AUTHOR=Jiang Li-jie , Xiao Xia , Yan Ke-xu , Deng Tian , Wang Zhi-qiang 

TITLE=Ex Vivo Pharmacokinetics and Pharmacodynamics Modeling and Optimal Regimens Evaluation of Cefquinome Against Bovine Mastitis Caused by Staphylococcus aureus

JOURNAL=Frontiers in Veterinary Science

VOLUME=9

YEAR=2022

URL=https://www.frontiersin.org/journals/veterinary-science/articles/10.3389/fvets.2022.837882

DOI=10.3389/fvets.2022.837882

ISSN=2297-1769

ABSTRACT=<p>Cefquinome, the fourth-generation cephalosporin applied solely for veterinary medicine, is commonly used for bovine mastitis caused by <italic>Staphylococcus aureus</italic>. The present study aims to establish an optimal dose and provide a PK/PD Cutoff value (CO<sub>PD</sub>) for cefquinome against <italic>S. aureus</italic> based on <italic>ex vivo</italic> pharmacokinetics and pharmacodynamics (PK/PD) integration. This study investigated the pharmacokinetics (PK) of cefquinome when administered as three consecutive intramammary (IMM) doses of cefquinome in three healthy dairy cows at 75 mg/gland. Drug concentration was determined by HPLC-MS/MS assay. The <italic>ex vivo</italic> pharmacodynamics (PD) of cefquinome were evaluated by using a milk sample from a PK experiment. The relationship between the AUC/ MIC of cefquinome and bacterial loading reduction was simulated using a Sigmoid Emax model. The cefquinome concentration in milk attained a maximum level of 1.55 ± 0.21 mg/mL at 1.8 h after the third administration. The mean value of the area under the concentration-time curve (AUC<sub>0−24</sub>) was 26.12 ± 2.42 mg·h/mL after the third administration. The elimination half-life was 10.6 h. For PD profile, the MICs of cefquinome in milk were 2–4 times higher than those in the broth. <italic>In vitro</italic> time-killing curve shows that initial bacterial concentration has a huge impact on antibacterial effect on three strains. The antibacterial effect was weakened with the initial bacterial concentration increasing from 10<sup>6</sup> to 10<sup>8</sup> CFU/mL. The AUC<sub>0−24h</sub>/MIC index correlated well with <italic>ex vivo</italic> efficacy both for the initial inoculum of 10<sup>6</sup> CFU/mL and 10<sup>8</sup> CFU/mL (<italic>R</italic><sup>2</sup> &gt; 0.84). According to the inhibitory sigmoid E<sub>max</sub> model analysis, the PK/PD surrogate (AUC<sub>0−24</sub>/MIC) values were 8,638, 1,397, and 3,851 for bactericidal effect (<italic>E</italic> = −3) with an initial inoculum of 10<sup>6</sup> CFU/mL, while the corresponding values were 12,266, 2,295, and 5,337, respectively, with the initial inoculum of 10<sup>8</sup> CFU/mL. The <italic>ex vivo</italic> PK/PD based population dose prediction indicated a target attainment rate (TAR) of 90% of 55 mg/gland/12 h. The CO<sub>PD</sub> for cefquinome against <italic>S. aureus</italic> was 2 μg/mL under the recommended dose of 55 mg/gland/12 h. However, it should be validated in clinical practice in future investigations. These results contribute to the rational use of cefquinome for mastitis treatment in clinical veterinary medicine.</p>