ABSTRACT
Introduction: Klebsiella pneumoniae is classified as a critical pathogen in both animals and humans and infections can be fatal in chickens resulting in substantial economic losses. However, the misuse of antibiotics can also lead to drug resistance and a potential transmission chain between animals and humans. Three K. pneumoniae strains with different susceptibility phenotypes were chosen to study the pharmacokinetic/pharmacodynamic (PK/PD) integration of enrofloxacin (ENR) and cefquinome (CEQ) alone and in combination. Results: Checkerboard assay results indicated that the combination treatment for type strain ATCC 700603 was synergistic effect with a fractional inhibitory concentration index (FICI) of ≤0.5. The other two clinical strains demonstrated an additive effect (FICI >0.5 to ≤1). Furthermore, static time-kill curves indicated that enrofloxacin and cefquinome added singly were effective in killing K. pneumoniae at concentrations of >2 MIC and ≥1 MIC, respectively. Additionally, the combination of enrofloxacin and cefquinome led to an enhanced antibacterial activity of cefquinome. The dynamic time-kill curves indicated that enrofloxacin and cefquinome had bactericidal and bacteriostatic activities, respectively at ≥1.5 mg/L (single-dose) and 4 mg/L (8 h split-dose) causing a decrease in bacterial counts of ≥4.45 and >2 log10 CFU/mL. Enrofloxacin possessed no bacteriostatic effects against K. pneumoniae at a constant concentration of 1× MIC. Cefquinome used in combination with 1× MIC enrofloxacin exhibited bactericidal activity at ≥4 mg/L (12 h split-dose) with reductions of ≥3.65 log10 CFU/mL. The PK/PD parameters were also analyzed to determine the concentration and duration of the drugs needed to reduce bacteria by 3 log10 CFU/mL. For enrofloxacin alone, the AUC24h/MIC was 23.29 h and the Cmax/MIC was 3.18. For cefquinome alone, the %T > MIC was 48.66 and when used in combination with enrofloxacin was 18.04. The combined use of cefquinome and enrofloxacin can increase the antibacterial activity of cefquinome against K. pneumoniae under a 12-h split-dose regimen regardless of individual drug susceptibility. Discussion: The static and dynamic time-kill curves indicated that enrofloxacin exhibited concentration-dependent activity, while cefquinome exhibited time-dependent activity. In the in vitro dynamic model, enrofloxacin alone exhibited better antimicrobial effects against K. pneumoniae compared to cefquinome alone. However, the antibacterial effect of cefquinome can be enhanced by combining it with enrofloxacin. These findings suggest a potentially effective approach for combating K. pneumoniae infections.
ABSTRACT
Tilmicosin is a semi-synthetic macrolide for veterinary use with strong antibacterial effect on respiratory bacteria. In this study, the pharmacokinetic/pharmacodynamic (PK/PD) integration of tilmicosin against Pasteurella multocida (P. multocida) was evaluated by establishing a piglet tissue cage infection model. Concentration of tilmicosin and bacterial numbers of P. multocida in the tissue-cage fluid were monitered. After the population of P. multocida was equal to or greater than 107 CFU/mL in a tissue cage, piglets received an oral administration of tilmicosin at a dose of 30, 40, 50, and 60 mg/kg b.w., once daily for 3 days, respectively. Bacteria were counted every 24 h after drug administration and at 48 and 72 h after the last administration. A sigmoidal Emax model was used to fit the relationship between PK/PD parameters and the antibacterial effect. AUC24h/MIC was the best PK/PD index that correlated with effectiveness of tilmicosin against P. multocida. The magnitude of AUC24h/MIC required for continuous 1/3-log, 1/2-log, and 3/4-log reductions were 19.65 h, 23.86 h, and 35.77 h, respectively, during each 24 h treatment period. In this study, when the dosage was >50 mg/kg, the AUC24h/MIC was still >35.77 h in the period of 24-48 h after the last administration due to the slow elimination, that is, tilmicosin exhibited a potent antibacterial effect against P. multocida after three successive daily administrations. The data provide meaningful guidance to optimize regimens of tilmicosin to treat respiratory tract infections caused by P. multocida.
ABSTRACT
The pigeon breeding industry employs a high-rearing pattern to achieve economic benefits. However, too many squabs consume more energy of the breeding pigeons causing adverse effects on their breeding performance. To determine the optimal rearing patterns and the effects of different numbers of squabs on reproductive performance, oxidative stress, and glucolipid metabolism of lactating breeding pigeons in winter, three rearing patterns consisting of "2 + 2â³, "2 + 3â³ and "2 + 4" (a pair of breeding pigeons feeding two, three and four squabs, respectively) were adopted using European Mimas white pigeons breed. The feed intake, bodyweight loss, feed-to-meat ratio, and squab mortality were linearly increased with the number of squabs during lactation, while the bodyweight recovery rate and squab growth performance were significantly slowed down after lactation. Similarly, the laying rate was linearly decreased on days 16, 17, and 18 of lactation, with a similar pattern on the re-laying rate on days 11, 12, and 13 after first laying. In addition, the number of non-laying pigeons in the second batch was significantly increased, implying that the number of squabs significantly affected the reproductive performance of female pigeons. The eggshell weight and thickness in the "2 + 3â³ group were significantly increased. However, the number of squabs in the "2 + 3â³ group had no significant effect on plasma calcium (Ca) and phosphorus (P) levels. Analysis of the glucolipid metabolism index and oxidative stress level of pigeons further revealed that the contents of triglyceride (TG), total cholesterol (T-CHO), and low-density lipoprotein cholesterol (LDL-C) in the plasma of male pigeons were significantly decreased with the increase in the number of squabs, but there was no obvious oxidative stress. On the contrary, glucose (GLU), TG, malondialdehyde (MDA) in the plasma of female pigeons were significantly increased, total antioxidant capacity (T-AOC) were significantly decreased, implying that the female pigeons suffered more oxidative stress and more dramatic changes in glucolipid metabolism. Metabolomics revealed that the differential metabolites in the plasma of female pigeons in "2 + 2â³, "2 + 3â³, and "2 + 4â³ groups were significantly enriched in the fatty acid, phospholipid, sphingolipid metabolism, and the Krebs cycle pathways, especially under "2 + 4â³ rearing pattern. Overall, in female pigeons, the available lipids were reduced; hence, their body turned to sugar dysplasia and protein utilization mode, increasing the oxidative stress level and decreasing their reproductive performance. Therefore, an increased number of squabs significantly affects the body condition and reproductive performance of breeding pigeons. The "2 + 3â³ rearing pattern is the most suitable for winter breeding pigeon production under the current nutrition level.
ABSTRACT
The purpose of this study was to investigate the biodistribution of Salvianolic acid B in rats blood and brain after intranasal administration and explore its feasibility and evaluate its brain targeting effect. The concentration of Salvianolic acid B in blood and brain following nasal administration (32 mgckg-1) was measured combining with microdialysis sampling and liquid chromatograph-mass spectrometer/MS detection technology. After the microdialysis samples were corrected with in vivo recoveries, the pharmacokinetic parameters were obtained by using non-compartment model and the brain targeting evaluated by the value of drug targeting index (DTI). The Cmax in blood and brain by intravenous injection were higher than intranasal administration, but the intranasal administration of MRT0-∞ significantly prolonged and increased by nearly 2.03 and 1.86 times, respectively. The DTI value of Salvianolic acid B was 5.54 and bioavailability (F) was 43.98%. After nasal administration of Salvianolic acid B, it has a certain brain targeting, which could become a new drug system for the treatment of brain diseases.
