Abstract
Aerosolized delivery of antibiotics is hindered by poor penetration within distal and plugged airways. Antibacterial perfluorocarbon ventilation (APV) is a proposed solution in which the lungs are partially or totally filled with perfluorocarbon (PFC) containing emulsified antibiotics. The purpose of this study was to evaluate emulsion stability and rheological, antibacterial, and pharmacokinetic characteristics. This study examined emulsion aqueous droplet diameter and number density over 24 hr and emulsion and neat PFC viscosity and surface tension. Additionally, Pseudomonas aeruginosa biofilm growth was measured after 2-hr exposure to emulsion with variable aqueous volume percentages (0.25, 1, and 2.5%) and aqueous tobramycin concentrations (Ca=0.4, 4, and 40 mg/mL). Lastly, the time course of serum and pulmonary tobramycin concentrations was evaluated following APV and conventional aerosolized delivery of tobramycin in rats. The initial aqueous droplet diameter averaged 1.9±0.2 μm with little change over time. Initial aqueous droplet number density averaged 3.5±1.7×10(9) droplets/mL with a significant (p<0.01) decrease over time. Emulsion and PFC viscosity were not significantly different, averaging 1.22±0.03×10(-3) Pa·sec. The surface tensions of PFC and emulsion were 15.0±0.1×10(-3) and 14.6±0.6×10(-3) N/m, respectively, and the aqueous interfacial tensions were 46.7±0.3×10(-3) and 26.9±11.0×10(-3) N/m (p<0.01), respectively. Biofilm growth decreased markedly with increasing Ca and, to a lesser extent, aqueous volume percentage. Tobramycin delivered via APV yielded 2.5 and 10 times larger pulmonary concentrations at 1 and 4 hr post delivery, respectively, and significantly (p<0.05) lower serum concentrations compared with aerosolized delivery. The emulsion is bactericidal, retains the rheology necessary for pulmonary delivery, is sufficiently stable for this application, and results in increased pulmonary retention of the antibiotic.
Highlights
Bacterial Biofilms are a key pathologic feature of chronic airway infections and an important cause of morbidity.[1,2,3] Limited diffusion from the epithelial lining fluid into the biofilm mass and enhanced resistance make biofilm-based infections refractory to the concentration of antibiotics typically achieved with systemic administration.[4]. Inhaled aerosolized antibiotics have shown the ability to achieve higher intrapulmonary antibiotic concentrations while limiting systemic toxicity and, as a result, have established an important role in treatment.[4,5,6] there are still many shortcomings associated with inhaled antibiotics in the treatment of bacterial respiratory infections, making aerosolized delivery less than ideal
Antibacterial perfluorocarbon ventilation (APV) could be used in a variety of respiratory infection cases, it would be best suited for patients already on a ventilator due to the need for the patient to be intubated during the therapy
It has proven able to remove mucus and inflammatory exudates,(16–18) to distribute uniformly within injured lungs, and to provide respiratory support in animal models[19,20,21,22] and in humans with acute respiratory distress syndrome.[17,23,24,25] PFC-based antibiotic delivery has been previously explored, primarily through the use of solid particle suspensions.[26,27,28] ventilation with such suspensions has shown some promise, it has failed to demonstrate treatment benefit over systemic antibiotic delivery in conjunction with liquid ventilation.[27]. In the current study, we examined the stability and rheological, anti-biofilm, and pharmacokinetic characteristics of an emulsion consisting of aqueous tobramycin in a PFC vehicle
Summary
Bacterial Biofilms are a key pathologic feature of chronic airway infections and an important cause of morbidity.[1,2,3] Limited diffusion from the epithelial lining fluid into the biofilm mass and enhanced resistance make biofilm-based infections refractory to the concentration of antibiotics typically achieved with systemic administration.[4]. Lungs resulting in more spatially uniform distribution and increased pulmonary residence time could significantly improve the treatment of chronic respiratory infections.[6,10]. Respiratory bacterial infections in cystic fibrosis, chronic obstructive pulmonary disease, and bronchiectasis are common and often exacerbate the disease state, often requiring the patient to be mechanically ventilated. Such patient groups could greatly benefit from APV with very little added procedures or discomfort. Antibacterial perfluorocarbon ventilation (APV) is a proposed solution in which the lungs are partially or totally filled with perfluorocarbon (PFC) containing emulsified antibiotics. Conclusions: The emulsion is bactericidal, retains the rheology necessary for pulmonary delivery, is sufficiently stable for this application, and results in increased pulmonary retention of the antibiotic
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