title: Dynamic Computational Model of Symptomatic Bacteremia to Inform Bacterial Separation Treatment Requirements.
abstract: The rise of multi-drug resistance has decreased the effectiveness of antibiotics, which has led to increased mortality rates associated with symptomatic bacteremia, or bacterial sepsis. To combat decreasing antibiotic effectiveness, extracorporeal bacterial separation approaches have been proposed to capture and separate bacteria from blood. However, bacteremia is dynamic and involves host-pathogen interactions across various anatomical sites. We developed a mathematical model that quantitatively describes the kinetics of pathogenesis and progression of symptomatic bacteremia under various conditions, including bacterial separation therapy, to better understand disease mechanisms and quantitatively assess the biological impact of bacterial separation therapy. Model validity was tested against experimental data from published studies. This is the first multi-compartment model of symptomatic bacteremia in mammals that includes extracorporeal bacterial separation and antibiotic treatment, separately and in combination. The addition of an extracorporeal bacterial separation circuit reduced the predicted time of total bacteria clearance from the blood of an immunocompromised rodent by 49%, compared to antibiotic treatment alone. Implementation of bacterial separation therapy resulted in predicted multi-drug resistant bacterial clearance from the blood of a human in 97% less time than antibiotic treatment alone. The model also proposes a quantitative correlation between time-dependent bacterial load among tissues and bacteremia severity, analogous to the well-known 'area under the curve' for characterization of drug efficacy. The engineering-based mathematical model developed may be useful for informing the design of extracorporeal bacterial separation devices. This work enables the quantitative identification of the characteristics required of an extracorporeal bacteria separation device to provide biological benefit. These devices will potentially decrease the bacterial load in blood. Additionally, the devices may achieve bacterial separation rates that allow consequent acceleration of bacterial clearance in other tissues, inhibiting the progression of symptomatic bacteremia, including multi-drug resistant variations.
authors.affiliation: Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Sinead E
authors.initials: SE
authors.lastname: Miller
authors.affiliation: Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Charleson S
authors.initials: CS
authors.lastname: Bell
authors.affiliation: Department of Medicine, Division of Infectious Disease, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
authors.forename: Mark S
authors.identifier: http://orcid.org/0000-0002-9857-4883
authors.initials: MS
authors.lastname: McClain
authors.affiliation: Department of Medicine, Division of Infectious Disease, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.|Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee, United States of America.
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Cover
authors.affiliation: Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Todd D
authors.initials: TD
authors.lastname: Giorgio