Antibacterial Perfluorocarbon Ventilation: A Novel Treatment Method for Bacterial Respiratory Infections.

Abstract

Bacterial respiratory infections significantly contribute to the morbidity and mortality associated with lung diseases such as cystic fibrosis, chronic obstructive pulmonary disease, and bronchiectasis. These patients feature abnormal mucus production and rheology that can impair host immune defenses, ultimately leading to chronic lung infection. Inhaled antibiotic delivery is currently used to treat these patients; however, its effectiveness is limited by an intrinsic dependence on airflow within the lung. Poor ventilation due to mucus plugging and lung damage restricts antibiotic delivery to the most burdened regions of the lung. In order to address these shortcomings, this research proposes a novel method of treatment entitled antibacterial perfluorocarbon ventilation (APV). During APV the lungs are filled with a breathable liquid [perfluorocarbon (PFC)] containing emulsified, micron-scale droplets of aqueous antibiotic. Such delivery has removed dependence on airflow and is thus capable of achieving more spatially uniform delivery. APV should also be able to actively remove infected mucus from the airways as well as promote a return to normal lung function via anti-inflammatory properties of PFC. This work represents an in-depth analysis and characterization of the emulsions used during APV. Initial efforts evaluated the feasibility of the emulsion’s use during liquid ventilation as well as its ability to effectively kill the tenacious bacterial biofilms found in the airways during infection. Following studies utilized both in vitro and in vivo methods to better understand the effects of emulsion formulation on the pharmacokinetics and availability of delivered drug and any potential cytotoxicity associated with the emulsion. A rat model of bacterial respiratory infection was developed and used at multiple points throughout this work to assess the potential treatment benefits of APV. Great strides were made in developing and optimizing the emulsion. The emulsions have been shown to be an adequate ventilation medium and a viable means of pulmonary drug delivery during APV. Final efforts resulted in a promising emulsion formulation that exhibited no cytotoxic effects and drastically improved drug availability relative to those previously assessed in vivo. Further in vivo work is required to determine if this optimized emulsion formulation provides a treatment benefit over inhaled antibiotics.