in bacterial virulence

Long-term macrolide treatment for chronic respiratory disease

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