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Cefquinome, the fourth-generation cephalosporin applied solely for veterinary medicine, is commonly used for bovine mastitis caused by  Staphylococcus aureus . The present study aims to establish an optimal dose and provide a PK/PD Cutoff value (CO PD ) for cefquinome against  S. aureus  based on  ex vivo  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  ex vivo  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 0−24 ) 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.  In vitro  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 6  to 10 8  CFU/mL. The AUC 0−24h /MIC index correlated well with  ex vivo  efficacy both for the initial inoculum of 10 6  CFU/mL and 10 8  CFU/mL ( R  2  &amp;gt; 0.84). According to the inhibitory sigmoid E max  model analysis, the PK/PD surrogate (AUC 0−24 /MIC) values were 8,638, 1,397, and 3,851 for bactericidal effect ( E  = −3) with an initial inoculum of 10 6  CFU/mL, while the corresponding values were 12,266, 2,295, and 5,337, respectively, with the initial inoculum of 10 8  CFU/mL. The  ex vivo  PK/PD based population dose prediction indicated a target attainment rate (TAR) of 90% of 55 mg/gland/12 h. The CO PD  for cefquinome against  S. aureus  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.

frontiers in veterinary science

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