| Despite our continually improving understanding of antibiotics and their use, antibiotic treatment failure remains a problem, even in the absence of antibiotic resistance. Part of the solution is the development of more effective antibiotic treatment protocols, but this cannot be accomplished without a quantitative understanding of the effects of antibiotics on bacterial growth, death, dissemination, and persistence within immunocompetent hosts. This thesis investigates the population dynamics of acute Escherichia coli O18:K1:H7 infection in the mouse thigh infection model (MTI) in immunocompetent mice and its treatment with antibiotics. In vivo and in vitro experiments were performed to investigate the within host dynamics of lethal and nonlethal thigh infections, and three hypotheses were proposed and tested that could account for the infection dynamics observed. The pharmacokinetics and pharmacodynamics of treatment of these thigh infections with streptomycin and tetracycline was studied. The population dynamics of bacterial killing varied with inoculum density and the age of infection, and immediate treatment was always more successful than treatment given eight hours after infection. For streptomycin, survivorship of mice treated at eight hours after infection was improved by giving additional doses of the drug over a four day period, and experimental results suggest this may be due to control of dissemination of the bacteria from the thigh. Phenotypic tolerance, a phenomenon that allows the survival of genetically susceptible bacteria to antibiotic exposure, is studied in vitro and its potential clinical implications are explored with mathematical models. |
