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Tracheostomy tubes act as foreign bodies, predisposing the surrounding airway to respiratory infections. Initial treatment for infections is topical - nebulized tobramycin - although guidelines for standardized treatment are lacking. To quantify tobramycin delivery to simulated, tracheostomized children to inform future administration guidelines. A breathing simulator was programmed for volume-controlled ventilation at 6 mL.kg -1 , for a 3 kg and a 16 kg child representing under or over 6-yrs, respectively. Nebulized tobramycin doses based on current guidelines for non-tracheostomized children (80 mg, or 300 mg, under and over 6-yrs, respectively) were delivered using standard hospital protocol, collected on filters, and assayed with chromatography to quantify average tobramycin delivered dose from six replicate measurements. The jet nebulizer delivered more tobramycin than the vibrating mesh nebulizer from an 80 mg (ages <6-yrs) dose for both a 3 kg child: 2.1 vs. 0.7 mg (3 mm, p = 0.047) and a 16 kg child: 8.7 vs. 3.5 mg (5 mm size, p = 0.022), 11.4 vs. 8.3 mg (4 mm size, p = 0.2). The jet nebulizer delivered more tobramycin than the vibrating mesh nebulizer for both a 3 kg child: 8.4 vs. 3.7 mg (3 mm, p = 0.00076) and a 16 kg child: 33.2 vs. 25 mg (5 mm, p = 0.2) but not for a 16 kg child: 39.4 vs. 46.5 mg (4 mm, p = 0.18) The low amount and poor distribution of drug delivered warrants consideration and review of dosing regimens for treatment. Future research should investigate improving the efficiency of drug delivery to tracheostomized children and the safety and efficacy of higher-dosage regimens., (Copyright © 2024. Published by Elsevier Masson SAS.)

Background: Current treatments for respiratory infections are severely limited. Ethanol's unique properties including antimicrobial, immunomodulatory, and surfactant-like activity make it a promising candidate treatment for respiratory infections if it can be delivered safely to the airway by inhalation. Here, we explore the safety, tolerability, and pharmacokinetics of inhaled ethanol in a phase I clinical trial., Methods: The study was conducted as a single-centre, open-label clinical trial in 18 healthy adult volunteers, six with no significant medical comorbidities, four with stable asthma, four with stable cystic fibrosis, and four active smokers. A dose-escalating design was used, with participants receiving three dosing cycles of 40, 60%, and then 80% ethanol v/v in water, 2 h apart, in a single visit. Ethanol was nebulised using a standard jet nebuliser, delivered through a novel closed-circuit reservoir system, and inhaled nasally for 10 min, then orally for 30 min. Safety assessments included adverse events and vital sign monitoring, blood alcohol concentrations, clinical examination, spirometry, electrocardiogram, and blood tests., Results: No serious adverse events were recorded. The maximum blood alcohol concentration observed was 0.011% immediately following 80% ethanol dosing. Breath alcohol concentrations were high (median 0.26%) following dosing suggesting high tissue levels were achieved. Small transient increases in heart rate, blood pressure, and blood neutrophil levels were observed, with these normalising after dosing, with no other significant safety concerns. Of 18 participants, 15 completed all dosing cycles with three not completing all cycles due to tolerability. The closed-circuit reservoir system significantly reduced fugitive aerosol loss during dosing., Conclusion: These data support the safety of inhaled ethanol at concentrations up to 80%, supporting its further investigation as a treatment for respiratory infections. Clinical trial registration: identifier ACTRN12621000067875., Competing Interests: BC is a director of Inspiring Pty Ltd. who are developing the reservoir spacer system for commercialisation. WD has shares in Inspiring and has been contracted by Inspiring to perform aerosol testing in the past. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Hancock, Ditcham, Ferguson, Karpievitch, Stick, Waterer and Clements.)

Background: Structural lung disease and neutrophil-dominated airway inflammation is present from 3 months of age in children diagnosed with cystic fibrosis after newborn screening. We hypothesised that azithromycin, given three times weekly to infants with cystic fibrosis from diagnosis until age 36 months, would reduce the extent of structural lung disease as captured on chest CT scans., Methods: A phase three, randomised, double-blind, placebo-controlled trial was done at eight paediatric cystic fibrosis centres in Australia and New Zealand. Infants (aged 3-6 months) diagnosed with cystic fibrosis following newborn screening were eligible. Exclusion criteria included prolonged mechanical ventilation in the first 3 months of life, clinically significant medical disease or comorbidities other than cystic fibrosis, or macrolide hypersensitivity. Participants were randomly assigned (1:1) to receive either azithromycin (10 mg/kg bodyweight orally three times per week) or matched placebo until age 36 months. Randomisation was done with a permuted block strategy and an interactive web-based response system, stratified by study site. Unblinding was done once all participants completed the trial. The two primary outcomes were the proportion of children with radiologically defined bronchiectasis, and the percentage of total lung volume affected by disease. Secondary outcomes included clinical outcomes and exploratory outcomes were inflammatory markers. Analyses were done with the intention-to-treat principle. This study is registered at ClinicalTrials.gov (NCT01270074)., Findings: Between June 15, 2012, and July 10, 2017, 281 patients were screened, of whom 130 were enrolled, randomly assigned, and received first study dose. 68 participants received azithromycin and 62 received placebo. At 36 months, 88% (n=50) of the azithromycin group and 94% (n=44) of the placebo group had bronchiectasis (odds ratio 0·49, 95% CI 0·12 to 2·00; p=0·32), and total airways disease did not differ between groups (median difference -0·02%, 95% CI -0·59 to 0·56; p=0·96). Secondary outcome results included fewer days in hospital for pulmonary exacerbations (mean difference -6·3, 95% CI -10·5 to -2·1; p=0·0037) and fewer courses of inhaled or oral antibiotics (incidence rate ratio 0·88, 95% CI 0·81 to 0·97; p=0·0088) for those in the azithromycin group. For the preplanned, exploratory analysis, concentrations of airway inflammation were lower for participants receiving azithromycin, including interleukin-8 (median difference -1·2 pg/mL, 95% CI -1·9 to -0·5; p=0·0012) and neutrophil elastase activity (-0·6 μg/mL, -1·1 to -0·2; p=0·0087) at age 36 months, although no difference was noted between the groups for interleukin-8 or neutrophil elastase activity at 12 months. There was no effect of azithromycin on body-mass index at age 36 months (mean difference 0·4, 95% CI -0·1 to 0·9; p=0·12), nor any evidence of pathogen emergence with the use of azithromycin. There were few adverse outcomes with no differences between the treatment groups., Interpretation: Azithromycin treatment from diagnosis of cystic fibrosis did not reduce the extent of structural lung disease at 36 months of age; however, it did reduce airway inflammation, morbidity including pulmonary exacerbations in the first year of life and hospitalisations, and improved some clinical outcomes associated with cystic fibrosis lung disease. Therefore we suggest thrice-weekly azithromycin is a strategy that could be considered for the routine early management of paediatric patients with cystic fibrosis., Funding: Cystic Fibrosis Foundation., Competing Interests: Declaration of interests During the conduct of the trial, SMS and HAWMT had a patent pending for the PRAGMA-CT scoring method used to analyse the CT scans in this trial (PCT/AU2016/000079). CW is on the International Advisory Board for Vertex Pharmaceuticals. HAWMT is Chief Medical Officer for Thirona. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)