PK/PD integration and pharmacodynamic cutoff of cefquinome against cow mastitis due to Escherichia coli.

Abstract

Cefquinome is the fourth generation of cephalosporin approved solely in animal usage. In order to slow down the resistance development of E.coli to cefquinome, and to protect and maintain the effectiveness of cefquinome, an ex vivo PK/PD modeling of cefquinome against E.coli in cows after intramammary infusion administration was conducted. The epidemiologic cutoff (ECOFF) and pharmacodynamic cutoff (COPD) of cefquinome against E.coli in lactation cows after intramammary infusion administration were recommended. The MICs of cefquinome against 1073clinical E.coli isolates ranged from 0.015 to >64μg/ml, and the ECOFF was defined as 0.125μg/ml. The pharmacokinetic results showed that cefquinome maintained high concentration in milk for a long period with the T1/2β of 10.60h after intramammary infusion in dairy cows. The drug concentration in skimmed milk was still as high as 0.15mg/ml after 48h. Cefquinome displayed bacterial killing effect at 2× MIC with the initial inoculum of 106 cfu/ml in vitro; however, the same effect was attained with a concentration as high as 32× MIC with the initial inoculum of 108 cfu/ml both in artificial medium and in skimmed milk. The initial inoculum is an important factor on time-killing curve accounting for weakened killing pattern of cefquinome. The AUC0-24h /MIC index correlated well with ex vivo efficacy. The AUC0-24h /MIC values for bactericidal effect were 50, 016, and 67,644, respectively, for initial inoculum of 106 and 108 cfu/ml, indicating the bacterial loading or the severity of infection would infect the PK/PD modeling results. The ex vivo PK/PD-based population dose prediction indicated a target attainment rate (TAR) at the existing daily dose (75mg/udder) of 84.77% against E.coli. Thus, it was recommended as rational dosage. The COPD of cefquinome against E.coli was determined as 8μg/ml at the dose of 75mg/udder. The derived ECOFF, COPD, together with ex vivo PK/PD-based population dose prediction served as important steps in the establishment of optimum dose regimen and provided a useful interpretative criterion to categorize the antimicrobial susceptibility testing results of cefquinome.