Sputum Tobramycin Concentrations in Cystic Fibrosis Patients with Repeated Administration of Inhaled Tobramycin

Abstract

Background: Dosing of tobramycin solution for inhalation (TSI) in cystic fibrosis (CF) patients was based on single-dose pharmacokinetic studies. This investigation was prompted by evidence of possible antibiotic accumulation in respiratory secretions with repeated dosing. The objectives were to evaluate whether tobramycin accumulates in respiratory secretions with repeated inhalation, compare total and biologically active tobramycin concentrations in CF sputum, and evaluate sputum induction for obtaining secretions for drug concentration assay. Methods: Individuals with CF ‡ 10 years of age were enrolled at the beginning of a course of TSI, 300 mg twice daily for 28 days. Two study visits were conducted, 1-2 days and 24-28 days after initiation of TSI treatment. Induced sputum and expectorated sputum samples were collected for measurement of trough and peak tobramycin concentrations at each visit. Total tobramycin concentrations were measured by high-pressure liquid chromatography and bioactive concentrations by bioassay. Results: Twenty participants completed the study. Trough concentrations were similar at visits 1 and 2, as were peak concentrations. Trough bioactive and total tobramycin concentrations were similar (mean ratio 1.2, 95% CI 0.56, 1.87), but peak bioactive concentrations were significantly lower than peak total concentrations (mean ratio 0.33, 95% CI 0.23, 0.44). Sputum induction was well tolerated. Conclusions: No evidence of significant drug accumulation in respiratory secretions with repeat dosing of TSI was seen. Peak bioactive concentrations, although lower than peak total concentrations, were still generally well within the bactericidal range. Sputum induction as a method for determining airway drug concentrations appears safe and feasible.

Carbon Sources Tune Antibiotic Susceptibility in Pseudomonas aeruginosa via Tricarboxylic Acid Cycle Control

“…In particular, mannitol (Barraud et al, 2013) and arginine (Lebeaux et al, 2014) have been shown to resensitize P. aeruginosa biofilms to aminoglycosides; however, in the case of mannitol, most of the effect seemed to be due to osmotic effects, and arginine required very high aminoglycoside concentrations. In contrast, fumarate appears to potentiate tobramycin in the physiologically relevant concentration ranges achievable by intravenous (Vandenbussche and Homnick, 2012) or inhaled administration (Ruddy et al, 2013). Finally, although the present work primarily focuses on fumarate, we anticipate that other lower TCA cycle and lower glycolysis carbon sources could also have therapeutic value as potential adjuvants.…”

EnhancedIn VitroFormation and Antibiotic Resistance of Nonattached Pseudomonas aeruginosa Aggregates through Incorporation of Neutrophil Products

“…In all cases, these agents were the same pharmaceuticals used in the clinical care of CF patients. Antibiotic concentrations tested in the biofilm and planktonic samples were 100 g/ml tobramycin (TOBI; Novartis) and 20 g/ml azithromycin (APP Pharmaceuticals), which are concentration ranges observed in CF sputum (29,30). DNase concentration tested was 30 g/ml.…”

Clinical experimentation with aerosol antibiotics: current and future methods of administration

“…Future direction towards an efficient aerosol antibiotic treatment comes from a group of patients in need of daily treatment. Studies in children and young adults with cystic fibrosis indicate that the next generation of aerosol antibiotic treatments should be delivered in less time and less dose frequency during the day 144. Moreover, a patient-friendly device that increases adherence and possibly enables monitoring of treatment should be investigated further 118.…”