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Huanzhong Ding - One of the best experts on this subject based on the ideXlab platform.

  • Murine Thigh Microdialysis to Evaluate the Pharmacokinetic/Pharmacodynamic Integration of Cefquinome Against Actinobacillus pleuropneumoniae.
    Frontiers in veterinary science, 2020
    Co-Authors: Longfei Zhang, Xiangguang Shen, Zichong Zhou, Sixiu Huang, Huanzhong Ding
    Abstract:

    This study aimed to explore the application of microdialysis in pharmacokinetic (PK)/pharmacodynamic (PD) integration of Cefquinome against Actinobacillus pleuropneumoniae. After the A. pleuropneumoniae population reached 106 CFU/thigh, the mice received 0.04, 0.16, 0.63, 2.5, and 10 mg/kg Cefquinome by subcutaneous injection. Plasma samples were collected by retro-orbital puncture for 4 h, and thigh dialysate was obtained by microdialysis at a flow rate of 1.5 μL/min for 6 h for the PK study. For the PD experiment, the infected mice were treated with a 4-fold-increase in the total Cefquinome dose, ranging from 0.01 to 10 mg/kg/24 h, divided into one, two, three, four, and eight doses. The number of bacteria was determined and an inhibitory sigmoid maximum effect (Emax) model was used to analyse the relationships between PK/PD parameters and efficacy. The mean penetration of Cefquinome from plasma to the thigh was 0.591. The PK data for PK/PD integration were obtained by extrapolation. The fittest PK/PD parameter for efficacy evaluation was %fT>MIC (the percentage of time that free drug concentrations exceed the MIC). The magnitudes of %fT>MIC to achieve net bacterial stasis, 1-log10 CFU reduction, 2-log10 CFU reduction, and 3-log10 CFU reduction were 19.56, 28.65, 41.59, and 67.07 % in plasma and 21.74, 36.11, 52.96, and 82.68% in murine thigh, respectively. Microdialysis was first applied to evaluate the PK/PD integration of Cefquinome against A. pleuropneumoniae. These results would provide valuable references when we apply microdialysis to study the PK/PD integration model and use Cefquinome to treat animal diseases caused by A. pleuropneumoniae.

  • Microdialysis Determination of Cefquinome Pharmacokinetics in Murine Thigh From Healthy, Neutropenic, and Actinobacillus pleuropneumoniae-Infected Mice.
    Frontiers in pharmacology, 2019
    Co-Authors: Longfei Zhang, Zilong Huang, Zheng Kang, Xiangguang Shen, Lihua Yao, Huanzhong Ding
    Abstract:

    This study was aimed at applying microdialysis to explore Cefquinome pharmacokinetics in thigh and plasma of healthy, neutropenic, and Actinobacillus pleuropneumoniae-infected mice. The relative recoveries (RRs) were tested in vitro by dialysis and retrodialysis and in vivo by retrodialysis. ICR mice were randomly divided into four groups: H-40 mg/kg (healthy mice receiving Cefquinome at 40 mg/kg), H-160 mg/kg, N-40 mg/kg (neutropenic mice), and I-40 mg/kg (thigh infected-mice with A. pleuropneumoniae). After Cefquinome administration, plasma was collected by retro-orbital puncture and thigh dialysate was collected by using a microdialysis probe with Ringer's solution at a perfusion rate of 1.5 L/min. Plasma and thigh dialysate samples were assessed by HPLC-MS/MS and analysed by a non-compartment model. The mean in vivo recoveries in the thigh were 39.35%, 38.59%, and 37.29% for healthy, neutropenic, and infected mice, respectively. The mean plasma protein binding level was 16.40% and was independent of drug concentrations. For all groups, the mean values of the free AUCinf in plasma were higher than those in murine thigh, while the elimination T1/2β for plasma were lower than those for murine thigh. Cefquinome penetration (AUCthigh/AUCplasma) from the plasma to thigh was 0.70, 0.81, 0.49, and 0.98 for H-40, N-40, I-40, and H-160 mg/kg, respectively. These results indicated that infection significantly affected Cefquinome pharmacokinetics in murine thigh. In conclusion, we successfully applied a microdialysis methods to evaluate the pharmacokinetics of Cefquinome in murine thigh of healthy, neutropenic, and A. pleuropneumonia-infected mice and the pharmacokinetics of Cefquinome was obviously affected by infection in thigh.

