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The objective of this study was to assess the impact of the vehicle of administration and the prandial state of post weaning piglets on the indices of therapeutic efficacy for different broad-spectrum antibiotic/pathogen combinations. Pharmacokinetic data were retrieved from previous studies, in which we orally administered oxytetracycline (OTC), fosfomycin (FOS), or amoxicillin (AMX) according to the following treatments: dissolved in soft water to fasted or non-fasted piglets, dissolved in hard water to fasted or non-fasted piglets, and mixed with feed. Minimum inhibitory concentration (MIC) values for susceptible strains of bacteria causing swine diseases were obtained from the database of European Committee on Antimicrobial Susceptibility Testing (EUCAST) for each antibiotic. Pharmacokinetic/pharmacodynamic (PK/PD) indices of therapeutic efficacy-drug exposure over the dosing interval (fAUC/MIC) for OTC and FOS; time that free drug concentration remains above MIC (%fT>MIC) for AMX-were calculated for each antibiotic/pathogen combination under each treatment. After all OTC and in-feed FOS and AMX treatments, the indices of therapeutic efficacy were below the target value for all the study microorganisms. When FOS or AMX were delivered dissolved in soft or hard water, the indices were above the target value over which therapeutic efficacy would be expected for Escherichia coli treated with FOS and, Glaesserella parasuis, Pasteurella multocida, and Actinobacillus pleuropneumoniae treated with AMX. The prandial state of piglets showed no influence on the indices of therapeutic efficacy. Pharmacokinetic profiles of broad-spectrum antibiotics, specifically the ability to achieve target concentrations, may be largely reduced due to drug interactions with components present in feed or water resulting in a discrepancy with PK/PD principles of prudent and responsible use of antibiotics.

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Feed and water components may interact with drugs and affect their dissolution and bioavailability. The impact of the vehicle of administration (feed and water) and the prandial condition of weaner piglets on amoxicillin´s oral bioavailability was evaluated. First, amoxicillin's in vitro dissolution and stability in purified, soft, and hard water, as well as release kinetics from feed in simulated gastric and intestinal media were assessed. Then, pharmacokinetic parameters and bioavailability were determined in fasted and fed pigs using soft water, hard water, or feed as vehicles of administration following a balanced incomplete block design. Amoxicillin showed similar dissolution profiles in soft and hard water, distinct from the dissolution profile obtained with purified water. Complete dissolution was only achieved in purified water, and merely reached 50% in soft or hard water. Once dissolved, antibiotic concentrations decreased by around 20% after 24 h in all solutions. Korsmeyer-Peppas model best described amoxicillin release from feed in simulated gastric and intestinal media. Feed considerably reduced antibiotic dissolution in both simulated media. In vivo, amoxicillin exhibited significantly higher bioavailability when delivered via water to fasted than to fed animals, while in-feed administration yielded the lowest values. All treatments showed a similar rate of drug absorption. In conclusion, we demonstrated that water and feed components, as well as feed present in gastrointestinal tract of piglets decrease amoxicillin´s oral bioavailability. Therefore, the use of oral amoxicillin as a broad-spectrum antibiotic to treat systemic infections in pigs should be thoroughly revised.

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OBJECTIVE: To describe citrullinemia profiles during the weaning transition and correlate citrulline production with stress and growth in a commercial pig farm. ANIMALS: 240 healthy piglets of homogenous weight, weaned from second and third parity sows, were selected at weaning and subjected to the farm's routine management practices in May to July 2020 and May to July 2021. PROCEDURES: Piglets were weighed at weaning, then 15 and 49 days later in order to calculate daily weight gain during the first 15 and 49 days after weaning. Blood samples were collected from each piglet to determine citrulline and cortisol profiles during the early postweaning period. RESULTS: Citrullinemia decreased dramatically during the first week postweaning and then increased progressively to reach preweaning values by 15 days postweaning. Citrulline production during the first 2 weeks postweaning was negatively correlated with cortisol production (r: -0.2949) and positively correlated with mean daily weight gain during the first 15 (ρ: 0.5450) and 49 (ρ: 0.6603) days postweaning. CLINICAL RELEVANCE: Citrullinemia profile of piglets during the early postweaning period showed a temporal negative impact of stress (assessed by plasmatic cortisol levels) on intestinal enterocytes' mass and function, which resulted in a lower average daily weight gain. We demonstrated that a single biomarker, plasmatic citrulline, is useful to describe intestinal metabolism during the early postweaning period and that the greater the citrulline production during the first days after weaning, the higher the weight gain during the entire postweaning period.

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The incorporation of natural essential oils to the pigs' diet in intensive production systems is a potential tool to improve gut health and prevent infections without using antibiotics. Nevertheless, different products, even containing the same compounds, coming from the same botanical species, may exert dissimilar biological effects due differences in the technological processes by which they are produced and preserved. For this reason, suitability of a given product based on natural extracts, intended for swine production must be thoroughly evaluated. In the present study, we assessed the effects of three additives containing oregano (Lippia origanoides) essential oil, alone or in combination with clover (Eugenia caryophillata) essential oil, with or without being microencapsulated, on gastrointestinal health and on some performance parameters in a commercial pig production farm. Recently weaned piglets were randomly divided in four groups, and basal diet or essential oil-supplemented diet (OCE; MOCE; MOE) was randomly assigned to each of the groups from weaning to finishing. Blood samples were collected at pre-established days after weaning. Intestinal sampling took place at 42 and 72 days of age. Pigs consuming the supplemented diets showed higher intestinal metabolic activity during the post-weaning period, decreasing the impact of weaning stress on enterocytes' metabolism. Intestinal barrier function was not affected in pigs consuming microencapsulated products. All treated groups showed improved intestinal architecture, increased digestive enzymes activity and caecal VFA concentrations. The incorporation of the dietary essential oils products brought beneficial effects on gastrointestinal health that were reflected in improved performance parameters.

