The relationship between serum and sputum levels of azithromycin and clinical endpoints in patients with bronchiectasis using azithromycin maintenance treatment

Background: Azithromycin (AZM) is a macrolide antibiotic with distinct pharmacokinetic properties and is increasingly used as maintenance treatment in patients with bronchiectasis in order to reduce infectious exacerbations and improve pulmonary symptoms. The exact mechanism of action is not known and the relation between azithromycin dose level, local and systemic drug levels and clinical effect however, has not been extensively studied yet. Objectives: To explore the relation between AZM serum and sputum concentrations, clinical effect parameters and side effects. Methods: Azithromycin concentrations were measured in serum and sputum samples of bronchiectasis patients receiving one year of AZM treatment (250mg OD) enrolled in the Bronchiectasis and Azithromycin Treatment (BAT) trial, a double blind, randomised placebo-controlled trial. Results were correlated with data on AZM dose level, exacerbation frequency, lung function (forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC), quality of life and symptoms collected within the same year. Results: 83 sputum samples from 31 patients and 151 serum samples from 43 patients were available for analysis. Mean AZM dose-level ranged from 18.8 to 39.8 mg/kg body weight/ week, generating mean AZM concentrations of 7.57 mg/L (SD 9.49) in sputum and 0.11 mg/L (SD 0.085) in serum. No correlation was found between side effects and AZM dose level, sputumor serum concentrations. Signifi cant correlation was found between AZM sputum concentration and CRP-level (r= -0.6). Conclusion: High and stable AZM sputum levels were reached during long term treatment, as opposed to low AZM levels in serum. Apart from CRP-levels to AZM sputum concentration, no other outcome parameter showed signifi cant correlation to AZM serumor sputum levels. AZM doseor exposure levels were not predictive for the occurrence of side effects. The relationship between serum and sputum levels of azithromycin and clinical endpoints in patients with bronchiectasis using azithromycin maintenance treatment Published: July 16, 2019 020 chronic respiratory infections, such as non-CF bronchiectasis (hereafter referred to as ‘bronchiectasis’) and COPD after favourable results of clinical trials [3-6]. Bronchiectasis –abnormal dilated bronchi, resulting from a vicious circle of mucus retention, bacterial colonization and in lammationis a chronic lung disease, characterized by a variable course. Stable periods with a mild productive cough are interspersed with infectious exacerbations which importantly contribute to reduced quality of life. Since 2012 three randomised clinical trials have con irmed the ef icacy of long term macrolide treatment in bronchiectasis.7-9 Patients treated with azithromycin (250 OD or 500 mg three times weekly) or erythromycin (400 mg BD) showed a marked reduction of infectious exacerbations annually. Favourable effects were also noted with respect to lung function and quality of life but these were not consistent between studies. The pharmacokinetics (PK) and exposure after a single dose or short courses of azithromycin are well known. Exposure after chronic use in CF patients has been investigated by measuring azithromycin in blood and in sputum. CF patients on chronic azithromycin show a wide inter-individual variation in clinical ef icacy but also in blood-, sputum and tissue concentrations of AZM, even at the same dose level. The intra individual variation in sputum concentration showed a stable concentration when measured at monthly intervals during 3 months. A relationship between exposure in blood and sputum and clinical ef icacy has never been investigated neither in CF treatment nor in treatment of bronchiectasis. We report the results of a study towards the relationship between individual exposure and clinical ef icacy of chronic azithromycin therapy in patients with bronchiectasis.