Inhaled amikacin versus placebo to prevent ventilator-associated pneumonia: the AMIKINHAL double-blind multicentre randomised controlled trial protocol

IntroductionPre-emptive inhaled antibiotics may be effective to reduce the occurrence of ventilator-associated pneumonia among critically ill patients. Meta-analysis of small sample size trials showed a favourable signal. Inhaled antibiotics are associated with a reduced emergence of antibiotic resistant bacteria. The aim of this trial is to evaluate the benefit of a 3-day course of inhaled antibiotics among patients undergoing invasive mechanical ventilation for more than 3 days on the occurrence of ventilator-associated pneumonia.Methods and analysisAcademic, investigator-initiated, parallel two group arms, double-blind, multicentre superiority randomised controlled trial. Patients invasively ventilated more than 3 days will be randomised to receive 20 mg/kg inhaled amikacin daily for 3 days or inhaled placebo (0.9% Sodium Chloride). Occurrence of ventilator-associated pneumonia will be recorded based on a standardised diagnostic framework from randomisation to day 28 and adjudicated by a centralised blinded committee.Ethics and disseminationThe protocol and amendments have been approved by the regional ethics review board and French competent authorities (Comité de protection des personnes Ouest I, No.2016-R29). All patients will be included after informed consent according to French law. Results will be disseminated in international scientific journals.Trial registration numbersEudraCT 2016-001054-17 and NCT03149640.

Prevalence of Aspergillus colonization and sensitization in patients of cystic fibrosis

Background: Aspergillus fumigatus and other fungal species are common pathogens isolated in CF patients and they lead to a variety of diseases like ABPA and invasive aspergillosis. Aims and Objectives: To study the prevalence of Aspergillus colonization, sensitization and ABPA in our cohort of CF patients. Also, to study the various risk factors for Aspergillus colonization and ABPA in these patients. Methodology: This was a observational study in which 30 patients of cystic fibrosis between 0 to 18 years were enrolled visiting a tertiary care hospital in north India during January 2019 till December 2020. Data was collected on pre-structured proforma on cough swab and sputum c/s for bacteria and fungus, skin prick test for Aspergillus fumigatus, total IgE, Aspergillus specific IgE, Aspergillus specific IgG, galactomannan and CXR. Prevalence of Aspergillus colonization, sensitization and ABPA was calculated, Odds ratio for all the postulated risk factors for Aspergillus colonization and ABPA were calculated and further Chi square test was applied to check association of ABPA with pulmonary exacerbation. Results: Patients enrolled were between the age group of 4 months till 18 years of age with the median age being 4.75 years (IQR: 2.25 -11.75). 16.67% (n=5), 36.67% (n=11) of the patients enrolled in our study were colonized and sensitized with Aspergillus fumigatus respectively. While, 23.34% (n=7) of the patients had ABPA. We found positive association of Aspergillus colonization with multiple risk factors under study, in the following order of decreasing odds ratio, inhaled antibiotics (OR: 4.75) followed by use of azithromycin (OR: 3.5), inhaled corticosteroids (OR: 2.6), and atopy (OR: 1.3). Conclusion: Aspergillus fumigatus is a common colonizer in patients of cystic fibrosis (16.67%), and can lead to an inflammatory response and ABPA (23.34%). Use of azithromycin, inhaled antibiotics, inhaled corticosteroids and atopy increases the chances of Aspergillus colonization.

