Chronic Macrolide Therapy in Inflammatory Airways Diseases

doi:10.1378/chest.10-0196

Chest

Volume 138, Issue 5, November 2010, Pages 1202-1212

https://doi.org/10.1378/chest.10-0196 Get rights and content

Long-term therapy with the macrolide antibiotic erythromycin was shown to alter the clinical course of diffuse panbronchiolitis in the late 1980s. Since that time, macrolides have been found to have a large number of antiinflammatory properties in addition to being antimicrobials. These observations provided the rationale for many studies performed over the last decade to assess the usefulness of macrolides in other inflammatory airways diseases, such as cystic fibrosis, asthma, COPD, and bronchiolitis obliterans syndrome. This review summarizes the immunomodulatory properties of macrolides and the results of these recent studies demonstrating their potential for being disease-modifying agents.

Section snippets

Immunomodulatory Effects of Macrolide Antibiotics

Macrolide antibiotics belong to an expansive family of compounds that are characterized by the presence of a macrocyclic lactone ring.⁷ This family includes compounds that mainly have immunosuppressant activity (eg, FK 506 and rapamycin) or antifungal activity with antineoplastic properties (eg, bafilomycins).⁷ Macrolides exert their antimicrobial effect by binding to 50S ribosomes of both prokaryotic and eukaryotic organisms and inhibiting transpeptidation or translocation of nascent peptides.⁸

Cystic Fibrosis

Cystic fibrosis (CF) is an autosomal recessive disorder affecting one in 32,000 live white births in the United States. CF is caused by a defect in the cystic fibrosis transmembrane regulator.⁴¹ Alterations in epithelial cell ion transport as a result of defective CF transmembrane regulator lead to increased sputum viscosity, which causes stasis of secretions, recurrent respiratory infections, and chronic progressive bronchiectasis.⁴² Long-term effects of the bronchiectasis include impaired

Idiopathic Bronchiectasis

The effectiveness of long-term macrolides in DPB and CF led to interest in using these agents in patients with bronchiectasis not caused by CF (grouped as idiopathic bronchiectasis despite the fact that, in some instances, the cause of the bronchiectasis is known, such as ciliary dyskinesia, posttuberculous). There is ample evidence that, regardless of cause, bronchiectasis involves cyclical infection, inflammation, and mediator release.51, 56

Patients with idiopathic bronchiectasis have an

Asthma

Asthma is a chronic inflammatory disorder of the airways involving many cell types and numerous inflammatory mediators.⁶⁵ The recurrent cough, wheeze, dyspnea, chest tightness, and episodic airflow limitation are caused by intermittent inflammation. Some suggest that chronic infection of the lower respiratory tract with Mycoplasma pneumoniae and/or Chlamydia pneumoniae may be an important contributor to the pathophysiology.⁶⁶ The presence of chronic inflammation and possible chronic infection

COPD

COPD develops in susceptible smokers as a result of peripheral airway remodeling (ie, bronchiolitis) and parenchymal destruction (ie, emphysema).75, 76 Bronchial biopsies, BALF, and induced sputum all show increased numbers of neutrophils, macrophages, and CD8⁺ T cells.77, 78, 79 During the past decade numerous studies have confirmed the importance of chronic inflammation in both the airways and lung parenchyma.80, 81, 82 A variety of microbes stimulate the inflammatory process and precipitate

Posttransplant Bronchiolitis Obliterans Syndrome

Bronchiolitis obliterans syndrome (BOS) is a manifestation of chronic rejection (lung or bone marrow) and is responsible for the large majority of deaths following lung transplantation.⁸⁹ Up to 50% of lung transplant recipients surviving at least 3 months will develop BOS.⁹⁰ Given the substantial morbidity and mortality associated with BOS, combined with the limited effectiveness and common side effects of traditional antirejection therapies, there has been recent interest in assessing the

Other Airway Disorders

Organizing pneumonia is an inflammatory disease affecting the distal airways and alveoli. Stover and Mangino⁹⁹ reported three patients with idiopathic bronchiolitis obliterans organizing pneumonia (BOOP) (now called cryptogenic organizing pneumonia) and three patients with radiation-related BOOP who responded to macrolide therapy. They recommended considering macrolide therapy for BOOP in patients with minimal symptoms and/or minimal physiologic impairment, as adjuvant therapy in patients

Conclusion

The introduction of chronic low-dose macrolide therapy for the treatment of DPB has altered the natural history of this disease and beneficial effects have been described in patients with many other inflammatory airways diseases. Numerous studies have described broad immunomodulatory effects of macrolides such that modulation of host-pathogen interactions, signaling pathways, cytokine responses, oxidative stress, and innate immunity likely contribute to these benefits. Although additional

