title: Once versus three-times daily regimens of tobramycin treatment for pulmonary exacerbations of cystic fibrosis--the TOPIC study: a randomised controlled trial.
abstract: BACKGROUND
  Intravenous tobramycin (three-times daily) is widely used for pulmonary exacerbations in patients with cystic fibrosis who have chronic Pseudomonas aeruginosa infection. We undertook a double-blind, randomised controlled trial to assess the safety and efficacy of once versus three-times daily tobramycin in these patients.
  
  
  METHODS
  244 patients from 21 cystic-fibrosis centres in the UK were randomly assigned to once or three-times daily tobramycin (with ceftazidime) for 14 days. Treatment was given as 30-min infusions of tobramycin in 0.9% saline. Primary outcome measure was change in forced expiratory volume in 1s (FEV1), over the 14 days of treatment, expressed as a percentage of the predicted normal value for age, sex, and height. We also measured the change in FEV1 expressed as a percentage of baseline. Secondary outcomes included change in serum creatinine. The study was powered for equivalence, and primary analysis was per protocol.
  
  
  RESULTS
  219 patients (107 once daily, 112 three-times daily) completed the study per protocol. None was lost to follow-up, although 20 discontinued intervention. Of 122 patients assigned to once daily treatment, three did not receive the study regimen. The mean change in FEV1 (% predicted) over 14 days was similar on the two regimens (10.4% [once daily] vs 10.0% [three-times daily]; adjusted mean difference 0.4% [95% CI -3.3 to 4.1]). Mean% change in FEV1 from baseline was also similar in both treatments (21.9% vs 22.1%; -0.1% [-8.0 to 7.9]). There was no significant difference in% change in creatinine from baseline (-1.5% [once daily] vs 1.7% [three-times daily]). However, in children, once daily treatment was significantly less nephrotoxic than was thrice daily (mean% change in creatine -4.5% [once daily] vs 3.7% [thrice daily]; adjusted mean difference -8.0%, 95% CI -15.7 to -0.4). No patients developed hearing loss during the study, although two reported acute dizziness and were withdrawn from the study.
  
  
  CONCLUSIONS
  Intravenous tobramycin has equal efficacy if given once or three-times daily (with ceftazidime) for pulmonary exacerbations of cystic fibrosis. The once daily regimen might be less nephrotoxic in children.
authors.affiliation: Department of Child Health, University of Nottingham and Nottingham City Hospital, Nottingham, UK. alan.smyth@nottingham.ac.uk
authors.forename: Alan
authors.initials: A
authors.lastname: Smyth
authors.forename: Kelvin H-V
authors.initials: KH
authors.lastname: Tan
authors.forename: Pauline
authors.initials: P
authors.lastname: Hyman-Taylor
authors.forename: Michael
authors.initials: M
authors.lastname: Mulheran
authors.forename: Sarah
authors.initials: S
authors.lastname: Lewis
authors.forename: David
authors.initials: D
authors.lastname: Stableforth
authors.forename: Alan
authors.initials: A
authors.lastname: Prof Knox
mesh_terms: D000118:Acetylglucosaminidase / Q000652:urine; D000293:Adolescent; D000328:Adult; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000009:adverse effects; D002442:Ceftazidime / Q000008:administration & dosage; D002648:Child; D002675:Child, Preschool; D002908:Chronic Disease; D003404:Creatinine / Q000097:blood; D003550:Cystic Fibrosis / Q000382:microbiology* / Q000503:physiopathology; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination / Q000008:administration & dosage; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D011552:Pseudomonas Infections / Q000150:complications / Q000188:drug therapy*; D014031:Tobramycin / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D000900:Anti-Bacterial Agents; D002442:Ceftazidime; D003404:Creatinine; D000118:Acetylglucosaminidase; D014031:Tobramycin