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Feed and drinking water are the most frequently used vehicles for administration of antibiotics in intensive pig production. Interactions of drugs with feed and water components may affect dissolution and bioavailability. Therefore, antibiotic formulations should be tested in order to assure their suitability for oral use. In this study, an oral fosfomycin (FOS) formulation was evaluated considering dissolution in water (soft and hard), release kinetics from feed in simulated gastrointestinal fluids and bioavailability after oral administration blended into feed or dissolved in water (soft and hard), to fed and fasted piglets. FOS reached immediate dissolution in soft and hard water. The presence of feed significantly decreased antibiotic dissolution in simulated intestinal medium. Bioavailability was lower when feed was used as a vehicle for FOS administration than when the drug was dissolved in water (soft or hard). The fed or fasted condition of piglets did not affect bioavailability. Probably, FOS interactions with feed components alter its dissolution in the gastrointestinal tract, and only a fraction of the dose would be available for absorption. This information must be considered to support decisions on eligibility of antibiotic pharmaceutical formulations and the vehicle for their administration in order to pursue a responsible use of antibiotics.

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Water hardness is a critical factor that affects oxytetracycline dissolution by chelation with cations. These interactions may lead to impaired dosing and consequently decrease absorption. Moreover, feed present in gastrointestinal tract may interact with antibiotic and alter pharmacokinetic parameters. In the present study, dissolution profiles of an oxytetracycline veterinary formulation were assessed in purified, soft and hard water. Furthermore, oxytetracycline absolute bioavailability, after oral administration of the drug dissolved in soft or hard water, was evaluated in fed and fasted piglets. A maximum dissolution of 86% and 80% was obtained in soft and hard water, respectively, while in purified water dissolution was complete. Results from in vivo study reconfirmed oxytetracycline's very low oral bioavailability. The greatest values were attained when antibiotic was dissolved in soft water and in fasted animals. Statistically significant lower absolute bioavailability was achieved when hard water was used and/or animals were fed. Moreover, Cmax attained in all treatments was lower than MIC90 of most important swine pathogens. For these reasons, the oral use of OTC formulations, that have demonstrated low oral bioavailability, should be avoided to treat systemic diseases in pigs.

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Weaning is a challenging stage of pig farming. Animals undergo environmental, social and dietary changes leading to weaning stress syndrome. In order to compensate for the detrimental effects of weaning stress, antibiotics and natural extracts are used as feed additives, sometimes without fully understanding the interactions between them or even with low concentrations of mycotoxins that are frequently present in feed. The aim of this study was to evaluate the effect of fosfomycin (FOS), Cynara scolymus extract (CSE), deoxynivalenol (DON) and their combined administration on intestinal health of weaned piglets. The experiment was designed as a 2 × 2 × 2 factorial arrangement with 3 factors (FOS, CSE and DON treatments), 2 levels each (presence and absence) and 3 repeats. Weaned piglets (n = 24) were randomly divided in groups to receive the different treatments, namely DON administered in diet (50 µg/kg BW), FOS administered into the drinking water (30 mg/kg BW), CSE administered in diet (15 mg/kg BW) and all their combinations. After 15 d, the animals were euthanized and gastrointestinal tract samples were immediately taken to evaluate gastrointestinal pH, Enterobacteriaceae to lactic acid bacteria (E:L) ratio, volatile fatty acid (VFA) concentrations, disaccharidase (lactase, sucrase and maltase) activity, histology (intestinal absorptive area [IAA] and goblet cells count) and mucus ability to adhere pathogenic Escherichia coli. From our results, FOS and CSE treatments, individually or combined, produced a lower E:L ratio, an enhanced production of butyrate, increased disaccharidase activity (particularly maltase), and a greater IAA and goblet cells count along with an increase in pathogenic bacteria adherence to intestinal mucus. Deoxynivalenol did not show interactions with the other factors and its administration produced decreases on VFA, disaccharidase activity and goblet cells count. In conclusion, weaning piglets receiving diets containing FOS, CSE or both exhibited evident beneficial intestinal effects compared to animals receiving diets free from these compounds. On the contrary, the presence of DON at sub-toxic concentrations produced detrimental effects on intestinal health. The knowledge of the physiological and pathological gut changes produced by these compounds contributes to understand their potential productive consequences.

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The objective of this study was to document the effect of social ranking on the internal exposure of pigs to an antibiotic (fosfomycin) administered either in food or in drinking water. Signs of aggression were recorded at the feeder and drinker. The interindividual variability explained by the social rank was even greater when the test antibiotic was given in food despite the fact that the water consumption was less variable than the food intake. The range of plasma concentrations after administration of fosfomycin either in food or drinking water leads to a number of pigs in the treated group being exposed to rather low and highly variable concentrations of fosfomycin and not able to maintain adequate plasma concentrations above the typical minimum inhibitory concentration (MIC). Social rank clearly influences the level of exposure of pigs to fosfomycin both in food and drinking. However, its administration in drinking water is likely to be the best option to optimize antibiotic efficacy.

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