Effects of prolonged use of azithromycin in patients with cystic fibrosis: A meta-analysis

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Abstract

Azithromycin has been studied as potential therapeutic anti-inflammatory agent for cystic fibrosis (CF) patients. Azithromycin (AZM) has been used as an immunomodulating agent, based on few small studies. Considering the cost and potential side effects of long-term azithromycin therapy, it is important to identify the group of patients that would benefit the most. Weighted mean difference was used for pulmonary function tests, and risk ratios for all other variables. The random-effects model was applied for all reports. Combining four studies (N = 368), azithromycin showed increase in FEV1 (3.53%, 95% CI 0.00, 7.07, p = 0.05; I2 = 38%) and FVC (4.24%, 95% CI 2.02, 6.45, p = 0.0002; I2 = 0%). When trials were analyzed by baseline Pseudomonas sputum colonization, the heterogeneity decreased (I2 = 0%), FEV1 significantly increased to 4.66% (95% CI 1.18, 8.15, p = 0.009), and FVC increased to 4.64% (95% CI 2.11, 7.17, p = 0.0003). The GI side effects were 72% higher with azithromycin use (RR 1.72, 95% CI 1.33, 2.21, p = 0.00003), the main side effects being nausea (RR 2.04, 95% CI 1.19, 3.45, p = 0.009), and diarrhea (RR 2.12, 95% CI 1.10, 4.08, p = 0.02). Azithromycin improves lung function of CF patients, especially in the subgroup colonized with Pseudomonas. However, nausea and diarrhea are significantly more frequent with azythromycin.

Introduction

Cystic fibrosis (CF) is an autosomal recessive disease primarily affecting the lungs. The median survival of CF patient has been steadily increasing to 36.9 years [1] as a result of better antibiotic treatment, standardization of care, and establishment of multidisciplinary CF Care Centers [2], [3]. CF physicians primarily follow lung disease quarterly by measurement of the forced expiratory volume at 1 s (FEV1), with increased frequency during pulmonary exacerbations of disease.

The pathophysiology of cystic fibrosis lung disease is related to the abnormal cystic fibrosis transmembrane receptor (CFTR) present in the apical cell membrane of airway epithelial cells. Abnormal CFTR results in excessive efflux of sodium from the airway surface layer with resultant loss of chloride and water from the airway mucus layer [4], [5]. Dehydration of mucus compromises ciliary clearance resulting in airway obstruction. Patients with CF have cough as the sole mechanism to clear the abnormally thick sputum.

Retained mucus in the lungs of these patients serves as a growth medium for many bacteria, mainly Pseudomonas aeruginosa. The neutrophilic response to this infection creates an inflammatory milieu in airways, causing damage to the airway walls and development of progressive bronchiectasis, contributing further to impaired mucus clearance. The cycle of airway obstruction combined with recurrent infections, inflammation and bronchiectasis progresses to end stage lung disease and death or the need for lung transplantation.

Standard therapies for CF include chest physiotherapy to augment clearance of abnormal mucus [6], DNAse to decrease the viscosity of airway secretions [7], inhaled anti-pseudomonal antibiotics (tobramycin or colistin) to decrease the density of Pseudomonas colonization [8] and nebulized hypertonic saline [9]. Azithromycin has also recently become part of the standard CF maintenance therapy [10] despite limited supporting evidence, and it has been given a strong recommendation by the Cystic Fibrosis Foundation. We intend to perform a systematic review and meta-analysis to evaluate the efficacy and safety of azithromycin in CF patients.

Section snippets

Search strategy and inclusion criteria

We searched Cochrane Register of Controlled trials and PubMed database from inception to April 2008. No language or date restrictions were applied. The keywords used were cystic fibrosis, azithromycin, macrolides, randomized, and clinical trial. Two reviewers independently performed the search and disagreements were resolved by consensus among authors.

Inclusion criteria

We included randomized placebo controlled trials that assessed the long-term effects of azithromycin treatment on pulmonary function tests,

Results

The initial search of the database produced 18 potentially relevant studies (Fig. 1). Nine studies were selected as randomized placebo controlled trials involving treatment with azithromycin in patients with CF. One article was excluded because it was a meta-analysis of three previously published studies [13]. The rest of the articles were reviewed in detail and only four studies qualified as randomized placebo controlled studies [10], [11], [12], [13], [14], [15], [16]. The study by Equi et

Discussion

Chronic inflammation is a key pathophysiological feature in CF accounting for progressive pulmonary disease. Recently, azithromycin has been included in the therapeutic armamentarium for CF patients. Azithromycin probably has combined mechanisms of action: modulation of the pro-inflammatory effects of the bacteria at the level of airways and alteration of the virulence factors of Pseudomonas aeruginosa [17]. Azithromycin modulates inflammatory pathways by interfering with neutrophil

Conflicts of interest

None of the authors has any personal interest or received any financial support from an organization with financial interest in the subject of matter.

Institutional Review Board

Our manuscript does not include a statement of patient consent and Internal Review Boards approval since it is a meta-analysis of previously published articles.

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