Tobramycin Inhalation Research Articles

66 Efficacy of tobramycin inhalation powder (TIP) versus other inhaled antibiotics in cystic fibrosis (CF) patients with chronic P. aeruginosa infection: a network meta-analysis

66 Efficacy of tobramycin inhalation powder (TIP) versus other inhaled antibiotics in cystic fibrosis (CF) patients with chronic P. aeruginosa infection: a network meta-analysis

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

67 Trends in health-related quality of life (HRQoL) in cystic fibrosis with tobramycin inhalation powder: the EDIT trial

67 Trends in health-related quality of life (HRQoL) in cystic fibrosis with tobramycin inhalation powder: the EDIT trial

69 Efficacy on lung function and safety of multiple courses of tobramycin 300mg/4mL nebuliser solution (Bramitob) in patients with cystic fibrosis and chronic Pseudomonas aeruginosa infection: results from a 48-week extension phase

Objectives: Chronic treatment with inhaled antibiotics is part of the treatment regimen for cystic fibrosis patients chronically colonized with Pseudomonas aeruginosa. Previously available treatments included nebulized antibiotics, but use of available preparations could be burdensome for patients and families. Two “newgeneration” formulations recently become available in Canada. We describe early experiences with Tobramycin Inhalation Powder (TIP, TOBI® Podhaler®) in a large pediatric CF centre. Methods: Patients who had initiated therapy with TIP were identified by retrospective chart review and demographic information was recorded (patient age, sex, CFTR mutation, culture results over 12 months, and treatment before starting TIP). Patients who ceased using TIP were identified. Data: TIP first became commercially available in Canada in April 2011. There are 170 patients between the ages of 6−18 years enrolled in the CHU-Sainte Justine clinic. As of January 2012, 32 patients had started therapy with TIP (mean age: 13.4 years (range 6−18 years, SD = 3.1 years), 14 females/18 males. 22 DF508 homozygous, 7 others with one DF508 allele). All were chronically colonized with P. aeruginosa; 31 also had other organisms. Before TIP, 12 were treated with TOBI®, 8 tobramycin, 9 colymycin, 1 tobramycin + colymycin, and 2 untreated. Three patients stopped therapy: 1 due to poor Podhaler technique, 1 bronchospasm, and 1 negative cultures for P. aeruginosa for 1 year. Conclusion: Early clinical experience with TIP in our centre has been positive, with initiation of therapy in 32 patients to date. Only 3 have stopped therapy, 2 due to factors associated with TIP.

68 Early clinical experience with tobramycin inhalation powder (TIP)

68 Early clinical experience with tobramycin inhalation powder (TIP)

Efficacy of inhaled tobramycin in severe nosocomial pneumonia

Nosocomial pneumonia (NP) is one of the most prevalent complications in ICUs. The efficacy of inhaled antibiotics in treatment of NP was shown in several research works. The aim of this study was to estimate the efficacy of inhaled tobramycin (IT) as an adjunct to systemic antibiotics in the treatment of severe NP.

Tobramycin for the treatment of bacterial pneumonia in children

Introduction: Common etiological agents for community-acquired lower respiratory tract infection (LRTI) include Streptococcus pneumoniae, Hemophilus influenzae and Mycoplasma pneumoniae and can be easily managed with oral or intravenous antibiotics. However, LRTI in patients with underlying illnesses, such as cystic fibrosis (CF) and immune deficiency, or on ventilator support is difficult to manage because these are caused by Gram-negative bacilli. Tobramycin has been shown to be effective in the management of these patients.Areas covered: Information about the antimicrobial activity, pharmacological aspects (including pharmacokinetics and pharmacodynamics), clinical efficacy, safety and side effects of tobramycin have been covered in this review.Expert opinion: A major advance for the use of tobramycin has occurred with its use by the inhalational route, in children with CF. The inhalation route provides the advantage of ease of administration for prolonged periods at home and allows use of very high doses. Systematic reviews suggest that tobramycin inhalation improves outcome, decreases the need for hospitalization and decreases the need for use of frequent systemic antibiotics in CF patients colonized with pseudomonas. Data on the efficacy of inhaled tobramycin in non-CF bronchiectasis are scarce, as are data on the prevention and treatment of ventilator-associated pneumonia, and on the role of combining inhaled tobramycin with systemic tobramycin. Despite limitations, this drug has the potential to be used in various conditions other than CF.