Acknowledgments

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

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Azithromycin therapy in infants hospitalized for respiratory syncytial virus bronchiolitis: Airway matrix metalloproteinase-9 levels and subsequent recurrent wheeze
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Early life respiratory syncytial virus (RSV) bronchiolitis is a significant risk factor for childhood asthma. In vitro and in vivo studies suggested that decreasing levels of airway matrix metalloproteinase (MMP)-9 during RSV bronchiolitis may be associated with clinical benefits.
To investigate whether azithromycin therapy during severe RSV bronchiolitis reduces upper airway MMP-9 levels, whether upper airway MMP-9 levels correlate with upper airway interleukin IL-8 levels, and whether MMP-9 level reduction is associated with reduced post-RSV recurrent wheeze (RW).
A total of 200 otherwise healthy 1- to 18-month-old infants hospitalized with RSV bronchiolitis were randomized into a double-blind, placebo-controlled trial of oral azithromycin (10 mg/kg daily for 7 days followed by 5 mg/kg daily for 7 days) or placebo. Infants were followed for 2 to 4 years for the outcome of RW (3 or more wheezing episodes). Nasal lavage samples for MMP-9 levels were obtained at baseline, day 14 (end of the study treatment), and after 6 months.
Upper airway MMP-9 levels were highly correlated with IL-8 levels at all 3 time points: randomization, day 14, and 6 months (r = 0.80; P < .0001 for all time points). MMP-9 levels were similar between treatment groups at randomization, were lower on day 14 among children treated with azithromycin (P = .0085), but no longer different after 6 months. MMP-9 levels at baseline and change from baseline to day 14 were not associated with the development of RW (P = .49, .39, respectively).
Azithromycin therapy in children hospitalized with RSV bronchiolitis had a short-term anti-inflammatory effect in reducing upper airway MMP-9 levels. However, the reduction in MMP-9 levels did not relate to subsequent RW post-RSV.
This study is a secondary analysis of the Azithromycin to Prevent Wheezing following severe RSV bronchiolitis-II clinical trial registered at Clinicaltrials.gov (NCT02911935).
Scoping review: The state of research on cryptogenic organizing pneumonia therapeutics
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Cryptogenic organizing pneumonia is a diffuse interstitial lung disease that starts in the alveolar wall and subsequently expands to the alveolar ducts and respiratory bronchioles. Randomized controlled trials are lacking to guide the treatment of cryptogenic organizing pneumonia, so treatment decisions and practice guidelines are often based upon observations from case series or expert clinical opinions. The backbone of treatment involves immunosuppression via corticosteroids. In refractory cases, cytotoxic therapy is considered. The evidence that supports the use of these regimens are limited. The goal of this scoping review is to conduct a systematic search of the literature to determine what regimens have been utilized to treat steroid refractory organizing pneumonia and to characterize the evidence supporting their use.
3.25 - Microbiome Therapeutics in Respiratory Illnesses
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Respiratory diseases are a major cause of morbidity and mortality worldwide. Non communicable diseases such as Chronic Obstructive Pulmonary Disease, asthma, Interstitial Lung Disease and Cystic Fibrosis are difficult to manage and rely largely on symptomatic treatment. There is a need for new therapies that can alter the course of disease. Knowledge of human microbiome in recent times has led to newer approaches for future therapeutics which are being investigated for human use.
The azithromycin to prevent wheezing following severe RSV bronchiolitis-II clinical trial: Rationale, study design, methods, and characteristics of study population
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Severe respiratory syncytial virus (RSV) bronchiolitis in early life is a significant risk factor for future recurrent wheeze (RW) and asthma. The goal of the Azithromycin to Prevent Wheezing following severe RSV bronchiolitis II (APW-RSV II) clinical trial is to evaluate if azithromycin treatment in infants hospitalized with RSV bronchiolitis reduces the occurrence of RW during the preschool years.
The APW-RSV II clinical trial is a double-blind, placebo-controlled, parallel-group, randomized trial, including otherwise healthy participants, ages 30 days-18 months, who are hospitalized due to RSV bronchiolitis. The study includes an active randomized treatment phase with azithromycin or placebo for 2 weeks, and an observational phase of 18–48 months. Two hundred participants were enrolled during three consecutive RSV seasons beginning in the fall of 2016 and were randomized to receive oral azithromycin 10 mg/kg/day for 7 days followed by 5 mg/kg/day for an additional 7 days, or matched placebo. The study hypothesis is that in infants hospitalized with RSV bronchiolitis, the addition of azithromycin therapy to routine bronchiolitis care would reduce the likelihood of developing post-RSV recurrent wheeze (≥3 episodes). The primary clinical outcome is the occurrence of a third episode of wheezing, which is evaluated every other month by phone questionnaires and during yearly in-person visits.
A secondary objective of the APW-RSV II clinical trial is to examine how azithromycin therapy changes the upper airway microbiome composition, and to determine if these changes are related to the occurrence of post-RSV RW. Microbiome composition is characterized in nasal wash samples obtained before and after the study treatments.
This clinical trial may identify the first effective intervention applied during severe RSV bronchiolitis to reduce the risk of post-RSV RW and ultimately asthma.
Question 4: Is there a role for antibiotics in infantile wheeze?
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Acute wheezing episodes are frequent in young children and are associated with high morbidity and healthcare utilization. The role of respiratory viruses in triggering acute wheezing is well known. There is also accumulating evidence that airway bacteria, either alone or as part of bacteria–virus interaction, are important determinants of acute asthma exacerbations. Targeting airway bacteria with antibiotics to reduce the severity of acute wheezing episodes and prevent recurrent wheezing among preschool children has been recently evaluated in three randomized, double-blind, placebo-controlled trials. The results of these studies are controversial. An interventional approach with azithromycin in young children during acute wheezing episodes cannot be generically incorporated into clinical practice, due to the potential consequences of widespread use of antibiotics in such a common clinical setting. This intervention may be reserved for children with really severe, recurrent wheezing episodes. Future research should focus on risk factors that facilitate acquisition of bacterial airway infection in young children and better understanding how virus and bacteria interact with each other during wheezing attacks. Identifying objective biomarkers that may direct the treatment to specific groups of children may represent a significant step forward in the clinical approach of acute wheezing.
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Chest

