Tobramycin Inhalation Research Articles

Effect of adjunctive tobramycin inhalation versus placebo on early clinical response in the treatment of ventilator-associated pneumonia: the VAPORISE randomized-controlled trial

Effect of adjunctive tobramycin inhalation versus placebo on early clinical response in the treatment of ventilator-associated pneumonia: the VAPORISE randomized-controlled trial

Treatments for preventing recurrence of infection with Pseudomonas aeruginosa in people with cystic fibrosis.

Chronic infection with Pseudomonas aeruginosa (PA) in cystic fibrosis (CF) is a source of much morbidity and mortality. Eradication of early PA infection is possible, but can recur in many individuals. We sought to examine strategies to delay the time to PA recurrence in people with CF. To establish whether secondary prevention strategies, using antibiotics or other therapies, increase the chances of people with CF remaining free from PA infection following successful eradication therapy. We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched ongoing trials registries and the reference lists of relevant articles and reviews. Date of last search: 21 August 2019. Randomised controlled trials (and quasi-randomised trials where the risk of bias was low) comparing any treatment modality aimed at preventing recurrence of PA infection with placebo, standard therapy or any other treatment modality in people with CF who have undergone successful eradication of PA. Two review authors independently assessed trials for inclusion and risk of bias. Quality of the evidence was assessed using GRADE. Conflicts were resolved by discussion and the opinion of a third review author was sought where necessary. Only a subset of participants in the included trial were eligible, therefore individual participant data were requested and obtained from the trial investigators. We included one trial (n = 306) in the review; however, only 253 participants had undergone successful eradication of PA, so fulfilling the inclusion criteria for our review. Information presented relates only to the included subset of participants. The trial recruited children aged one to 12 years (mean (standard deviation (SD)) age of 5.8 (3.5) years), 129 participants (51.0%) were female and the median follow-up was 494 days. We compared cycled therapy with tobramycin inhalation solution (TIS), in which participants underwent 28 days of TIS every three months, with culture-based therapy, in which participants were only prescribed medication when a quarterly sputum sample was positive for PA. Reasons for downgrading the quality of the evidence included applicability (only included children), incomplete outcome data and a small number of participants. The time to next isolation of PA was probably shorter with cycled TIS therapy than with culture-based therapy, hazard ratio (HR) 2.04 days (95% confidence interval (CI) 1.28 to 3.26) (moderate-quality evidence). This is in contrast to the main publication of the only included trial, which examined rate of PA positivity rather than time to PA infection and included participants not eligible for inclusion in this review. At the end of the trial, there was no difference between the cycled and culture-based groups in the change from baseline in forced expiratory volume in one second (FEV1) L, mean difference (MD) 0.0 L (95% CI -0.09 to 0.09) or in FEV1 % predicted, MD 0.70% (95% CI -4.33 to 5.73) (both very low-quality evidence). There was no difference in the change from baseline for FVC between the groups. There was also no difference in the frequency of pulmonary exacerbations between groups, MD -0.18 (95% CI -0.51 to 0.14) (moderate-quality evidence). Similarly, there was no difference between groups in the risk of participants developing novel resistant bacteria, RR 1.00 (95% CI 0.67 to 1.5) (moderate-quality evidence). There were more severe adverse events in the cycled group, but the type of treatment probably makes little or no difference to the results, RR 0.65 (95% CI 0.39 to 1.11) (moderate-quality evidence). There was no difference between groups in the change in weight or height from baseline or in rates of adherence to tobramycin or all trial medicines. The included trial did not assess changes in quality of life, the time to chronic infection with PA or the cost-effectiveness of treatment. Cycled TIS therapy may be beneficial in prolonging the time to recurrence of PA after successful eradication, but further trials are required, specifically addressing this question and in both adults and children.