Experience of the use of tobramycin for inhalation in children with cystic fibrosis

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Use of Inhaled Tobramycin for the Treatment of Severe Nosocomia Pneumonia

Objective: The objective of the study was to estimate the efficacy and safety of Inhaled Tobramycin (IT) as an adjunct to systemic antibiotics in the treatment of severe Nosocomial Pneumonia (NP). Patients and methods: 25 mechanically ventilated patients (out of 165 screened) were enrolled in the current observational single-center study. They were randomized to receive either IT (300mg, BID; group 1, n=15) as an adjunct to systemic antibiotics or for a correction of the regimen of systemic antibiotics (group 2, n=10). The primary outcome measure was resolution of NP and acute respiratory insufficiency. The CPIS, signs of Systemic Inflammatory Response Syndrome (SIRS) and oxygenation index were used as objective indicators of the clinical progress. Results: The following signs of IT efficacy were detected in 87% of group 1 patients: a decrease of SIRS and CPIS scores within 2, 3 ± 1, 2 days of IT therapy (p<0,05); decrease of microbes titer to 103-104 CFU/ml (p<0,05); increase of microbes sensitivity to systemic antibiotics in 40% of patients; positive X-ray dynamics in 60% of patients within 9, 0 ± 2, 5 days of IT therapy. No serious side effects of IT were observed. Conclusion: Administration of IT as an adjunct to systemic antibiotics is efficient and safe in 87% of patients with severe NP caused by multi resistant gram-negative bacteria.

Therapeutic approaches to chronic cystic fibrosis respiratory infections with available, emerging aerosolized antibiotics

Chronic airway infection and inflammation are key events in the clinical course of cystic fibrosis (CF). The most relevant, best investigated strain of bacteria in these circumstances is Pseudomonas aeruginosa. Since pulmonary infection with P. aeruginosa is localized in the lower conducting airways, treatment is accessible with the use of inhaled aerosolized antibiotics. Tobramycin inhalation solution was the first antibiotic to be developed and approved (in 1998) for use as an aerosolized antibiotic in patients with CF. The only other aerosolized antibiotic indicated for this use is aztreonam lysine solution for inhalation, which has been approved by both European and US authorities. In prospective, randomized, controlled trails, both agents exhibited a very acceptable safety profile, along with an increase in forced expiratory volume in 1 second and other clinically relevant endpoints. New developments focus on such components as reducing the treatment burden by using dry power inhalers, decreasing inhalation frequency to once daily, penetrating P. aeruginosa biofilms, and combining two antibiotics in one solution for inhalation. However, the ideal aerosolized antibiotic regimen for the treatment of chronic P. aeruginosa infection has yet not been selected.

Tobramycin Inhalation Powder™: a novel drug delivery system for treating chronic Pseudomonas aeruginosa infection in cystic fibrosis

Lung disease in cystic fibrosis (CF) is typified by the development of chronic airways infection culminating in bronchiectasis and progression to end-stage respiratory disease. Pseudomonas aeruginosa, a ubiquitous Gram-negative bacteria, is the archetypical CF pathogen and is associated with an accelerated clinical decline. The development and widespread use of chronic suppressive aerosolized antibacterial therapies, in particular Tobramycin Inhalation Solution (TIS), in CF has contributed to reduced lung function decline and improved survival. However, the requirement for the aerosolization of these agents through nebulizers has been associated with increased treatment burden, reduced quality of life and remain a barrier to broader uptake. Tobramycin Inhalation Powder (TIP™) has been developed by Novartis with the express purpose of delivering the same benefits as TIS in a time-effective manner. Administered via the T-326™ (Novartis) Inhaler in four individual 28-mg capsules, TIP can be administered in a quarter of the time of traditional nebulizers and is inherently portable. In clinical studies, TIP has been shown to be safe, result in equivalent or superior reductions in P. aeruginosa sputum density and produce similar improvements in pulmonary function. TIP offers significant advantages in time saving, portability and convenience over traditional nebulized TIS with comparable clinical outcomes for individuals with CF.

Tobramycin administered by the TOBI&amp;reg; Podhaler&amp;reg; for persons with cystic fibrosis: a review

