In Vitro and In Silico Evaluation of Polymyxin B Aerosol Delivery in Adult Mechanical Ventilation

<b>Background:</b> Nebulized polymyxin B (PMB) therapy is widely used in intensive care units for treating hospital-acquired and ventilator-associated pneumonia caused by multidrug-resistant Gram-negative bacteria, yet its pulmonary delivery performance during invasive mechanical ventilation remains poorly characterized. <b>Methods:</b> An in vitro adult mechanical ventilation model was used. We evaluated two nebulizers (vibrating mesh nebulizer [VMN] and jet nebulizer [JN]) at three positions (standalone nebulizer, 15 cm from the Y-piece, and the humidifier's dry end) with two artificial airway types (endotracheal and tracheostomy tubes). Lung deposition was predicted using the multiple-path particle dosimetry model, incorporating the Yeh/Schum five-lobe adult lung model. <b>Results:</b> In the standalone setup, the percentage of delivered dose of VMN and JN was approximately 40% and 34%, respectively. Mechanical ventilation significantly reduced the delivered dose (all <i>p</i> ≤ 0.0085), with VMN at the humidifier's dry end delivering only 2.14-2.99% of the nominal dose. In all the tested ventilation scenarios, both the use of the JN and positioning the nebulizer 15 cm from the Y-piece significantly increased aerosol delivery (all <i>p</i> ≤ 0.021). While the ventilator circuit reduced the total drug amount, it filtered larger aerosols. This resulted in a smaller mass median aerodynamic diameter and a higher fine particle fraction (all <i>p</i> < 0.0001), which doubled the predicted alveolar deposition fraction (from 13-14% in standalone to 23-28% in ventilation scenarios) and eliminated extrathoracic deposition. <b>Conclusions:</b> This study provides the first in vitro and in silico assessment of PMB aerosol delivery during invasive mechanical ventilation. Nebulizer type, its placement within the circuit, and the artificial airway are critical factors that significantly alter the pulmonary delivery of PMB aerosol and subsequently impact its lung deposition.