Tobramycin Nebuliser Solution Research Articles

Antibiotic strategies for eradicating Pseudomonas aeruginosa in people with cystic fibrosis.

Antibiotic strategies for eradicating Pseudomonas aeruginosa in people with cystic fibrosis.

Assessment of recent nebulizer delivery systems using urinary pharmacokinetics method and aerodynamic characteristics of TOBI® nebulized dose following inhalation

BackgroundChronic infections with Pseudomonas aeruginosa are a leading cause of morbidity in patients with cystic fibrosis (CF). Tobramycin nebulizer solution (TNS) is indicated for maintenance therapy in CF patients. TOBI® is a tobramycin nebulizer solution (TNS) approved by FDA for maintenance therapy for patient with CF. Adherence to recommended therapy in CF has always been a challenge and new generation nebulizers are increasingly used “off label” to reduce the time required for inhalation, potentially improving patient compliance. ObjectivesTo assess the performance of selected recent nebulizer delivery systems for determination the optimum combinations to deliver TOBI®. Using the relative lung bioavailability of TOBI® to the lungs in healthy volunteers, following inhalation from selected nebulizer delivery systems, using a urinary pharmacokinetics method. In vitro aerodynamic characteristics of the nebulized dose were also determined. MethodsSerial urine samples were collected from 12 healthy volunteers up to 24 h post-inhalation of TOBI® inhaled solution following delivery by Pari LC Plus®, Sidestream®, NE-U22-E Omron® and Aeroneb® Go nebulizers. In vitro aerodynamic characteristics of the nebulized dose were also determined according to the CEN (Committee European de Normalization) method. ResultsThe mean (SD) relative lung bioavailability from Pari LC Plus®, Sidestream®, Omron®, and Aeroneb® Go nebulizers was 4.9 (0.5), 3.9 (0.5), 7.1 (1.3), and 7.7 (0.7) %, respectively. The mean (SD) mass median aerodynamic diameter (MMAD) of the drug particles from the same systems was 2 (0.2), 2 (0.2), 1.2 (0.03) and 2.0 (0.1) μm, and the corresponding fine particle doses (FPD) were 2.2 (0.23), 1.5 (0.2), 3.44 (0.3) and 2.8 (0.3) mg. ConclusionThe data obtained from in-vitro and in-vivo studies reflect poor relative lung bioavailability of tobramycin following jet nebulization.

In vitro aerodynamic characterization of the dose emitted during nebulization of tobramycin high strength solution by novel and jet nebulizer delivery systems

BackgroundChronic infections with Pseudomonas aeruginosa are a leading cause of morbidity in patients with cystic fibrosis (CF). The aim of tobramycin inhalation therapy in CF patients with chronic pulmonary infection is to deliver high amounts of drug directly to the site of infection. TOBI® is a tobramycin nebulizer solution (300 mg/5 ml) approved by FDA for maintenance therapy for patient with CF. The 20% tobramycin sulfate solution was reported as the optimal and maximal concentration. MethodsNebulization of high strength tobramycin solution (20% tobramycin sulfate) (HSTS) has been assessed in this study by using different selected high performance nebulizer delivery systems: two different designs of jet nebulizers, and three new nebulizers based on vibrating mesh technology. The aerosol particle size distribution and output characteristics were measured for in vitro performance assessment of the nebulizer systems. The methodology was adapted from the current European standard, EN 13544-1:2001E. ResultsThe particle size distribution characteristic measurements showed that all tested nebulizers may be suitable for inhalation of HSTS. The mean (SD) of highest percentage of fine particles (<5 μm) was 77.64 (2.3) % for Sidestream®, at flow rate 16 L/min. The highest respirable inhaled mass was for Pari LC Plus® combined with PariBoyN® compressor, with mean (SD) 90.85 (8.6) mg. The mean (SD) of highest drug wastage percentage was 63.9 (3.9) % for Sidestream® jet nebulizer combined with compressed air cylinder at flow rate 16 L/min, while the lowest was 2.3 (0.26) % for NE-U22 Omron® (high frequency). ConclusionsThe HSTS can be nebulized by all tested nebulisers but the high frequency NE-U22 Omron® and Aeroneb Go® are more efficient. When the HSTS compared to TOBI®, the respirable inhaled dose was increased to more than 73%.

