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Inhaled siRNA therapy has a unique potential for treatment of severe lung diseases, such as cystic fibrosis (CF). Nevertheless, a drug delivery system tackling lung barriers is mandatory to enhance gene silencing efficacy in the airway epithelium. We recently demonstrated that lipid-polymer hybrid nanoparticles (hNPs), comprising a poly(lactic-co-glycolic) acid (PLGA) core and a lipid shell of dipalmitoyl phosphatidylcholine (DPPC), may assist the transport of the nucleic acid cargo through mucus-covered human airway epithelium. To study in depth the potential of hNPs for siRNA delivery to the lungs and to investigate the hypothesized benefit of PEGylation, here, an siRNA pool against the nuclear factor-κB (siNFκB) was encapsulated inside hNPs, endowed with a non-PEGylated (DPPC) or a PEGylated (1,2-distearoyl- sn -glycero-3-phosphoethanolamine-poly(ethylene glycol) or DSPE-PEG) lipid shell. Resulting hNPs were tested for their stability profiles and transport properties in artificial CF mucus, mucus collected from CF cells, and sputum samples from a heterogeneous and representative set of CF patients. Initial information on hNP properties governing their interaction with airway mucus was acquired by small-angle X-ray scattering (SAXS) studies in artificial and cellular CF mucus. The diffusion profiles of hNPs through CF sputa suggested a crucial role of lung colonization of the corresponding donor patient, affecting the mucin type and content of the sample. Noteworthy, PEGylation did not boost mucus penetration in complex and sticky samples, such as CF sputa from patients with polymicrobial colonization. In parallel, in vitro cell uptake studies performed on mucus-lined Calu-3 cells grown at the air-liquid interface (ALI) confirmed the improved ability of non-PEGylated hNPs to overcome mucus and cellular lung barriers. Furthermore, effective in vitro NFκB gene silencing was achieved in LPS-stimulated 16HBE14o- cells. Overall, the results highlight the potential of non-PEGylated hNPs as carriers for pulmonary delivery of siRNA for local treatment of CF lung disease. Furthermore, this study provides a detailed understanding of how distinct models may provide different information on nanoparticle interaction with the mucus barrier.

The in vitro activity of ceftolozane-tazobactam (C-T) was evaluated comparatively to other antibiotics against 188 Pseudomonas aeruginosa isolates collected from cystic fibrosis (CF) patients. Overall, the activity of C-T was comparable to colistin (susceptibility rate: 85.1% vs. 89.4%) but significantly higher than other antimicrobials. Particularly, C-T was active against 70% of meropenem nonsusceptible isolates and 64.1% of those nonsusceptible to beta-lactams. C-T was active against 70%, 58.1%, and 100% of multidrug-resistant, extensively drug-resistant (XDR), and pandrug-resistant isolates, respectively. No differences in C-T activity were found between isolates from children and adult patients, except for XDR ones significantly more susceptible in older patients. C-T and colistin exhibited comparable susceptibility rate (91.1% vs. 86.7%) also against 68 isolates collected during pulmonary exacerbations. Activity of C-T towards mucoid isolates was less than colistin (82.9% vs. 97.6%) but higher compared with other antibiotics. C-T represents a promising agent for treating CF lung infections., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Several advances in the medical field are often dependent on the ability to fight infections with the use of antibiotics, including joint replacements, organ transplants, and cancer therapy. The capacity of the bacteria to adapt to and escape from the mechanisms of action of antibiotics makes the antimicrobial resistance a serious public health problem worldwide. Polymyxin E colistin has rarely been used because of its nephrotoxicity and neurotoxicity. More recently, the emergence of multi-drug resistant bacteria as carbapenem-resistant Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa and the re-evaluation of its pharmacokinetic properties have led to a resurgence of colistin as a treatment option, contributing to select resistant strains. Investigating the phenomenon of colistin-resistance in gram-negative bacteria, especially P. aeruginosa, is now mandatory, particularly after identification of a plasmid-mediated mechanism for the resistance to colistin (mcr) in Enterobacteriaceae strains, a mechanism transferable to other species. In this study, we investigated colistin-resistance in gram-negative bacteria isolated from respiratory secretions of cystic fibrosis patients in follow-up at Children's Hospital Bambino Gesù of Rome. [ABSTRACT FROM AUTHOR]