Pharmacokinetics and pharmacodynamics of a novel amoxicillin/sulbactam/prednisolone intramammary infusion in lactating cows after repeated administrations

Abstract

ABSTRACT:The aim of this study was to assess the pharmacokinetics (PK) and pharmacodynamics (PD) of a novel anti-mastitis preparation, amoxicillin/sulbactam/prednisolone intramammary infusion (CAIMM), containing 200 mg amoxicillin, 50 mg sulbactam and 10 mg prednisolone per 3 g formulation, in healthy lactating cows after repeated administrations. A parallel study was performed using the available combination product (Synulox ® LC) from Pfizer, with the aim of comparing the two formulations. The concentrations of drugs in quarter milk were determined using the ultra-high performance liquid chromatography tandem mass spectrometric (UPLC-MS/MS) method. No significant difference in the major PK parameters (C max , T max , MRT, t 1/2λ , and AUC last ) was observed. The MIC 90 determined in 106 isolated Staphylococcus spp., 64 Streptococcus spp. and 18 Escherichia coli strains was 0.5, 0.25 and 2 μg/ml, respectively. The PK/PD evaluation showed that the effective duration of action (t > MIC 90 ) for CAIMM (42 ± 2.46 h) was increased by 0.86 times compared with Synulox ® LC (34 ± 3.17 h), but the difference was not significant (P > 0.05). This pharmacokinetic and pharmacodynamic study revealed that CAIMM maintained high concentrations in quarter milk for the three ingredients after repeated intramammary administrations and a similar efficacy was achieved with Synulox ® LC.

Distribution of hydrophilic and lipophilic antibacterial drugs in skim milk, cream, and casein

“…In the in vitro stage of the study, different amounts of amoxicillin (0.04, 0.4, 4, 40, and 400 μg/g) and tylosin (0.05, 0.5, 5, and 50 μg/g) were spiked to drug-free milk samples obtained from the cattle before the in vivo study. These levels were determined according to the MRL and maximum drug concentration (Cmax) in milk of amoxicillin (European Union, 2010; Li et al, 2014) and tylosin (European Union, 2010; Avci and Elmas, 2014), respectively.…”

“…Although many studies have determined the presence of amoxicillin and tylosin residues in milk, there are no data on the distribution of amoxicillin and tylosin in milk fractions (Luo et al, 1997;Dudriková et al, 1999;Khaskheli et al, 2008;Wang et al, 2008;Martínez-Huelamo et al, 2009;Avci and Elmas, 2014;Li et al, 2014). The aims of this study were (1) to determine the distribution of amoxicillin and tylosin in cream, skim milk, and casein and whether the withdrawal time for different fractions of milk differs according to the physicochemical properties of the drugs; and (2) to determine whether the in vitro assay accurately reflects the distribution of drugs in the different fractions of milk in vivo.…”

Establishment of the Maximum Residual Limit in the Milk of Dairy Cows Injected Intramuscularly with Prednisolone

“…Residual concentrations of PSL in milk samples collected at 12 and 24 h were 0.81-235 ng/mL and 0.81-4.3 ng/mL, respectively [27]. In a study on mastitis-infected cows [28], 10 mg of PSL was injected into a cow's udder three times at 24 h intervals, resulting in a PSL milk concentration of 110 ng/mL at 12 h. Similarly, in a study on healthy cows not infected with mastitis [29], 10 mg of PSL was injected into a cow's udder three times at 24 h intervals, resulting in a PSL milk concentration of 1.1 ng/mL at 12 h. In this study, 100 mg and 200 mg of PSL were administered intramuscularly to milking cows once, resulting in residual PSL concentrations in milk below the LOQ (0.2 ng/mL) at 12 h after administration. Compared to previous research results, the residual concentration of PSL in milk was very low, which may be due to differences in the administration dose and route of administration of PSL.…”

Determination of milk/plasma ratio and milk and plasma pharmacokinetics of amoxicillin after intramuscular administration in lactating cows

“…No studies related to milk pharmacokinetics of amoxicillin after IM administration in dairy cows were found. The elimination half‐life of amoxicillin was found to be 7.17 and 5.34 hr in a study by Li, Wu, Tang, Xiao, and Li () comparing the milk pharmacokinetics of two different intramammary formulations of amoxicillin in dairy cows at the same dosage regimen (200 mg dose every 12 hr for three consecutive days). In cows with mastitis, this value was determined as 8.1 hr after a single intramammary administration of amoxicillin at a dose of 200 mg (Burmańczuk, Tomasz, Gbylik‐Sikorska, Gajda, & Kowalski, ).…”

“…The minimum inhibitory concentration (MIC) value for amoxicillin and its combination with β‐lactamase inhibitors was above 0.25 and 0.125 μg/ml, respectively, for most susceptible bacteria (Bingen et al., ; De Oliveira, Watts, Salmon, & Aarestrup, ; Diarrassouba et al., ; Ding et al., ; Gianneechini, Concha, & Franklin, ; Li et al., ; Maisak, Tipmongkolsilp, & Wongtavatchai, ; McDougall, Hussein, & Petrovski, ; Payne et al., ). Amoxicillin level above 0.125 μg/ml was maintained for >12 hr in plasma and 8 hr in milk when the aforementioned amoxicillin MIC values were compared with the values in the present study.…”