Population Pharmacokinetics/Pharmacodynamics Modelling Of Enrofloxacin For The Three Major Trout Pathogens Aeromonas Salmonicida, Flavobacterium Psychrophilum And Yersinia Ruckeri
AQUACULTURE(2021)
摘要
Enrofloxacin is a fluoroquinolone antimicrobial agent used in freshwater rainbow trout against the main pathogenic bacteria Aeromonas salmonicida, Yersinia ruckeri and Flavobacterium psychrophilum. However, the current "standard" dose (10 mg/kg/day for 10 days) was based only on some old, rather limited experimental data, and needed to be re-assessed. Thus, a pharmacokinetic-pharmacodynamic (PKPD) approach was used by combining a population PK model with new epidemiological data (Minimum Inhibitory Concentrations (MIC)) of the three bacterial species to determine optimal enrofloxacin doses in rainbow trout.Ninety-six rainbow trout (half diploid, half triploid) were randomly assigned to four different groups and received oral (gavage) and then intravenous administration of enrofloxacin at four different doses (range 5-60 mg/kg). Individual blood samples were taken to develop a population PK model.Enrofloxacin should be considered as a long-acting drug in trout due to the observed long plasma half-life (>100 h), which is therefore inadequate with the "standard" dosage based on daily oral administrations. Moreover, the fish ploidy had an impact on the PK of enrofloxacin with a longer persistence of enrofloxacin in triploid individuals, which raises the question of the withdrawal period to apply. The absolute bioavailability of oral enrofloxacin was estimated at similar to 88%.For F. psychrophilum, the provisional epidemiological cut-off value (CONRI), calculated according to the NRI method, was equal to 0.03 mu g/mL. For A. salmonicida and Y. ruckeri, however, no clear bimodal distribution of MIC could be observed, and therefore no relevant CONRI could be obtained.According to our model, a single oral dose of similar to 5 mg/kg should provide sufficient exposure to treat the wild-type population of F. psychrophilum for 4 days, while complying with the PKPD breakpoints. Then, a maintenance dose of similar to 2.5 mg/kg could possibly be re-administered every 4 days. The absence of a CONRI did not allow to predict an optimal dose for the two other bacteria. As more than 70% of A. salmonicida isolates in our data set have an enrofloxacin MIC >= 0.25 mu g/mL, it seems that enrofloxacin should not be recommended against this bacterium.The PKPD approach allowed us to refine the dosing regimens in rainbow trout, for a more sustainable approach. These new dosing regimens have yet to be clinically confirmed.
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关键词
Enrofloxacin, Rainbow trout, Aeromonas salmonicida, Yersinia ruckeri, Flavobacterium psychrophilum, Population pharmacokinetics
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