Introduction Azithromycin (AZ) is an azalide subclass of macrolide (a semi-synthetic 9-N-methylation derivative of erythromycin), with broad-spectrum antibiotic activity against gram-positive, gram-negative, and atypical bacterial infections that lead to pneumonia. 1,2 AZ is approved by the U.S. Food and Drug Administration (FDA) against pneumonia and chronic obstructive pulmonary disease exacerbations. 2 The in vivo effects of AZ combine antibacterial, bronchodilatation and importantly, anti-inflammatory activities (by supressing the activation of NF-kB and the synthesis of proinflammatory cytokines IL-6 and IL-8). 3 The use of AZ extends also to treat chronic lung diseases, where reducing the impact of infection, inflammation and subsequent tissue injury is of major importance. 4 AZ in particular, is administered against inflammatory recurrent chronic airways infections caused by Pseudomonas aeruginosa (Pa) 5,6 occurring in cystic fibrosis (CF) 7,8 , diffuse panbronchiolitis 9 and bronchiectasis. 10 Long-term treatment with AZ for instance, is included in the current guidelines for CF patients aged ≥ 6 years. 11 Either to treat pneumonia or chronic lung inflammations, AZ is administered by oral or parenteral routes. 12,4 These systemic routes, however, lead to off-target diffusion, poor bioavailability and, consequently, higher doses to attain the necessary concentrations in the lung, especially in the epithelial lining fluid. 13 The inhalatory route constitutes a direct pathway to airways, that circumvents the problem of the poor penetration of intravenously administered antibiotics into lung parenchymal tissue and bronchial secretions. It also provides a fast action onset, minimizing the access to circulation and therefore to the generation of unwanted systemic effect. 14 Indeed, different to the intravenous, the inhalatory route is compatible with chronic administration of medicines. 15 AZ moreover, has got poor gastric tolerability in the long term use. 16,17 In view of such circumstances, inhalable formulations of AZ are expected to improve current therapies against lung infections. The principal weakness of inhaled antibiotics against by Pa infections, however, is the low antibiotic exposure in the vicinity of biofilm colonies, a fact that results in diminished anti-pseudomonal efficacy after repeated uses. A suitable nanocarrier for AZ may help to overcome such drawbacks, because of their ability to modify drug's pharmacokinetics, biodistribution and pharmacodynamics (if needed), to selective and efficiently delivery drugs to diseased targets. To that aim however, nanocarriers structure must be tuned as a function of target site and administration route. 18 Not surprisingly, nanocarriers have started to attract interest as tools to improve the therapeutic index of inhalable antibiotics. Examples of that are the nebulized liposomal ciprofloxacins Pulmaquin and Lipoquin 19 , developed by Aradigm 20 , and Arikayce, a liposomal amikacin developed by Insmed. 21,22 Arikayce is the first and only medication app...
