| Cefquinome is a fourth-generation cephalosporin applied as veterinary medicine solely Cefquinome is stable to common plasmid-and chromosome-mediated beta-lactamases exhibiting antibacterial activity against a broad spectrum of Gram-positive and Gram-negative bacterial species.Cefquinome is used by the intramammary route in lactating cows for the treatment of clinical mastitis caused by cefquinome sensitive organisms,like Streptococcus uberis,Streptococus dysgalactiae,Staphylococcus aureus and Escherichia coli,with a treatment regimen of three infusions of 75 mg cefquinome per affected quarter immediately after each of three successive milkings.This work aimed to study the pharmacokinetic/pharmacodynamics(PK/PD)characteristics of cefquinome following an intramammary administration,achieve the target magnitude of PK/PD index,and asscess clinical recommended regimens using PK/PD modeling and Monte Carlo SimulationPK profiles of cefquinome in both plasma and mammary gland tissue had been evaluated following intramammary infusion of a single dose cefquinome of 12.5,25,50,100,200,400,and 800 ?g/gland.Blood and mammary gland samples were harvested at the following time points:5 min,10 min,15min,0.5 h,0.75 h,1 h,2 h,3 h,4 h,6 h,8 h,12 h,and 24 h after administration.The drug concentrations were determined using high-performance liquid chromatography(HPLC)method and PK porfiles were analyzed by WinNonlin 5.2 software Plasma PK were calculated using first-order absorbtion of one-compartment model with lowest AIC value.After administration,cefquinome was rapidly absorbed in blood and then elimited fast,with half-life of absorbtion T1/2?=0.08±0.02 h,time to peak concentration TmaX=0.22±0.03 h,and half-life of elimination T1/2?=0.4±0.06 h,respectively.Profiles of PK in gland tissue were analyzed via non-compartmental and one-compartmental models,respectively.Elimination half-life t1/2? MG of about 12 h,indicating the PK characteristic in glandular tissue was eliminated exponentially,or following first-order kinetics.Based on PK study in both blood and mammary gland,cefquinome can be absorbed in blood quickly,but most drugs were distributed in mammary gland for a long duration,which can develop the potential of cefquinome against mastitisIn this work,only S.aureus and E.coli has been detected in clinical mastitis cases,so mouse mastitis model induced by these two pathogens has been established.When the dose level was exceeding 400 mg/gland and with 8 or 12 h dosing intervals at the same time,antibacterial activity of 1.5-logCFU/gland bacterial reductions was observed in treatment of S.aureus mastitis.On the contrary,A 7-log CFU/gland killing activity which almost eliminated the infection was achieved using 400 ?g/gland dosing regimens in E.coli mastitisThe antimicrobial effect of cefquinome was analyzed applying the Sigmoid Emax model of inhibitory effects against S.aureus mastitis and E.coli mastitis,respectively.The corresponding target PK/PD parameter of AUC0-24/MIC was 16571.55 and 13492.40 h for S.aureus and E.coli mastitis respectively,which was extrapolated to cows applying the Monte Carlo simulation.Consequently,administration of twice or three times infusions of cefquinome into bovine mammary glands with 75 mg per quarter can achieve a 100%cure rate against E.coli mastitis.However,for S.aureus mastitis,three times administration may only achieve a 76.67%cure rateTo sum up,this study is the first time ever compare the PK profiles in both plasma and mammary gland tissue,in which influence of blood-milk barrier on cefquinome distribution has been highlighted.Following an intramammary infusion of cefquinome,PK/PD modeling has been integrated in mouse model of S.aureus and E.coli mastitis,respectively,and the target PK/PD magnitude has been calculated.In addition,clinical recommended dosing regimens of cefquinome against bovine mastitis has been assessed based on data of drug susceptibility distribution,PK/PD characteristics of cefquinome in bovine,and the PK/PD target value. |
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