Exploring the mechanisms of macrolides in cystic fibrosis

Abstract

Several studies have reported clinical improvements in cystic fibrosis (CF) patients on macrolide antibiotics although the mechanism of action remains unclear. We conducted an open-label study of azithromycin (500 mg daily for 2 weeks) in 9 adult CF patients to explore 3 possible mechanisms: up-regulation of the multi-drug resistance (MDR) or cystic fibrosis transmembrane regulator (CFTR) proteins, correction of epithelial ion transport and reduced bacterial adherence. End-points included nasal potential difference (PD) measurements, nasal epithelial MDR and CFTR mRNA levels and Pseudomonas aeruginosa adherence to nasal epithelium. Forced expiratory volume in the 1st second (FEV(1)) increased significantly after 2 weeks of azithromycin (pre- 41.1 [5.0]%; post- 44.6 [5.8]%; P<0.05), although improvements in forced vital capacity (FVC) did not reach significance (pre- 61.3 [4.0]%; post- 67.1 [5.4]%, NS). Before treatment all subjects had nasal PD measurements characteristic of CF. Treatment led to no significant group differences in any measures of either sodium absorption or chloride secretion. Neither CFTR nor MDR mRNA levels had altered significantly and the adherence of P. aeruginosa did not decrease. We conclude that these are unlikely to be significant contributing mechanisms accounting for the consistent beneficial results observed in clinical trials of macrolides in CF.

Azithromycin reduces spontaneous and induced inflammation in ΔF508 cystic fibrosis mice

“…However, it has been clearly demonstrated that the apparent beneficial effects of these drugs on pulmonary outcome in CF are not mediated by modulation of ion transport [ 34 ]. An open-label study [ 35 ] concluded that neither up-regulation of multi-drug resistance or CFTR proteins nor reduced bacterial adherence appear to be significant contributing mechanisms accounting for the beneficial results in clinical trials of macrolides in CF. We show that treatment with the macrolide in CF mice attenuated cellular infiltration in spontaneous and induced inflammatory conditions and inhibited pro-inflammatory cytokine release in LPS-induced inflammation.…”

Macrolides: from in vitro anti-inflammatory and immunomodulatory properties to clinical practice in respiratory diseases

“…Secondly, macrolides reduce sputum viscoelasticity and airway adhesion of P. aeruginosa [189][190][191]. Moreover, they reduce inflammatory response in CF [36, 86,[192][193][194]. Several studies using macrolides either in short-term or in long-term administration have provided positive results regarding reduction of exacerbations and stabilising or increasing respiratory capacity (Table 2) [52, 67,.…”

Chronic Inflammation in the Cystic Fibrosis Lung: Alterations in Inter- and Intracellular Signaling

“…Subsequent studies indeed showed that macrolides decrease secretion of chemokines such as IL-8 and pro-inflammatory cytokines such as TNF-α in tissue culture and animal models, which do not depend on their antimicrobial activities [164][165][166][167]. The actual mechanisms of these effects and the relevance of individual mechanisms of action in vivo have not yet been fully elucidated, however.…”