Journal Article

IVIS, Xenogen, Xen39

Unlike many localized infections, the development and resolution of bacteremia involves physical and immunological interactions between many anatomic sites. In an effort to better understand these interactions, we developed a computational model of bacteremia as a dynamical system fashioned after multicompartmental pharmacodynamic models, incorporating bacterial proliferation and clearance in the blood, liver, spleen, and lungs, and the transport of pathogens between these sites. A system of four first-order homogeneous ODEs was developed. Blood and organ bacterial burdens were measured at various time points from 3 to 48 h postinoculation using an LD25 murine model of Staphylococcus epidermidis bacteremia. Using these empiric data, solutions to the mathematical model were recovered. A bootstrap resampling method was used to generate 95% confidence intervals around the solved parameters. The validity of the model was examined in parallel experiments using animals acutely immunocompromised with cyclophosphamide; the model captured abnormalities in bacterial partitioning previously described with this antineoplastic agent. Lastly, the approach was used to explore possible benefits to clinically observed hyperdynamic blood flow during sepsis: in simulation, normal mice, but not those treated with cyclophosphamide, enjoyed significantly more rapid bacterial clearance from the bloodstream under hyperdynamic conditions.