From its introduction, the antibiotic tobramycin has been an important tool in the management of persons with cystic fibrosis (CF) and chronic Pseudomonas aeruginosa lung infections. Initially an intravenous rescue treatment for pulmonary exacerbations, tobramycin delivered by inhalation has become a mainstay of chronic suppressive CF infection management. Platforms for tobramycin aerosol delivery have steadily improved, with increased lung deposition complimented by decreased device complexities, loaded tobramycin doses, delivery times, and treatment burdens. Most recently, a unique tobramycin inhalation powder (TIP) formulation with a portable delivery system, the TOBI® Podhaler® (Novartis AG, Basel, Switzerland) has been developed and approved in Europe, Canada, and Chile. Four capsules, each containing 28 mg of TIP are successively pierced and inhaled via the T-326 Dry Powder Inhaler Device (Novartis AG, Basel, Switzerland). No external power source is required to deliver an efficacious tobramycin dose in minutes. By comparison, tobramycin inhalation solution (TIS) (TOBI®; Novartis), is delivered by LC® Plus (PARI Respiratory Equipment Inc, Midlothian, VA) jet nebulizer powered by an air compressor over 15–20 minutes. Comparative pharmacokinetics, safety, and efficacy studies of TIS and TIP in CF subjects with P. aeruginosa ≥ 6 years old demonstrate that: tobramycin lung deposition with 112 mg TIP is comparable to that attained with 300 mg TIS, TIP is more effective than placebo and not inferior to TIS with respect to pulmonary function benefit, and TIP has significantly faster treatment times and achieves higher patient satisfaction than TIS. TIP is associated with an increased frequency of mild to moderate local adverse events (cough, dysphonia, and dysgeusia) compared with TIS, however, these become less frequent as subjects gain TIP experience. These results suggest that the TOBI Podhaler may better meet the needs of many CF patients and families by reducing treatment time and complexity and improving patient satisfaction compared with TIS.

Reduced mortality in cystic fibrosis patients treated with tobramycin inhalation solution

Though tobramycin inhalation solution has been used for over a decade to improve lung function and reduce exacerbations in patients with cystic fibrosis (CF), its effects on mortality have not been well-described. This study aimed to assess the association between use of tobramycin inhaled solution and mortality in patients with CF and chronic Pseudomonas aeruginosa (PA) infection. Longitudinal logistic regression was used to assess the association between current-year reported use of tobramycin inhalation solution and subsequent-year mortality of patients meeting recommended criteria for tobramycin inhalation solution use in the United States Cystic Fibrosis Foundation's Patient Registry (1996-2008). Among 12,740 patients meeting inclusion criteria, 2,538 deaths were observed during a median follow-up of 6 years. After regression adjustment, use of tobramycin inhaled solution was associated with a 21% reduction in the odds of subsequent year mortality (odds ratio (95% CI): 0.79 (0.72-0.88), P < 0.001). In our model, use of dornase alfa was also associated with a 15% reduction in the odds of subsequent year mortality (odds ratio (95% CI): 0.85 (0.76-0.95), P = 0.005). Underweight for age, CF-related diabetes, female gender, worse lung function and cultures positive for Pseudomonas aeruginosa or Burkholderia cepacia complex, among multiple other patient characteristics, were associated with significantly increased mortality. Adjusted mortality rates for patients reporting tobramycin inhalation solution use in all versus none of the follow-up years were 1.3% versus 2.1% at 2 years, 5.2% versus 8.0% at 5 years, and 9.9% versus 15.0% at 10 years. After adjustment for multiple patient characteristics and known risk factors, use of tobramycin inhalation solution was associated with significantly reduced mortality among patients with CF.

Detectable serum tobramycin concentrations in a patient with renal dysfunction receiving tobramycin by inhalation

It is well-known that inhaled tobramycin is safe and effective for the treatment of Pseudomonas lung infections.[1][1] The majority of investigations of inhaled tobramycin have involved patients with cystic fibrosis. Inhalation of tobramycin delivers the drug directly to the site of infection in the

83* Sinonasal inhalation of tobramycin in cystic fibrosis patients with P. aeruginosa colonization of the upper airways – results of a multicentric placebo-controlled pilot study

83* Sinonasal inhalation of tobramycin in cystic fibrosis patients with P. aeruginosa colonization of the upper airways – results of a multicentric placebo-controlled pilot study

84 Pulmosphere(tm) DPI technology reduces time burden in cystic fibrosis: the lesson of tobramycin inhalation powder (TIP(tm))

84 Pulmosphere(tm) DPI technology reduces time burden in cystic fibrosis: the lesson of tobramycin inhalation powder (TIP(tm))

82* Microbiological and clinical response to tobramycin inhalation powder (TIP(tm)) in cystic fibrosis patients with chronic Pseudomonas aeruginosa (Pa) infection

82* Microbiological and clinical response to tobramycin inhalation powder (TIP(tm)) in cystic fibrosis patients with chronic Pseudomonas aeruginosa (Pa) infection

