The relationship between serum and sputum levels of azithromycin and clinical endpoints in patients with bronchiectasis using azithromycin maintenance treatment
Article Sidebar
Main Article Content
Abstract
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, sputum- or serum concentrations. Significant 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 significant correlation to AZM serum- or sputum levels. AZM dose- or exposure levels were not predictive for the occurrence of side effects.
Article Details
Copyright (c) 2019 Altenburg J, et al.
This work is licensed under a Creative Commons Attribution 4.0 International License.
Van BF, Tulkens PM. Macrolides: pharmacokinetics and pharmacodynamics. Int J Antimicrob Agents. 2001; 18: S17-S23. PubMed.: https://www.ncbi.nlm.nih.gov/pubmed/11574190
Di PA, Barbara C, Chella A, Angeletti CA, Del Tacca M. Pharmacokinetics of azithromycin in lung tissue, bronchial washing, and plasma in patients given multiple oral doses of 500 and 1000 mg daily. Pharmacol Res. 2002; 46: 545-550. PubMed.: https://www.ncbi.nlm.nih.gov/pubmed/12457629
Albert RK, Connett J, Bailey WC, Casaburi R, Cooper JA Jr, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011; 365: 689-698. PubMed.: https://www.ncbi.nlm.nih.gov/pubmed/21864166
Uzun S, Djamin RS, Kluytmans JA, Mulder PG, van't Veer NE, et al. Azithromycin maintenance treatment in patients with frequent exacerbations of chronic obstructive pulmonary disease (COLUMBUS): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2014; 2: 361-368. PubMed.: https://www.ncbi.nlm.nih.gov/pubmed/24746000
Brusselle GG, Vanderstichele C, Jordens P, Deman R, Slabbynck H, et al. Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax. 2013; 68: 322-329. PubMed.: https://www.ncbi.nlm.nih.gov/pubmed/23291349
Chalmers JD, Elborn JS. Reclaiming the name 'bronchiectasis'. Thorax. 2015; 70: 399-400. PubMed.: https://www.ncbi.nlm.nih.gov/pubmed/25791834
Altenburg J, de Graaff CS, Stienstra Y, Sloos JH, van Haren EH, et al. Effect of azithromycin maintenance treatment on infectious exacerbations among patients with non-cystic fibrosis bronchiectasis: the BAT randomized controlled trial. JAMA. 2013; 309: 1251-1259. PubMed.: https://www.ncbi.nlm.nih.gov/pubmed/23532241
Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, et al. Lung volumes and forced ventilatory flows. Report Working Party Standardization of Lung Function Tests, European Community for Steel and Coal. Official Statement of the European Respiratory Society. Eur Respir J Suppl. 1993; 16: 5-40. PubMed.: https://www.ncbi.nlm.nih.gov/pubmed/8499054
Altenburg J, Wortel K, de Graaff CS, van der Werf TS, Boersma WG. Validation of a visual analogue score (LRTI-VAS) in non-CF bronchiectasis. Clin Respir J. 2016; 10: 168-175. PubMed.: https://www.ncbi.nlm.nih.gov/pubmed/25103370
Jones PW. St. George's Respiratory Questionnaire: MCID. COPD. 2005; 2: 75-79. PubMed.: https://www.ncbi.nlm.nih.gov/pubmed/17136966
Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A self-complete measure of health status for chronic airflow limitation. The St. George's Respiratory Questionnaire. Am Rev Respir Dis. 1992; 145: 1321-1327. PubMed.: https://www.ncbi.nlm.nih.gov/pubmed/1595997
Wilson CB, Jones PW, O'Leary CJ, Cole PJ, Wilson R. Validation of the St. George's Respiratory Questionnaire in bronchiectasis. Am J Respir Crit Care Med. 1997; 156: 536-541. PubMed.: https://www.ncbi.nlm.nih.gov/pubmed/9279236