  • pharmacokinetic pharmacodynamic integration of Cefquinome against pasteurella multocida in a piglet tissue cage model
    Journal of Veterinary Pharmacology and Therapeutics, 2019
    Co-Authors: Longfei Zhang, Zilong Huang, Zheng Kang, Yuqin Chen, Xiangguang Shen, Qinren Cai, Huanzhong Ding
    Abstract:

    To explore the in vivo antimicrobial activity of Cefquinome against Pasteurella multocida in piglets, a piglet tissue cage infection model was used in this study. After the population of P. multocida reached 107  CFU/mL in a tissue cage, piglets received an intramuscular administration of Cefquinome at 0.2, 0.4, 0.8, 1, 2, and 4 mg/kg once daily for 3 days. To assess the tissue cage pharmacokinetics (PKTCF) of Cefquinome, tissue cage fluid was collected for Cefquinome analysis at 1, 3, 6, 9, 12, and 24 hr after each of the 3 daily drug administrations. Bacteria were counted every 24 hr after drug administration and at 48 and 72 hr after the last administration. Evaluation of the relationship between pharmacokinetic/pharmacodynamic (PK/PD) parameters and the antibacterial effect showed that the surrogate of %T > minimum inhibitory concentration (MIC) (R2  = 0.981) was the best PK/PD index that correlated with effectiveness of Cefquinome against P. multocida. The respective values of %T > MIC required for continuous 1/3-log, 1/2-log, and 1-log reductions were 14.23, 34.45, and 73.44%, respectively, during each 24-hr treatment period. In conclusion, Cefquinome exhibited a potent antibacterial effect against P. multocida. When %T > MIC reached 73.44%, Cefquinome exhibited a bactericidal effect against P. multocida after three successive daily administrations.

  • Pharmacokinetic/pharmacodynamic integration of Cefquinome against Pasteurella Multocida in a piglet tissue cage model.
    Journal of veterinary pharmacology and therapeutics, 2018
    Co-Authors: Longfei Zhang, Zilong Huang, Zheng Kang, Yuqin Chen, Xiangguang Shen, Qinren Cai, Huanzhong Ding
    Abstract:

    To explore the in vivo antimicrobial activity of Cefquinome against Pasteurella multocida in piglets, a piglet tissue cage infection model was used in this study. After the population of P. multocida reached 107  CFU/mL in a tissue cage, piglets received an intramuscular administration of Cefquinome at 0.2, 0.4, 0.8, 1, 2, and 4 mg/kg once daily for 3 days. To assess the tissue cage pharmacokinetics (PKTCF) of Cefquinome, tissue cage fluid was collected for Cefquinome analysis at 1, 3, 6, 9, 12, and 24 hr after each of the 3 daily drug administrations. Bacteria were counted every 24 hr after drug administration and at 48 and 72 hr after the last administration. Evaluation of the relationship between pharmacokinetic/pharmacodynamic (PK/PD) parameters and the antibacterial effect showed that the surrogate of %T > minimum inhibitory concentration (MIC) (R2  = 0.981) was the best PK/PD index that correlated with effectiveness of Cefquinome against P. multocida. The respective values of %T > MIC required for continuous 1/3-log, 1/2-log, and 1-log reductions were 14.23, 34.45, and 73.44%, respectively, during each 24-hr treatment period. In conclusion, Cefquinome exhibited a potent antibacterial effect against P. multocida. When %T > MIC reached 73.44%, Cefquinome exhibited a bactericidal effect against P. multocida after three successive daily administrations.