PRS64 CONTENT VALIDATION OF THE RESPIRATORY SYMPTOMS SUBSCALE (RSS) OF THE QUALITY OF LIFE QUESTIONNAIRE-BRONCHIECTASIS (QOL-B) IN NON-CYSTIC FIBROSIS BRONCHIECTASIS (NON-CF BE)

To evaluate whether the content of QoL-B RSS (items 29-37) relates to patients’ experiences of symptoms included in the dose-finding study for tobramycin inhalation powder in non-CF BE, iBEST-1 (NCT02712983). Qualitative, semi-structured, open-ended telephone interviews were conducted with a subsample of patients completing the study at four sites in the United Kingdom. Patients were asked to describe the symptoms they experienced and their feedback was collected on the understandability, meaning, relevance of the items and response options contained within the RSS. Seven patients comprising four females were interviewed with age range 40-72 years, disease duration 4-60 years and a median baseline QoL-B RSS score of 55.6 (range 40.7-77.8). The items of the RSS were found to be highly relevant to patients’ experiences of BE symptoms (sputum, cough, breathlessness, chest pain, wheezing, and chest congestion). However, some patients conflated the concepts of congestion and chest tightness. While four patients reported that they had experienced all colors of sputum listed under response options of item 32, three patients reported experiencing a non-listed color. Patients were able to relate the changes in sputum color to changes in symptoms with darker colors corresponding to a deterioration in symptoms. Response scales were considered distinct, appropriate, easy to use and representing the full range of severity or frequency levels of the changes experienced. Patients reported that any change would be positive and noticeable but for a change on the RSS to be considered as meaningful, an improvement of at least 1-point would need to occur in several respiratory symptoms. Although based on only seven interviews, these results provide supportive evidence for the content validity of the QOL-B RSS. Further confirmation is warranted through additional interviews. This study has received support from the EU/EFPIA IMI-JU iABC grant agreement n° 115721.

Amikacin liposome inhalation suspension for chronic Pseudomonas aeruginosa infection in cystic fibrosis

BackgroundShortcomings of inhaled antibiotic treatments for Pseudomonas aeruginosa infection in patients with cystic fibrosis (CF) include poor drug penetration, inactivation by sputum, poor efficiency due to protective biofilm, and short residence in the lung. MethodsEligible patients with forced expiratory volume in 1 s (FEV1) ≥25% of predicted value at screening and CF with chronic P. aeruginosa infection were randomly assigned to receive 3 treatment cycles (28 days on, 28 days off) of amikacin liposome inhalation suspension (ALIS, 590 mg QD) or tobramycin inhalation solution (TIS, 300 mg BID). The primary endpoint was noninferiority of ALIS vs TIS in change from baseline to day 168 in FEV1 (per-protocol population). Secondary endpoints included change in respiratory symptoms by Cystic Fibrosis Questionnaire-Revised (CFQ-R). ResultsThe study was conducted February 2012 to September 2013. ALIS was noninferior to TIS (95% CI, −4.95 to 2.34) for relative change in FEV1 (L) from baseline. The mean increases in CFQ-R score from baseline on the Respiratory Symptoms scale suggested clinically meaningful improvement in both arms at the end of treatment in cycle 1 and in the ALIS arm at the end of treatment in cycles 2 and 3; however, the changes were not statistically significant between the 2 treatment arms. Treatment-emergent adverse events (TEAEs) were reported in most patients (ALIS, 84.5%; TIS, 78.8%). Serious TEAEs occurred in 17.6% and 19.9% of patients, respectively; most were hospitalisations for infective pulmonary exacerbation of CF. ConclusionsCyclical dosing of once-daily ALIS was noninferior to cyclical twice-daily TIS in improving lung function.ClinicalTrials.gov Identifier: NCT01315678

Efficacy and safety of tobramycin inhalation powder in bronchiectasis patients with P. aeruginosa infection: Design of a dose-finding study (iBEST-1)

In patients with bronchiectasis (BE), infection with Pseudomonas aeruginosa (Pa) results in disease progression, frequent pulmonary exacerbations and lung function decline. However, at present, no inhaled antibiotics have been approved for the treatment of these patients. Tobramycin inhalation powder (TIP), approved for treatment of Pa infection in cystic fibrosis, could be a promising candidate.We aimed to assess effective and well-tolerated doses and regimens of TIP in BE patients with Pa infection.In this phase II, double-blind, placebo-controlled, randomised study, three different daily doses of TIP are administered either as continuous or cyclical regimens. The study protocol comprises 7–28 days of screening, 112 days of double-blind treatment and 56 days of follow-up. The plan was to enrol 180 patients (aged ≥18 years) with BE, documented Pa infection and a history of exacerbations. The primary outcome is change in sputum Pa density from baseline. Key secondary outcomes include number of pulmonary exacerbations, use of antipseudomonal antibiotics, serum and sputum tobramycin concentrations, quality of life and safety. Exploratory endpoints include lung clearance index, sputum inflammatory markers and microbiome analysis.As of October 2018, 107/180 patients were enrolled at 34 sites (six countries) following which recruitment was closed for administrative reasons unrelated to safety findings. Despite a reduced sample size from initially planned enrolment, the unique design may inform the benefit-risk profile of TIP in BE patients with chronic Pa infection. Moreover, several novel and exploratory endpoints (lung clearance index, inflammatory biomarkers, lung microbiome), will contribute to the advancement of research in this area.

