Search

Established treatment regimens for the autosomal dominant hyperimmunoglobulin E syndrome, denominated Job syndrome, are lacking. Thus, Job syndrome still exerts a dramatic impact on patients’ quality of life. Our aim was to present safety and effectiveness of a regimen including co-trimoxazole, omalizumab and inhaled tobramycin in Job syndrome. A 26-year-old woman diagnosed with Job syndrome since infancy through sequencing revealing G342D mutation in STAT3 gene was initiated in the above mentioned treatment regimen; she was followed for 6 months, and to date, none recurrent pulmonary or skin infection was noticed. Furthermore, a considerable improvement in skin lesions was observed. A combination of anti-IgE and longitudinal use of inhaled antibiotics seems well-founded in Job syndrome.

Pseudomonas aeruginosa is the most common pathogen infecting the lungs of people with cystic fibrosis (CF), causing both acute and chronic infections. Intrinsic and acquired antibiotic resistance, coupled with the physical barriers resulting from desiccated CF sputum, allow P. aeruginosa to colonize and persist in spite of antibiotic treatment. As well as the specific difficulties in eradicating P. aeruginosa from CF lungs, P. aeruginosa is also subject to the wider, global issue of antimicrobial resistance. Glatiramer acetate (GA) is a peptide drug, used in the treatment of multiple sclerosis (MS), which has been shown to have moderate antipseudomonal activity. Other antimicrobial peptides (AMPs) have been shown to be antibiotic resistance breakers, potentiating the activities of antibiotics when given in combination, restoring and/or enhancing antibiotic efficacy. Growth, viability, MIC determinations, and synergy analysis showed that GA improved the efficacy of tobramycin (TOB) against reference strains of P. aeruginosa, reducing TOB MICs and synergizing with the aminoglycoside. This was also the case for clinical strains from people with CF. GA significantly reduced the MIC50 of TOB for viable cells from 1.69 mg/L (95% confidence interval [CI], 0.26 to 8.97) to 0.62 mg/L (95% CI, 0.15 to 3.94; P = 0.002) and the MIC90 for viable cells from 7.00 mg/L (95% CI, 1.18 to 26.50) to 2.20 mg/L (95% CI, 0.99 to 15.03; P = 0.001), compared to results with TOB only. Investigation of mechanisms of GA activity showed that GA resulted in significant disruption of outer membranes, depolarization of cytoplasmic membranes, and permeabilization of P. aeruginosa and was the only agent tested (including cationic AMPs) to significantly affect all three mechanisms. IMPORTANCE The antimicrobial resistance crisis urgently requires solutions to the lost efficacy of antibiotics. The repurposing of drugs already in clinical use, with strong safety profiles, as antibiotic adjuvants to restore the efficacy of antibiotics is an important avenue to alleviating the resistance crisis. This research shows that a clinically used drug from outside infection treatment, glatiramer acetate, reduces the concentration of tobramycin required to be effective in treating Pseudomonas aeruginosa, based on analyses of both reference and clinical respiratory isolates from people with cystic fibrosis. The two agents acted synergistically against P. aeruginosa, being more effective combined in vitro than predicted for their combination. As a peptide drug, glatiramer acetate functions similarly to many antimicrobial peptides, interacting with and disrupting the P. aeruginosa cell wall and permeabilizing bacterial cells, thereby allowing tobramycin to work. Our findings demonstrate that glatiramer acetate is a strong candidate for repurposing as an antibiotic resistance breaker of pathogenic P. aeruginosa.

