In Vivo Pharmacokinetic/Pharmacodynamic(Pk/PD) Profile Of Danofloxacin Against Salmonella Typhimurium In Rabbits

Danofloxacin is a synthetic fluoroquinolone developed solely for use in veterinary medicine.It possesses a wide spectrum of antimicrobial activity which includes mycoplasmas,most Gram-negative and some Gram-positive bacteria.Danofloxacin has been approved to use in cattle,pig,rabbit and chicken in many countries.To date,the research of danofloxacin has been reported in pigs,acipenser schrenckiis and chickens,but the researches in small mammals are absent.The aims of this investigation were:(1)to estabilish the serum concentration-time profile and to derive PK date for danofloxacin in rabbits after oral administration at the doses of 1,10 and 30 mg/kg;(2)to determine MIC,MBC of danofloxacin against Salmonella typhimurium in LB broth and serum of rabbit,to determine MPC,in vitro time kill curve in LB medium;(3)to investigate the in vivo antibacterial activity of danofloxacin in blood,lung,spleen and liver against one clinical isolates of Salmonella typhimurium;and(4)to model PK and PD date for danofloxacin as a basis for dosage prediction.The results of in virto pharmacodymics of danofloxacin against Salmonella typhimurium showed that the MIC is 0.0625 ?g/mL in LB broth and serum of rabbit,the MBC are 0.125?g/mL(2-fold MIC)in both medium,and the MPC is 0.5?g/mL(8-fold MIC).The concentration-kill curve of danofloxacin showed that the antibacterial effect of danofloxacin was intensified with the concentration of danofloxacin,it shows that danofloxacin is concentration-dependent drug.The Salmonella typhimurium isolated from the clinical case was used to establish the disease model.0.5mL 108CFU/mL bacteria solution of Salmonella typhimurium was injected to healthy rabbits via ear vein,followed with the same amount bacteria 12h later.The bacterium capacity in body can be remained at 106CFU/mL.Danofloxacin was administrated to the infected rabbits orally at low,middle and high dose(1,10,30 mg/kg b.w.).The plasma concentration-time data of the danofloxacin were analyzed with non-compartmental model using WinNonlin software.The pharmacokinetics parameters of T1/2p,AUC,Cmax were 15.30±6.09h,2.37±0.64 ?g h/mL and 0.18±0.04 ?g/mL;14.01±9.34 h,14.74±4.94 ?g·h/mL,1.80±0.98?g/mL;11.38±3.16h,36.07±3.65?g·h/mL,3.49±0.91?g/mL respectivety in low,middle and high dose group.The Tmax in the three groups are 1.60±0.55h,1.80±1.30h and 1.40±0.55h respectively.A significant correlation between doses,and AUC24h or Cmax were observed(R2=0.9935 and 0.9592 foe doses:AUC24h and doses:Cmax,respectively).The bacterium capacity was measured pre-and post-treatment by viable count in rabbits after danofloxacin administration at dose of 30,20,15,10,7.5,5,2.5,1,and Omglkg.The relationships between AUC24h/MIC and the change of number of Salmonella typhimurium pre-and post-treatment were fitted using the Sigmoid E-ax model.The AUC24/MIC correlated well with the in vivo antibacterial effectiveness at diffrent organs.R2 were 0.8971,0.9186,0.9581,and 0.8708 in blood,liver,spleen and lung,respectively.AUC24h/MIC ratios for 3×Logio reductions in bacterial count from the initial inoculum count were 60.65,177.14,108.32 and 114.33 in blood,liver,spleen and lung,respectively.The results indicated that the selection of target organ in PD evaluation is very important for PK/PD modeling and parameter calculation.