  • Pharmacokinetic/pharmacodynamic assessment of Cefquinome against Actinobacillus Pleuropneumoniae in a piglet tissue cage infection model.
    Veterinary microbiology, 2018
    Co-Authors: Longfei Zhang, Zilong Huang, Xiangguang Shen, Qinren Cai, Nan Zhang, Huanzhong Ding
    Abstract:

    To evaluate the relationship between the pharmacokinetic/pharmacodynamic (PK/PD) parameters and the antibacterial effect of Cefquinome against Actinobacillus pleuropneumoniae, a tissue cage infection model was established in piglets. In this model, an initial count of A. pleuropneumoniae of approximately 106 CFU/mL was exposed to different concentrations of Cefquinome after multiple administration at dosages of 0.2, 0.4, 0.8, 1, 2, 4 mg/kg body weight once a day for 3 days. Concentration of Cefquinome and bacterial numbers of A. pleuropneumoniae in the tissue-cage fluid (TCF) were monitered. An inhibitory form of sigmoid maximum effect (Emax) model was used to estimate the relationship between the antibacterial effect and PK/PD indices of Cefquinome against A. pleuropneumoniae. The minimum inhibitory concentration of Cefquinome against A. pleuropneumoniae was 0.016 μg/mL in TCF. The total maximum antibacterial effect was a 3.96 log10 (CFU/mL) reduction. In addition, the cumulative percentage of time over a 24 h period that the drug concentration exceeds the MIC (%T > MIC) was the pharmacokinetic-pharmacodynamic (PK-PD) index that best correlated with the antibacterial efficacy (R2 = 0.967). The estimated %T > MIC values were 11.59, 27.49, and 59.81% for a 1/3-log10 (CFU/mL) reduction, a 2/3-log10 (CFU/mL) reduction, and a 1-log10 (CFU/mL) reduction, respectively, during the 24h administration period of Cefquinome. In conclusion, Cefquinome exhibits excellent antibacterial activity and time-dependent characteristics against A. pleuropneumoniae in vivo. Furthermore, these data provide meaningful guidance to optimize regimens of Cefquinome to treat respiratory tract infections caused by A. pleuropneumoniae.

Yahong Liu - One of the best experts on this subject based on the ideXlab platform.

  • In Vivo Pharmacokinetics/Pharmacodynamics of Cefquinome in an Experimental Mouse Model of Staphylococcus Aureus Mastitis following Intramammary Infusion.
    PloS one, 2016
    Co-Authors: Yufeng Zhou, Jian Sun, Mei-ren Chen, Gui-lin Qiao, Xiao-ping Liao, Yahong Liu
    Abstract:

    Staphylococcus aureus remains the major cause of morbidity of bovine mastitis worldwide leading to massive economic losses. Cefquinome is a fourth generation cephalosporin, which preserves susceptibility and antibacterial activity against S. aureus. This work aims to study the pharmacokinetic (PK) and pharmacodynamic (PD) modeling following intramammary administration of Cefquinome against S. aureus mastitis. The mouse model of S. aureus mastitis was developed for the PK/PD experiments. The plasma PK characteristics after intramammary injection of Cefquinome at various single doses of 25, 50, 100, 200, 400 μg per gland (both fourth pairs of glands: L4 and R4) were calculated using one-compartment and first-order absorption model. PD study was investigated based on twenty-one intermittent dosing regimens, of which total daily dose ranged from 25 to 4800 μg per mouse and dosage intervals included 8, 12 or 24 h. The sigmoid Emax model of inhibitory effect was employed for PK/PD modeling. The results of PK/PD integration of Cefquinome against S. aureus suggested that the percentage of duration that drug concentration exceeded the minimal inhibitory concentration (%T>MIC) and the ratio of area under time-concentration curve over MIC (AUC/MIC) are important indexes to evaluate the antibacterial activity. The PK/PD parameters of %T>MIC and AUC0-24/MIC were 35.98% and 137.43 h to obtain a 1.8 logCFU/gland reduction of bacterial colony counts in vivo, against S. aureus strains with Cefquinome MIC of 0.5μg/ml.

