| Swine dysentery and Avian colibacilosis are serious infectious diseases in intensified raising farms.They caused great economic losses in farming in recent years.Cyadox,a new quinoxaline antimicrobial agent for animal,has wide antibacterial spectrum and great potential in the treatment of Swine dysentery and Avian colibacilosis according to antibacterial effect that have been reported.This subject intends to study the the prevention and treatment of cyadox on Swine dysentery and Avian colibacilosis,predict and develop a reasonable treatment plan through PK-PD model.The clinical efficacy of prevention and treatment of cyadox against common diseases in livestock and poultry will be illuminated.Cyadox is expected to be a substitute for quinoxaline drugs and that will be very significant for animal husbandry.1 Pharmacokinetics of cyadox in swine ileum content12 healthy piglets weighing about 15 kg were randomly divided into two groups,and then the T cannula were installed in ileum of 12 piglets.6 piglets in experiment group were infected with B.hyodysenteriae B204 and 6 piglets in control group kept healthy.Both of two groups were given 30 mg/kg.bw cyadox by oral administration only once a day.Ileum contents were collected at 0.5?0.75?1?2?3?4?6?8?12?24 h after administration by T cannula.The concentration of cyadox in ileum contents were determined by High Performance Liquid Chromatography(HPLC).The PK data of cyadox were analyzed by Winnonlin software.The results showed that in healthy piglets Cmax was 34.55 ?g/mL,AUC was 123.56 h·?g/mL,T1/2 was 3.25 h,CL-F was 0.24 L/h/kg,MRT was 4.20 h,and in infected piglets Cmax was 33.36 ?g/mL,AUC was 120.27 h·?g/mL,T1/2was 3.01 h,CL-F was 0.25 L/h/kg,MRT was 4.08 h.2 Pharmacokinetics of cyadox in broiler ileum content120 broilers weighing about 1.2 kg were selected and divided into two groups.Experiment group was infected with E.coli AH245 and control group kept healthy.Both of two groups were given 30 mg/kg.bw cyadox by oral administration only once a day.Ileum contents were collected at 0.5?1?2?3?4?6?8?12?24 h after administration by killing broilers.The concentration of cyadox in ileum contents were determined by HPLC.The PK data of cyadox were analyzed by Winnonlin software.The results showed that in healthy broilers Tmax was 1.15 h,Cmax was 157.9 ?g/mL,AUC was 392.83 h·?g/mL,T>mic was 7.01 h,T1/2 was 0.65 h,CL-F was 0.076 L/h/kg,and in infected broilers Tmax was 1.31 h,Cmax was 111.12 ?g/mL,AUC was 322.52 h·?g/mL,T>MIc was 7.65 h,T1/2 was 0.74 h,CL-F was 0.093 L/h/kg.3 Pharmacodynamics study of cyadoxThe minimal inhibitory concentration(MIC)and minimal bactericidal concentration(MBC)of cyadox against E.coli AH245 and B.hyodysenteriae B204 were determined in anaerobic condition by Broth dilution method.The results showed that MIC of cyadox against E.coli AH245 was 2 ?g/mL,MBC was 8 ?g/mL.MIC of cyadox against B.hyodysenteriae B204 was 0.0625 ?g/mL,MBC was 0.25 ?g/mL.The mutant prevention concentration(MPC)of cyadox was evaluated by agar culture method.The MPC of cyadox against E.coli AH 245 was 128 ?g/mL,and then the MSW was 2?128?g/mL.The MPC of cyadox against B.hyodysenteriae B204 was 0.25 ?g/mL,and then the MSW was 0.0625?0.25 ?g/mL.According to MIC values,prepared a series concentration cyadox broth of 0 MIC?1/2 MIC?1 MIC?2 MIC?4 MIC?8 MIC?16 MIC?32 MIC to get the vitro bactericidal curve.The results showed that cyadox was typical concentration-dependent according to the bacterical killing profile.The antibacterial activity of cyadox against AH245 is increasing with the concentration raising.Bacteria had been completely killed at 4 MIC,but bateria recovered growthing at 18 h at 1MIC.The antibacterial activity of cyadox against B.hyodysenteriae B204 is increasing with the concentration raising.Bacteria had been completely killed at 8 MIC.The growthing of bacterial was inhibited at 1?2 MIC.Filter the ileum contents collected at different time points in pharmacokinetic experiments with sterile membrane,and then inoculated with AH245 or B204 culture,count the number of bacteria with coated plate method at different time points and plot the ex-vivo bactericidal curve.Ex-vivo inhibition curve of cyadox showed that cyadox was concentration-dependent in broiler cileum contents and pig ileum contents,that were in accordance with the bactericidal effect in-vitro.4 Fitting PK-PD model and dosage regimenFor PK-PD modeling,AUC24h/MIC data obtained after 24h incubation from ex-vivo bacterial growth inhibition curves were modelled to the sigmoidal Emax equation.We found that cyadox was a concentration-dependent antibiotic according to killing curve both in-vitro and ex-vivo.AUG24h/MIC was selected as parameter to fit Sigmoid Emax.The Hill equation of disease model in brolier as follow:E = 2.698.63*C1.97/200.791.97+C1.97.The value of ex-vivo AUC/MIC were 134.31,280.74,376.40 respectively when E=0,-3,-4(inhibition,sterilization,eradication).Connected with the administration equation:Dose=(AUC24/MIC)×MIC×CL/fu×F,the dose were 24.98 mg/kg/d,52.22 mg/kg/d,70.01 mg/kg/d,that can be used to control E.coli in broilers.Hill equation of disease model in pig as follow:E=2.43-7.87*C3.71/487.393.71+C3.71.The value of ex-vivo AUC/MIC were 360.37,569.81,695.19 respectively when E=0,-3,-4(inhibition,sterilization,eradication).Connected with the administration equation,the dose were 5.85 mg/kg/d,8.83 mg/kg/d,11.35 mg/kg/d,that can be used to control Swine dysentery.5 Model validationIn order to verify the clinical efficacy of the resulting dosage,the broilers were infected with E.coli AH 245,fed with cyadox at 250 ppm.The result showed that the protection rate in experiment group was 88.89%.The piglets were infected with B.hyodysenteriae B204,fed with cyadox at 160 ppm.The result showed that the protection rate in experiment group was 83.33%.In summary,this study illustrates the characteristics of cyadox against E.coli AH 245 and B.hyodysenteriae B204,and pharmacokinetic characteristics in digestive tract of broilers and pigs.Reasonable dosage regimen was designed through PK-PD model,that gave scientific guidance for the reasonable use of cyadox in clinical application. |
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