| The emergence of antimicrobial resistance poses a critical challenge to public health in the 21st century. The current practice to treat microbes relies on single minimum inhibitory concentration (MIC) data to define the optimal clinical dose. This over simplified approach disregards the adaptive nature of microbial response, which leads to emergence of drug resistant microbes over time. In order to overcome antimicrobial resistance, the time course relationships of drug and microbial behavior must first be delineated. In this dissertation, the development of novel mechanism-based pharmacokinetic/ pharmacodynamic (PKPD) models was described using new molecular and genetic findings. The resulting mathematical models provide insight into the complex PKPD relationships necessary to optimize antimicrobial treatments.;The two hypotheses tested were dormant and compensatory mutation hypotheses. A thorough model selection process identified the compensatory mutation model to the best model to describe the PKPD relationship. Dynamic kill-curve experiments were conducted for ciprofloxacin against a clinical isolate of Pseudomonas aeruginosa to further test the PKPD models. Aminoglycosides, but not most beta-lactams, appeared to retain the bactericidal activities against the emerged resistant strains following ciprofloxacin treatment. The induction of resistance was not limited to ciprofloxacin as shown with aztreonam.;The PD model was applied to a clinical study of ceftobiprole in healthy volunteers. The free fraction of drugs collected in several tissues in this study using microdialysis techniques were used to develop a novel population PBPK model. Target attainments using relevant tissue data were predicted for various dosing schemes. Model also implied one-hour intravenous infusion can produce similar PD effects as two-hour IV infusion. Scenarios of resistance were simulated by combining the PD model with the population PBPK model to explore dosing strategy in case of resistance development.;In summary, mechanism-based PKPD model was developed to test hypotheses, design laboratory experiments, and predict clinical drug resistance scenarios. Dynamic kill-curve revealed that aminoglycoside favorably suppress the resistant subpopulations emerged from ciprofloxacin treatment. (Full text of this dissertation may be available via the University of Florida Libraries web site. Please check http://www.uflib.ufl.edu/etd.html). |
