In Vivo Pharmacokinetics/Pharmacodynamics Modeling Of Enrofloxacin Against Escherichia Coli In Broiler Chicken

Enrofloxacin is the third generation of fluoroquinolone developed solely for veterinary usage.It possesses a wide spectrum of antimicrobial activity which includes mycoplasmas,most Gram-negative and some Gram-positive bacteria.At present,many countries have approved the use of animals such as cattle,pigs and chickens to treat infections caused by bacteria or myco-plasma.Though pharmacokinetics and in vitro or in vivo pharmacodynamic studies of enrofloxacin are reported in many kinds of animals such as pigs,chickens and sturgeons,in vivo pharmacodynamic data is sparse.The purpose of this study was to establish an in vivo pharmacokinetic/pharmacodynamics(PK/PD)model of enrofloxacin against E.coli in order to optimize the efficacy of enrofloxacin and decrease the emergence of drug-resistant bacteria.The minimal inhibitory concentration(MIC),minimal bacteria concentration(MBC),and mutant prevention concentration(MPC)of enrofloxacin against E.coli 078 was determined.Seven-day old broiler chickens was experimentally infected with E.coli 078.The PKs of enrofloxacin after oral administration at dose of 1,10,20 mg/kg body weight(B.W.)in the infected broilers was evaluated with high-performance liquid chromatography(HPLC)method.The in vivo pharmacodynamics(PDs)of enrofloxacin against E.coli 078 in dif-ferent organs were evaluated after nine different dosage administration for three successive days.Both the MIC and MBC of enrofloxacin against E.coli 078 is 0.5 μ,g/mL.The MIC of ciprofloxa-cin against E.coli is 0.5 μg/mL and the MBC of ciprofloxacin against E.coli is 1 μg/mL,the MPC of enrofloxacin against E.coli is 3.2 μg/mL.The peak concentration(Cmax),and the area under the concentrations-time curve from 0 to 24 h(AUC0-24)of enrofloxacin and ciprofloxacin in-creased in a dose-dependent manner from 1 to 20 mg/kg.The relationship between AUC0-24/MIC of enrofloxacin or the combination of enrofloxaicn and ciprofloxacin,and bacterial loading reduction in each organ were simulated with Sigmoid Emax model.The AUC0-24/MIC correlated well with the in vivo antibacterial effectiveness at different organs with r2 of 0.90,0.85,and 0.91 in blood,liver,and lung,respectively.The results showed that the in vivo effectiveness of enrofloxacin against E.coli in different target organs varied with Emax ranging from-4.4 to-5.8 Logio cfu/mL or cfu/g.Both the surrogate AUC0-24/MIC of enrofloxacin or AUC0-24/MIC of the combination of enrofloxaicn and ciproflox-aicn correlated well with effectiveness in each organ.The AUC0-24/MIC ratio of the combination of enrofloxaicn and ciprofloxaicn producing bactericidal,and elimination effect were 21.29,32.13 in blood;41.68,and 58.52 in liver;and 27.65,46.22 in lung respectively.The results indicated that,the in vivo effectiveness of enrofloxacin against E.coli in different or-gans was not identical,after the same dosage administration.To describe the magnitude of PK/PD parameter exactly,bacterial loading reduction in different organs as PD endpoints should be eval-uated and compared in PK/PD modeling and the selection of target organ for PDs evaluation is critical in rational dosage recommendation.