Acute lower respiratory infections cause more disease and death than any other infection in the US. In most cases, bacterial infections are treated with systemic or inhaled antibiotics. However, large groups of patients still suffer from severe infections with significant morbidity and mortality and could benefit from improved treatment techniques. This is particularly true for severe cases of pneumonia, bacterial infections superimposed on chronic lung disease states, and bronchiectasis. Antibiotic perfluorocarbon ventilation (APV) could improve treatment of severe bacterial infections if used as an adjunct to traditional systemic or inhaled antibiotic therapy. In this treatment, the lung is tidally ventilated with a perfluorocarbon liquid (PFC) containing emulsified antibiotics for a perid of up to a few hours. This technique could accelerate standard antibiotic therapy in several ways. First, the tidal flow of PFCs actively removes infected mucus from airway walls due to fluid shear and reduced mucus surface tension. The mucus is then convectively transported from the lungs, aided by buoyant force, and removed easily from the PFC ventilator. Second, antibiotic is delivered directly to the source of infection, allowing for higher concentrations in he lung and lower systemic concentrations and toxicity. However, unlike treatment with inhaled antibiotics, which can only deliver antibiotics to areas of effective gas ventilation, convective transport of the antibiotic in PFC will allow much more uniform distribution down to the alveolar level. Active mucus removal should also allow antibiotics to more easily access previously plugged airways, both during APV and treatment with inhaled antibiotics thereafter. Lastly, PFC has anti- inflammatory properties that may promote lung healing and a return towards normal mucociliary clearance. Ultimately, APV may decrease morbidity, mortality, and the cost of treatment from severe respiratory infections. To establish the effectiveness of APV, we will infect rats with mucoid Pseudomonas aeruginosa. We will then compare treatment of this infection with either 1) inhaled tobramycin alone, 2) perfluorocarbon ventilation followed by inhaled tobramycin, 3) perfluorocarbon ventilation with emulsified tobramycin followed by inhaled tobramycin, or 4) perfluorocarbon ventilation with emulsified tobramycin and no further treatment. We hypothesize that bacterial load and inflammation following treatment will be from lowest to highest: group 3, 4, 2, and 1. These studies will provide preliminary data and guidance towards future studies that seek to optimize treatment by examining different ventilation settings and emulsion characteristics.

Public Health Relevance

This project will determine if antibacterial perfluorocarbon ventilation (APV) can improve treatment of severe bacterial lower respiratory infections. APV is intended as an adjunct therapy to systemic or inhaled antibiotics. It utilizes a tidal flow of perfluorocarbon (PFC) containing emulsified antibiotics to actively wash infected mucus from the lungs, deposit antibiotics directly at the infection, and reduce lung inflammation due to a reduced bacterial load and inherent anti-inflammatory properties of PFCs.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Small Research Grants (R03)
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Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
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Taylor, Christopher E,
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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Orizondo, Ryan A; Nelson, Diane L; Fabiilli, Mario L et al. (2017) Effects of Fluorosurfactant Structure and Concentration on Drug Availability and Biocompatibility in Water-in-Perfluorocarbon Emulsions for Pulmonary Drug Delivery. Colloid Polym Sci 295:2413-2422
Orizondo, Ryan A; Fabiilli, Mario L; Morales, Marissa A et al. (2016) Effects of Emulsion Composition on Pulmonary Tobramycin Delivery During Antibacterial Perfluorocarbon Ventilation. J Aerosol Med Pulm Drug Deliv 29:251-9
Orizondo, Ryan A; Babcock, Charlene Irvin; Fabiilli, Mario L et al. (2014) Characterization of a reverse-phase perfluorocarbon emulsion for the pulmonary delivery of tobramycin. J Aerosol Med Pulm Drug Deliv 27:392-9