PK/PD Modeling to Assess Rifaximin Clinical Dosage in a Mouse Model of Staphylococcus aureus-Induced Mastitis

Abstract

Staphylococcus aureus (S. aureus) is a common pathogen that causes mastitis, an infection of the milk-secreting tissue of the udder, in dairy cows, and presents a huge economic problem for the dairy industry worldwide. Thus, control and treatment of mastitis in dairy cows is vital in order to reduce the costs associated with the disease. The main purpose of the current work was to examine the current dosage of rifaximin for the treatment mastitis in cows caused by S. aureus using pharmacokinetic/pharmacodynamic integration in a mouse mastitis model. The mouse mastitis model was established via injection of S. aureus Newbould 305 (400 CFU/gland) into the mouse mammary gland. A single dose of 50, 100, 200, or 400 μg/gland, administered via intramammary infusion, was used to study the pharmacokinetics of rifaximin. The pharmacokinetic parameters were analyzed by non-compartment and non-linear mixed-effect models using Phoenix software (version 8.1; Pharsight, USA). In vivo pharmacodynamics was used to examine 18 therapeutic regimens covering various doses ranging from 25 to 800 μg/gland and three dosing intervals of 8, 12, and 24 h per 24 h experiment cycle. The antibacterial effect of rifaximin was elevated with higher concentrations of rifaximin or shorter intervals of administration. The percentage of time that drug concentrations exceeded the MIC during a dose interval (%T > MIC) was generally 100% for rifaximin and was not better than AUC24/MIC in the sigmoid Emax model of inhibitory effect. The optimal antibacterial effect was 2log10CFU/gland when the magnitude of AUC24/MIC reached 14,281.63 h. A total of 14,281.63 h of AUC24/MIC was defined as a target value in the Monte Carlo simulation. The clinically recommended dosage regimen of 100 mg/gland every 8 h in 1 day achieved an 82.97% cure rate for the treatment of bovine mastitis caused by Staphylococcus aureus infection.

A PK/PD model for the evaluation of clinical rifaximin dosage for the treatment of dairy cow mastitis induced by Escherichia coli

“…In our previous study, we administered rifaximin to one mammary gland of the fourth pair of mice, and the results showed that the drug concentration was not detected or close to the detection limit in the untreated mammary gland on opposite side [ 17 ]. Histologically, the close link between secretory cells at their apex by tight junctions in the lactating udder forms the blood–milk barrier, which accounts for the passive transport of drugs between the blood and milk [ 26 ].…”

“…The mammary glands of the fourth pair are independent of each other and can be used as two independent samples for analysis. This method has been reported in our previous studies [ 17 ]. Four single-dose groups, with doses of 50, 100, 200, and 400 µg/gland, were used in the pharmacokinetics experiments.…”

“…The processing method of mammary gland samples is similar to the method used in our previously published papers [ 17 ]. Briefly, mammary gland samples were homogenized, and 0.5 g of mammary gland samples were transferred into a 10-mL polypropylene centrifuge tube.…”

“…The mouse mastitis model caused by E. coli was based on previous reports [ 16 , 17 , 19 ]. In brief, the offspring were removed from lactating mice at 2 h before the experiment.…”

The pharmacokinetics and pharmacodynamics of cefquinome against Streptococcus agalactiae in a murine mastitis model

“…The PK/PD indexes comprised the AUC/MIC (area under the time-concentration curve divided by MIC), %T > MIC (the percentage time for which the drug concentration exceeded MIC), and C max /MIC (peak concentration divided by MIC). The relationship between in vivo antibacterial effects (△log CFU/MG) and the PK/PD indexes were described using an inhibitory sigmoid E max model [ 31 , 32 ].…”