Catheter-associated blood stream infections (CABSIs) are serious, yet common, outcomes in both human and animals with indwelling catheters. The increasing rate of these infections is partially due to hindered knowledge on how to stop the spred of these pathogens, this due, in part, to inadequate animal models. Current experimental models fail to mimic various aspects of sepsis pathogenesis, diverse clinical symptomology, and in most cases lack the ability to test novel therapies for use in human medicine. In response to the urgent need for a more clinically relevant animal model of CAS, this large animal model was conceptualized and validated through this prospective study. Eight clinically healthy domestic cross-bred mature female sheep were obtained and double-lumen peripherally inserted central catheters (PICCs) were nonsurgically placed in the left jugular veins. A novel inoculation method was developed using a luminal volume of Klebsiella pneumoniae subsp. pneumoniae 43816Rif^Risolate and blood mixture (1:3). The mixture was injected into the lumen and was allowed to clot where is remainded for the duration of the study, enabling the development of a chronic catheter infection with the slow prolonged release of bacteria. This continual shedding of bacteria more closely mimicks the natural pathogenesis of catheter-associated sepsis (CAS) in clinical settings. A diverse yet dose-dependent host immune response was observed including; tachypneas, tachycardias, pyrexias, leukopeneas, neutrophilias, thrombocytopenias, hyperlacemias, and in some sheep biochemical signs of organ injury/damage with SOFA scores reaching ≥5. Please see paper for full abstract.