Therapeutic Approach of Chronic Pseudomonas Infection in Cystic Fibrosis—A Network Meta-Analysis

Pseudomonas infection is a major determinant of morbidity and mortality in cystic fibrosis (CF). Maintaining optimal lung function in CF patients carrying Pseudomonas remains a challenge. Our study aims to investigate the efficacy of antipseudomonal inhaled antibiotics in CF patients with chronic Pseudomonas infection. A Bayesian network meta-analysis of randomized controlled trials was conducted. The main outcomes were changes in: (a) forced respiratory volume (FEV1), (B) Pseudomonas aeruginosa sputum density, and (c) CF Questionnaire Revised Respiratory Symptom Score (CFQR-RSS) at 4 weeks follow-up. Eighteen trials which reported on treatment with aztreonam lysine, tobramycin, colistin, levofloxacin, fosfomycin/tobramycin, and amikacin in various dosages were eligible for inclusion. In terms of change in FEV1%, aztreonam lysine (t.i.d., 75 mg) with a 28-day run in the tobramycin phase, aztreonam lysine (b.i.d., 75 mg) with a 28-day run in the tobramycin phase had the highest probability of being the most effective treatment (SUCRAs were 77, 76%, respectively). Regarding change in Pseudomonas sputum density, aztreonam lysine (b.i.d., 75 mg) with a 28-day run in the tobramycin phase, aztreonam lysine (t.i.d., 75 mg) with a 28-day run in the tobramycin phase had the highest probability of being the most effective treatment (SUCRAs were 90, 86%, respectively). Regarding change in CFQR-RSS, aztreonam lysine (t.i.d., 75 mg) and aztreonam lysine (b.i.d., 75 mg) with a 28-day run in the tobramycin inhalation solution phase had the highest probability of being the most effective treatments (SUCRA:74% and 72%, respectively). Regarding changes in FEV1% and Pseudomonas sputum density, aztreonam lysine with a run in tobramycin phase may be the best treatment option in treating chronic Pseudomonas in CF. According to CFQR-RSS no significant differences were found. Given the limitations of the studies included, validation trials are called for.

Long-Term Antibiotics in Bronchiectasis

A significant proportion of bronchiectasis patients are chronically infected by potentially pathogenic microorganisms which may lead to frequent exacerbations and worse clinical outcomes. Current bronchiectasis guidelines recommend long-term inhaled antibiotics and/or oral macrolides as a part of patient management. In recent years, an increasing amount of evidence assessing the impact of these treatments on patient outcomes has been collected. Inhaled antibiotics have demonstrated significant improvements in sputum bacterial load, but their impact on patient quality of life, lung function, and exacerbation rate has not been consistent across trials. In this regard, recent post hoc analyses of inhaled antibiotics trials in bronchiectasis patients have shown that sputum bacterial load may be a key biomarker to predict treatment response in these patients. Oral macrolides, on the other hand, have proven to reduce exacerbation frequency and improve quality of life, but potential drug-related adverse effects and the increase in bacterial resistance are relevant. This review aims to summarize current important evidence for long-term antibiotic treatment in bronchiectasis patients.

Lung function in children with cystic fibrosis in the USA and UK: a comparative longitudinal analysis of national registry data

RationaleA previous analysis found significantly higher lung function in the US paediatric cystic fibrosis (CF) population compared with the UK with this difference apparently decreasing in adolescence and adulthood. However, the cross-sectional nature of the study makes it hard to interpret these results.ObjectivesTo compare longitudinal trajectories of lung function in children with CF between the USA and UK and to explore reasons for any differences.MethodsWe used mixed effects regression analysis to model lung function trajectories in the study populations. Using descriptive statistics, we compared early growth and nutrition (height, weight, body mass index), infections (Pseudomonas aeruginosa, Staphylococcus aureus) and treatments (rhDnase, hypertonic saline, inhaled antibiotics).ResultsWe included 9463 children from the USA and 3055 children from the UK with homozygous F508del genotype. Lung function was higher in the USA than in the UK when first measured at age six and remained higher throughout childhood. We did not find important differences in early growth and nutrition, or P.aeruginosa infection. Prescription of rhDNase and hypertonic saline was more common in the USA. Inhaled antibiotics were prescribed at similar levels in both countries, but Tobramycin was prescribed more in the USA and colistin in the UK. S. aureus infection was more common in the USA than the UK.ConclusionsChildren with CF and homozygous F508del genotype in the USA had better lung function than UK children. These differences do not appear to be explained by early growth or nutrition, but differences in the use of early treatments need further investigation.