Antibiotic treatment failure might be due to bacterial resistance or suboptimal exposure at target site and there is a lack of knowledge on the interaction between antimicrobial pharmacodynamics (PD) and the immune response to bacterial infections. Therefore, it is crucial to develop tools to increase the understanding of drug disposition to better evaluate antibiotic candidates in drug development and to elucidate the role of the immune system in bacterial infections. Colistin is used as salvage therapy against multidrug resistant Gram-negative infections. In this work, a whole-body physiologically based pharmacokinetic model (WBPBPK) was developed to characterize the pharmacokinetics (PK) of colistin and its prodrug colistin methanesulfonate (CMS) in animal and human. The scalability of the model from animal to human was assessed with satisfactory predictive performance for CMS and demonstrating the need for a mechanistic understanding of colistin elimination. The WBPBPK model was applied to investigate the impact of pathophysiological changes commonly observed in critically ill patients on tissue distribution of colistin and to evaluate different dosing strategies. Model predicted concentrations in tissue were used in combination with a semi-mechanistic PKPD model to predict bacterial killing in tissue for two strains of Pseudomonas aeruginosa. Finally, a toxicokinetic (TK) model was constructed to describe the time course of E. coli endotoxin concentrations in plasma and the effect on pro-inflammatory cytokine release. The model adequately described the concentration-time profiles of endotoxin and its stimulation of IL-6 and TNF-α production using an indirect response model combined with a transit compartment chain with a tolerance component to endotoxemia. The WBPBPK model developed in this work increased the knowledge on colistin tissue exposure under various conditions and could be used in drug development process to assess antibiotic efficacy or to test new drug combinations. The model describing endotoxin TK and its effect on cytokines is a new tool to be further applied in longitudinal studies to explore the immune response cascade induced by bacterial infections. The methodology applied in this thesis contributes to the development of an integrated modeling framework including physiology, drug distribution, bacterial growth and killing as well as the immune response to infection.

<p>Between October 2001 and May 2012 approximately 70% of U.S. military personnel killed in action and 75% wounded in action were the direct result of exposure to an explosion. As of 2008, it was estimated that close to 20% of all Operation Iraqi Freedom and Operation Enduring Freedom (OIF/OEF) veterans had sustained some form of traumatic brain injury (TBI). Further, blast exposure is also a civilian problem due to the increased usage of explosives in terrorist attacks. Blast injury research has historically focused on the pulmonary system and the other air-containing organs which have been shown through extensive experimentation to be susceptible to blast overpressure injury. A shift in injury pattern during recent conflicts is characterized by decreased incidence of pulmonary injuries with an increase in TBI thought to be associated with blast exposure. This increase in observation of blast TBI has resulted in a large research effort to understand mechanisms and thresholds. However, due to the relatively sudden shift, much of this research is being conducted without a proper understanding and consideration of blast mechanics and interspecies scaling effects.</p><p>This dissertation used experimental and computational finite element (FE) analysis to investigate some large questions surrounding blast TBI research. An experimental investigation was conducted to determine the effects of modern thoracic body armor usage on blast pressure exposure seen by the body. To improve FE modeling capabilities, brain tissue mechanics in common blast TBI animal model species were investigated experimentally and computationally to determine viscoelastic constitutive behavior and measure interspecies variation. Meta-analysis of blast pulmonary literature was conducted to update interspecies scaling and injury risk models. To derive interspecies scaling and injury risk models for blast neurotrauma endpoints a meta-analysis of existing experimental data was used.</p><p>This dissertation makes major contributions to the field of injury biomechanics and blast injury research. Research presented in this dissertation showed that modern thoracic body armor has the ability to lower the risk of pulmonary injury from blast exposure by attenuating and altering blast overpressure. The study shows that the use of soft body armor results in the pulmonary injury threshold being similar to that for neurotrauma. The use of hard body armor results in the threshold for pulmonary injury occurring at higher levels than that of neurotrauma. This finding is important, as it helps to explain the recent shift in injury types observed and highlights the importance of continued widespread usage of body armor not only for ballistic protection but for protection from blast as well.</p><p>This dissertation also shows the importance of interspecies scaling for investigation of blast neurotrauma. This work looks at existing in vivo animal model data to derive appropriate scaling across a wide range of brain size. Appropriate scaling for apnea occurrence and fatality for blast isolated to the head was found to be approximately equal to a characteristic length scaling of brain size, assuming similar brain geometry. By combining the interspecies scaling developed and existing tests data, injury risk models were derived for short duration blast exposures.</p><p>The contributions and conclusions of this dissertation serve to inform the injury biomechanics field and to improve future research efforts. The consideration by researchers of the recommendations presented in this dissertation for in vivo animal model testing will serve to maximize the value gained from experimentation and improve our understanding of blast injury mechanisms and thresholds. The injury risk models presented in this work help to improve our ability to prevent, diagnose, and treat blast neurotrauma.</p> / Dissertation