PK/PD Analysis of Marbofloxacin by Monte Carlo Simulation against Mycoplasmaagalactiae in Plasma and Milk of Lactating Goats after IV, SC and SC-Long Acting Formulations Administration

Abstract

Contagious agalactia is a mycoplasmosis affecting small ruminants that have become an important issue in many countries. However, PK/PD studies of antibiotics to treat this problem in lactating goats affected by Mycoplasma (M.) agalactiae, the main CA-causing mycoplasma are almost non-existent. The aims of this study were to evaluate the plasma and milk disposition of marbofloxacin in lactating goats after intravenous (IV), subcutaneous (SC) and subcutaneous poloxamer P407 formulations with and without carboxy-methylcellulose (SC-P407-CMC and SC-P407) administration. Marbofloxacin concentrations were analysed by the High Performance Liquid Chromatography (HPLC) method. Minimum inhibitory concentrations (MIC) of M. agalactiae field isolates from mastitic goat’s milk were used to calculate surrogate markers of efficacy. Terminal half-lives of marbofloxacin after IV, SC, SC-P407 and SC-P407-CMC administration were 7.12, 6.57, 13.92 and 12.19 h in plasma, and the half-lives of elimination of marbofloxacin in milk were 7.22, 7.16, 9.30 and 7.74 h after IV, SC, SC-P407 and SC-P407-CMC administration, respectively. Marbofloxacin penetration from the blood into the milk was extensive, with Area Under the Curve (AUCmilk/AUCplasma) ratios ranged 1.04–1.23, and maximum concentrations (Cmax-milk/Cmax-plasma) ratios ranged 0.72–1.20. The PK/PD surrogate markers of efficacy fAUC24/MIC and the Monte Carlo simulation show that marbofloxacin ratio (fAUC24/MIC > 125) using a 90% of target attainment rate (TAR) need a dose regimen between 8.4 mg/kg (SC) and 11.57 mg/kg (P407CMC) and should be adequate to treat contagious agalactia in lactating goats.

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

“…Statistical comparison of fAUC 24 / MIC ratios obtained with both models for each growth medium and inoculum tested show significant differences. These findings suggest the PK/PD cutoff points determined are highly dependent on the growth medium and bacterial density [ 15 , 23 ]. The highest values have always been obtained in serum and milk, which are more representative biological fluids than artificial media [ 13 ].…”

“…For low and high inoculum, median values close to 50–120, 80–160 and 100–175 were obtained in CAMHB, serum, and milk, respectively, and fall in the range of standardized values for fluoroquinolones of 50–125 that have been widely described [ 9 ]. However, it is necessary to indicate that the numerical values recommended to establish the PK/PD cutoff points for concentration-dependent antimicrobial drugs as fluoroquinolones have been generated in experimental infections in laboratory animals or in human clinical trials [ 23 , 44 ]; thus, these observed ratios might not be applicable to goat infections or to other infections in ruminants [ 45 , 46 , 47 , 48 , 49 ]. In the same way, fAUC / MIC ratios for ruminant species have been described in different experiments with TKC with values lower than 100 or higher than 180, especially with high bacterial densities [ 15 , 23 ].…”

“…However, it is necessary to indicate that the numerical values recommended to establish the PK/PD cutoff points for concentration-dependent antimicrobial drugs as fluoroquinolones have been generated in experimental infections in laboratory animals or in human clinical trials [ 23 , 44 ]; thus, these observed ratios might not be applicable to goat infections or to other infections in ruminants [ 45 , 46 , 47 , 48 , 49 ]. In the same way, fAUC / MIC ratios for ruminant species have been described in different experiments with TKC with values lower than 100 or higher than 180, especially with high bacterial densities [ 15 , 23 ]. In addition, other factors, such as the immunocompetence of the host and the post-antibiotic effect of fluoroquinolones, should be considered cautiously with these ratios [ 47 ].…”

“…Test tubes with 0.25, 2, 16 and 64× MIC in each medium were evaluated. Samples of 100 μL were taken at 0, 2, 8 and 24 h and were measured by the HPLC method, previously described by our research group [ 23 ].…”

“…Before the development of the models, drug concentrations in each fluid were transformed to free concentrations using the unbound fractions in plasma and milk, previously determined in our laboratory, with values of 0.71 for milk, and 0.73 for serum [ 23 ]. On the other hand, it was also determined in CAMHB with a value close to 0.923.…”