118 Efficacy and safety of colistimethate sodium in a paediatric population: Results from the FREEDOM trial

Objectives Colistimethate sodium is approved for the management of chronic pulmonary Pseudomonas aeruginosa (PA) infection in patients with cystic fibrosis (CF) ≥6 years. We aimed to compare the efficacy and safety of colistimethate dry powder inhaler (CMS DPI) to tobramycin nebulizer solution in paediatric patients with CF and chronic PA infection. Methods In this 24-week, phase-3, open label, active-controlled study, patients ≥6 years with forced expiratory volume in 1 second (FEV 1 ) 25–75% predicted were randomized 1:1 to twice-daily CMS DPI 125 mg (continuous therapy) or nebulized tobramycin 300 mg (three consecutive 28-day on-off cycles). The primary outcome – change from baseline in FEV 1 % predicted at week 24 – was analyzed in paediatric patient subgroups (6–12 y or 13–17 y). Antibiotic sensitivity testing and adverse events (AEs) monitoring were conducted. Results Of 154 paediatric patients included in the intention-to-treat population, 72 received CMS DPI. At week 24, adjusted differences (95% CI) in FEV 1 % predicted were 0.26 (–5.96, 6.47) and –3.04 (–8.96, 2.89) for patients aged 6–12 y and 13–17 y. While the overall incidence of colistin-resistant isolates was low in paediatric patients, there was a notable increase in the percentage of tobramycin-resistant isolates in patients 6–12 y. The occurrence of AEs, SAEs, and discontinuations due to AEs were similar between treatment groups. Conclusion In pediatric patients with CF and chronic pulmonary PA infection, the efficacy of colistimethate DPI was similar to nebulized tobramycin, but without antibiotic resistance. Colistimethate was well tolerated, and data suggest that CMS DPI can be safely administered to pediatric patients.

Inhaled aztreonam lysine vs. inhaled tobramycin in cystic fibrosis: A comparative efficacy trial

BackgroundOpen-label, parallel-group, international trial comparing aztreonam for inhalation solution (AZLI) and tobramycin nebulizer solution (TNS) for cystic fibrosis patients with airway Pseudomonas aeruginosa. Methods273 patients (≥6years); randomized to three 28-day courses (AZLI 75mg [three‐times/day] or TNS 300mg [twice/day]); 28 off-days separated each course. Results268 patients were treated (AZLI/TNS: 136/132). Mean baseline FEV1 was 52% predicted. Mean relative changes after 1 course (AZLI: 8.35%; TNS: 0.55%; p<0.001) and mean actual changes across 3 courses (AZLI: 2.05%; TNS: −0.66%; p=0.002) indicated AZLI statistical superiority vs. TNS. AZLI-treated patients had fewer respiratory hospitalizations (p=0.044) and respiratory events requiring additional antipseudomonal antibiotics (p=0.004); both treatments were well tolerated. 133 patients received 1 to 3 courses of AZLI treatment in the open-label extension-period (28-day courses separated by 28days off-treatment); lung function improvements were comparable regardless of whether patients had received TNS or AZLI in the preceding comparative period. ConclusionsAZLI demonstrated statistical superiority in lung function and a reduction in acute pulmonary exacerbations compared to TNS over 3 treatment courses (ClinicalTrials.gov: NCT00757237).

WS5.6 A challenging double-blind, placebo-controlled study of tobramycin inhalation powder in cystic fibrosis: results of the EDIT trial

WS5.5 A randomised, open label phase 3 study to evaluate the efficacy and safety of a dry powder formulation of inhaled colistimethate sodium (Colobreathe®) versus tobramycin nebuliser solution (TNS) in cystic fibrosis subjects with chronic Pseudomonas aeruginosa lung infection M. Goldman1, A. Schuster2, C. Halliburn3, G. Doring4, The Freedom Study Group. 1Forest Laboratories UK Ltd, Medical, Dartford, Kent, United Kingdom; 2University of Dusseldorf, Paediatrics, Dusselfdorf, Germany; 3Hartington Data Managment and Statitistics, Statistics, London, United Kingdom; 4University of Tubingen, Institute of Medical Microbiology and Hygiene, Tubingen, Germany

