title: 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.
authors.affiliation: Department of Gene Therapy, National Heart and Lung Institute, Imperial College, London, UK.
authors.forename: Amanda C
authors.initials: AC
authors.lastname: Equi
authors.forename: Jane C
authors.initials: JC
authors.lastname: Davies
authors.forename: Hazel
authors.initials: H
authors.lastname: Painter
authors.forename: Stephen
authors.initials: S
authors.lastname: Hyde
authors.forename: Andrew
authors.initials: A
authors.lastname: Bush
authors.forename: Duncan M
authors.initials: DM
authors.lastname: Geddes
authors.forename: Eric W F W
authors.initials: EW
authors.lastname: Alton
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000328:Adult; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017963:Azithromycin / Q000494:pharmacology* / Q000627:therapeutic use; D002448:Cell Adhesion / Q000187:drug effects; D003550:Cystic Fibrosis / Q000188:drug therapy / Q000503:physiopathology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D017136:Ion Transport / Q000187:drug effects; D008297:Male; D009297:Nasal Mucosa / Q000187:drug effects* / Q000382:microbiology / Q000502:physiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D015854:Up-Regulation; D014797:Vital Capacity
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000900:Anti-Bacterial Agents; D012333:RNA, Messenger; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D017963:Azithromycin