BackgroundInhaled tobramycin powder/solution (TIP/S) use has resulted in improved clinical outcomes in patients with cystic fibrosis (CF) with chronic Pseudomonas aeruginosa. However, TIP/S effect on the CF sputum microbiome has not been explored. We hypothesised that TIP/S has additional ‘off-target’ effects beyond merely P. aeruginosa and that baseline microbiome prior to initiation of therapy is associated with subsequent patient response.MethodsWe drew sputum samples from a prospectively collected biobank. Patients were included if they had one sputum sample in the 18 months before and after TIP/S. Bacterial 16S rRNA gene profiling was used to characterise the sputum microbiome.ResultsForty-one patients met our inclusion criteria and 151 sputum samples were assessed. At baseline, median age was 30.4 years (IQR 24.2–35.2) and forced expiratory volume in 1 (FEV1) second was 57% predicted (IQR 44–74). Nineteen patients were defined a priori as responders having no net decrease in FEV1 in the year following TIP/S. No significant changes were observed in key microbiome metrics of alpha (within-sample) or beta (between-sample) diversity for samples collected before and after TIP/S. However, significant beta-diversity (Bray-Curtis) differences were noted at baseline between patients based on response status. Notably, responders were observed to have a higher abundance of Staphylococcus in pretherapy baseline samples.ConclusionsOur longitudinal study demonstrates that the sputum microbiome of patients with CF is relatively stable following inhaled tobramycin over many months. Intriguingly, our findings suggest that baseline microbiome may associate with patient response to TIP/S—suggesting the sputum microbiome could be used to personalise therapy.

OBJECTIVE Early antibiotic therapy has the potential to eradicate initial Pseudomonas aeruginosa infection and postpone chronic infection. There are limited data evaluating the efficacy and safety of inhaled tobramycin in patients with cystic fibrosis (CF) who are younger than 1 year. The objective of this study was to evaluate the effectiveness of inhaled tobramycin in early eradication of P aeruginosa in infants with CF. METHODS This retrospective study evaluated patients with CF younger than 1 year with first time infection with P aeruginosa. The primary outcome was the frequency of P aeruginosa eradication. Secondary outcomes were sustained culture negativity at 12 and 18 months and safety assessments. RESULTS Of 18 patients included in the study, 9 received inhaled tobramycin and an enteral fluoroquinolone and 9 received inhaled tobramycin alone. Microbiologic clearance of respiratory cultures was observed in 83% patients at end of therapy and 78% of patients at 1 month posttherapy. Eradication of P aeruginosa was observed in 56% of patients at 6 months posttreatment with sustained culture negativity observed in 39% of patients up to 18 months. CONCLUSIONS Inhaled-tobramycin therapy is effective in early eradication of P aeruginosa infection and is well tolerated in infants younger than 1 year.

Introduction: In recent years, administration of inhaled aminoglycosides has gained popularity in tracheostomy-dependent pediatric patients because of medication delivery to the target site of action while minimizing systemic absorption and adverse effects. A recent report of detectable serum tobramycin concentrations in critically ill children receiving inhaled tobramycin 300 mg every 12 h prompted our investigation in tracheostomy-dependent pediatric patients receiving inhaled tobramycin 80 mg every 8 h. Methods: Serum tobramycin trough concentrations were obtained from tracheostomy-dependent pediatric patients receiving treatment with inhaled tobramycin 80 mg every 8 h for the treatment of tracheitis. Patient data, including demographic data, medical history, renal function, and serum concentrations, were collected. Results: Twelve patients with a median age of 0.5 (0.3–6.1) years had serum tobramycin concentrations evaluated. Eleven of the 12 patients had undetectable trough concentrations (

Background Antimicrobial susceptibility testing (AST) is a cornerstone of infection management. Cystic fibrosis (CF) treatment guidelines recommend AST to select antimicrobial treatments for CF airway infection but its utility in this setting has never been objectively demonstrated. Methods We conducted a systematic review of primary published articles designed to address two PICO (patient, intervention, comparator, outcome) questions: 1) “For individuals with CF, is clinical response to antimicrobial treatment of bacterial airways infection predictable from AST results available at treatment initiation?” and 2) “For individuals with CF, is clinical response to antimicrobial treatment of bacterial airways infection affected by the method used to guide antimicrobial selection?” Relationships between AST results and clinical response (changes in pulmonary function, weight, signs and symptoms of respiratory tract infection, and time to next event) were assessed for each article and results were compared across articles when possible. Results Twenty-five articles describing the results of 20 separate studies, most of which described Pseudomonas aeruginosa treatment, were identified. Thirteen studies described pulmonary exacerbation (PEx) treatment and seven described ‘maintenance’ of chronic bacterial airways infection. In only three of 16 studies addressing PICO question #1 was there a suggestion that baseline bacterial isolate antimicrobial susceptibility was associated with clinical response to treatment. None of the four studies addressing PICO question #2 suggested that antimicrobial selection methods influenced clinical outcomes. Conclusions There is little evidence that AST predicts the clinical outcome of CF antimicrobial treatment, suggesting a need for careful consideration of current AST use by the CF community.

