Once versus three-times daily regimens of tobramycin treatment for pulmonary exacerbations of cystic fibrosis--the TOPIC study: a randomised controlled trial

Lancet. 2005 Feb 12-18;365(9459):573-8. doi: 10.1016/S0140-6736(05)17906-9.

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.

Findings: 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 No patients developed hearing loss during the study, although two reported acute dizziness and were withdrawn from the study.

Interpretation: 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.

Publication types

  • Clinical Trial
  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylglucosaminidase / urine
  • Adolescent
  • Adult
  • Anti-Bacterial Agents / administration & dosage*
  • Anti-Bacterial Agents / adverse effects
  • Ceftazidime / administration & dosage
  • Child
  • Child, Preschool
  • Chronic Disease
  • Creatinine / blood
  • Cystic Fibrosis / microbiology*
  • Cystic Fibrosis / physiopathology
  • Double-Blind Method
  • Drug Administration Schedule
  • Drug Therapy, Combination / administration & dosage
  • Female
  • Forced Expiratory Volume
  • Humans
  • Infusions, Intravenous
  • Male
  • Middle Aged
  • Pseudomonas Infections / complications
  • Pseudomonas Infections / drug therapy*
  • Tobramycin / administration & dosage*
  • Tobramycin / adverse effects

Substances

  • Anti-Bacterial Agents
  • Ceftazidime
  • Creatinine
  • Acetylglucosaminidase
  • Tobramycin