title: Impact of azithromycin on the clinical and antimicrobial effectiveness of tobramycin in the treatment of cystic fibrosis.
abstract: BACKGROUND
  Concomitant use of oral azithromycin and inhaled tobramycin occurs in approximately half of US cystic fibrosis (CF) patients. Recent data suggest that this combination may be antagonistic.
  
  
  METHODS
  Test the hypothesis that azithromycin reduces the clinical benefits of tobramycin by analyses of clinical trial data, in vitro modeling of P. aeruginosa antibiotic killing, and regulation of the MexXY efflux pump.
  
  
  RESULTS
  Ongoing administration of azithromycin associates with reduced ability of inhaled tobramycin, as compared with aztreonam, to improve lung function and quality of life in a completed clinical trial. In users of azithromycin FEV1(L) increased 0.8% during a 4-week period of inhaled tobramycin and an additional 6.4% during a subsequent 4-week period of inhaled aztreonam (P<0.005). CFQ-R respiratory symptom score decreased 1.8 points during inhaled tobramycin and increased 8.3 points during subsequent inhaled aztreonam (P<0.001). A smaller number of trial participants not using azithromycin had similar improvement in lung function and quality of life scores during inhaled tobramycin and inhaled aztreonam. In vitro, azithromycin selectively reduced the bactericidal effects tobramycin in cultures of clinical strains of P. aeruginosa, while up regulating antibiotic resistance through MexXY efflux.
  
  
  CONCLUSIONS
  Azithromycin appears capable of reducing the antimicrobial benefits of tobramycin by inducing adaptive bacterial stress responses in P. aeruginosa, suggesting that these medications together may not be optimal chronic therapy for at least some patients.
authors.affiliation: Department of Pediatrics, Seattle Children's Hospital, University of Washington School of Medicine, Seattle, WA, United States. Electronic address: David.Nichols@seattlechildrens.org.
authors.forename: Dave P
authors.initials: DP
authors.lastname: Nichols
authors.affiliation: Department of Pediatrics, National Jewish Health, Denver, CO, United States.
authors.forename: Carrie L
authors.initials: CL
authors.lastname: Happoldt
authors.affiliation: Department of Pediatrics, National Jewish Health, Denver, CO, United States.
authors.forename: Preston E
authors.initials: PE
authors.lastname: Bratcher
authors.affiliation: Department of Medicine, National Jewish Health, Denver, CO, United States; University of Colorado School of Medicine, Aurora, CO, United States.
authors.forename: Silvia M
authors.initials: SM
authors.lastname: Caceres
authors.affiliation: Department of Pediatrics, Rainbow Babies & Children's Hospital, Case Western Reserve University School of Medicine, Cleveland, OH, United States.
authors.forename: James F
authors.initials: JF
authors.lastname: Chmiel
authors.affiliation: Department of Medicine, National Jewish Health, Denver, CO, United States; University of Colorado School of Medicine, Aurora, CO, United States.
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Malcolm
authors.affiliation: Department of Medicine, National Jewish Health, Denver, CO, United States; University of Colorado School of Medicine, Aurora, CO, United States.
authors.forename: Milene T
authors.initials: MT
authors.lastname: Saavedra
authors.affiliation: Department of Pediatrics, Columbia University Medical Center, New York, NY, United States.
authors.forename: Lisa
authors.initials: L
authors.lastname: Saiman
authors.affiliation: Department of Pediatrics, National Jewish Health, Denver, CO, United States; Department of Medicine, National Jewish Health, Denver, CO, United States; University of Colorado School of Medicine, Aurora, CO, United States.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Taylor-Cousar
authors.affiliation: Department of Medicine, National Jewish Health, Denver, CO, United States; University of Colorado School of Medicine, Aurora, CO, United States.
authors.forename: Jerry A
authors.initials: JA
authors.lastname: Nick
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D017963:Azithromycin / Q000008:administration & dosage / Q000493:pharmacokinetics; D001398:Aztreonam / Q000008:administration & dosage / Q000493:pharmacokinetics; D003550:Cystic Fibrosis / Q000150:complications / Q000382:microbiology / Q000523:psychology; D004333:Drug Administration Routes; D004347:Drug Interactions; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D006801:Humans; D008297:Male; D011552:Pseudomonas Infections / Q000175:diagnosis / Q000188:drug therapy; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D012129:Respiratory Function Tests / Q000379:methods; D014031:Tobramycin / Q000008:administration & dosage / Q000493:pharmacokinetics; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D017963:Azithromycin; D001398:Aztreonam; D014031:Tobramycin
keywords: Azithromycin; Clinical trial; Cystic fibrosis; Drug interaction; Inhaled antibiotics; MexXY; Pseudomonas aeruginosa; Tobramycin