WS5.5 A randomised, open label phase 3 study to evaluate the efficacy and safety of a dry powder formulation of inhaled colistimethate sodium (Colobreathe®) versus tobramycin nebuliser solution (TNS) in cystic fibrosis subjects with chronic Pseudomonas aeruginosa lung infection

WS5.5 A randomised, open label phase 3 study to evaluate the efficacy and safety of a dry powder formulation of inhaled colistimethate sodium (Colobreathe®) versus tobramycin nebuliser solution (TNS) in cystic fibrosis subjects with chronic Pseudomonas aeruginosa lung infection

285 Pharmacokinetics of tobramycin nebulizer solution (Bramitob®) administered by Pari e-Flow Rapid vs Pari LC Plus nebulizer in patients with cystic fibrosis and Pseudomonas aeruginosa infection

285 Pharmacokinetics of tobramycin nebulizer solution (Bramitob®) administered by Pari e-Flow Rapid vs Pari LC Plus nebulizer in patients with cystic fibrosis and Pseudomonas aeruginosa infection

Lung delivery of a new tobramycin nebuliser solution (150 mg/1.5 ml) by an investigational eFlow® nebuliser is equivalent to TOBI® but in a fraction of time

Lung delivery of a new tobramycin nebuliser solution (150 mg/1.5 ml) by an investigational eFlow® nebuliser is equivalent to TOBI® but in a fraction of time

Erratum to: Tobramycin nebulizer solution in severe COPD patients colonized with Pseudomonas Aeruginosa: Effects on bronchial inflammation

Erratum to: Tobramycin nebulizer solution in severe COPD patients colonized with Pseudomonas Aeruginosa: Effects on bronchial inflammation

Tobramycin Nebulizer Solution in severe COPD patients colonized with Pseudomonas aeruginosa: effects on bronchial Inflammation

Airway colonization with Pseudomonas aeruginosa is frequent in severe chronic obstructive pulmonary disease (COPD) and may lead to progressive inflammatory damage. Inhaled Tobramycin Nebulizer Solution (TNS; a preservative-free formulation) is an effective therapy in chronic P aeruginosa infection in cystic fibrosis and bronchiectasis. In this study we aimed to investigate the effects of a TNS short course on inflammatory markers in bronchial secretions from multiresistant P aeruginosa-colonized patients with severe COPD. To the authors' knowledge, this is the first study to examine this in cases of severe COPD. Thirteen COPD patients (GOLD criteria 3-4; mean age 72.7+/- 8 years; mean basal forced expiratory volume in 1 second (FEV(1)) 34.8%+/-8.1%; mean FEV(1)/forced vital capacity 0.6+/-0.1) were enrolled. All patients were colonized with P aeruginosa and resistant to oral/intravenous specific antibiotics. Eosinophilic cationic protein (ECP), interleukin-1 beta (IL-1beta), interleukin-8 (IL-8), tumor necrosis factor alfa (TNF-alpha), and cell counts were measured in spontaneous secretions before and after a 2-week TNS course (300 mg twice daily). The TNS course induced a significant reduction in IL-1beta (P<0.03), IL-8 (P<0.02), ECP (P<0.01) concentrations, and in eosinophil count (P<0.01). TNF-alpha levels, and neutrophil and lymphocyte counts were not significantly affected. The second week of treatment proved crucial in terms of efficacy. P aeruginosa density was lowered after 6 months; severe acute exacerbations were reduced by 42%. TNS reduced the inflammatory impact of P aeruginosa in multiresistant, P aeruginosa-colonized patients with severe COPD. A therapeutic role for TNS can be strongly suggested in these particular conditions.

Inhaled tobramycin nebulizer solution for treatment of early Pseudomonas aeruginosa infection: the ELITE study

