Efficacy, safety, and local pharmacokinetics of highly concentrated nebulized tobramycin in patients with cystic fibrosis colonized with Pseudomonas aeruginosa

Paediatr Drugs. 2007;9 Suppl 1:11-20. doi: 10.2165/00148581-200709001-00003.

Abstract

Background and aim: Progressive respiratory failure due to Pseudomonas aeruginosa colonization is the most significant morbidity in patients with cystic fibrosis (CF). This trial was designed to investigate the efficacy and safety of a highly concentrated (300mg/4mL) tobramycin solution for inhalation (TSI) [Bramitob] in patients with CF and P. aeruginosa infection.

Methods: Fifty-nine patients were randomized to receive a 4-week treatment with tobramycin or placebo administered twice daily via the Pari LC Plus nebulizer and Pari TurboBoy compressor, followed by a 4-week run-out phase. Pulmonary function (forced expiratory volume in 1 second [FEV(1)], forced vital capacity [FVC], and forced expiratory flow at the midportion of vital capacity [FEF(25-75%)]), P. aeruginosa susceptibility, microbiologic results, and in vitro minimum inhibitory concentration for 90% of strains (MIC(90)) were the efficacy outcome measures, while safety was monitored by the recording of adverse events, audiometry (bone conduction at 250-8,000Hz frequency), laboratory tests, physical examination and general health condition. The concentration of tobramycin attained in sputum was measured in a cohort of 21 patients.

Results: FEV(1) significantly increased from baseline in the tobramycin group compared with no change in the placebo group: the absolute difference between groups (intent-to-treat population) of predicted normal was 13.2% at week 2 (p = 0.002) and 13.3% at week 4 (p = 0.003). Significant differences in favor of the tobramycin group were also observed for FVC and FEF(25-75%). The microbiologic results at the end of the treatment period (P. aeruginosa-negative culture, persistence, superinfection) showed a significantly better outcome in the tobramycin group compared with placebo (p = 0.033). The effects of tobramycin on pulmonary function and microbiology were not maintained at the end of the run-out phase. Mean sputum concentrations of tobramycin after the first dose (695.6 +/- 817.0 microg/mL) were similar to those measured after the last dose (716.9 +/- 799 microg/mL) and were superior to the detected specific MIC(90). The proportion of patients with drug-related adverse events was lower in the tobramycin group and no signs of renal or auditory toxicity were observed.

Conclusions: The 4-week administration of a highly concentrated TSI significantly improved pulmonary function and microbiologic outcome compared with placebo and was well tolerated. The results of this study should be confirmed in further long-term trials in larger populations.

Publication types

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

MeSH terms

  • Administration, Inhalation
  • Adolescent
  • Adult
  • Anti-Bacterial Agents / administration & dosage
  • Anti-Bacterial Agents / adverse effects
  • Anti-Bacterial Agents / pharmacokinetics
  • Anti-Bacterial Agents / therapeutic use*
  • Child
  • Cystic Fibrosis / complications
  • Cystic Fibrosis / drug therapy*
  • Double-Blind Method
  • Female
  • Humans
  • Male
  • Nebulizers and Vaporizers
  • Prospective Studies
  • Pseudomonas Infections / complications
  • Pseudomonas Infections / drug therapy*
  • Pseudomonas aeruginosa
  • Tobramycin / administration & dosage
  • Tobramycin / adverse effects
  • Tobramycin / pharmacokinetics
  • Tobramycin / therapeutic use*
  • Treatment Outcome

Substances

  • Anti-Bacterial Agents
  • Tobramycin