Abstract
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 (COPD) 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 (AUC0−24) 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 106 to 108 CFU/mL. The AUC0−24h/MIC index correlated well with ex vivo efficacy both for the initial inoculum of 106 CFU/mL and 108 CFU/mL (R2 > 0.84). According to the inhibitory sigmoid Emax model analysis, the PK/PD surrogate (AUC0−24/MIC) values were 8,638, 1,397, and 3,851 for bactericidal effect (E = −3) with an initial inoculum of 106 CFU/mL, while the corresponding values were 12,266, 2,295, and 5,337, respectively, with the initial inoculum of 108 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 COPD 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.
Highlights
Bovine mastitis is known as a serious disease in the dairy industry due to deterioration in the quality of milk, veterinary care expenses, and prohibitive labor costs for producers
Sixty-three S. aureus strains isolated from clinical bovine mastitis individuals in Jiangsu China were evaluated in this study
The MIC distributions of antimicrobials against S. aureus (n = 63) isolated from clinical mastitis in Jiangsu China are shown in Supplementary Table S2
Summary
Bovine mastitis is known as a serious disease in the dairy industry due to deterioration in the quality of milk, veterinary care expenses, and prohibitive labor costs for producers. Bovine mastitis usually results from bacterial, yeast, and even fungal or algae infection that accounts for almost 90% of all diagnoses [1]. Staphylococcus aureus is one of the most common etiologic agents, which could result in chronic, contagious, and intractable bovine mastitis [2]. S. aureus infection is extremely difficult to control [3], as it can release exotoxin, and survive in the intracellular where the drug concentration is often low. Antimicrobial approaches have been the best way to control bovine mastitis. The resistance rate of S. aureus had been raised obviously and the number of multiple drug resistance (MDR) S. aureus has increased sharply, meaning the treatment of mastitis will become more difficult in the future [4, 5]
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