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.

Objectives: To develop a sensitive CT outcome measure to phenotype and quantify lung disease in bronchiectasis (BE) patients. Methods: Collection of the most recent CT scan of BE patients with chronic Pseudomonas aeruginosa infection enrolled in the iBEST-1 study, an RCT of inhaled tobramycin. Volumetric CT scans with a slice thickness ≤ 3 mm were included. In the BE scoring technique for CT (BEST-CT), grid cells were annotated on 10 axial slices. Scoring items in hierarchical order: consolidation/ atelectasis, BE with mucus plugging (MP), BE without MP, airway wall thickening (AWT), MP, ground-glass opacities (GGO), emphysema/ bullae, healthy airways, and healthy parenchyma. Low attenuation regions were scored on expiratory scans. Subscores are expressed as median [IQR] as % of total lung volume. CT scans were also scored using the Hartmann method developed for immunodeficiency patients, and 20 scans were rescored for agreement analyses. Results: We collected 99 CT scans, and included 85 CT scans. Median BE was 3.0% [1.4-5.1], MP 2.7% [1.5-6.1], AWT 0.1 [0-0.2], total airway disease (BE + MP + AWT) 6.2% [3.4-11.8], consolidation/ atelectasis 1.5% [0.6-3.2], GGO 0.3% [0.1-1.1], and emphysema/ bullae 0% [0-0] of total lung volume. Besides BE, atelectasis/ consolidation (84/85), MP (83/85), GGO (68/85), and AWT (55/85) were most frequent annotated abnormalities. Emphysema/ bullae were annotated the least often (13/85). To be performed: inter-and intra-observer agreement analyses and comparison with the Hartmann method. Conclusion: BEST-CT is a quantitative scoring method for BE. Subscores can be used for phenotyping and as outcome measures in clinical trials.

Introduction Cystic fibrosis (CF) is a life-limiting, hereditable condition, with the highest prevalence in Europe. CF treatments have led to improvements in clinical symptoms, disease management and decelerated disease progression. However, little is known about the health state utility (HSU) associated with CF disease states, adverse events, and changes in disease severity. Although HSU data have contributed to existing health economic modelling studies, a lack of such data have been highlighted. This systematic review aims to provide a summary of HSU-related research in CF and highlight related research gaps. Methods Online searches were performed in six databases and studies in any of the following categories were included: (1) estimation of HSUs in CF; (2) mapping studies between patient-reported outcome measures (PROMs) and HSUs; (3) economic evaluations on the management of CF that report primary HSU data; and (4) any CF clinical trial that reported HSU as an outcome. Results A total of 17 studies were reviewed, of which 12 provided HSU values for specific CF populations. The remaining five articles provided HSU data that were broken down by CF relevant health states, including lung transplantations, pulmonary exacerbation (PEx) events and forced expiratory volume in 1 s (FEV1). Conclusion Current HSU data in CF are limited and there is considerable scope for further research, both in providing HSU values for CF and in investigating methods for HSU elicitation/evaluation in CF populations. Electronic supplementary material The online version of this article (10.1007/s41669-019-0144-1) contains supplementary material, which is available to authorized users.

Nosocomial pneumonia is the second most common nosocomial infection in critical care units and most common in ALV patients (9—27%). The purpose of this literature review is to discuss the latest domestic and foreign body of evidence concerning the use of inhaled antibiotics в critical care. Search for domestic publications (literature reviews, observation studies, double blind randomized studies) was carried out in elibrary.ru database, for foreign — in PubMed. Database for the period of yrs. 2005—2017. The following search enquiries were used: «inhaled antibiotics», «nosocomial pneumonia», «inhaled tobramycin», «inhaled colistin». The analysis includes 67 publications of yrs. 2007—2017 and 1 publication of yr. 2000. The literature review includes drug descriptions, contemporary capabilities of inhaled antibiotic therapy for nosocomial pneumonia, the advantages and drawbacks of this method of treatment. Special attention is focused on the use of inhaled aminoglycosides and inhaled colistin during nosocomial pneumonia in critical care units.

