The PK/PD Interactions Of Danofloxacin Against Escherichia Coli In A Chicken Lung Tissue Model

Danofloxacin had the characteristics of strong bactericidal activity,broad antibacterial spectrum,and no cross-resistance with other antimicrobial drugs.It was often used clinically to treat diseases such as Escherichia coli infection,chicken mycoplasma infection,and cattle,swine pneumonia and porcine infectious pleuropneumonia.This study determined the in vivo antibacterial activity of danofloxacin against Escherichia coli,and established an Escherichia coli model of respiratory infection.PK/PD model in vivo was successfully established.It was proposed that this model which set up different doses will be used to provide reliable reference for designing dosage regimen.The minimum inhibitory concentration（MIC）of danofloxacin against an Escherichia coli clinical strain（XQ₃）was determined by micro-broth dilution technique according to Clinical and Laboratory Standard Institute（CLSI）reference methods.The value of MIC was0.0625μg/m L.The results of static time-killing curves with constant drug concentration showed that danofloxacin had obvious antibacterial activity against Escherichia coli when the concentration exceed 1 MIC.There was no obvious antibacterial effect compared with the growth control group when the concentration of danofloxacin was lower than 1/2 MIC.When Escherichia coli was exposed to 1～32 MIC drug concentration for 24 h,the maximum range of bacterial decline was 3.76～5.04 Log₁₀CFU/m L,and all of which reached the bactericidal effect.The results of bactericidal rate fitting showed that the bactericidal rate increases linearly with the increase of the concentration of danofloxacin within 0～1 h.The bactericidal rate at 0～1 h was significantly greater than that at 1～2 h,indicating that danofloxacin could rapidly produce antibacterial effect on Escherichia coli.In general,the antibacterial effect of danofloxacin increased with the concentration of drugs,the more obvious the bactericidal effect.The respiratory tract infection model was established,and then chickens were given by gavage once a day for three days at four doses（2.5,5,10,and 20 mg/kg b.w.）.The chickens were killed at 0.25,0.5,1,2,4,6,8,12,24,25,26,28,32,36,48,49,50,52,56,60 and 72h after the first administration of the drug.Lung tissue samples were collected and the concentration of danofloxacin were analyzed by high performance liquid chromatography（HPLC）.The Lung tissue samples collected at 24 h after every drug administration were analyzed to count the reduction of bacteria(log₁₀CFU/m L)for seven dosage regimens（1,2.5,5,7.5,10,15,and 20 mg/kg b.w.）.The results showed that achieved antibacterial effect when the values were 1.27～2.98 log₁₀CFU/m L in 1 to 10 doses;and maximum antibactericidal effect when the values were 3.14～3.51 log₁₀CFU/m L in 15 to 20 doses.The correlation coefficients between AUC_24h/MIC,C_max/MIC,%T>MIC and antibacterial effect were 0.90,0.89 and 0.81,respectively,by analyzing of the inhibitory Sigmoid E_max model.The results showed that AUC_24h/MIC was the best PK/PD parameter for predicting the antimicrobial activity of danofloxacin against Escherichia coli.The inhibitory Sigmoid E_max model also was used to estimate the values of AUC_24h/MIC required for 1/2 log₁₀ reduction and 1 log₁₀reduction,during 24 h against Escherichia coli the values were 29.96 h and 231.8 h,respectively.