Pharmacokinetic/pharmacodynamic modeling in plasma and milk and Monte Carlo simulations of marbofloxacin against Staphylococcus aureus and Mycoplasma agalactiae in lactating sheep

Abstract

In livestock ruminants such as sheep, different infectious diseases such as mastitis or contagious agalactia are originated from pathogens as Staphylococcus aureus and Mycoplasma agalactiae. Fluoroquinolones are authorized in dairy animals, including their extralabel use, as an alternative when other treatment failed in the European Union (EU), however, in the United States, are prohibited from extralabel drug use in food-producing animals. Marbofloxacin, a well-known fluoroquinolone is commonly used in dairy cattle in the EU at 10 mg/kg. However, their off-label use in sheep also has been described. Nevertheless, the dose extrapolations from dairy cows should include pharmacokinetic (PK) studies because of interspecies differences and the potential risks of antimicrobial resistance or toxicity. In this regard, the aims of this research were to (1) describe the i.v. and i.m. PK analysis of marbofloxacin in plasma and milk of lactating sheep at 10 mg/kg, (2) determine the MIC and calculate the tentative epidemiological cutoff values (TECOFF) for Mycoplasma agalactiae and Staphylococcus aureus wild-type isolates from sheep, and (3) conduct a pharmacokinetic and pharmacodynamic (PK/PD) analysis with the Monte Carlo simulation to obtain the probability of target attainment for different MIC values, known as the PK/PD cutoff values. The results of this study could help to establish the efficacy of a 10 mg/kg dosage regimen of marbofloxacin in lactating sheep. Plasma and milk concentrations were described with a nonlinear mixed effects model. The intramuscular bioavailability was 88%, and the volume of distribution was 1.31 L/kg with a clearance value of 0.38 L/h/kg. Half-lives after i.v. and i.m. dosing were 6.53 and 7.09 h in plasma, and 6.62 and 6.65 h in milk, respectively. High concentrations were determined in milk with area under the curve (AUC) milk/plasma ratios close to 1.28. The MIC values for Staphylococcus aureus and Mycoplasma agalactiae were obtained, and TECOFF values of 1.0 and 2.0 µg/mL, respectively, were determined. The Monte Carlo simulations predicted that the dosage regimen of 10 mg/kg per 24 h in lactating sheep can be adequate for intermediate and high MIC values of 0.5 and 1.0 μg/mL, respectively, and could be useful for populations with a target AUC/MIC ratio ≤48 for Staphylococcus aureus, but not for Mycoplasma agalactiae. Results derived for this study could be taken as previous tentative points for further studies of marbofloxacin in lactating and nonlactating sheep in a clinical context