Objective: To evaluate the level of self-referenced treatment adherence (TA) and its association with clinical and sociodemographic variables in patients with cystic fibrosis assisted at a reference center, as well as compare the level of self-referenced TA with that presumed by the multidisciplinary team. Methods: This is a cross-sectional study that included children and adolescents aged between 0-20 years with cystic fibrosis. Adolescents older than 14 years or their guardians, when younger than 14 years old, were interviewed using a standardized questionnaire. Professionals from the multidisciplinary clinic filled out another form with their impressions of the patients’ TA. Clinical and laboratory data were obtained in the medical records. The TA was considered satisfactory if the total adherence index (TAI) was equal or higher than 80%. Results: 53 patients were included with a median age of 112 months. The mean TAI was 83.2%. The mean TAIs for dornase alfa, pancreatic enzymes, continued use of inhaled tobramycin, vitamins supplements, nutritional supplements and dietary orientation was respectively: 86.1; 96.6; 78.6; 88.1; 51.8 and 78%. Children younger than 14 years presented better TA (p=0.021). The correlation between the self-referenced TA and the one presumed by the multidisciplinary team ranged from 0,117 to 0.402, being higher for Psychology and Nutrition professionals. Conclusions: The TAI was high particularly among children younger than 14 years. There was a positive correlation between the self-referenced TA and the one presumed by the Psychology (p=0.032) and the nutrition (p=0.012) professionals. RESUMO Objetivo: Avaliar o grau de adesão ao tratamento (AT) autorreferida e pesquisar sua associação com variáveis clínicas e sociodemográficas em pacientes com fibrose cística (FC) de um centro de referência e comparar o grau de AT autorreferida com o presumido pela equipe multidisciplinar. Métodos: Estudo transversal, incluindo crianças e adolescentes com FC entre zero e 20 anos. Foram realizadas entrevistas com os adolescentes maiores de 14 anos ou com os responsáveis dos mais jovens, utilizando-se formulário padronizado. Profissionais do centro preencheram outro formulário com suas impressões da AT dos pacientes. Registraram-se dados clínicos por meio da revisão de prontuários. A AT foi considerada satisfatória se o índice de adesão global (IAG) fosse igual ou superior a 80%. Resultados: Foram incluídos 53 pacientes, com mediana de idade de 112 meses. O IAG médio foi de 83,2%. Os índices de adesão à terapêutica (IAT) médios para alfadornase, enzimas pancreáticas, tobramicina inalatória de uso contínuo, suplementos vitamínicos, suplementos nutricionais e orientações dietéticas foram, respectivamente, 86,1; 96,6; 78,6; 88,1; 51,8 e 78%. Crianças com idade inferior a 14 anos apresentaram melhor AT (p=0,021). As correlações entre a AT autorreferida e a presumida pelos profissionais variaram de 0,117 a 0,402, sendo maiores para a psicologia e a nutrição. Conclusões: A taxa global de AT foi elevada, principalmente para menores de 14 anos. Houve correlação positiva entre a AT autorreferida e as avaliações da psicologia (p=0,032) e da nutrição (p=0,012).

The aim of this study was to investigate efficacy and safety of early supplemental administration of inhaled tobramycin for prevention and treatment of hospital-acquired pneumonia (HAP) in patients with severe multiple trauma. Methods. Fifty four patients with severe multiple trauma were divided into 2 groups: the study group (n = 27) who took inhaled tobramycin added to systemic antibiotics and the control group (n = 27) who took standard systemic antibacterial treatment. Baselines characteristics did not differ between the groups. The patients' status was assessed daily using APACHE II and CPIS scales. Results. Frequency of HP in the study group was as twice as rare compared to the controls with correspondent reduction in days in ICU. The groups did not differ in mechanical ventilation parameters and frequency of sepsis. CPIS and APACHE II scores did not increase in the inhaled tobramycin group whereas CPIS total score increased and APACHE II score did not improve in the control group. To the 5 th day, significant between-group difference was found in CPIS (p = 0.0028) and APACHE-II (р = 0.0004). Conclusion. Early administration of inhaled tobramycin 600 mg daily added to the standard systemic antibacterial therapy is safe and effective in prevention and treatment of HAP in patients with severe multiple trauma. Such therapy decreased frequency of pulmonary infectious complications and significantly reduced duration of treatment in ICU.