The benefit of early antibiotic intervention in treating P. aeruginosa in patients with cystic fibrosis (CF) is increasingly acknowledged. However, the effect of different treatment periods in this early intervention is unclear. In the open-label, randomized, multicentre ELITE (EarLy Inhaled Tobramycin for Eradication) study, CF patients 6 months of age with early P. aeruginosa infection were treated twice daily with tobramycin nebulizer solution (TNS; 300mg in 5ml) for 28 or 56 days and followed up for 27 months. The primary objective was to determine the median time to recurrence of any strain of P. aeruginosa. Secondary objectives were (a) assessment of the proportion of patients free of P. aeruginosa 1 month after completion of TNS treatment and (b) a safety evaluation of TNS. All patients were initially given TNS for 28 days. Eligible patients were then randomized 1:1 either to stop TNS treatment or to receive a further 28 days of treatment. The study recruited 123 patients at 21 European CF centres; 35 patients were not randomized due to the presence of P. aeruginosa antibodies at baseline. Of the 88 randomized patients, 46 received 28 days and 42 received 56 days of treatment. Genotyping of P. aeruginosa isolates obtained at baseline and on recurrence was conducted using random amplified polymorphic DNA polymerase chain reaction and pulsed-field gel electrophoresis for similar strains. Safety monitoring assessed treatment-emergent adverse events, serum tobramycin levels, renal function, and audiometry. Study recruitment was completed in November 2005, and the last patient completed follow-up in January 2008. Final results of the study will be presented at the meeting. Supported by: Novartis Pharma AG.

Open follow-up study of tobramycin nebuliser solution and colistin in patients with cystic fibrosis

A previous study of tobramycin nebuliser solution (TNS) compared with colistin [C] in cystic fibrosis (CF) patients, chronically infected with pseudomonas, showed benefit for the TNS treated patients over one treatment cycle only. The current report is of an extension of that study. An open randomised cross-over study of TNS compared with C was conducted on 21 patients who had previously been on the 1 cycle study. They continued for a further 5 months and then crossed over to the alternate treatment. There was an advantage for TNS over C in FEV 1 % predicted change over time. The C slope was − 0.88% per month and the TNS slope 0.35% per month ( p = 0.0002). This suggests advantages of TNS over C in a study with a small number of patients. Larger studies are required.

100 Safety of inhaled tobramycin nebuliser solution for treatment of early Pseudomonas aeruginosa infection: First results from the ELITE study

100 Safety of inhaled tobramycin nebuliser solution for treatment of early Pseudomonas aeruginosa infection: First results from the ELITE study

Economic evaluation of Tobramycin nebuliser solution in cystic fibrosis

Background: The cost effectiveness of inhaled TOBI R tobramycin nebuliser solution (TNS) in CF and chronic pulmonary Pseudomonas aeruginosa infection has been shown in US but not in European studies. Methods: An economic evaluation of TNS was undertaken in children and adults. Lung function and resource utilisation were recorded for 24 months before and during TNS therapy. Interventions were costed. Results: Forty-one patients received TNS; 30 of them matched with a paired control on usual therapy. TNS cases received more inhaled and IV antibiotics in the year before TNS than controls, and were hospitalised more. In the TNS treated group mean days in hospital before and after (change) were 32.0, 24.2 (−7.8); days on IV antibiotics 55.4, 38.9 (−16.4); total cost £22 102, £28 394 (+£6292), composed of cost of TNS £0, £10 010 (+£10 010), cost of hospitalisation £10 897, £8552 (−£2345), cost of drugs £11 205, £9832 (−£1374). In 19 patients aged <18 the change in days hospitalised was −10.7 and days on IVs −20.2. Incremental cost was £3830. Conclusions: TNS was associated with clinically and socially important reductions of hospital attendances and parenteral antibiotics. This would improve patients’ quality of life and reduce interference with work and schooling. Its maximal acquisition cost of £10 010 may be reduced by delays in prescribing and dispensing, and was offset by savings of approximately £3500–6200.

Insights into cystic fibrosis microbiology from the European tobramycin trial in cystic fibrosis

The infection of the airways of cystic fibrosis patients by Pseudomonas aeruginosa is a complex, multistaged process that is associated with a deterioration of lung function. The complexity of the formation of biofilms and their interaction with the immune system means that treatment with antibiotics has been an uncertain science. Tobramycin nebuliser solution (TNS) is a novel formulation of the antibiotic tobramycin developed specifically for inhalation. A recent large trial comparing TNS with inhaled colistin provided an opportunity to define further the effect of antibiotic treatment on microbial infection. In the TNS group, the percentage of patients with a tobramycin minimal inhibitory concentration (MIC) ⩾4 mg l −1 increased from 38 to 49%, and the percentage of patients with a colistin MIC⩾4 mg l −1 remained at 55%. In the colistin group, the percentage of patients with a colistin MIC⩾4 mg l −1 remained at 34%, whereas the percentage of patients with a tobramycin MIC⩾4 mg l −1 decreased from 27 to 16%. Furthermore, clinical and bacterial response to TNS and colistin was independent of the MIC at baseline. Neither antimicrobial therapy was associated with infection by Burkholderia cepacia or other inherently resistant pathogens. We conclude that conventional measures of antimicrobial resistance may underestimate the effectiveness of tobramycin and colistin when delivered at the high concentrations achieved with the TNS formulation.

