title: Azithromycin maintenance treatment in patients with frequent exacerbations of chronic obstructive pulmonary disease (COLUMBUS): a randomised, double-blind, placebo-controlled trial.
abstract: BACKGROUND
  Macrolide resistance is an increasing problem; there is therefore debate about when to implement maintenance treatment with macrolides in patients with chronic obstructive pulmonary disease (COPD). We aimed to investigate whether patients with COPD who had received treatment for three or more exacerbations in the previous year would have a decrease in exacerbation rate when maintenance treatment with azithromycin was added to standard care.
  
  
  METHODS
  We did a randomised, double-blind, placebo-controlled, single-centre trial in The Netherlands between May 19, 2010, and June 18, 2013. Patients (≥18 years) with a diagnosis of COPD who had received treatment for three or more exacerbations in the previous year were randomly assigned, via a computer-generated randomisation sequence with permuted block sizes of ten, to receive 500 mg azithromycin or placebo three times a week for 12 months. Randomisation was stratified by use of long-term, low-dose prednisolone (≤10 mg daily). Patients and investigators were masked to group allocation. The primary endpoint was rate of exacerbations of COPD in the year of treatment. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00985244.
  
  
  RESULTS
  We randomly assigned 92 patients to the azithromycin group (n=47) or the placebo group (n=45), of whom 41 (87%) versus 36 (80%) completed the study. We recorded 84 exacerbations in patients in the azithromycin group compared with 129 in those in the placebo group. The unadjusted exacerbation rate per patient per year was 1·94 (95% CI 1·50-2·52) for the azithromycin group and 3·22 (2·62-3·97) for the placebo group. After adjustment, azithromycin resulted in a significant reduction in the exacerbation rate versus placebo (0·58, 95% CI 0·42-0·79; p=0·001). Three (6%) patients in the azithromycin group reported serious adverse events compared with five (11%) in the placebo group. During follow-up, the most common adverse event was diarrhoea in the azithromycin group (nine [19%] patients vs one [2%] in the placebo group; p=0·015).
  
  
  CONCLUSIONS
  Maintenance treatment with azithromycin significantly decreased the exacerbation rate compared with placebo and should therefore be considered for use in patients with COPD who have the frequent exacerbator phenotype and are refractory to standard care.
  
  
  BACKGROUND
  SoLong Trust.
authors.affiliation: Department of Respiratory Medicine, Amphia Hospital, Breda, Netherlands.
authors.forename: Sevim
authors.initials: S
authors.lastname: Uzun
authors.affiliation: Department of Respiratory Medicine, Amphia Hospital, Breda, Netherlands.
authors.forename: Remco S
authors.initials: RS
authors.lastname: Djamin
authors.affiliation: Department of Microbiology, Amphia Hospital, Breda, Netherlands.
authors.forename: Jan A J W
authors.initials: JA
authors.lastname: Kluytmans
authors.affiliation: Amphia Academy, Amphia Hospital, Breda, Netherlands.
authors.forename: Paul G H
authors.initials: PG
authors.lastname: Mulder
authors.affiliation: Hospital Pharmacy, Amphia Hospital, Breda, Netherlands.
authors.forename: Nils E
authors.initials: NE
authors.lastname: van't Veer
authors.affiliation: Laboratory for Clinical Chemistry and Haematology, Amphia Hospital, Breda, Netherlands.
authors.forename: Anton A M
authors.initials: AA
authors.lastname: Ermens
authors.affiliation: Centre of Research on Psychology in Somatic Diseases, University of Tilburg, Tilburg, Netherlands.
authors.forename: Aline J
authors.initials: AJ
authors.lastname: Pelle
authors.affiliation: Department of Respiratory Medicine, Erasmus Medical Centre, Rotterdam, Netherlands.
authors.forename: Henk C
authors.initials: HC
authors.lastname: Hoogsteden
authors.affiliation: Department of Respiratory Medicine, Amphia Hospital, Breda, Netherlands; Department of Respiratory Medicine, Erasmus Medical Centre, Rotterdam, Netherlands.
authors.forename: Joachim G J V
authors.initials: JG
authors.lastname: Aerts
authors.affiliation: Department of Respiratory Medicine, Erasmus Medical Centre, Rotterdam, Netherlands. Electronic address: m.vandereerden@erasmusmc.nl.
authors.forename: Menno M
authors.initials: MM
authors.lastname: van der Eerden
mesh_terms: D000368:Aged; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D017963:Azithromycin / Q000627:therapeutic use*; D018450:Disease Progression; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D060046:Maintenance Chemotherapy / Q000379:methods*; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy*; D012008:Recurrence; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D017963:Azithromycin