To determine the percentage of detectable tobramycin troughs and acute kidney injury in critically ill children without cystic fibrosis on inhaled therapy.Historic cohort.Academic hospital.Forty children less than 18 years receiving inhaled tobramycin across 6.5 years.None.The primary objective was to determine the percentage of detectable tobramycin troughs greater than or equal to 0.5 µg/mL. Secondary objectives included a comparison of acute kidney injury in children with and without detectable troughs. Twenty-two (55%) had trough concentrations obtained. Ten of these (45.5%) had detectable concentrations, with a median of 0.85 µg/mL (interquartile range, 0.5-2.0). There was no statistical significance between the detectable and nondetectable groups in age, gender, and method of administration. However, patients in the detectable group tended to be younger than nondetectable group and more likely to have a tracheotomy. There was a clinically significant decrease in estimated glomerular filtration rate in the detectable trough group.Detectable troughs were noted in almost half of patients with concentrations obtained. A clinically significant decrease in estimated glomerular filtration rate was noted in patients with detectable concentrations. Continued work should be directed to better understand outcomes and monitoring in children requiring inhaled tobramycin.

Summary Introduction Aerosolized tobramycin is a standard of care for chronic Pseudomonas aeruginosa (Pa) infection in patients with cystic fibrosis (CF). Objectives The long-term safety and efficacy of intermittent (28-day “on”/“off” cycles) inhaled tobramycin nebulization solution 300 mg/4 ml (TNS4, Bramitob®/Bethkis®) was assessed over 56 weeks in CF patients aged ≥6 years having baseline 1 sec forced expiratory volume (FEV1) 40–80% predicted. Methods Patients were initially randomized in an 8-week open-label trial (core phase) to compare TNS4 (N = 159) and tobramycin 300 mg/5 ml (TNS5, TOBI®) (N = 165). A subset of patients continued in a 48-week, single-arm extension receiving TNS4 only. The primary endpoint of the core phase was to demonstrate the non-inferiority of TNS4 compared to TNS5 in terms of absolute change from baseline to week 4 in FEV1 % predicted. The assessment of long-term safety was the primary purpose of the extension phase. Throughout all phases of the study, microbiological assessments, adverse events, and audiometry findings were also evaluated. Results In the core phase (N = 321), FEV1 (% predicted) increased from baseline (absolute change) following a single on-treatment cycle for both TNS4 (7.0%) and TNS5 (7.5%) and the non-inferiority between treatments was met [difference between treatments of −0.5 (95% CI: −2.6; 1.6)]. These improvements were maintained throughout the extension phase (N = 209), ranging throughout the study between 5.1% (95% CI: 3.2; 6.9) and 8.1% (95% CI: 6.8; 9.4) compared to baseline. Pa sputum count reductions ranged between 0.6 (95% CI: 0.2; 0.9) to 2.3 (95% CI: 2.0; 2.6) log10 CFU/g throughout the 56 weeks. No remarkable safety issues were identified throughout both study phases, with similar percentages of patients reporting adverse events in the two treatment groups during the 8-week core phase [TNS4 (31.4%); TNS5 (28.0%)]. Conclusions Overall, TNS4 demonstrated short-term clinical benefits similar to TNS5 which were maintained during the long-term use of TNS4 and was also associated with a favorable tolerability profile. Pediatr Pulmonol. 2014; 49:1076–1089. © 2014 Wiley Periodicals, Inc.

The KDIGO guidelines for acute kidney injury (AKI) are designed to assist health-care providers around the world in managing patients with AKI. Clinical guidelines are intended to help the clinician make an informed decision based on review of the currently available evidence. Due to the generic nature of guidelines, it is sometimes difficult to translate a guideline for a particular individual patient who may have specific clinical circumstances. To illustrate this point, we have discussed the interpretation of the KDIGO guideline in patients who have subtleties in their clinical presentation, which may make treatment decisions less than straightforward.