  • in vivo pharmacokinetics pharmacodynamics of Cefquinome in an experimental mouse model of staphylococcus aureus mastitis following intramammary infusion
    PLOS ONE, 2016
    Co-Authors: Yufeng Zhou, Jian Sun, Mei-ren Chen, Gui-lin Qiao, Xiao-ping Liao, Yahong Liu
    Abstract:

    Staphylococcus aureus remains the major cause of morbidity of bovine mastitis worldwide leading to massive economic losses. Cefquinome is a fourth generation cephalosporin, which preserves susceptibility and antibacterial activity against S. aureus. This work aims to study the pharmacokinetic (PK) and pharmacodynamic (PD) modeling following intramammary administration of Cefquinome against S. aureus mastitis. The mouse model of S. aureus mastitis was developed for the PK/PD experiments. The plasma PK characteristics after intramammary injection of Cefquinome at various single doses of 25, 50, 100, 200, 400 μg per gland (both fourth pairs of glands: L4 and R4) were calculated using one-compartment and first-order absorption model. PD study was investigated based on twenty-one intermittent dosing regimens, of which total daily dose ranged from 25 to 4800 μg per mouse and dosage intervals included 8, 12 or 24 h. The sigmoid Emax model of inhibitory effect was employed for PK/PD modeling. The results of PK/PD integration of Cefquinome against S. aureus suggested that the percentage of duration that drug concentration exceeded the minimal inhibitory concentration (%T>MIC) and the ratio of area under time-concentration curve over MIC (AUC/MIC) are important indexes to evaluate the antibacterial activity. The PK/PD parameters of %T>MIC and AUC0-24/MIC were 35.98% and 137.43 h to obtain a 1.8 logCFU/gland reduction of bacterial colony counts in vivo, against S. aureus strains with Cefquinome MIC of 0.5μg/ml.

  • pharmacokinetic pharmacodynamic correlation of Cefquinome against experimental catheter associated biofilm infection due to staphylococcus aureus
    Frontiers in Microbiology, 2016
    Co-Authors: Yufeng Zhou, Jian Sun, Wei Shi, Mengting Tao, Yan Q Xiong, Yahong Liu
    Abstract:

    Biofilm formations play an important role in Staphylococcus aureus pathogenesis and contribute to antibiotic treatment failures in biofilm-associated infections. The aim of this study was to evaluate the pharmacokinetic/pharmacodynamic (PK/PD) profiles of Cefquinome against an experimental catheter-related biofilm model due to S. aureus, including three clinical isolates and one non-clinical isolate. The minimal inhibitory concentration (MIC), minimal biofilm inhibitory concentration (MBIC), biofilm bactericidal concentration (BBC), minimal biofilm eradication concentration (MBEC) and biofilm prevention concentration (BPC) and in vitro time-kill curves of Cefquinome were studied in both planktonic and biofilm cells of study S. aureus strains. The in vivo post-antibiotic effects (PAEs), PK profiles and efficacy of Cefquinome were performed in the catheter-related biofilm infection model in murine. A sigmoid E max model was utilized to determine the PK/PD index that best described the dose-response profiles in the model. The MICs and MBICs of Cefquinome for the four S. aureus strains were 0.5 and 16 μg/mL, respectively. The BBCs (32-64 μg/mL) and MBECs (64-256 μg/mL) of these study strains were much higher than their corresponding BPC values (1-2 μg/mL). Cefquinome showed time-dependent killing both on planktonic and biofilm cells, but produced much shorter PAEs in biofilm infections. The best-correlated PK/PD parameters of Cefquinome for planktonic and biofilm cells were the duration of time that the free drug level exceeded the MIC (fT > MIC, R (2) = 96.2%) and the MBIC (fT > MBIC, R (2) = 94.7%), respectively. In addition, the AUC24h/MBIC of Cefquinome also significantly correlated with the anti-biofilm outcome in this model (R (2) = 93.1%). The values of AUC24h/MBIC for biofilm-static and 1-log10-unit biofilm-cidal activity were 22.8 and 35.6 h; respectively. These results indicate that the PK/PD profiles of Cefquinome could be used as valuable guidance for effective dosing regimens treating S. aureus biofilm-related infections.

