Macrolides show antimicrobial activity against P. aeruginosa in eukaryotic media through increased uptake and reduced efflux. These data may help explain the clinical efficacy of macrolides against pseudomonal infections.

Cystic fibrosis (CF) patients receive chronic treatment with macrolides for their antivirulence and anti-inflammatory properties. We, however, previously showed that , considered as naturally resistant to macrolides, becomes susceptible when tested in a eukaryotic medium rather than a conventional broth.We therefore looked for specific macrolide resistance determinants in 333 CF isolates from four European CF centres in comparison with 48 isolates from patients suffering from hospital-acquired pneumonia (HAP).Minimum inhibitory concentrations (MICs) of macrolides and ketolides measured in eukaryotic medium (RPMI-1640) were higher towards CF than HAP isolates. Gene sequencing revealed mutations at three positions (2045, 2046 and 2598) in domain V of 23S rRNA of 43% of sequenced CF isolates, but none in HAP isolates. Enzymes degrading extracellular polymeric substances also reduced MICs, highlighting a role of the mucoid, biofilm-forming phenotype in resistance. An association between high MICs and chronic azithromycin administration was evidenced, which was statistically significant for patients infected by the Liverpool Epidemic Strain.Thus, ribosomal mutations are highly prevalent in CF isolates and may spread in epidemic clones, arguing for prudent use of oral macrolides in these patients. Measuring MICs in RPMI-1640 could be easily implemented in microbiology laboratories to phenotypically detect resistance.

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The aim of this work was to prepare and characterize inhalation dry powders of human parathyroid hormone (PTH), as well as to assess their efficacy for systemic delivery of the peptide and safety in rats. The powders were prepared by spray-drying using PTH, sugars, dipalmitoylphosphatidylcholine, and/or albumin. They presented an average primary particle diameter of 4.5 mm and tap density of 0.06 g/cm 3 , a mass median aerodynamic diameter between 3.9 and 5.9 mm, and reached up to 98% emitted dose and up to 61% fine particle fraction in the multi-stage liquid impinger using a Spinhaler inhaler device. Varying the airflow rate from 30 to 100 L/min had limited influence on the aerodynamic behavior of the aerosols. The absolute PTH bioavailability was 21% after intratracheal administration of the powder formed of PTH/albumin/ lactose/dipalmitoylphosphatidylcholine and 18% after subcutaneous injection in rats. Equilibrium dialysis revealed a 78% binding of PTH to albumin and the withdrawal of albumin from the powder increased absolute bioavailability after inhalation from 21 to 34%. No acute inflammation appeared in the lung up to 48 h after a single inhalation. The increased bioavailability of the optimized powder aerosol of PTH makes it a promising alternative to subcutaneous injection. ß