Recent Advances in Chest MedicineChronic Macrolide Therapy in Inflammatory Airways Diseases

Section snippets

Immunomodulatory Effects of Macrolide Antibiotics

Cystic Fibrosis

Idiopathic Bronchiectasis

Asthma

COPD

Posttransplant Bronchiolitis Obliterans Syndrome

Other Airway Disorders

Conclusion

Acknowledgments

Chest

Biochem Biophys Res Commun

Am J Transplant

Int J Antimicrob Agents

Gen Pharmacol

Int J Antimicrob Agents

J Allergy Clin Immunol

Pharmacol Res

Clin Chest Med

Lancet

Chest

Chest

Chest

Chest

Ann Allergy Asthma Immunol

Chest

Chest

J Heart Lung Transplant

J Heart Lung Transplant

Chest

Chest

Phenotypes of chronic obstructive pulmonary disease

COPD

Chronic obstructive pulmonary disease surveillance—United States, 1971–2000

MMWR Surveill Summ

Surveillance for asthma—United States, 1980–1999

MMWR Surveill Summ

Immunomodulatory effects of antimicrobials in the therapy of respiratory tract infections

Curr Opin Infect Dis

Clinical implications of the immunomodulatory effects of macrolides

Am J Med

Improvement of survival in patients with diffuse panbronchiolitis treated with low-dose erythromycin

Am J Respir Crit Care Med

Cellular and molecular effects of macrolides on leukocyte function

Curr Pharm Des

The macrolide antibiotics: a pharmacokinetic and pharmacodynamic overview

Curr Pharm Des

Anti-inflammatory effects of macrolides in lung disease

Pediatr Pulmonol

Immunomodulatory properties of macrolides: overview and historical perspective

Am J Med

Azithromycin inhibits quorum sensing in Pseudomonas aeruginosa

Antimicrob Agents Chemother

Quorum-sensing antagonistic activities of azithromycin in Pseudomonas aeruginosa PAO1: a global approach

Antimicrob Agents Chemother

Azithromycin retards Pseudomonas aeruginosa biofilm formation

J Clin Microbiol

Buccal adherence of Pseudomonas aeruginosa in patients with cystic fibrosis under long-term therapy with azithromycin

Infection

Effects of erythromycin on Pseudomonas aeruginosa adherence to collagen and morphology in vitro

Eur Respir J

Azithromycin blocks quorum sensing and alginate polymer formation and increases the sensitivity to serum and stationary-growth-phase killing of Pseudomonas aeruginosa and attenuates chronic P. aeruginosa lung infection in Cftr(-/-) mice

Antimicrob Agents Chemother

Effect of subinhibitory concentrations of macrolides on expression of flagellin in Pseudomonas aeruginosa and Proteus mirabilis

Antimicrob Agents Chemother

Erythromycin increases bactericidal activity of surface liquid in human airway epithelial cells

Am J Physiol Lung Cell Mol Physiol

Molecular mechanisms of anti-inflammatory action of erythromycin in human bronchial epithelial cells: possible role in the signaling pathway that regulates nuclear factor-kappaB activation

Antimicrob Agents Chemother

Clarithromycin suppresses lipopolysaccharide-induced interleukin-8 production by human monocytes through AP-1 and NF-kappa B transcription factors

J Antimicrob Chemother

Suppression of matrix metalloproteinase production from nasal fibroblasts by macrolide antibiotics in vitro

Eur Respir J

Azithromycin selectively reduces tumor necrosis factor alpha levels in cystic fibrosis airway epithelial cells

Antimicrob Agents Chemother

Azithromycin reduces airway neutrophilia and interleukin-8 in patients with bronchiolitis obliterans syndrome

Am J Respir Crit Care Med

Azithromycin suppresses activation of nuclear factor-kappa B and synthesis of pro-inflammatory cytokines in tracheal aspirate cells from premature infants

Recent Advances in Chest Medicine
Chronic Macrolide Therapy in Inflammatory Airways Diseases