Introduction Ataluren functions by interacting with ribosomes to promote read-through of nonsense mutations in CF. Ataluren9s activity was shown to be inhibited by certain aminoglycosides such as tobramycin that also bind to the ribosome. Aim To investigate the effect of ataluren on lung function (LF) and pulmonary exacerbations. Methods A post-hoc analysis was performed on a recent randomized, double-blind, placebo-controlled, phase 3 study to determine the efficacy and safety of ataluren in patients with nonsense mutation cystic fibrosis (nmCF) (Kerem E, et al. Lancet Respir Med. 2014;2:539-47) on %-predicted FEV 1 (ppFEV 1 ) and exacerbations by use of chronic inhaled tobramycin at baseline. Results Patients not receiving chronic inhaled tobramycin (non-TOBI; n=146), showed a 5.7% difference in relative ppFEV 1 between ataluren and placebo (−0.7% vs −6.4%; p=0.0082) and 40% fewer exacerbations (1.42 vs 2.18; p=0.0061). Non-TOBI patients ≥6 to 1 between ataluren and placebo (4.9% vs −3.3%; p=0.026) and a 60% lower exacerbation rate favoring ataluren (p=0.030). In all intent-to-treat patients (N=232) at week 48, including tobramycin patients, neither relative change from baseline in ppFEV 1 (−2.5% vs −5.5%; p=0.12), nor number of exacerbations (1.42 vs 1.78; p=0.099) significantly differed between ataluren and placebo. Conclusions Ataluren significantly reduced exacerbations and improved LF in nmCF patients not receiving chronic inhaled tobramycin, with markedly improved treatment effect in children and adolescents. Ataluren thus shows promise as a disease-modifying therapy in nmCF.

Background CFF practice guidelines recommend patients ≥age 6 use dornase alfa and hypertonic saline daily, and those ≥age 6 colonized with Pseudomonas aeruginosa use inhaled tobramycin and oral azithromycin to improve lung function and reduce pulmonary exacerbations. A decline in FEV1 was noted in our 2008 CF Center Report. We hypothesized that increasing adherence to prescribing guidelines for these pulmonary medications would improve mean FEV1. Methods This was a quality improvement project completed at a US CF center. CFF practice guidelines were reviewed with the center physicians. Patients were identified that were eligible to receive recommended therapies and it was determined whether they were prescribed the therapies. Baseline FEV1 data was collected. Adherence rates and FEV1 were followed quarterly for 1 year. Providers received a quarterly report card with adherence rates, mean FEV1 compared to colleagues, and a list of eligible patients that were not prescribed recommended therapies. Results Ninety-two patients were included. At baseline, the overall adherence rate was 59%. Overall adherence increased quarterly (P =

Objective To examine cystic fibrosis (CF) physician adherence to the 2007 CF Foundation (CFF) Pulmonary Guidelines for Chronic Medications. Specifically adherence and barriers to prescribing level A medication recommendations (i.e., inhaled tobramycin and dornase alfa) and level B medication recommendations (i.e., macrolide antibiotics and hypertonic saline) were studied. Methods During Spring 2010, the CFF emailed survey invitations to directors of 136 accredited CF care centers treating 50+ CF patients. Directors were asked to forward the invitations to their physician colleagues. One hundred thirty-three surveys were included in the analyses, representing 92 centers. Barriers were conceptualized based on Cabana et al.'s framework for adherence to guidelines. Adherence was assessed via a case vignette. Results Logistic regression analysis revealed that higher outcome expectancy (OR = 1.099, CI 1.010–1.196) and fewer environmental/system barriers (OR = 1.484, CI 1.158–1.902) were significantly associated with Vignette Adherence. A trend for an association between Familiarity and Vignette Adherence (OR = 1.642, CI 0.953–2.828) was evident, while no demographic variables were significantly associated with Vignette Adherence. Conclusion Targeting outcome expectancy and external barriers with multifaceted, ongoing interventions may improve guideline adherence. Pulmonologists are clearly looking for empirical evidence that these medications benefit their patients over the long-term and offset patient treatment burden with improved health. Pediatr Pulmonol. 2012; 47:434–440. © 2012 Wiley Periodicals, Inc.