  • Pharmacokinetics and bioavailability of Cefquinome in healthy ducks.
    American journal of veterinary research, 2011
    Co-Authors: Liguo Yuan, Jian Sun, Rui Wang, Lihua Sun, Lixiang Zhu, Xianyang Luo, Binghu Fang, Yahong Liu
    Abstract:

    To determine pharmacokinetics and bioavailability of Cefquinome administered IV, IM, or PO to healthy ducks. Thirty-six 2-month-old Muscovy ducks. Ducks were randomly assigned to 3 groups of 12 birds each for a single IV, IM, or PO administration at a dose of 5 mg/kg. Blood samples were collected before and at various intervals after each administration. Cefquinome concentration was determined by use of high-performance liquid chromatography at 268 nm with a UV detector, and pharmacokinetics were analyzed. The disposition of Cefquinome following IV or IM administration was best described by a 2-compartment model. After IV administration, mean ± SD elimination halflife was 1.57 ± 0.06 hours, clearance value was 0.22 ± 0.02 L/kg·h, and apparent volume of distribution at steady state was 0.41 ± 0.04 L/kg. After IM administration, elimination half-life was 1.79 ± 0.13 hours, peak concentration time was 0.38 ± 0.06 hours, peak drug concentration was 9.38 ± 1.61 μg/mL, and absolute mean ± SD bioavailability was 93.28 ± 13.89%. No Cefquinome was detected in plasma after PO administration. Results indicated that Cefquinome was absorbed quickly and had excellent bioavailability after IM administration, but absorption after PO administration was poor.

Longfei Zhang - One of the best experts on this subject based on the ideXlab platform.

  • Murine Thigh Microdialysis to Evaluate the Pharmacokinetic/Pharmacodynamic Integration of Cefquinome Against Actinobacillus pleuropneumoniae.
    Frontiers in veterinary science, 2020
    Co-Authors: Longfei Zhang, Xiangguang Shen, Zichong Zhou, Sixiu Huang, Huanzhong Ding
    Abstract:

    This study aimed to explore the application of microdialysis in pharmacokinetic (PK)/pharmacodynamic (PD) integration of Cefquinome against Actinobacillus pleuropneumoniae. After the A. pleuropneumoniae population reached 106 CFU/thigh, the mice received 0.04, 0.16, 0.63, 2.5, and 10 mg/kg Cefquinome by subcutaneous injection. Plasma samples were collected by retro-orbital puncture for 4 h, and thigh dialysate was obtained by microdialysis at a flow rate of 1.5 μL/min for 6 h for the PK study. For the PD experiment, the infected mice were treated with a 4-fold-increase in the total Cefquinome dose, ranging from 0.01 to 10 mg/kg/24 h, divided into one, two, three, four, and eight doses. The number of bacteria was determined and an inhibitory sigmoid maximum effect (Emax) model was used to analyse the relationships between PK/PD parameters and efficacy. The mean penetration of Cefquinome from plasma to the thigh was 0.591. The PK data for PK/PD integration were obtained by extrapolation. The fittest PK/PD parameter for efficacy evaluation was %fT>MIC (the percentage of time that free drug concentrations exceed the MIC). The magnitudes of %fT>MIC to achieve net bacterial stasis, 1-log10 CFU reduction, 2-log10 CFU reduction, and 3-log10 CFU reduction were 19.56, 28.65, 41.59, and 67.07 % in plasma and 21.74, 36.11, 52.96, and 82.68% in murine thigh, respectively. Microdialysis was first applied to evaluate the PK/PD integration of Cefquinome against A. pleuropneumoniae. These results would provide valuable references when we apply microdialysis to study the PK/PD integration model and use Cefquinome to treat animal diseases caused by A. pleuropneumoniae.

