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Ex Vivo Pharmacokinetic/Pharmacodynamic Integration Model of Cefquinome Against Escherichia coli in Foals

Tiantian Gao,Xuesong Liu,Di Qiu,Yanan Li,Zongsheng Qiu,Jingjing Qi,Shuxin Li,Xiaoyan Guo,Yan Zhang,Ziqi Wang,Xiang Gao,Yuhui Ma,Tianwen Ma

Simple SummaryBacterial infection is a major cause of death in foals.Escherichia coli(E. coli) is a Gram-negative bacterium that causes sepsis, which can be life-threatening in horses. Cefquinome has broad-spectrum antimicrobial activity and is widely used in the treatment of animal diseases. At the same time, it is the fourth generation of cephalosporin antibiotics for veterinary use, and it has good antibacterial activity against both Gram-positive and Gram-negative bacteria. Cefquinome is utilized for the treatment of septicemia induced byE. coli, as well as respiratory infections caused byStreptococcus equisubsp.zooepidemicusin foals. However, there is a lack of studies using cefquinome to targetE. colias a pathogen of sepsis. Pharmacokinetic/pharmacodynamic (PK/PD) modeling is a fundamental step in semi-mechanical methodology aimed at improving dose planning of systemically active antimicrobial agents. PK/PD models can determine the relationship between drug concentration, antibacterial action, and time, deriving the most effective dosing regimen. This study was based on this model to verify the optimal dosing regimen forE. coliinfection in foals and to provide a theoretical basis for the precision treatment of foals.Cefquinome is used to treat septicemia caused byEscherichia coli(E. coli) and respiratory infections caused byStreptococcus equisubsp.zooepidemicusin foals. However, studies reporting the use of cefquinome to targetE. colias pathogens of sepsis are lacking. Therefore, this study aimed to determine the optimal dosage regimen for cefquinome againstE. coliusing a PK/PD model. After the administration of 1 mg/kg cefquinome (intramuscularly or intravenously), blood samples were collected at different time points to determine the serum concentration of cefquinome via HPLC. The pharmacokinetic parameters were evaluated via NCA (WinNonlin 5.2.1 software). The main pharmacokinetic parameters of cefquinome in foals were as follows: after intravenous administration, the elimination half-life (T1/2β) was 2.35 h, the area under the curve (AUC0–last) was 12.33 μg·h/mL, the mean residence time (MRT0–last) was 2.67 h, and the clearance rate (CL) was 0.09 L/h/kg. After intramuscular administration, the peak concentration (Cmax) was 0.89 μg/mL, the time to reach the maximum serum concentration (Tmax) was 2.16 h, T1/2βwas 4.16 h, AUC0–lastwas 5.41 μg·h/mL, MRT0–lastwas 4.92 h, CL was 0.15 L/h/kg, and the absolute bioavailability (F) was 43.86%. An inhibitory sigmoid Emax model was used to integrate the PK/PD indices with ex vivo antimicrobial effects to identify pharmacodynamic targets (PDTs). According to the dose calculation formula, the doses of intramuscularly administered cefquinome required to achieve bacteriostatic effects, bactericidal effects, and bactericidal elimination were 1.10, 1.66, and 2.28 mg/kg, respectively. However, further studies are warranted to verify the therapeutic efficacy of cefquinome in clinical settings.