Home videos of cystic fibrosis patients using tobramycin inhalation powder: Relation of flow and cough.

BackgroundMany cystic fibrosis (CF) patients chronically infected with Pseudomonas aeruginosa are on maintenance tobramycin inhalation therapy. Cough is reported as a side effect of tobramycin inhalation powder (TIP) in 48% of the patients. Objectives of this study were to investigate the association between the inspiratory flow of TIP and cough and to study the inhalation technique. We hypothesized that cough is related to a fast inhalation.Materials and MethodsIn this prospective observational study, CF patients ≥ 6 years old on TIP maintenance therapy from four Dutch CF centers were visited twice at home. Video recordings were obtained and peak inspiratory flow (PIF) was recorded while patients inhaled TIP. Between the two home visits, the patients made three additional videos. CF questionnaire‐revised, spirometry data, and computed tomography scan were collected. Two observers scored the videos for PIF, cough, and mistakes in inhalation technique. The associations between PIF and cough were analyzed using a logistic mixed‐effects model accounting for FEV1% predicted and capsule number.ResultsTwenty patients were included, median age 22 (18–28) years. No significant associations were found between PIF and cough. The risk of cough was highest after inhalation of the first capsule when compared to the second, third, and fourth capsule (P ≤ .015). Fourteen patients (70%) coughed at least once during TIP inhalation. A breath‐hold of less than 5 seconds after inhalation and no deep expiration before inhalation were the most commonly observed mistakes.ConclusionPIF is not related to cough in CF patients using TIP.

Pharmacokinetics and safety of tobramycin nebulization with the I-neb and PARI-LC Plus in children with cystic fibrosis: A randomized, crossover study.

AimsWe aimed to compare the pharmacokinetics (PK) and safety profile of tobramycin inhalation solution (TIS) using the I‐neb device to the standard PARI‐LC Plus nebulizer in children with cystic fibrosis.MethodsA randomized, open‐label, crossover study was performed. In 2 separate study visits, blood samples from 22 children were collected following TIS nebulization with I‐neb (75 mg) and PARI‐LC Plus (300 mg). Study visits were separated by 1 month, in which 1 of the study nebulizers was used twice daily. Tobramycin PK for both nebulizers was established using measured tobramycin concentrations and Bayesian PK modelling software. Hearing and renal function tests were performed to test for aminoglycoside associated toxicity. In addition to standard estimated glomerular filtration rate values, biomarkers for tubular injury (KIM‐1 and NAG) were measured. Patient and nebulizer satisfaction were assessed.ResultsInhalations were well tolerated and serum trough concentrations below the predefined toxic limit were reached with no significant differences in PK parameters between nebulizers. Results of audiometry and estimated glomerular filtration rate revealed no abnormalities. However, increased urinary NAG/creatinine ratios at visit 2 for both nebulizers suggest TIS‐induced subclinical tubular kidney injury. Nebulization time was 50% shorter and patient satisfaction was significantly higher with the I‐neb.ConclusionsNebulization of 75 mg TIS with the I‐neb in children with cystic fibrosis resulted in comparable systemic exposure to 300 mg TIS with the PARI‐LC Plus and was well tolerated and preferred over the PARI‐LC Plus. Long‐term safety of TIS nebulization should be monitored clinically, especially regarding the effects on tubular kidney injury.

