This program project application will enable Ordway investigators to further studies of a new paradigm for robustly determining doses and schedules of drugs to treat patients infected with the Bioterror pathogens Bacillus anthracis, Yersinia pestis and the Pox viruses Vaccinia Virus and Cowpox Virus. An interdisciplinary program project will facilitate concurrent investigation of this paradigm in several pathogens and enable investigators to learn more about the pharmacodynamics of drugs intended for therapy. Because of the seriousness of these illnesses, drug doses and schedules have to be right the first time. In addition to being able to set drug exposure targets employing a validated (in bacteria as well as in multiple HIV studies) in vitro hollow fiber infection model, the investigators have developed a robust approach employing Monte Carlo simulation for translating the insights from the in vitro system and animal models to man. Ordway has the expertise locally, with our New York State Health Department relationships, and in our US Army Medical Research Institute of Infectious Diseases (USAMRIID) collaborators as well as the infrastructure support to help solve this serious national problem. In order to correctly determine the right dose for man, there are four pieces of knowledge required. The first is a drug exposure target (ADC/MIC ratio, Peak/MIC ratio, Time > MIC, etc). The second is to have a measure of the variability of the pharmacokinetics of the agent in the population. The third is to have a measure of the distribution of MIC's for different strains of the pathogen of interest for the drug in question. The final piece of knowledge is to have a measure of the impact of protein binding on the microbiological activity of the drug. The program project application will develop this required knowledge through four integrated projects: (1) Determining therapeutic regimens for Bacillus anthracis in the hollow fiber system, (2) Determining therapeutic regimens for Yersinia pestis in the hollow fiber system, (3) Determining therapeutic regimens for the Variola major surrogates Vaccinia Virus and Cow Pox in the hollow fiber system and in an animal model, and (4) Examining the predictions of the hollow fiber model system in inhalational animal models of Anthrax and Plague. These projects will be supported by analytical, computational, and administrative cores to facilitate thematic integration. The Ordway investigators have already had significant success in addressing these issues. One example is the identification of an exposure to a fluoroquinolone antimicrobial that would achieve the desired goal of therapy for Bacillus anthracis. Indeed, the predictions from the hollow fiber system were evaluated in a Balb/c mouse model at USAMRIID, as well as in a rhesus monkey challenge and shown to be correct.
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