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A Novel Treatment Method for Bacterial Respiratory Infections

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A Novel Treatment Method for Bacterial Respiratory Infections Antibacterial Perfluorocarbon Ventilation: A Novel Treatment Method for Bacterial Respiratory Infections by Ryan A. Orizondo A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Biomedical Engineering) in the University of Michigan 2015 Doctoral Committee: Professor Joseph L. Bull, Co-chair Associate Professor Keith E. Cook, Co-chair, Carnegie Mellon University Professor J. Brian Fowlkes Adjunct Professor John G. Younger © Ryan A. Orizondo 2015 ACKNOWLEDGEMENTS First and foremost, I would like to thank my research advisor, Keith Cook. He has served as an unparalleled mentor to me over the past eight years. He has inspired my career path and had a positive and lasting impact on my life. I would also like to thank my dissertation committee; this work could not have been completed without the valuable insight and guidance that they have contributed. Charlene Babcock and Mario Fabiilli have also contributed valuable work to this project as well as significantly aided in my growth as a researcher. Additionally, many members of my lab have played an important role in carrying out this work. In particular I would like to thank Erin Ebsch, Chi Chi Do-Nguyen, Marissa Morales, Diane Nelson, Josh Pohlmann, and Erin Rocci. Lastly, and perhaps most importantly, I would like to recognize those who have supported me in this endeavor outside of the laboratory. My parents have always provided me with loving support and countless opportunities, ultimately enabling me to pursue my passions. My sister, Carissa Orizondo, and girlfriend, Catalina Moreno, have been a never-ending source of support, counsel, and assurance during the entirety of this work. I am certain that this dissertation would not have been possible without the unwavering support and encouragement from my friends and family throughout this long, and often times testing, journey. ii TABLE OF CONTENTS ACKNOWLEDGEMENTS ............................................................................................................ ii LIST OF FIGURES ....................................................................................................................... vi LIST OF TABLES .......................................................................................................................... x LIST OF ABBREVIATIONS ........................................................................................................ xi ABSTRACT ................................................................................................................................. xiii CHAPTER 1: Introduction ............................................................................................................. 1 1.1 Motivation and Objectives .................................................................................................... 1 1.2 Lung Disease and Infection ................................................................................................... 2 1.3 Current Antibiotic Treatment ................................................................................................ 7 1.4 Liquid Ventilation with Perfluorocarbons .......................................................................... 12 1.5 Effects of Perfluorocarbons on the Native Immune Response ........................................... 18 1.6 Perfluorocarbon-Based Drug Delivery................................................................................ 21 1.7 Antibacterial Perfluorocarbon Ventilation .......................................................................... 25 1.8 Summary of Study ............................................................................................................... 33 1.9 References ........................................................................................................................... 35 CHAPTER 2: Initial Characterization of a Water-in-Perfluorocarbon Emulsion for the Pulmonary Delivery of Tobramycin ............................................................................................. 44 2.1 Introduction ......................................................................................................................... 44 2.2 Methods ............................................................................................................................... 46 2.2.1 Emulsion Preparation ................................................................................................... 46 2.2.2 Particle Size and Number ............................................................................................. 47 2.2.3 Emulsion Viscosity ....................................................................................................... 47 2.2.4 Air and Aqueous Interfacial Tensions .......................................................................... 48 2.2.5 Anti-Biofilm Activity ................................................................................................... 48 iii 2.2.6 Pharmacokinetic Characterization ................................................................................ 50 2.2.7 Statistical Analysis ....................................................................................................... 54 2.3 Results ................................................................................................................................. 54 2.3.1 Emulsion Physical Properties ....................................................................................... 54 2.3.2 Anti-Biofilm Capacity .................................................................................................. 56 2.3.3 Pharmacokinetics .......................................................................................................... 57 2.4 Discussion ........................................................................................................................... 58 2.5 References ........................................................................................................................... 63 CHAPTER 3: Effects of Emulsion Formulation on the Pharmacokinetics of Pulmonary Tobramycin Delivery via Antibacterial Perfluorocarbon Ventilation .......................................... 65 3.1 Introduction ......................................................................................................................... 65 3.2 Methods ............................................................................................................................... 67 3.2.1 Emulsion Preparation ................................................................................................... 67 3.2.2 In Vitro Assessment of Emulsion Drug Dispersion ...................................................... 68 3.2.3 Pharmacokinetic Evaluation ......................................................................................... 69 3.2.4 Statistical Analysis ....................................................................................................... 73 3.3 Results ................................................................................................................................. 73 3.3.1 Emulsion Drug Dispersion ........................................................................................... 73 3.3.2 Pharmacokinetic Effects of Emulsion Formulation ...................................................... 75 3.4 Discussion ........................................................................................................................... 77 3.5 References ........................................................................................................................... 84 CHAPTER 4: In Vitro Evaluation of the Effects of Emulsion Formulation on Cytotoxicity and Drug Availability .......................................................................................................................... 85 4.1 Introduction ......................................................................................................................... 85 4.2 Methods ............................................................................................................................... 90 4.2.1 Emulsion Preparation ................................................................................................... 90 4.2.2 Evaluation of Drug Emulsification and Availability .................................................... 91 4.2.3 Cytotoxicity Evaluation ................................................................................................ 96 4.2.4 Statistical Analysis ....................................................................................................... 98 4.3 Results ................................................................................................................................. 98 4.3.1 Emulsion Formulation Effects on Drug Emulsification and Availability .................... 98 4.3.2 Cytotoxic Effects of Fluorosurfactants ....................................................................... 101 iv 4.4 Discussion ......................................................................................................................... 103 4.5 References ......................................................................................................................... 109 CHAPTER 5: In Vivo Treatment Efficacy of Antibacterial Perfluorocarbon Ventilation in a Rat Model of Bacterial Respiratory Infection ..................................................................................
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