Pharmacokinetics, milk penetration and PK/PD analysis by Monte Carlo simulation of marbofloxacin, after intravenous and intramuscular administration to lactating goats

Abstract

The main objectives of this study were (i) to evaluate the serum pharmacokinetic behaviour and milk penetration of marbofloxacin (MFX; 5 mg/kg), after intravenous (IV) and intramuscular (IM) administration in lactating goats and simulate a multidose regimen on steady-state conditions, (ii) to determine the minimum inhibitory concentration (MIC) and mutant prevention concentration (MPC) of coagulase negative staphylococci (CNS) isolated from caprine mastitis in Córdoba, Argentina and (iii) to make a PK/PD analysis by Monte Carlo simulation from steady-state pharmacokinetic parameters of MFX by IV and IM routes to evaluate the efficacy and risk of the emergence of resistance. The study was carried out with six healthy, female, adult Anglo Nubian lactating goats. Marbofloxacin was administered at 5 mg/kg bw by IV and IM route. Serum and milk concentrations of MFX were determined with HPLC/uv. From 106 regional strains of CNS isolated from caprine mastitis in herds from Córdoba, Argentina, MICs and MPCs were determined. MIC and MPC were 0.4 and 6.4 μg/ml, respectively. MIC and MPC-based PK/PD analysis by Monte Carlo simulation indicates that IV and IM administration of MFX in lactating goats may not be adequate to recommend it as an empirical therapy against CNS, because the most exigent endpoints were not reached. Moreover, this dose regimen could increase the probability of selecting mutants and resulting in emergence of resistance. Based on the results of Monte Carlo simulation, the optimal dose of MFX to achieve an adequate antimicrobial efficacy should be 10 mg/kg, but it is important take into account that fluoroquinolones are substrates of efflux pumps, and this fact may determine that assumption of linear pharmacokinetics at high doses of MFX may be incorrect.

In Vivo Pharmacokinetic/Pharmacodynamic Profiles of Danofloxacin in Rabbits Infected With Salmonella typhimurium After Oral Administration

“…The MIC and MBC for danofloxacin against S. typhimurium in rabbit serum were twice those in artificial broth, which could be explained by the protein binding ratio of danofloxacin in serum ( Qu et al, 2015 ) and the differences of matrix. In accordance with previous reports, in which the MPC was eight times higher than the MIC ( Lorenzutti et al, 2017 ), the ratio of MPC/MIC in this study was 8, indicating that the mutant selection window is wide. The in vitro time-killing curve of danofloxacin showed concentration dependence against S. typhimurium , which was similar to a previous publication ( Lei et al, 2017 ).…”

Effect of supportive therapy on the pharmacokinetics of intravenous marbofloxacin in endotoxemic sheep

“…Marbofloxacin is recommended to the use at 2 mg/kg dose by EMA (1999) in livestock animals. However, the results of simulation and therapeutic studies proposed use at 10 mg/kg dose to achieve an adequate antimicrobial efficacy (Kacar, Batmaz, Yilmaz, & Mecitoglu, 2018; Lorenzutti et al, 2018; Paulin, Schneider, Dron, & Woehrle, 2018; Valle, Schneider, Galland, Giboin, & Woehrle, 2012). In this study, sheep received marbofloxacin at 10 mg/kg dose.…”

Pharmacokinetic evaluation of marbofloxacin after intravenous administration at different ages in llama crias, and pharmacokinetic/pharmacodynamic analysis by Monte Carlo simulation

“…Serum concentrations of MFX were determined by high‐performance liquid chromatography with ultraviolet detection (HPLC/uv), as described by Schneider, Thomas, Boisrame, and Deleforge () with some modifications (Lorenzutti et al., ). Marbofloxacin and ofloxacin (used as internal standard), were purchased by Fluka Aldrich and Sigma Chemical, respectably.…”