Orphan designation: Tobramycin (inhalation powder), Treatment of Pseudomonas aeruginosa lung infection in cystic fibrosis

Orphan designation: Tobramycin (inhalation powder), Treatment of Pseudomonas aeruginosa lung infection in cystic fibrosis

Clinical significance of lung microbiota and efficiency of the inhaled antibacterial therapy of cystic fibrosis in children

The objective: to study clinical and microbiological features of the injuries of the respiratory organs and to assess the effectiveness of elimination therapy in chronic sinus infection in children in the regional center for cystic fibrosis. The specialists of Omsk center for cystic fibrosis made a retrospective analysis of 48 case histories and assessed clinical and functional parameters depending on the age and microbiological status of the respiratory tract. They presented a comparative assessment of the effectiveness of the original and generic tobramycin inhalation. The results. An association of microorganisms was identified in the majority of bacterial cultures of cystic fibrosis patients’ sputum (66.7%). Among the clinically relevant pathogens there were Staphylococcus aureus (18.9%) and Pseudomonas aeruginosa (16.6%) with the significant prevalence of non-mucoid forms. From 2011 to 2016 the amount of Pseudomonas aeruginosa strains, sensitive to all usable antibiotics, decreased, especially significant sensitivity decline was registered to amikacin – 21.35% and с iprofloxacin – 26.1%. The children infected by Pseudomonas aeruginosa had more deviations of lung function measured by the computed bronchophonography and spirometry, they more often had changes at chest computed tomography than patients free of Pseudomonas aeruginosa infection. Usage of generic tobramycin instead of original tobramycin didn’t lead to the elevation of respiratory syndrome exacerbation rates, didn’t increase requirement in the intravenous antibacterial treatment and didn’t influence to the degree of microbial colonization of sputum. The conclusion. There was noted an increase in the resistance of Pseudomonas aeruginosa to anti-pseudomuscular drugs, which justifies the introduction of highly concentrated inhaled forms of antibiotics. Replacing the original inhaled tobramycin with a generic drug did not cause a deterioration in the clinical and functional status of the patients and did not change their microbiological status.

Azithromycin for Early Pseudomonas Infection in Cystic Fibrosis. The OPTIMIZE Randomized Trial.

New isolation of Pseudomonas aeruginosa (Pa) is generally treated with inhaled antipseudomonal antibiotics such as tobramycin inhalation solution (TIS). A therapeutic approach that complements traditional antimicrobial therapy by reducing the risk of pulmonary exacerbation and inflammation may ultimately prolong the time to Pa recurrence. To test the hypothesis that the addition of azithromycin to TIS in children with cystic fibrosis and early Pa decreases the risk of pulmonary exacerbation and prolongs the time to Pa recurrence. The OPTIMIZE (Optimizing Treatment for Early Pseudomonas aeruginosa Infection in Cystic Fibrosis) trial was a multicenter, double-blind, randomized, placebo-controlled, 18-month trial in children with CF, 6 months to 18 years of age, with early Pa. Azithromycin or placebo was given 3× weekly with standardized TIS. The primary endpoint was the time to pulmonary exacerbation requiring antibiotics and the secondary endpoint was the time to Pa recurrence, in addition to other clinical and safety outcomes. A total of 221 participants (111 placebo, 110 azithromycin) out of a planned 274 were enrolled. Enrollment was stopped early by the NHLBI because the trial had reached the prespecified interim boundary for efficacy. The risk of pulmonary exacerbation was reduced by 44% in the azithromycin group as compared with the placebo group (hazard ratio, 0.56; 95% confidence interval, 0.37-0.83; P = 0.004). Weight increased by 1.27 kg in the azithromycin group compared with the placebo group (95% confidence interval, 0.01-2.52; P = 0.046). No significant differences were seen in microbiological or other clinical or safety endpoints. Azithromycin was associated with a significant reduction in the risk of pulmonary exacerbation and a sustained improvement in weight, but had no impact on microbiological outcomes in children with early Pa. Clinical trial registered with clinicaltrials.gov (NCT02054156).

