It is critical that we respond to the threat of intentional release CDC Category A pathogens with developing information on the correct doses and schedules of a number of different antimicrobial agents. The hollow fiber infection model (HFIM) system is useful for the design of doses and schedules of drugs. The application of innovative mathematical modeling methodologies ensures that the doses chosen will be rational and have a high probability of providing adequate therapy for a very large proportion of the population. However, in order to obtain an indication for therapy from the FDA, the """"""""two animal rule"""""""" needs to be followed. Consequently, we will examine the doses and schedules of drugs identified in the hollow fiber system as being likely to provide adequate therapy for the pathogens B. anthracis and Y. pestis. The objective is to use murine models of inhalational anthrax and inhalationinduced plague pneumonia/septicemia to validate the predictions of failure or success made in hollow fiber models of B. anthracis and Y. pestis infection for several treatment regimens using purely murine PKs of the drug and a dosing regimen that """"""""humanizes"""""""" the concentration-time profile of the antibiotics in the mouse. Our central hypothesis is that application of PD principles and mathematical models to our novel in-vitro hollow fiber infection model (HFIM) can be used to identify antimicrobial agents and to design dose-optimized antibiotic regimens for the treatment of bioterror-related infections in humans and will serve as a robust tool for designing animal studies directed toward the validation of human dosing regimens. We further hypothesize that PD- based dosing of antibiotics will optimize outcome by maximizing the kill of drug-susceptible pathogens while preventing the amplification of drug-resistant subpopulations. Finally, because an intentional release could carry both pathogens, adding diagnostic confusion and causing inappropriate drug/dose/schedule choice, we also plan to develop and validate a murine model of mixed anthrax/plague inhalational challenge as well as look for any changes in pathophysiology that might be wrought by a dual challenge. We will examine our most active agents with potency against both pathogens to define appropriate doses and schedules of the drugs for this circumstance.
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