BackgroundReducing nebulisation times for tobramycin solution for inhalation in cystic fibrosis (CF) may improve compliance.MethodsIn this single-dose, open-label, two-way crossover study, 13 subjects (7 CF, 6 healthy) were randomised to receive tobramycin via eFlow rapid or LC Plus jet nebuliser. Drug deposition in the lung using gamma scintigraphic imaging, nebulisation times, pharmacokinetics, and safety were evaluated.ResultsIn CF patients, whole-lung deposition was 40% less with the eFlow rapid compared with LC Plus nebulisers was (8.9±0.8%, and 15.1±6.0%, p>0.05). Nebulisation time was shorter with eFlow rapid compared to LC Plus (7.0min versus 20.0min, p

Background Patients with cystic fibrosis spend as much 30 min a day inhaling tobramycin. Could a new rapid system deposit the equivalent amount of tobramycin faster? Methods Six healthy adult males inhaled 5 ml (300 mg) of tobramycin from a breath enhanced nebulizer and either 125 mg (n = 3) or 150 mg (n = 3) from a vibrating membrane system with a large or small aerosol mixing chamber respectively. A radiolabel was added to the solution and shown to “track” with the tobramycin. Imaging was done with a dual headed gamma camera. Because the radiolabel will be cleared by mucociliary action during administration, algorithms were developed to allow the comparison of a slower system to a faster one. Results Both formulations were well tolerated. The lung deposition was 16.6 ± 3.2% (mean ± SD) of the charge dose delivered in 10.9 ± 1.0 min for the breath enhanced nebulizer versus 32.0 ± 5.1% delivered in 2.5 ± 0.4 min from the vibrating membrane system. The absolute pulmonary delivery of tobramycin was 49.9 ± 9.6 versus 43.9 ± 4.8 mg for the two systems respectively, differences that were statistically significant (pair t-test) but unlikely to be clinically significant. There was a similar deposition of tobramycin for the 125 and 150 mg dose. Conclusions It is possible to deliver an equivalent amount of tobramycin in a shorter period of time with the new vibrating membrane system and a more concentrated formulation. These data will allow the design of a comparison in patients with CF. Pediatr Pulmonol. 2008; 43:753–759. © 2008 Wiley-Liss, Inc.

Laryngeal aspergillosis is most commonly seen as a result of secondary invasion from the lungs and tracheobronchial tree in immunocompromised hosts. Primary aspergillosis of the larynx is, however, rare with few cases documented over the past fifty years. We report a case of a 73-year-old woman who presented with persistent hoarseness. She is a nonsmoker with a history of asthma and chronic bronchiectasis treated with bronchodilators, inhaled and oral corticosteroids, and nebulized tobramycin. Direct laryngoscopy with vocal cord stripping confirmed the diagnosis of invasive aspergillosis with no manifestations elsewhere. The patient was successfully treated with oral voriconazole with no signs of recurrence. Although several major risk factors contributing to the development of primary aspergillosis of the larynx have been discussed in the literature, there has been no mention of inhaled antibiotics causing this rare presentation to the best of our knowledge. We, therefore, highlight the use of inhaled tobramycin as a unique catalyst leading to the rapid onset of this rare presentation.

This study evaluates drug cost outcomes related to automatic therapeutic substitution of branded tobramycin solution for inhalation (TOBI(®)) with inhaled generic preservative-free intravenous tobramycin (PFIT). A retrospective single-center evaluation of inhaled tobramycin use from 2008 through 2012 was performed. Number of doses dispensed and acquisition costs were obtained. Hourly wage data was acquired, pharmacy production costs were estimated and total cost-savings calculated. Days of therapy (DOTs) were determined for each year. Quality assurance and safety data was collected. In 2008, TOBI(®) drug costs and doses dispensed were $118,665 and 1769, respectively. Following implementation of the interchange in May 2009, TOBI(®) utilization ceased. PFIT costs in 2010 through 2012 averaged $34,775 annually and TOBI(®) cost-avoidance exceeded $94,000 annually when accounting for pharmacy production costs, which were determined to be at most $5.28 per dose. The maximum estimated pharmacy production cost ranged from $8812 to $11,299 annually. PFIT doses dispensed exceeded 1650 each year and annual DOTs ranged from 815 to 1069. The 40-month savings were calculated to be $374,706. Quality assurance and safety data identified one patient who refused PFIT due to odor complaints and one patient who was inappropriately administered a dose orally. Therapeutic substitution of TOBI(®) with PFIT can produce immediate and sustained savings with an acceptable safety profile.

