Pharmacokinetic and Pharmacodynamic Evaluation of Marbofloxacin and PK/PD Modeling against Escherichia coli in Pigs

Abstract

The aim of this study was to evaluate the activity of marbofloxacin and establish the optimal dose regimens for decreasing the development of fluoroquinolone resistance in pigs against <i>Escherichia coli</i> with <i>ex vivo</i> pharmacokinetic/pharmacodynamic (PK/PD) modeling. The recommended dose (2 mg/kg body weight) of marbofloxacin was orally administered in healthy pigs. The ileum content and plasma were both collected for the determination of marbofloxacin. The main parameters of C_max, AUC_{0-24 h}, AUC, Ke, t_1/2ke, MRT and Cl_b were 11.28 μg/g, 46.15, 77.81 μg⋅h/g, 0.001 h^-1, 69.97 h, 52.45 h, 0.026 kg/h in ileum content, and 0.55 μg/ml, 8.15, 14.67 μg⋅h/ml, 0.023 h^-1, 30.67 h, 34.83 h, 0.14 L/h in plasma, respectively In total, 218 <i>E. coli</i> strains were isolated from most cities of China. The antibacterial activity <i>in vitro</i> and <i>ex vivo</i> of marbofloxacin against <i>E. coli</i> was determined following CLSI guidance. The MIC₉₀ of sensitive strains (142) was calculated as 2 μg/ml. The minimum inhibitory concentration (MIC) of HB197 was 2 and 4 μg/ml in broth and ileum fluids, respectively. <i>In vitro</i> mutant prevention concentration, growth and killing-time <i>in vitro</i> and <i>ex vivo</i> of marbofloxacin against selected HB197 were assayed for pharmacodynamic studies. According to the inhibitory sigmoid E_max modeling, the value of AUC_{0-24 h}/MIC produced in ileum content was achieved, and bacteriostatic, bactericidal activity, and elimination were calculated as 16.26, 23.54, and 27.18 h, respectively. Based on Monte Carlo simulations to obtain 90% target attainment rate, the optimal doses to achieve bacteriostatic, bactericidal, and elimination effects were 0.85, 1.22, and 1.41 mg/kg.bw for 50% target, respectively, and 0.92, 1.33, and 1.53 mg/kg.bw for 90% target, respectively, after oral administration. The results in this study provided a more optimized alternative for clinical use and demonstrated that the dosage 2 mg/kg of marbofloxacin by oral administration could have an effect on bactericidal activity against <i>E. coli</i>.