Antimicrobial resistance (AMR) is a global health threat, and antimicrobial usage and AMR in animal production is one of its contributing sources. Poultry is one of the most widespread types of meat consumed worldwide. Poultry flocks are often raised under intensive conditions using large amounts of antimicrobials to prevent and treat disease, as well as for growth promtoion. AMR in poultry pathogens may result in treatment failure, leading to economic losses, but also be a source of resistance bacteria/genes (including zoonotic bacteria) that may represent a risk to human health. Here we reviewed data on antimicrobial resistance in 12 poultry pathogens (avian pathogenic Escherichia coli, APEC), Salmonella Pullorum/Gallinarum, Pasteurella multocida, Avibacterium paragallinarum, Gallibacterium anatis, Ornitobacterium rhinotracheale (ORT), Bordetella avium, Clostridium perfringens, Mycoplasma spp., Erysipelothrix rhusiopathiae, and Riemerella anatipestifer). A number of studies have demonstrated increases in resistance over time for Salmonella Pullorum/Gallinarum, Mycoplasma gallisepticum, and Gallibacterium anatis. Among Enterobacteriaceae, APEC isolates had median resistance levels over >80%for ampicillin, amoxicillin, tetracycline across studies; these resistance levels were considerably higher compared with S. Pullorum/Gallinarum. Among the Gram-negative, non-Enterobacteriaceae pathogens, ORT had the highest levels of phenotypic resistance with median levels of AMR against cotrimoxazole, enrofloxacin, gentamicin, amoxicillin and ceftiofur all exceeding 50%. In contrast, levels of resistance among P. multocida isolates were less than 20% for all antimicrobials. The study highlights considerable disparities in methodologies, as well as in criteria for phenotypic antimicrobial susceptibility testing and result interpretation. It is necessary to increase efforts to harmonize testing practices, and to promote free access to data on AMR in order to improve treatment guidelines as well as to monitor the evolution of AMR in poultry bacterial pathogens.

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Antimicrobial Resistance in Bacterial Poultry Pathogens: A Review

In vitro to in vivo extrapolation for high throughput prioritization and decision making.

Toxicokinetic models and related tools in environmental risk assessment of chemicals.

An insight into medicinal chemistry of anticancer quinoxalines

This review provides a tutorial for individuals interested in quantitative veterinary pharmacology and toxicology and offers a basis for establishing guidelines for physiologically based pharmacokinetic (PBPK) model development and application in veterinary medicine. This is important as the application of PBPK modeling in veterinary medicine has evolved over the past two decades. PBPK models can be used to predict drug tissue residues and withdrawal times in food-producing animals, to estimate chemical concentrations at the site of action and target organ toxicity to aid risk assessment of environmental contaminants and/or drugs in both domestic animals and wildlife, as well as to help design therapeutic regimens for veterinary drugs. This review provides a comprehensive summary of PBPK modeling principles, model development methodology, and the current applications in veterinary medicine, with a focus on predictions of drug tissue residues and withdrawal times in food-producing animals. The advantages and disadvantages of PBPK modeling compared to other pharmacokinetic modeling approaches (i.e., classical compartmental/noncompartmental modeling, nonlinear mixed-effects modeling, and interspecies allometric scaling) are further presented. The review finally discusses contemporary challenges and our perspectives on model documentation, evaluation criteria, quality improvement, and offers solutions to increase model acceptance and applications in veterinary pharmacology and toxicology.

Mathematical modeling and simulation in animal health - Part II: principles, methods, applications, and value of physiologically based pharmacokinetic modeling in veterinary medicine and food safety assessment.

Yang, F., Sun, N., Sun, Y. X., Shan, Q., Zhao, H. Y., Zeng, D. P., Zeng, Z. L. A physiologically based pharmacokinetics model for florfenicol in crucian carp and oral-to-intramuscular extrapolation. J. vet. Pharmacol. Therap. 36, 192–200.



In this study, an oral physiologically based pharmacokinetics (PBPK) model was developed for florfenicol in crucian carp (Carassius auratus). Subsequently, oral-to-intramuscular extrapolation was performed and the two models were used to predict florfenicol concentrations in the edible tissues of crucian carp. The oral model gave good predictions in most tissues, except for kidney and liver in which the florfenicol concentrations were underestimated at the later time points. In contrast, using the intramuscular model, the concentrations in the kidney were overestimated at the later time points. Both models had the best predictive ability in the main edible tissue, the muscle. The oral model also accurately predicted the florfenicol concentrations in the muscle after multiple doses. The present study demonstrated the feasibility of predicting florfenicol concentrations in the edible tissues of crucian carp using a route-to-route extrapolation method.

A physiologically based pharmacokinetics model for florfenicol in crucian carp and oral-to-intramuscular extrapolation.

Pharmacokinetics of mequindox and its metabolites in rats after intravenous and oral administration.

In this study, a physiologically based pharmacokinetics (PBPK) model was firstly developed for danofloxacin in healthy broiler chickens after a single oral administration at 5 mg/kg bw. Then, the model extrapolation from healthy chickens to those infected with Pasteurella multocidaones was performed. The healthy model was validated through a comparison of predicted and previously published concentrations, which indicated that the healthy PBPK model had good predictive ability in plasma, lung, muscle, liver, and kidney, especially at the later sampling time points. Multiple dosing of administration was incorporated into the healthy and infected models. In addition, a Monte Carlo simulation (MCS) included 1000 iterations was further incorporated into both models to predict the withdrawal times of danofloxacin in healthy and infected chickens, which were estimated to be 3 and 2 days, respectively.

Estimating danofloxacin withdrawal time in broiler chickens based on physiologically based pharmacokinetics modeling.

Molecular characterization of the antimicrobial resistance of Riemerella anatipestifer isolated from ducks.

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Papers

A physiologically based pharmacokinetics model for florfenicol in crucian carp and oral-to-intramuscular extrapolation.

Pharmacokinetics of mequindox and its metabolites in rats after intravenous and oral administration.

Estimating danofloxacin withdrawal time in broiler chickens based on physiologically based pharmacokinetics modeling.

Molecular characterization of the antimicrobial resistance of Riemerella anatipestifer isolated from ducks.