Dynamics of Inhaled Tobramycin Concentration in Blood and Bronchoalveolar Lavage Fluid during Nosocomial Pneumonia (Preliminary Report)

This study was aimed to evaluate the dynamics of inhaled tobramycin concentration in bronchoalveolar lavage fluid and blood in victims with nosocomial pneumonia.Materials and Methods. The study is presented as a series of clinical observations: 5 patients with severe concomitant craniocerebral injury were included, who were treated in the general resuscitation unit (men 4 (87.5%), women 1 (12.5%); age 36Ѓ}12 years; Injury Severity Score (ISS) 40.9Ѓ}8.3; acute blood loss volume 2356Ѓ}997 ml; mean bed-days 12.50 days; mortality 16.7%). Statistical analysis of data obtained was carried out using Statistica 10.0 software. Difference was considered significant at p<0.05.Results. The dynamics of tobramycin concentrations was as follows: 1 hr. blood/BAL 0.96Ѓ}0.44 μg/ml / 49.6 μg/ml; 3 hrs. blood/BAL 0.98Ѓ}0.82 μg/ml / 15.5 μg/ml; 5 hrs. blood/BAL 0.79Ѓ}0.83 μg/ml / 3.5 μg/ml. Conclusion.The results obtained confirm significant local concentrations of tobramycin in sputum and low in blood, which corresponds to the results of pharmacokinetic studies and clinical studies of inhaled tobramycin efficacy. At present, gathering of material for the study continues.

P031 Home registrations of inhalations with tobramycin inhalation powder - the relation between inspiratory flow and cough

P031 Home registrations of inhalations with tobramycin inhalation powder - the relation between inspiratory flow and cough

Eradication of early P. aeruginosa infection in children

ObjectiveAntibiotic eradication treatment is the standard-of-care for cystic fibrosis (CF) patients with early Pseudomonas aeruginosa (Pa)-infection; however, evidence from placebo-controlled trials is limited. MethodsThis double-blind, placebo-controlled trial randomised CF patients <7 years (N = 51) with early Pa-infection to tobramycin inhalation solution (TOBI 300 mg) or placebo (twice daily) for 28 days with an optional cross-over on Day 35. Primary endpoint was proportion of patients having throat swabs/sputum free of Pa on Day 29. ResultsOn Day 29, 84.6% patients in the TOBI versus 24.0% in the placebo group were Pa-free (p < 0.001). At the end of the cross-over period, 76.0% patients receiving TOBI in the initial 28 days were Pa-free compared to 47.8% receiving placebo initially. Adverse events were consistent with the TOBI safety profile with no differences between TOBI and placebo. ConclusionTOBI was effective in eradicating early Pa-infection with a favourable safety profile in young CF patients.Trial registration number: NCT01082367

Treatment compliance in cystic fibrosis patients with chronic Pseudomonas aeruginosa infection treated with tobramycin inhalation powder: The FREE study.

A high treatment burden with nebulised therapies in cystic fibrosis (CF) patients is the major limitation for treatment compliance; moreover, studies on treatment compliance with inhaled antibiotics are limited. This study assessed compliance to TOBI® Podhaler™ (TIP) treatment in CF patients with chronic Pseudomonas aeruginosa (Pa) infections in a real-world setting using the Italian Treatment Adherence CF Questionnaire (ITA-CFq). This longitudinal, multicentre, cohort study included 2 follow-up (FU) visits: FU-1 at 3-months±15-days from the baseline visit and FU-2 at the end of third TIP cycle (or 6-months after enrolment, whichever occurred first). The effect of TIP on quality-of-life (QoL) and treatment satisfaction were evaluated using Cystic Fibrosis Questionnaire-Revised (CFQ-R) and Treatment Satisfaction Questionnaire for Medication (TSQM), respectively. Overall compliance to treatments was assessed using ITA-CFq. Eighty-two patients (mean age, 24.8 ± 7.9 years), including 22 paediatric patients (age, <18 years), were enrolled in the study; 56 (68.3%) patients, including 17 paediatric patients, completed the study. At baseline, the mean compliance score to aerosol antibiotic treatment was 7.8 ± 3.2; upon introducing TIP, the compliance score improved to 9.4 ± 1.2 at the FU-1 and thereafter remained stable at 9.5 ± 1.2. TSQM was higher for the convenience domain (74.2 ± 17.1 at enrolment and slightly improved to 77.8 ± 15.9 at FU-2) following TIP initiation. No substantial effect of TIP was observed on the QoL when measured using the revised CFQ-R. The safety profile was in line with previous findings. TIP was convenient to use and led to improved treatment adherence in CF patients with chronic Pa-infection.

Economic Evaluation of Tobramycin Inhalation Powder for the Treatment of Chronic Pulmonary Pseudomonas aeruginosa Infection in Patients with Cystic Fibrosis.

