Establishing The Medication Regimen Forprevention Of Drug Resistance Using Enrofloxacin Against Aeromonas Hydrophilain Freshwater Fish

Antibiotic resistance has become a serious global problem. In aquaculture, thetherapeutic options for the treatment of A. hydrophila infection were only limited toseveral antibiotics, which contributed for the fast-speed emergence of drug tolerance.With the widespread use of antibiotics in aquaculture, bacterial resistance has becomemore and more serious. We need to development a medication regimen to prevent drugresistant bacteria for rational use of antibiotics. The study utilized pharmacodynamics(PD) parameters (include mutant prevent concentration and mutant selectionwindow)and pharmacokinetic (PK), to establish a medication regimen for mutantprevention concentration of enrofloxacin against the haemorrhagic septicemia of grasscarp ctenopharyngodon idella and crucian carp Carassius auratus gibelio caused byAeromonas hydrophila.Pharmacokinetic/Pharmacodynamic-modeling(PK/PD-modeling), which was used to study the variation of the pharmacologicaleffects with time. The model is a scientific tool to help developers select a rationaldosage regimen, and is widely used to optimize dosage regimens of antibacterial.Thismethods described in this study also can use for drawing dose guidelines of otheranti-bacterial drugs to prevent the selection of drug-resistance.The pharmacodynamic parameters of enrofloxacin against the haemorrhagicsepticemia of grass carp caused by Aeromonas hydrophila (AH10) were: the minimalinhibitory concentration (MIC) was0.5μg/mL; The post antibiotic effect (PAE) ofenrofloxacin on the pathogenic bacterial strains were1.44±0.36h、1.57±0.09h、1.83±0.21h at2MIC、4MIC、8MIC, respectively; Mutant prevention concentration(MPC) was3.0μg/mL; Mutant selection window (MSW) was0.53.0μg/mL. The mainpharmacokinetic parameters of grass carp in serum at different administration doses (10mg/kg、20mg/kg、30mg/kg) were: the half-life of distribution (T1/2α) was6.098h、4.186h、4.348h, respectively; the half-life of elimination (T1/2β) was42.728h、46.757h、93.363h, respectively; the area under the drug concentration-time curve from the timezero to24h (AUC24) was25.838μg/mL·h、67.585μg/mL·h、90.486μg/mL·h, respectively;the total body clearance (CL) was0.155/kg·h、0.100/kg·h、0.067L/kg·h, respectively; thetime required to reach Cmax in the interval (Tmax) was1.0h、0.5h、0.5h, respectively; the maximum concentration in the interval (Cmax) was2.837μg/mL、5.685μg/mL、7.151μg/mL, respectively. Intergrated enrofloxacin concentration-time curves in serumof grass carp at different administration doses. The time of enrofloxacin concentration inserum of grass carp above MPC was0h at the dosage of10mg/kg;10h at the dosageof20mg/kg,24h at the dosage of30mg/kg, respectively; PK/PD parameters:AUC24/MIC and Cmax/MIC of enrofloxacin in serum were51.68and5.68at thedosage of10mg/kg, respectively;135.17and11.37at the dosage of20mg/kg,respectively;180.97and14.30at the dosage of30mg/kg, respectively.The pharmacodynamic parameters of enrofloxacin against the haemorrhagicsepticemia of crucian carp caused by Aeromonas hydrophila (CAAh01) were: theminimal inhibitory concentration (MIC) was0.125μg/mL; The post antibiotic effect(PAE) of enrofloxacin on the pathogenic bacterial strains were1.67±0.42h、2.03±0.17h、2.38±0.06h at2MIC、4MIC、8MIC, respectively; Mutant prevention concentration(MPC) was1.125μg/mL; Mutant selection window (MSW) was0.1251.125μg/mL.The main pharmacokinetic parameters of crucian carp in serum at differentadministration doses (5mg/kg、10mg/kg、20mg/kg) were: the half-life of distribution(T1/2α) was2.535h、4.539h、5.312h, respectively; the half-life of elimination (T1/2β) was51.256h、115.988h、131.639h, respectively; the area under the drug concentration-timecurve from the time zero to24h (AUC24) was17.152μg/mL·h、35.644μg/mL·h、53.284μg/mL·h, respectively; the total body clearance (CL) was0.487/kg·h、0.353/kg·h、0.188L/kg·h, respectively; the time required to reach Cmax in the interval (Tmax) was6.0h、2.0h、1.0h, respectively; the maximum concentration in the interval (Cmax) was1.822μg/mL、5.178μg/mL、6.540μg/mL, respectively. Intergrated enrofloxacinconcentration-time curves in serum of crucian carp at different administration doses.The time of enrofloxacin concentration in serum of crucian carp above MPC was5h atthe dosage of5mg/kg;9.5h at the dosage of10mg/kg,23h at the dosage of20mg/kg,respectively; PK/PD parameters: AUC24/MIC and Cmax/MIC of enrofloxacin in serumwere137.22and15.05at the dosage of5mg/kg, respectively;285.25and41.43at thedosage of10mg/kg, respectively;426.25and52.32at the dosage of20mg/kg,respectively.Comprehenive the time of drug concentration in serum> MPC more than(24-PAE)h and AUC24/MIC≧100or Cmax/MIC>8.We suggested that use enrofloxacin against the haemorrhagic septicemia of grass carp caused by Aeromonas hydrophil(AH10), the recommendations of the dosing regimen is30mg/kg, at the intervals of24h.From the concentration-time equations of enrofloxacin at a dosage of30mg/kg inmuscle, the proposed withdrawal time in crucian carp should not be less than32d. Anduse enrofloxacin against the haemorrhagic septicemia of grass carp caused byAeromonas hydrophil (CAAh01), the recommendations of the dosing regimen is20mg/kg, at the intervals of24h. From the concentration-time equations of enrofloxacin ata dosage of20mg/kg in muscle, the proposed withdrawal time in crucian carp shouldnot be less than25d. The research also proved that the same drug in different aquaticmetabolism of the body have different rules, for different pathogenic strains havedifferent efficacy. Therefore, we should consideration of the applicable varieties ofdrugs and the efficacy of the pathogen to develop a reasonable regimen.