The PK/PD Interactions Of Cefquinome Against Pasteurella Multocidain A Piglet Tissue-cage Model

The in vivo PK/PD infection of cefquinome against Pasteurella multocida was investigated by using a piglet tissue-cage infection model.It is recommended that this model can be applied to optimize dosage regimens which treat diseases caused byPasteurella multocida,on the basis of achieving cure and minimizing the opportunity of the emergence of antimicrobial resistance.The minimum inhibitory concentration?MIC?of cefq uinome against a standard Pasteurella multocida?D:7?wasdetermined by micro-broth dilution technique,according to CLSI reference methods.And the value of MIC was 0.016?g/ml.Inoculum of Pasteurella multocida was added into Tryptic Soy Broth?final concentration approximately 10⁸CFU/mL?and incubated for 2h at 37?.After the antimicrobial was removed by ten-fold dilution,post-antibiotic effect?PAE?of cefquinome against Pasteurella multocida was tested and the value was 0.07h.Pasteurella multocida was added into TSB which included antimicrobial?final concentration abo ut 0.1×MIC,0.2×MIC and 0.3×MIC?to test the post-antibiotic sub-minimum inhibitory concentrations?PA-SMEs?and the values were1.71h,4.17h and4.78h.The tissue-cage infection model was established,and then the animals were injected intramuscularly once a day for three days at six doses?0.2,0.4,0.8,1,2,4mg/kg b.w.?.The tissue-cage fluid was collected prior to every drug administration,and at 1,3,6,9,12,24h after every administration and 48,72h after the last treatment.Theconcentration of cefquinome intissue-cage fluids were analyzed by high performance liquid chromatography-tandem mass spectrometry?HPLC-MS/MS?,the concentration-time data of cefquinome were analyzed using the non-compartmental method of the WinNonlin software 5.2.The values of AUC_0-24and the C_maxafter every administration ranged from0.313±0.125 to 5.329±1.884?g·h/mL and from0.026±0.004 to 0.457±0.180?g/mL.However,the results showed that the%T>MIC?R²=0.87?was the best corresponding index of three pharmacokinetics-pharmacodynamics?PK/PD?indexes which described the effectiveness of cefq uinome againstPasteurella multocida(R²=0.56 for AUC/MIC and R²=0.68 for C_max/MIC)by nonlinear regression analysis.The tissue-cage fluids were collected at 24h after every drug administration and 48hand 72h after the last administration to count the reduction of bacteria(log₁₀CFU/mL)forseveral dosage regimens?0.2,0.4,0.8,1,2and 4mg/kg?,and the values were1.49±0.03,2.00±0.14,2.87±0.57,3.66±0.22,3.67±0.35 and4.78±0.72,respectively.A inhibitory form of sigmoid maximum effect(E_max)model was used to estimate the values of%T>MIC required for 1/3-log₁₀reduction,1/2-log₁₀ reduction and 1-log₁₀ reduction during 24h against P.multocidaand the values were 8.13%,19.05%and 69.18%,respectively.