Aztreonam Lysine for Inhalation Solution in Cystic Fibrosis†

Aztreonam is a monobactam antibacterial with bactericidal activity against a wide range of aerobic Gram-negative bacteria, including Pseudomonas aeruginosa. Aztreonam lysine for inhalation solution (AZLI) does not contain the potentially inflammatory component arginine, which is used as a buffer in the intravenous formulation. Two phase III, randomized, placebo-controlled trials (AIR-CF1 and AIR-CF2) have been completed with AZLI in cystic fibrosis patients with pulmonary P. aeruginosa infection. In AIR-CF1, respiratory symptoms were significantly improved with AZLI compared with placebo, as assessed by the respiratory symptoms domain of the Cystic Fibrosis Questionnaire-Revised, a disease-specific, patient-reported outcome instrument. The mean treatment effect exceeded the minimal clinically important difference. In AIR-CF2, AZLI was compared with placebo following a 28-day course of tobramycin inhalation solution. AZLI was associated with a significant delay in the need for inhaled or intravenous antipseudomonal antibacterials, as determined by the presence of one of four predefined symptoms shown to be predictive of pulmonary exacerbations. An open-label extension of these trials (AIR-CF3) also demonstrated clinical efficacy with repeated courses of AZLI over 18 months and was not associated with sustained reductions in P. aeruginosa susceptibility. AZLI was also associated with improved pulmonary function and reductions in P. aeruginosa density in sputum in clinical trials. The tolerability profile of AZLI was generally similar to that of placebo in randomized controlled trials, with respiratory symptoms being the most frequently reported adverse events.

High-dose tobramycin inhibits lipopolysaccharide-induced MUC5AC production in human lung epithelial cells

Tobramycin inhalation therapy is an effective therapy for cystic fibrosis as well as severe bronchiectasis that is colonized with Pseudomonas aeruginosa. The mechanism responsible for the efficacy of tobramycin in the treatment of severe chronic infectious diseases has not been elucidated. We demonstrate that high-dose tobramycin decreases MUC5AC gene expression and protein production in NCI-H292 cell stimulated with lipopolysaccharide of P. aeruginosa. MUC5AC protein of NCI-H292 cell stimulated by lipopolysaccharide was analyzed by an enzyme-linked immunosorbent assay and MUC5AC expression at the mRNA level was analyzed by RT-PCR. Western blot was performed to examine a potential role for the signaling molecules upstream of NFκB. High-dose tobramycin (500 μg/ml) decreased the level of MUC5AC protein released into the supernatant of the NCI-H292 cell line at 24 h after lipopolysaccharide stimulation ( P < 0.001). The tobramycin treatment also inhibited MUC5AC mRNA expression at 12 h after lipopolysaccharide stimulation ( P < 0.05) and suppressed NFκB activation 60 min after lipopolysaccharide stimulation ( P < 0.001). Tobramycin suppressed the phosphorylation of extracellular signal-regulated protein kinase, p38 MAP kinase. These results suggest that high-dose tobramycin, such as inhalation therapy, can inhibit MUC5AC gene expression and MUC5AC protein production in NCI-H292 cells, in part through the mitogen-activated protein kinase pathway. Thus, the activation of TLR4 and the subsequent immune/inflammatory responses induced by chronic infections such as P. aeruginosa might be modulated by tobramycin. Our data may reveal one of the mechanisms responsible for the clinical effect of tobramycin inhalation therapy against severe chronic respiratory diseases due to P. aeruginosa.

Adherence with tobramycin inhaled solution and health care utilization

BackgroundAdherence with tobramycin inhalation solution (TIS) during routine cystic fibrosis (CF) care may differ from recommended guidelines and affect health care utilization.MethodsWe analyzed 2001-2006 healthcare claims data from 45 large employers. Study subjects had diagnoses of CF and at least 1 prescription for TIS. We measured adherence as the number of TIS therapy cycles completed during the year and categorized overall adherence as: low ≤ 2 cycles, medium >2 to <4 cycles, and high ≥ 4 cycles per year. Interquartile ranges (IQR) were created for health care utilization and logistic regression analysis of hospitalization risk was conducted by TIS adherence categories.ResultsAmong 804 individuals identified with CF and a prescription for TIS, only 7% (n = 54) received ≥ 4 cycles of TIS per year. High adherence with TIS was associated with a decreased risk of hospitalization when compared to individuals receiving ≤ 2 cycles (adjusted odds ratio 0.40; 95% confidence interval 0.19-0.84). High adherence with TIS was also associated with lower outpatient service costs (IQR: $2,159-$8444 vs. $2,410-$14,423) and higher outpatient prescription drug costs (IQR: $35,125-$60,969 vs. $10,353-$46,768).ConclusionsUse of TIS did not reflect recommended guidelines and may impact other health care utilization.