Date of Award

1987

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Veterinary Physiology, Pharmacology, and Toxicology (Veterinary Medical Sciences)

First Advisor

Charles R. Short

Abstract

The ultimate goals of this study were to develop and define a subcutaneous tissue chamber as a suitable device for establishing a Pasteurella haemolytica soft-tissue infection model in cattle and to use this model to study the in vivo efficacy and distribution of a potentiated sulfa antimicrobial. Developmental studies resulted in the selection of a suitable tissue chamber design that maximized the chamber penetration of an intravenously administered lipid-soluble drug. This chamber could be sampled with ease and contained enough chamber fluid to allow repetitive sampling. Cytological and chemical investigation revealed that the composition of fluid within chambers approached the theoretical composition of true interstitial fluid as time after implantation increased. Despite an ongoing low-grade chronic inflammatory reaction resulting in fibrous encapsulation of chambers, the vascularity of chamber tissue did not diminish with time after implantation. Pharmacokinetic studies conducted using lipid-soluble agents demonstrated that penetration from blood into chamber fluid could be described by a two-compartment pharmacokinetic model, where tissue chambers matched the description of a "deep" compartment. Diffusion of nonlipid-soluble agents suggested that the permeability characteristics of the diffusional barrier separating blood and chamber fluid were similar to those of capillary endothelial walls, and that tissue chambers formed true interstitial compartments. Inoculation of Pasteurella haemolytica into tissue chambers resulted in the establishment of a localized subcutaneous infection which was similar to the lung lesions seen in pneumonic pasteurellosis. Tissue chamber penetration of intravenously administered sulfadiazine/trimethoprim increased after infection. Despite the maintenance of chamber antimicrobial concentrations which exceeded minimum bacteriocidal levels established in vitro, the infections were not sterilized. This lack of efficacy was associated with decreased pH and increased protein concentrations in chamber fluid after inoculation. Infection with bovine viral diarrhea virus, which is thought to depress host defenses, had no effect on the response of Pasteurella haemolytica to sulfadiazine/trimethoprim therapy. Observation of responsive antibody titers, bacterial phagocytosis, and high leucocyte viability within Pasteurella haemolytica infected chambers demonstrate that the model can be used to study the response of bacteria to specific concentrations of antimicrobials in the presence of functional host defenses.

Pages

244

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