Inhaled tobramycin solution is indicated for use in the management of Pseudomonas aeruginosa in patients with cystic fibrosis (CF). Concerns have been raised regarding increasing off-label use of inhaled tobramycin, particularly for the management of COPD. We conducted an 8-year repeated cross-sectional study examining the indication for prescription claims for inhaled tobramycin in Ontario paid for by the Public Drug Benefit Program, which covers all Ontario residents with financial needs or aged 65 and older. Inhaled tobramycin prescription claims increased approximately 3 times greater from 86 prescriptions in the second quarter of 2007 to 261 prescriptions in the first quarter of 2015. Approximately half of all prescriptions (range: 46-65%) per quarter were dispensed to patients with CF. A large proportion of prescriptions (range: 31-36%) were dispensed to individuals who did not have a diagnosis of CF but had a diagnosis of COPD. In 2014, there were 324 unique users of inhaled tobramycin solution in the Ontario Public Drug Program (OPDP). Only half of users (54%; n=163) had a diagnosis of CF. Our study found increasing prescriptions of inhaled tobramycin from 2007 to 2015 in the OPDP with approximately half of these claims being for off-label use, mostly among patients with COPD.

Many new therapies are emerging for the treatment of CF. In the last 2 years, six agents have been approved by the Food and Drug Administration (FDA) and four agents have given an opinion in favor of granting a marketing authorization by the European Medicines Agency (EMA) representing dramatic results from decades of investment in basic and clinical science. In this month's journal, Assael and colleagues present data from a phase 3 open-label, randomized, parallel-group, active-comparator non-inferiority trial comparing aztreonam for inhalation solution (AZLI) and inhaled tobramycin nebulizer solution (TNS)...

73 Real world evidence on inhaled tobramycin use in CF patients: analysis of the RAMQ data (Canada) J. Lachaine1, M.-E. Lapierre2, C. Beauchemin2, G. Angyalosi3, M.-M. Balp3, F. Calado3, L. Debonnett4, J. Desforges5, A. Sagkriotis3. 1University of Montreal, Faculty of Pharmacy, Montreal, Canada; 2University of Montreal, Montreal, Canada; 3Novartis Pharma AG, Basel, Switzerland; 4Novartis Pharmaceuticals Corporation, New York City, United States; 5Novartis Pharmaceuticals Canada Inc., Dorval, Canada

73 Real world evidence on inhaled tobramycin use in CF patients: analysis of the RAMQ data (Canada) J. Lachaine1, M.-E. Lapierre2, C. Beauchemin2, G. Angyalosi3, M.-M. Balp3, F. Calado3, L. Debonnett4, J. Desforges5, A. Sagkriotis3. 1University of Montreal, Faculty of Pharmacy, Montreal, Canada; 2University of Montreal, Montreal, Canada; 3Novartis Pharma AG, Basel, Switzerland; 4Novartis Pharmaceuticals Corporation, New York City, United States; 5Novartis Pharmaceuticals Canada Inc., Dorval, Canada

year. Data are presented as Median (Interquartile Range) and 2-tailed, Wilcoxon signed-rank tests were used to compare parameters. Results: 11 patients [Median Age: 30 (19–61)] years, had 6-month data available. All patients tolerated the treatment well. The results are shown in the table below. Conclusions: Our experience and this data suggests a significant clinical benefit in the short term in a select group of acutely deteriorating adult CF patients and we continue to monitor its effects over the longer term.

Background Aerosolized tobramycin inhalation solution (TIS) may be absorbed and result in measurable serum concentrations. We assessed the significance of TIS dosing in the latter portion of the IV dosing interval on the calculation of pharmacokinetic (PK) parameters and dosing. Methods Twenty adult CF patients admitted to the hospital for treatment of a pulmonary exacerbation were enrolled. PK parameters of tobramycin were calculated before and after introduction of TIS, which was given 5–9h after the IV dose. Results Nine patients had a clinically significant change in tobramycin trough concentration. Fourteen patients had a reduced calculated elimination rate constant after TIS administration, which may be misinterpreted as a decreased clearance of IV tobramycin. Conclusion Trough tobramycin concentrations were significantly influenced in some CF patients (45%), suggesting that timing of the inhaled dose should be considered when interpreting PK measures of IV tobramycin dosing.

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.