Abstract
Pulmonary infections caused by Pseudomonas aeruginosa (PA) represent the leading cause of pulmonary morbidity in adults with cystic fibrosis (CF). In addition to tobramycin, colistin, and aztreonam, levofloxacin has been approved in Europe to treat PA infections. Nevertheless, no lung deposition data on inhaled levofloxacin are yet available. We conducted a Functional Respiratory Imaging (FRI) study to predict the lung deposition of levofloxacin in the lungs of patients with CF. Three-dimensional airway models were digitally reconstructed from twenty high-resolution computed tomography scans obtained from historical patients’ records. Levofloxacin aerosols generated with the corresponding approved nebuliser were characterised according to pharmacopeia. The obtained data were used to inform a computational fluid dynamics simulation of levofloxacin lung deposition using breathing patterns averaged from actual CF patients’ spirometry data. Levofloxacin deposition in the lung periphery was significantly reduced by breathing patterns with low inspiratory times and high inspiratory flow rates. The intrathoracic levofloxacin deposition percentages for moderate and mild CF lungs were, respectively, 37.0% ± 13.6 and 39.5% ± 12.9 of the nominal dose. A significant albeit modest correlation was found between the central-to-peripheral deposition (C/P) ratio of levofloxacin and FEV1. FRI analysis also detected structural differences between mild and moderate CF airways. FRI revealed a significant intrathoracic deposition of levofloxacin aerosols, which distributed preferentially to the lower lung lobes, with an influence of the deterioration of FEV1 on the C/P ratio. The three-dimensional rendering of CF airways also detected structural differences between the airways of patients with mild and moderate CF.
Highlights
Pulmonary infections caused by Pseudomonas aeruginosa (PA) represent the leading cause of pulmonary morbidity and mortality in adults with cystic fibrosis (CF) [1]
Progression, a high patient-to-patient variability can be expected in terms of lung deposition, which can be inferred to some extent from the wide ranges of antibiotic sputum concentrations reported in clinical studies of CF [6]
Colistin, and aztreonam, inhaled levofloxacin has been approved in Europe to treat PA infections in patients with CF [12]
Summary
Pulmonary infections caused by Pseudomonas aeruginosa (PA) represent the leading cause of pulmonary morbidity and mortality in adults with cystic fibrosis (CF) [1]. Lung deposition depends on several factors such as the aerosol characteristics, breathing pattern, and the structure of the airway tree Considering that the latter factors may be markedly affected by CF progression, a high patient-to-patient variability can be expected in terms of lung deposition, which can be inferred to some extent from the wide ranges of antibiotic sputum concentrations reported in clinical studies of CF [6]. Average estimations of the delivered lung dose are required for the regulatory approval of inhaled drug formulations They are usually determined using straightforward in vitro set-ups [7], which, neither provide data on lung distribution nor consider the respiratory pattern or the CF airways’ pathophysiological features. We first performed a characterisation of levofloxacin aerosols generated with the officially approved nebuliser, which was used in combination with breathing patterns averaged from spirometry data of actual CF patients to determine the lung deposition and the pulmonary distribution of a clinical dose of inhaled levofloxacin
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