Resistant cutoff values and optimal scheme establishments for florfenicol against Escherichia coli with PK-PD modeling analysis in pigs.

Abstract

Florfenicol, a structural analog of thiamphenicol, has broad-spectrum antibacterial activity against gram-negative and gram-positive bacteria. This study was conducted to investigate the epidemiological, pharmacokinetic-pharmacodynamic cutoff, and the optimal scheme of florfenicol against Escherichia coli (E.coli) with PK-PD integrated model in the target infectious tissue. 220 E.coli strains were selected to detect the susceptibility to florfenicol, and a virulent strain P190, whose minimum inhibitory concentration (MIC) was similar to the MIC50 (8μg/ml), was analyzed for PD study in LB and ileum fluid. The MIC of P190 in the ileum fluid was 0.25 times lower than LB. The ratios of MBC/MIC were four both in the ileum and LB. The characteristics of time-killing curves also coincided with the MBC determination. The recommended dosages (30mg/kg·body weight) were orally administrated in healthy pigs, and both plasma and ileum fluid were collected for PK study. The main pharmacokinetics (PK) parameters including AUC24hr , AUC0-∞ , Tmax , T1/2 , Cmax , CLb, and Ke were 49.83, 52.33μg*h/ml, 1.32, 10.58hr, 9.12μg/ml, 0.50L/hr*kg, 0.24hr-1 and 134.45, 138.71μg*hr/ml, 2.05, 13.01hr, 16.57μg/ml, 0.18L/hr*kg, 0.14hr-1 in the serum and ileum fluid, respectively. The optimum doses for bacteriostatic, bactericidal, and elimination activities were 29.81, 34.88, and 36.52mg/kg for 50% target and 33.95, 39.79, and 42.55mg/kg for 90% target, respectively. The final sensitive breakpoint was defined as 16μg/ml. The current data presented provide the optimal regimens (39.79mg/kg) and susceptible breakpoint (16μg/ml) for clinical use, but these predicted data should be validated in the clinical practice.