Dose Assessment of Cefquinome by Pharmacokinetic/Pharmacodynamic Modeling in Mouse Model of Staphylococcus aureus Mastitis

Abstract

This work aimed to characterize the mammary gland pharmacokinetics of cefquinome after an intramammary administration and integrate pharmacokinetic/pharmacodynamic model. The pharmacokinetic profiles of cefquinome in gland tissue were measured using high performance liquid chromatograph. Therapeutic regimens covered various dosages ranging from 25 to 800 μg/gland and multiple dosing intervals of 8, 12, and 24 h. The in vivo bacterial killing activity elevated when dosage increased or when dosing intervals were shortened. The best antibacterial effect was demonstrated by a mean 1.5 log₁₀CFU/gland visible count reduction. On the other hand, the results showed that the percentage of time duration of drug concentration exceeding the MIC during a dose interval (%T > MIC) was generally 100% because of the influence of drug distribution caused by the blood-milk barrier. Therefore, pharmacokinetic/pharmacodynamic parameter of the ratio of area under the concentration-time curve over 24 h to the MIC (AUC_0-24/MIC) was used to describe the efficacy of cefquinome instead of %T > MIC. When the magnitude of AUC_0-24/MIC exceeding 16571.55 h⋅mL/g, considerable activity of about 1.5 log₁₀CFU/g gland bacterial count reduction was observed in vivo. Based on the Monte Carlo simulation, the clinical recommended regimen of three infusions of 75 mg per quarter every 12 h can achieve a 76.67% cure rate in clinical treatment of bovine mastitis caused by Staphylococcus aureus infection.

Keywords: Monte Carlo simulation; PK/PD; cefquinome; dose assessment; mastitis.

FIGURE 1

Semi-logarithmic plot of gland tissue concentration versus time of cefquinome in CD-1 mice following an intramammary administration dose of 25, 50, 100, 200 μg/gland. Each time point represents the arithmetic mean of five mice (for gland tissue, n = 10).

FIGURE 2

Survived strains size of S. aureus wild isolate JP41 after treating with cefquinome at t = 24 h. Eighteen dose regimens comprised seven dose levels (25, 50, 100, 200, 400, and 800 μg/gland and three intervals (every 8, 12, and 24 h). A mean value of 7.28 log₁₀CFU/gland of initial bacterial load was represented as dotted line (n = 6 for glands). The limit of detection was shown as full line.

FIGURE 3

Relationship between PK/PD parameters in gland tissue and drug killing effectiveness (^Δlog₁₀ CFU/gland) of S. aureus JP41 analyzing by the sigmoid model. The dots represent the antimicrobial effectiveness of cefquinome (E = final log-unit – initial log-unit) and the lines denoting the predicted value of E which is simulated from the Winnonlin software. The correlation of observed and predicted E value was quite low in %T > MIC section because of the distribution of %T > MIC (either 100 or 0%), which is not appropriate for PK/PD integration.

FIGURE 4

Frequency distribution plots of AUC/MIC analyzed by Monte Carlo simulation mimicking cefquinome dosing regimens of 75 mg intramammary infusion once, twice, and three times.