The long-term use of inhaled tobramycin in patients with cystic fibrosis

Tobramycin nebuliser solution (TNS) has been investigated in several clinical trials, including a large, placebo-controlled study that demonstrated efficacy over a 24-week period. The open-label extension phase of this trial enabled observations to be conducted for an additional period of almost 18 months. Patients from both treatment arms ( n=396) entered the open-label phase and received up to nine 28-day on, 28-day off cycles of TNS 300 mg by aerosol twice daily (b.i.d.). Mean lung function in patients who had received placebo during the double-blind phase improved during the first three cycles of the open-label treatment. However, lung function in these patients did not recover to the levels seen in those patients who had received TNS throughout the double-blind and open-label phases. In both groups of patients, improvement was maintained during the study. Greater improvements were seen in adolescents compared with older patients. Adverse events were generally uncommon, with a notably lower incidence of fever, anorexia, abdominal pain and vomiting than was observed in the double-blind phase among patients who received placebo, and a generally low incidence of tinnitus. We conclude that long-term TNS administration is safe and effective.

Inhaled antibiotic therapy in evidence: what delivery device?

This paper evaluates the suitability of various compressors available in Europe to generate and deliver tobramycin nebulizer solution to cystic fibrosis patients from the PARI LC PLUS jet nebulizer. This evaluation has been undertaken (i) by establishing an in vitro equivalence to the DeVilbiss PulmoAide compressor (operating at 4.6 l/min) proven effective in US clinical trials, and (ii) by determining equivalent in vitro performance of the LC PLUS nebulizer driven by alternative airflows. Equivalent performance is judged as having both an aerosol output and aerosol size within ±10% of that obtained with the LC PLUS/PulmoAide combination. The two different in vitro methodologies applied to this investigation were based on the British Standard and a European Standard to assess nebulizer output. The results demonstrate that a wide range of compressed airflow rates generate aerosol output from the PARI LC PLUS equivalent to that obtained from the PulmoAide compressor. This range of airflows encompasses many compressors commonly available in Europe.

New clinical evidence from the European tobramycin trial in cystic fibrosis

The major cause of morbidity and mortality in patients with cystic fibrosis (CF) is respiratory disease (Penketh et al., Thorax 1987; 42: 526–532, [1]). Recent studies in the USA have shown that intermittent administration of inhaled tobramycin is beneficial to patients with CF who are chronically infected with Pseudomonas aeruginosa (Ramsey et al., N Engl J Med 1999; 340: 23–30, [3]; Ramsey et al., Proceedings of the 12th Annual North American Cystic Fibrosis Conference, 1998, Montreal, Canada; Ramsey et al., Abstract from 23rd European Cystic Fibrosis Conference, 1999, the Hague, Netherlands, [4]). In Europe, the use of nebulised colistin in patients chronically infected with P. aeruginosa is widespread. A recently published study compared the efficacy and safety of tobramycin nebuliser solution (TNS) and nebulised colistin in CF patients [6]. One hundred and fifteen patients were randomised to receive either TNS or colistin in a multi-centre open-labelled study that assessed change from baseline in FEV 1 and sputum P. aeruginosa density. TNS produced a mean 6.7% improvement in lung function ( P=0.006), whilst there was no significant improvement in the colistin-treated patients. The TNS-treated patients had a significantly greater improvement in lung function than those treated with colistin ( P=0.008). The safety profile of both treatments was good. We conclude that patients treated with TNS for 1 month experience improved lung function compared with patients treated with colistin.

TOBI: reducing the impact of pseudomonal infection.

Pseudomonas aeruginosa infection is associated with impaired lung function and reduced life expectancy in cystic fibrosis patients. Tobramycin nebulizer solution (TOBI, Chiron Corporation Ltd, Hounslow) has been specifically formulated for use against P. aeruginosa infection in the lung.