The PK/PD Interactions Of Tilmicosin Against Pasteurella Multocida In A Piglet Tissue-cage Model

Tilmicosin is a semi-synthetic macrolide antibiotic widely used in the treatment of pulmonary infectious diseases due to its special antibacterial potency and pharmacokinetic?PK?features.In this study,the in vitro antibacterial activity of tilmicosin against pasteurella multocida was investigated by establishing tissue-cage infection model in piglet.It was proposed that this model can be applied to optimize dosage regimens which can achieve clinical cure for diseases caused by pasteurella multocida,and minimize the opportunity of emergence of antimicrobial resistance.The minimum inhibitory concentration?MIC?of tilmicosin against a standard pasteurella multocida?D:7?was determined by micro-broth dilution technique according to Clinical and Laboratory Standard Institute?CLSI?reference methods.The value of MIC was 0.25?g/mL.We also tested the MIC of tilmicosin in tissue fluid,and it was the same as in broth medium.The tissue-cage infection model was established,and then piglets were given by gavage once a day for three days at four doses?30,40,50,60 mg/kg b.w.?.The tissue-cage fluid was collected prior to every drug administration,and at 1,3,6,9,12,24 h after every administration and 48,72 h after the last treatment.The concentration of tilmicosin in tissue-cage fluids were analyzed by high performance liquid chromatography-tandem mass spectrometry?HPLC-MS/MS?.The values of AUC_0-24h and the C_max after every administration ranged from 3.565±0.199 to 13.650±0.376?g·h/mL and from 0.200±0.031to 0.628±0.027?g/mL.The tissue-cage fluids collected at 24 h after every drug administration and 48 h and 72 h after the last administration were analyzed to count the reduction of bacteria(log₁₀CFU/mL)for several dosage regimens?30,40,50,60 mg/kg b.w.?,and the values were 1.14±0.14,2.82±0.10,3.39±0.11,3.52±0.15,respectively.However,the results showed that the AUC/MIC?R²=0.92?was the best corresponding parameter of three pharmacokinetics-pharmacodynamics?PK/PD?parameters which described the efficacy of tilmicosin against Pasteurella multocida?R²=0.90 for Cmax/MIC and R²=0.86for%T>MIC?by analyzing the sigmoid maximum effect(E_max)model.The sigmoid maximum effect(E_max)model also was used to estimate the values of AUC/MIC required for 1/3 log₁₀0 reduction,1/2 log₁₀ reduction and 3/4 log₁₀ reduction during 24 h against P.multocida and the values were 19.64,33.45 and 35.64 h,respectively.