BackgroundChronic lung infection with Pseudomonas aeruginosa occurs in approximately 50% of patients with cystic fibrosis (CF). This infection further compromises lung function, and significantly contributes to the increased healthcare costs.ObjectivesInhaled tobramycin, used to manage P. aeruginosa infection in CF patients, is available as powder (tobramycin inhalation powder, TIP) and solution (tobramycin inhalation solution, TIS). Evidence suggests increased adherence with the use of TIP over TIS. Hence, this analysis aimed to evaluate the potential pharmacoeconomic benefit of increased adherence with TIP over TIS in the US setting.MethodsA patient-level simulation model was developed to compare TIP with TIS. Both costs and benefits were predicted over a 10-year time horizon from a payer’s perspective, and were discounted annually at 3%. All costs were presented in 2016 US dollars.ResultsTIP was associated with greater quality-adjusted life-years (by 0.27) and lower total costs (by US$36,168) as compared with TIS over a 10-year time horizon. TIP-treated patients experienced a decreased mean number of exacerbations than TIS-treated patients (39.24 vs 50.20). Furthermore, administration of TIP via the T-326 Inhaler was associated with significant cost savings per patient, because of the nebulizer required for administering TIS (by US$1596) and exacerbation costs (by US$76,531). Probabilistic sensitivity analysis showed that TIP was dominant over TIS in 100% of the simulations.ConclusionTIP is likely to be a more cost-effective treatment than TIS, and therefore may reduce the economic burden of CF.

Population Pharmacokinetics of Tobramycin Inhalation Solution in Pediatric Patients With Cystic Fibrosis

Tobramycin inhalation solution given as a twice daily inhalation of nebulized aerosols of 300 mg is approved for the treatment of Pseudomonas aeruginosa infection in cystic fibrosis patients over 6 years of age. To investigate tobramycin pharmacokinetics (PK) after inhalation of tobramycin in pediatric cystic fibrosis patients below 7 years, a population PK approach was used to evaluate tobramycin PK data in patients 6 months to 44 years of age from 4 clinical studies. The final model used a 2-compartmental, first-order absorption model with effect of body mass index on the apparent central volume of distribution. Relative bioavailability in patients between 6 months and 7 years increased with age by a linear relationship, and was modeled as a ratio to that of patients over 7 years. Simulation showed that steady-state concentrations of tobramycin are lower in pediatric patients 6 months to 6 years than those in patients over 6 years. However, systemic exposure is not predictive of clinical efficacy due to direct dosing at the infection site. P aeruginosa eradication rate and safety profile in patients less than 7 years of age were similar to patients older than 6 years; therefore, no dose adjustment is warranted in the younger pediatric patients.

Ease of use of tobramycin inhalation powder compared with nebulized tobramycin and colistimethate sodium: a crossover study in cystic fibrosis patients with pulmonary Pseudomonas aeruginosa infection

Background:This study assessed the ease of use of tobramycin inhalation powder (TIP) administered via T-326 inhaler versus tobramycin inhalation solution (TIS) and colistimethate sodium (COLI), both administered via nebulizers, for the treatment of chronic pulmonary Pseudomonas aeruginosa infection in patients with cystic fibrosis (CF).Methods:A real-world, open-label, crossover, interventional phase IV study was conducted in CF patients aged ⩾6 years with forced expiratory volume in 1 second (FEV1) ⩾25% to ⩽90% predicted. Patients were assigned to one of the three treatment arms in Cycle 1; all patients received TIP in Cycle 2. Each cycle consisted of 28 days on and 28 days off the treatment.Results:A total of 60 patients [mean (standard deviation) age, 27.6 (8.4) years] were allocated to three treatment arms [TIS/TIP (n = 14); COLI/TIP (n = 28); TIP/TIP (n = 18)] in Cycle 1. The mean total administration time, which included device setup and cleaning, in Cycle 1 versus Cycle 2 for TIS/TIP, COLI/TIP, and TIP/TIP arms were 37.0 versus 5.0 min, 16.4 versus 3.8 min, and 4.2 versus 3.4 min, respectively. The difference in mean total administration time was significantly shorter in Cycle 2 than in Cycle 1 for TIS/TIP (p = 0.0112) and COLI/TIP (p = 0.0016) arms. Overall, 12 patients were found to have contaminated devices across the two treatment cycles. In the TIP/TIP arm, no contamination of the T-326 inhaler was observed in either cycle. Treatment satisfaction, assessed by the Treatment Satisfaction Questionnaire for Medication and ACCEPT® questionnaire, was better overall for TIP compared with TIS and COLI. There were no unexpected adverse events and most were mild or moderate in intensity.Conclusion:The T-326 inhaler used to deliver TIP was easy to use, required shorter total administration time, and was much less frequently contaminated than the nebulizers. The safety findings observed for TIP were generally consistent with its established safety profile.