Bhalla M, Turcios N, Aponte V, Jenkins M, Leitman BS, et al. Cystic fibrosis: scoring system with thin-section CT. Radiology. 1991; 179: 783-788. PubMed.: https://www.ncbi.nlm.nih.gov/pubmed/2027992
Beringer P, Huynh KM, Kriengkauykiat J, Bi L, Hoem N, et al. Absolute bioavailability and intracellular pharmacokinetics of azithromycin in patients with cystic fibrosis. Antimicrob Agents Chemother. 2005; 49: 5013-5017. PubMed.: https://www.ncbi.nlm.nih.gov/pubmed/16304166
Wilms EB, Touw DJ, Heijerman HG. Pharmacokinetics and sputum penetration of azithromycin during once weekly dosing in cystic fibrosis patients. J Cyst Fibros. 2008; 7: 79-84. PubMed.: https://www.ncbi.nlm.nih.gov/pubmed/17599845
Wilms EB, Touw DJ, Heijerman HG. Pharmacokinetics of azithromycin in plasma, blood, polymorphonuclear neutrophils and sputum during long-term therapy in patients with cystic fibrosis. Ther Drug Monit. 2006; 28: 219-225. PubMed.: https://www.ncbi.nlm.nih.gov/pubmed/16628134
Carbon C. Clinical relevance of intracellular and extracellular concentrations of macrolides. Infection. 1995; 23: S10-S14. PubMed.: https://www.ncbi.nlm.nih.gov/pubmed/7782109
Liu P, Allaudeen H, Chandra R, Phillips K, Jungnik A, et al. Comparative pharmacokinetics of azithromycin in serum and white blood cells of healthy subjects receiving a single-dose extended-release regimen versus a 3-day immediate-release regimen. Antimicrob Agents Chemother. 2007; 51: 103-109. PubMed.: https://www.ncbi.nlm.nih.gov/pubmed/17060516
Tamaoki J, Isono K, Sakai N, Kanemura T, Konno K. Erythromycin inhibits Cl secretion across canine tracheal epithelial cells. Eur Respir J. 1992; 5: 234-238. PubMed.: https://www.ncbi.nlm.nih.gov/pubmed/1559589
Tagaya E, Tamaoki J, Kondo M, Nagai A. Effect of a short course of clarithromycin therapy on sputum production in patients with chronic airway hypersecretion. Chest. 2002; 122: 213-218. PubMed.: https://www.ncbi.nlm.nih.gov/pubmed/12114361
McCormack J, Bell S, Senini S, Walmsley K, Patel K, et al. Daily versus weekly azithromycin in cystic fibrosis patients. Eur Respir J. 2007; 30: 487-495. PubMed.: https://www.ncbi.nlm.nih.gov/pubmed/17537764
Brown BA, Griffith DE, Girard W, Levin J, Wallace RJ Jr. Relationship of adverse events to serum drug levels in patients receiving high-dose azithromycin for mycobacterial lung disease. Clin Infect Dis. 1997; 24: 958-964. PubMed.: https://www.ncbi.nlm.nih.gov/pubmed/9142801
Wong C, Jayaram L, Karalus N, Eaton T, Tong C, et al. Azithromycin for prevention of exacerbations in non-cystic fibrosis bronchiectasis (EMBRACE): a randomised, double-blind, placebo-controlled trial. Lancet. 2012; 380: 660-667. PubMed.: https://www.ncbi.nlm.nih.gov/pubmed/22901887
Wilms EB, Touw DJ, Heijerman HG, van der Ent CK. Azithromycin maintenance therapy in patients with cystic fibrosis: a dose advice based on a review of pharmacokinetics, efficacy, and side effects. Pediatr Pulmonol. 2012; 47: 658-665. PubMed.: https://www.ncbi.nlm.nih.gov/pubmed/22684985
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, et al. Standardisation of spirometry. Eur Respir J. 2005; 26: 319-338. PubMed.: https://www.ncbi.nlm.nih.gov/pubmed/16055882
Serisier DJ, Martin ML, McGuckin MA, Lourie R, Chen AC, et al. Effect of long-term, low-dose erythromycin on pulmonary exacerbations among patients with non-cystic fibrosis bronchiectasis: the BLESS randomized controlled trial. JAMA. 2013; 309: 1260-1267. PubMed.: https://www.ncbi.nlm.nih.gov/pubmed/23532242