  • Microdialysis Determination of Cefquinome Pharmacokinetics in Murine Thigh From Healthy, Neutropenic, and Actinobacillus pleuropneumoniae-Infected Mice.
    Frontiers in pharmacology, 2019
    Co-Authors: Longfei Zhang, Zilong Huang, Zheng Kang, Xiangguang Shen, Lihua Yao, Huanzhong Ding
    Abstract:

    This study was aimed at applying microdialysis to explore Cefquinome pharmacokinetics in thigh and plasma of healthy, neutropenic, and Actinobacillus pleuropneumoniae-infected mice. The relative recoveries (RRs) were tested in vitro by dialysis and retrodialysis and in vivo by retrodialysis. ICR mice were randomly divided into four groups: H-40 mg/kg (healthy mice receiving Cefquinome at 40 mg/kg), H-160 mg/kg, N-40 mg/kg (neutropenic mice), and I-40 mg/kg (thigh infected-mice with A. pleuropneumoniae). After Cefquinome administration, plasma was collected by retro-orbital puncture and thigh dialysate was collected by using a microdialysis probe with Ringer's solution at a perfusion rate of 1.5 L/min. Plasma and thigh dialysate samples were assessed by HPLC-MS/MS and analysed by a non-compartment model. The mean in vivo recoveries in the thigh were 39.35%, 38.59%, and 37.29% for healthy, neutropenic, and infected mice, respectively. The mean plasma protein binding level was 16.40% and was independent of drug concentrations. For all groups, the mean values of the free AUCinf in plasma were higher than those in murine thigh, while the elimination T1/2β for plasma were lower than those for murine thigh. Cefquinome penetration (AUCthigh/AUCplasma) from the plasma to thigh was 0.70, 0.81, 0.49, and 0.98 for H-40, N-40, I-40, and H-160 mg/kg, respectively. These results indicated that infection significantly affected Cefquinome pharmacokinetics in murine thigh. In conclusion, we successfully applied a microdialysis methods to evaluate the pharmacokinetics of Cefquinome in murine thigh of healthy, neutropenic, and A. pleuropneumonia-infected mice and the pharmacokinetics of Cefquinome was obviously affected by infection in thigh.

  • pharmacokinetic pharmacodynamic integration of Cefquinome against pasteurella multocida in a piglet tissue cage model
    Journal of Veterinary Pharmacology and Therapeutics, 2019
    Co-Authors: Longfei Zhang, Zilong Huang, Zheng Kang, Yuqin Chen, Xiangguang Shen, Qinren Cai, Huanzhong Ding
    Abstract:

    To explore the in vivo antimicrobial activity of Cefquinome against Pasteurella multocida in piglets, a piglet tissue cage infection model was used in this study. After the population of P. multocida reached 107  CFU/mL in a tissue cage, piglets received an intramuscular administration of Cefquinome at 0.2, 0.4, 0.8, 1, 2, and 4 mg/kg once daily for 3 days. To assess the tissue cage pharmacokinetics (PKTCF) of Cefquinome, tissue cage fluid was collected for Cefquinome analysis at 1, 3, 6, 9, 12, and 24 hr after each of the 3 daily drug administrations. Bacteria were counted every 24 hr after drug administration and at 48 and 72 hr after the last administration. Evaluation of the relationship between pharmacokinetic/pharmacodynamic (PK/PD) parameters and the antibacterial effect showed that the surrogate of %T > minimum inhibitory concentration (MIC) (R2  = 0.981) was the best PK/PD index that correlated with effectiveness of Cefquinome against P. multocida. The respective values of %T > MIC required for continuous 1/3-log, 1/2-log, and 1-log reductions were 14.23, 34.45, and 73.44%, respectively, during each 24-hr treatment period. In conclusion, Cefquinome exhibited a potent antibacterial effect against P. multocida. When %T > MIC reached 73.44%, Cefquinome exhibited a bactericidal effect against P. multocida after three successive daily administrations.

