Bacteriophages have been identified as a potential treatment option to treat lung infection in the context of antibiotic resistance. We performed a preclinical study to predict the efficacy of delivery of bacteriophages against Pseudomonas aeruginosa (PA) when administered via nebulization during mechanical ventilation (MV). We selected a mix of four anti-PA phages containing two Podoviridae and two Myoviridae, with a coverage of 87.8% (36/41) on an international PA reference panel. When administered via nebulization, a loss of 0.30–0.65 log of infective phage titers was measured. No difference between jet, ultrasonic and mesh nebulizers was observed in terms of loss of phage viability, but a higher output was measured with the mesh nebulizer. Interestingly, Myoviridae are significantly more sensitive to nebulization than Podoviridae since their long tail is much more prone to damage. Phage nebulization has been measured as compatible with humidified ventilation. Based on in vitro measurement, the lung deposition prediction of viable phage particles ranges from 6% to 26% of the phages loaded in the nebulizer. Further, 8% to 15% of lung deposition was measured by scintigraphy in three macaques. A phage dose of 1 × 10⁹ PFU/mL nebulized by the mesh nebulizer during MV predicts an efficient dose in the lung against PA, comparable with the dose chosen to define the susceptibility of the strain.

Anatomical 3D-printed nasal casts are valuable models to investigate intranasal drug deposition, providing preclinical data that cannot be obtained in animal models. However, these models are limited since they are often derived from a single patient or represent a mean of several groups. The present study aimed to better characterize the anatomical differences of the nasal cavity in a European sub-population and to assess the potential impact of anatomical variations on intranasal deposition by medical devices. Ninety-eight cranial computed tomography scans of patients were selected and analyzed in 2D and 3D conformations. They showed symmetry of cavities and a high level of heterogeneity of measurements, especially volume and area, in the population. Three anatomical groups with distinct nasal geometry were identified and 3D nasal casts of the most representative patient of each group were printed. Fluorescein was administered using three medical devices: a nasal spray, a sonic jet nebulizer and a prototype mesh-nebulizer. The deposition profiles were compared with the Aeronose® as a reference. Our results show that anatomical variations influenced the deposition profiles depending on the device, with a higher variation with spray and the mesh-nebulizer. This work emphasises the importance of anatomical parameters on drug intranasal deposition and the need to evaluate inhaled drugs on different 3D nasal casts reflecting the target population.