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

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.