  • Pharmacokinetic/pharmacodynamic integration of Cefquinome against Pasteurella Multocida in a piglet tissue cage model.
    Journal of veterinary pharmacology and therapeutics, 2018
    Co-Authors: Longfei Zhang, Zilong Huang, Zheng Kang, Yuqin Chen, Xiangguang Shen, Qinren Cai, Huanzhong Ding
    Abstract:

    To explore the in vivo antimicrobial activity of Cefquinome against Pasteurella multocida in piglets, a piglet tissue cage infection model was used in this study. After the population of P. multocida reached 107  CFU/mL in a tissue cage, piglets received an intramuscular administration of Cefquinome at 0.2, 0.4, 0.8, 1, 2, and 4 mg/kg once daily for 3 days. To assess the tissue cage pharmacokinetics (PKTCF) of Cefquinome, tissue cage fluid was collected for Cefquinome analysis at 1, 3, 6, 9, 12, and 24 hr after each of the 3 daily drug administrations. Bacteria were counted every 24 hr after drug administration and at 48 and 72 hr after the last administration. Evaluation of the relationship between pharmacokinetic/pharmacodynamic (PK/PD) parameters and the antibacterial effect showed that the surrogate of %T > minimum inhibitory concentration (MIC) (R2  = 0.981) was the best PK/PD index that correlated with effectiveness of Cefquinome against P. multocida. The respective values of %T > MIC required for continuous 1/3-log, 1/2-log, and 1-log reductions were 14.23, 34.45, and 73.44%, respectively, during each 24-hr treatment period. In conclusion, Cefquinome exhibited a potent antibacterial effect against P. multocida. When %T > MIC reached 73.44%, Cefquinome exhibited a bactericidal effect against P. multocida after three successive daily administrations.

  • Pharmacokinetic/pharmacodynamic assessment of Cefquinome against Actinobacillus Pleuropneumoniae in a piglet tissue cage infection model.
    Veterinary microbiology, 2018
    Co-Authors: Longfei Zhang, Zilong Huang, Xiangguang Shen, Qinren Cai, Nan Zhang, Huanzhong Ding
    Abstract:

    To evaluate the relationship between the pharmacokinetic/pharmacodynamic (PK/PD) parameters and the antibacterial effect of Cefquinome against Actinobacillus pleuropneumoniae, a tissue cage infection model was established in piglets. In this model, an initial count of A. pleuropneumoniae of approximately 106 CFU/mL was exposed to different concentrations of Cefquinome after multiple administration at dosages of 0.2, 0.4, 0.8, 1, 2, 4 mg/kg body weight once a day for 3 days. Concentration of Cefquinome and bacterial numbers of A. pleuropneumoniae in the tissue-cage fluid (TCF) were monitered. An inhibitory form of sigmoid maximum effect (Emax) model was used to estimate the relationship between the antibacterial effect and PK/PD indices of Cefquinome against A. pleuropneumoniae. The minimum inhibitory concentration of Cefquinome against A. pleuropneumoniae was 0.016 μg/mL in TCF. The total maximum antibacterial effect was a 3.96 log10 (CFU/mL) reduction. In addition, the cumulative percentage of time over a 24 h period that the drug concentration exceeds the MIC (%T > MIC) was the pharmacokinetic-pharmacodynamic (PK-PD) index that best correlated with the antibacterial efficacy (R2 = 0.967). The estimated %T > MIC values were 11.59, 27.49, and 59.81% for a 1/3-log10 (CFU/mL) reduction, a 2/3-log10 (CFU/mL) reduction, and a 1-log10 (CFU/mL) reduction, respectively, during the 24h administration period of Cefquinome. In conclusion, Cefquinome exhibits excellent antibacterial activity and time-dependent characteristics against A. pleuropneumoniae in vivo. Furthermore, these data provide meaningful guidance to optimize regimens of Cefquinome to treat respiratory tract infections caused by A. pleuropneumoniae.