233 Early eradication therapy against P. aeruginosa using short-term tobramycin inhalation solution (TIS) in children with cystic fibrosis (CF)

233 Early eradication therapy against P. aeruginosa using short-term tobramycin inhalation solution (TIS) in children with cystic fibrosis (CF)

Physical Characterization of Tobramycin Inhalation Powder: II. State Diagram of an Amorphous Engineered Particle Formulation.

Tobramycin Inhalation Powder (TIP) is a spray-dried engineered particle formulation used in TOBI Podhaler, a drug-device combination for treatment of cystic fibrosis (CF). A TIP particle consists of two phases: amorphous, glassy tobramycin sulfate and a gel-phase phospholipid (DSPC). The objective of this work was to characterize both the amorphous and gel phases following exposure of TIP to a broad range of RH and temperature. Because, in principle, changes in either particle morphology or the solid-state form of the drug could affect drug delivery or biopharmaceutical properties, understanding physical stability was critical to development and registration of this product. Studies included morphological assessments of particles, thermal analysis to measure the gel-to-liquid crystalline phase transition (Tm) of the phospholipid and the glass transition temperature (Tg) of tobramycin sulfate, enthalpy relaxation measurements to estimate structural relaxation times, and gravimetric vapor sorption to measure moisture sorption isotherms of TIP and its components. Collectively, these data enabled development of a state diagram for TIP-a map of the environmental conditions under which physical stability can be expected. This diagram shows that, at long-term storage conditions, TIP is at least 50 °C below the Tg of the amorphous phase and at least 40 °C below the Tm of the gel phase. Enthalpy relaxation measurements demonstrate that the characteristic structural relaxation times under these storage conditions are many orders of magnitude greater than that at Tg. These data, along with long-term physicochemical stability studies conducted during product development, demonstrate that TIP is physically stable, remaining as a mechanical solid over time scales and conditions relevant to a pharmaceutical product. This met a key design goal in the development of TIP: a room-temperature-stable formulation (3-year shelf life) that obviates the need for refrigeration for long-term storage. This has enabled development of TOBI Podhaler-an approved inhaled drug product that meaningfully reduces the treatment burden of CF patients worldwide.

Aerosolized tobramycin for Pseudomonas aeruginosa ventilator-associated pneumonia in patients with acute respiratory distress syndrome

BackgroundVentilator-associated pneumonia (VAP) due to Pseudomonas aeruginosa has a high mortality and recurrence rate, especially in patients with acute respiratory distress syndrome (ARDS). Therefore, new therapeutic strategies against severe pneumonia are needed. This study evaluated the efficacy of aerosolized tobramycin for P. aeruginosa VAP in ARDS patients. MethodsA retrospective analysis was performed on patients who developed VAP caused by P. aeruginosa during the course of ARDS at the intensive care unit (ICU) of Kumamoto University Hospital. Aerosolized tobramycin inhalation solution (TIS) 240 mg was administered daily for 14 days in addition to systemic antibiotics. ResultsA total of 44 patients (TIS group, n = 22; control group, n = 22) were included in the analysis. No significant differences were found between the two groups in terms of clinical characteristics, including acute physiology and chronic health evaluation II score upon ICU admission. The TIS group had significantly lower recurrence of P. aeruginosa VAP (22.7% vs. 52.4%, P = 0.04) and ICU mortality (22.7% vs. 63.6%, P < 0.01) than the control group. Bacterial concentration in tracheal aspirate (mean log 10 cfu/mL ± SD on days 2–5: 1.2 ± 1.3 vs. 5.0 ± 2.3, P < 0.01) decreased more rapidly and markedly in the TIS group compared with the control group. ConclusionAerosolized tobramycin was an effective therapeutic strategy for P. aeruginosa VAP patients with ARDS.