Effects of Growth Medium and Inoculum Size on Pharmacodynamics Activity of Marbofloxacin against Staphylococcus aureus Isolated from Caprine Clinical Mastitis.

Augusto Matías Lorenzutti,Juan Manuel Serrano-Rodríguez,María Del Pilar Zarazaga,Manuel Ignacio San Andrés-Larrea,Ana María Molina-López,Emilio Fernández-Varón

doi:10.3390/antibiotics10111290

Abstract

Staphylococcus aureus (S. aureus) is an important pathogen that causes clinical mastitis in goats and produces infections difficult to cure. Different antimicrobials as fluoroquinolones have been used against S. aureus. However, the studies developed to evaluate the bacterial drug interaction only have used the MIC as a single reference point with artificial growth media. The aims of this study were to describe the effect of marbofloxacin on S. aureus isolated from mastitis goats’ milk by different approaches as the minimum inhibitory and bactericidal concentrations (MIC and MBC) in cation adjusted Mueller–Hinton broth (CAMHB), serum and milk of goats at two inoculum sizes of 105 and 108 CFU/mL, the determination and analysis of the time kill curves (TKC) by non-linear mixed effect models in each growth medium and inoculum size, as well as the estimation of their pharmacokinetics/pharmacodynamics (PK/PD) cutoff values. The results obtained indicate that MIC values were higher and increases 2,4-fold in serum and 3,6-fold in milk at high inoculum, as well as the EC50 values determined by each pharmacodynamics model. Finally, the PK/PD cutoff values defined as fAUC24/MIC ratios to achieve clinical efficacy were highly dependent on inoculum and growth medium, with median values of 60–180, especially at high inoculum in milk, suggesting that further studies are necessary to evaluate and optimize the best therapeutic strategies for treating S. aureus in lactating goats.

Highlights

Staphylococcus aureus is an important pathogen in ruminant species that can colonize the udder from where it can infect the mammary gland epithelium causing mastitis [1]
Statistical comparison between growth mediums showed that all parameters were significantly different with P values less than 0.05, with the exception of N0 and dkg. These results suggest that marbofloxacin activity was reduced at high bacterial density, and with high minimum inhibitory concentration (MIC) values, especially when S. aureus grew in milk
The main findings of this research suggest that firstly, the combined use of biological fluids such as serum or milk with different inoculum sizes showed that the ratios to predict clinical efficacy with fluoroquinolones are highly dependent on the growth medium and bacterial density

Summary

Introduction

Staphylococcus aureus is an important pathogen in ruminant species that can colonize the udder from where it can infect the mammary gland epithelium causing mastitis [1] In small ruminants, it is responsible for approximately 80% of cases of clinical mastitis in dairy ewes and is the most common cause in dairy goats [2,3]. The extent to which a drug has access into these compartments depends on its pharmacokinetic properties: lipophilicity, ionization, and binding protein [6] In this regard, fluoroquinolones exhibit good properties as high bioavailability and lipophilicity, large volume of distribution, low protein binding and milk excretion by passive diffusion, and active transport by BCRP protein [7]. These drugs distribute well into mammary glands with milk concentrations similar or higher than serum concentrations [8]

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