Investigation of the gallbladder host environment and small RNAs in the pathobiology of Campylobacter jejuni sheep abortion clone IA 3902

Campylobacter jejuni is an important zoonotic agent that is the leading cause of both human foodborne bacterial gastroenteritis worldwide, as well as ovine abortion in the United States. In particular, a single C. jejuni sheep abortion clone, of which IA 3902 is a prototypical isolate, has recently emerged as the dominant causative agent of sheep abortion due to Campylobacter sp. in the U.S. and has been increasingly identified in human outbreaks of disease. Multi-omics approaches to studying this hypervirulent strain have shown that it is remarkably similar to other common strains of C. jejuni such as 11168 that do not show the same ability to cause systemic clinical disease. Further work to elucidate the molecular mechanisms that allow for small changes in genomic structure to lead to large changes in virulence ability in this important zoonotic agent is warranted. A number of studies have demonstrated that the gallbladder of ruminants, as well as other domestic animal species, is often positive on culture for Campylobacter sp. following oral exposure, suggesting that this environment may serve as a chronic nidus of infection for maintenance of disease within populations. By utilizing a unique in vivo model of gallbladder infection, the work conducted within this dissertation has allowed identification of the preferred location of C. jejuni IA 3902 within the gallbladder host environment as well as demonstrated putative host factors that may play a role in its localization to that site. In addition, by utilizing emerging RNA sequencing technology, we were able to determine numerous protein coding genes and non-coding RNAs that were differentially expressed following exposure to the in vivo gallbladder host environment. One of these identified non-coding RNAs, CjNC110, was selected for further study. Inactivation of the CjNC110 non-coding RNA in IA 3902 allowed us for the first time to identify transcriptomic and phenotypic changes associated with loss of function of a small RNA in any species of Campylobacter. The collective results of these experiments provide additional evidence to begin to elucidate the role of gallbladder colonization and small RNAs in the pathobiology of the important zoonotic pathogen, C. jejuni IA 3902

The pharmacokinetics and pharmacodynamics of esomeprazole in sheep after intravenous dosing

Abomasal (gastric) ulceration is a morbidity in sheep, and currently, there is a paucity of pharmacokinetic and pharmacodynamic data for gastroprotectant drugs reported for this species. The proton pump inhibitor esomeprazole has been used in small animal and human patients for gastroprotection via increasing the gastric pH. The objective of this study was to report the pharmacokinetic parameters and pharmacodynamic effect of esomeprazole in sheep after single intravenous dosing. Four healthy adult Southdown cross ewes had blood collected over a 24  h time period after single intravenous dosing of esomeprazole at 1.0  mg/kg. Abomasal fluid was sampled over 24  h before and after esomeprazole administration. Plasma samples were analyzed for concentrations of esomeprazole and the esomeprazole metabolite, esomeprazole sulfone by high performance liquid chromatography. Pharmacokinetic and pharmacodynamic data were evaluated with specialized software. Esomeprazole was rapidly eliminated after IV administration. Elimination half-life, area under the curve, initial concentration (C0), and clearance were 0.2  h, 1,197  h*ng/mL, 4,321  ng/mL, and 0.83  mL/h/kg, respectively. For the sulfone metabolite elimination half-life, area under the curve and maximum concentration were 0.16  h, 22.5  h*ng/mL, and 65.0  ng/mL, respectively. Abomasal pH was significantly elevated from 1 to 6  h after administration and remained above 4.0 for at least 8 h after administration. No adverse effects were noted in these sheep. Esomeprazole was rapidly eliminated in sheep, similar to goats. Abomasal pH was increased, but future studies will be necessary to develop a clinical management approach to the use of esomeprazole in sheep

Pharmacokinetics of esomeprazole in goats (Capra aegagrus hircus) after intravenous and subcutaneous administration

Background: Stressed and hospitalized goats are at risk of developing abomasal (gastric) ulceration, but there is a paucity of pharmacokinetic studies for proton pump inhibiting drugs, such as, esomeprazole in goats. Objectives: The objectives for this study were to estimate plasma pharmacokinetic parameters for esomeprazole in adult goats after intravenous (IV) and subcutaneous (SQ) administration. A secondary objective was to describe the plasma kinetics of the metabolite esomeprazole sulfone after IV and SC administration in goats. Materials and methods: Esomeprazole was administered to 5 adult goats in a crossover study at doses of 1 mg/kg IV or 2 mg/kg SC. Plasma samples were collected over 36 h and analyzed via reverse phase HPLC to determine concentrations of esomeprazole and esomeprazole sulfone. Pharmacokinetic parameters were derived via non-compartmental analysis. Results: Following IV administration, mean values for plasma clearance (Cl), elimination half-life [T1/2 (λz)], C0, and volume of distribution (Vz) of esomeprazole were estimated at 24.9 mL/min/kg, 6 min, 2.324 μg/mL, and 0.23 L/kg, respectively. After SC administration elimination half-life, maximum concentration (Cmax) and time to maximum concentration (Tmax) of esomeprazole were estimated at 29 min, 1.038 μg/mL, and 22 minutes respectively. Maximum concentrations of the sulfone metabolite were 32 and 18 ng/mL after IV and SC administration. Conclusion: Esomeprazole was rapidly eliminated from plasma after both IV and SC injection in goats. The elimination half-life in goats appears to be shorter than reported in dogs, as well as less than that reported for pantoprazole in goats. The sulfone metabolite was detected and also rapidly eliminated from the plasma after both IV and SC administration. Additional pharmacodynamic investigations are needed to determine the efficacy of esomeprazole on abomasal (gastric) acid suppression in goats and could include larger doses or additional routes of administration.This article is published as Fladung R, Smith JS, Hines MT, Soto-Gonzalez WM, Fayne B, Rahn RR, Escher OG, Harvill L, Bergman J, Garcia JD, Kreuder AJ and Cox S (2022) Pharmacokinetics of esomeprazole in goats (Capra aegagrus hircus) after intravenous and subcutaneous administration. Front. Vet. Sci. 9:968973. DOI: 10.3389/fvets.2022.968973. Copyright 2022 Fladung, Smith, Hines, Soto-Gonzalez, Fayne, Rahn, Escher, Harvill, Bergman, Garcia, Kreuder and Cox. Attribution 4.0 International (CC BY 4.0). Posted with permission