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

Abstract

BACKGROUND:Following reports on the treatment of diffuse panbronchiolitis (DPB), recent studies demonstrate that long term therapy with azithromycin (AZM) is effective in cystic fibrosis (CF) patients. However, the underlying mechanisms remain uncertain. Some macrolides, including AZM, display inhibition of virulence factors and other antipseudomonal effects at subinhibitory levels in vitro.OBJECTIVES:Drug doses used for CF and DPB therapy were investigated to determine whether they achieve corresponding sputum drug levels in CF patients in vivo.METHODS:In an open, prospective study, 14 CF patients with chronic Pseudomonas aeruginosa airway infection received 250 mg AZM either daily ('high dose') or twice weekly ('low dose') for 12 weeks. Viscoelasticity of sputum was assessed by magnetic microrheology.RESULTS:AZM accumulated in sputum by two orders of magnitude over a period of four weeks. In the following steady state, median AZM concentrations in sputum were 9.5 µg/mL (0.6 to 79.3 µg/mL, interquartiles 1.4 to 33.4 µg/mL) and 0.5 µg/mL (range less than 0.1 [below detection level] to 5.2 µg/mL, interquartiles 0.2 to 1.4 µg/mL) in the high and low dose groups, respectively. Viscoelasticity improved in all patients but one.CONCLUSIONS: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.