Jian Sun - One of the best experts on this subject based on the ideXlab platform.

  • Relationship between Cefquinome PK/PD Parameters and Emergence of Resistance of Staphylococcus aureus in Rabbit Tissue-Cage Infection Model.
    Frontiers in microbiology, 2016
    Co-Authors: Mingpeng Xiong, Longfei Zhang, Zilong Huang, Shu-yi Zeng, Jian Sun, Huanzhong Ding
    Abstract:

    In order to explore the relationship between different antibiotic dosing regimens and selective enrichment of resistant strains, tissue-cage infection model was established in rabbits to study relationship between Cefquinome pharmacokinetic/pharmacodynamic parameters and the change of susceptibility of Staphylococcus aureus (S. aureus). In this model, above 108 CFU/ mL of S. aureus culture were exposed to Cefquinome concentrations below the MIC99 (the minimal concentration that inhibits colony formation by 99% in vitro, 0.3 µg/ mL ), between the MIC99 and the MPC (the mutant prevent concentration in vitro, 1.6 µg/ mL), and above the MPC after intramuscular injection with Cefquinome at doses of 4, 8, 16, 32 mg/kg of body weight once daily for 5 days or 4, 8, 16, 24 mg/kg of body weight twice daily for 2.5 days. Samples of tissue-cage fluid were collected from the tissue-cage at 2, 4, 6, 8, 10, 12, 24h after each dosing (one dosing daily) or at 2, 4, 6, 8, 10, 12h (two dosing daily). Cefquinome concentration, susceptibility of S. aureus to Cefquinome, and bacterial numbers at the infected site were monitored. The MICs of S. aureus and the fraction of resistant bacteria both increased when Cefquinome concentrations fluctuated between the MIC99 and MPC. Resistant bacteria were selected in vivo when %T>MPC was MIC99 was ≥ 70% of administration interval. These findings demonstrate that low-level Cefquinome-resistant S. aureus were selected predominantly when drug concentrations fell inside a concentration window in in vivo model, which was evidenced by pulsed field gel electrophoresis. The selection of resistant bacteria arose from both susceptible bacteria being killed and resistant bacteria re-growth. Keeping drug concentrations above the MPC for ≥ 58% of administration interval provides a strategy to achieve effective antibacterial activity and minimize the emergence of resistance to Cefquinome.

  • In Vivo Pharmacokinetics/Pharmacodynamics of Cefquinome in an Experimental Mouse Model of Staphylococcus Aureus Mastitis following Intramammary Infusion.
    PloS one, 2016
    Co-Authors: Yufeng Zhou, Jian Sun, Mei-ren Chen, Gui-lin Qiao, Xiao-ping Liao, Yahong Liu
    Abstract:

    Staphylococcus aureus remains the major cause of morbidity of bovine mastitis worldwide leading to massive economic losses. Cefquinome is a fourth generation cephalosporin, which preserves susceptibility and antibacterial activity against S. aureus. This work aims to study the pharmacokinetic (PK) and pharmacodynamic (PD) modeling following intramammary administration of Cefquinome against S. aureus mastitis. The mouse model of S. aureus mastitis was developed for the PK/PD experiments. The plasma PK characteristics after intramammary injection of Cefquinome at various single doses of 25, 50, 100, 200, 400 μg per gland (both fourth pairs of glands: L4 and R4) were calculated using one-compartment and first-order absorption model. PD study was investigated based on twenty-one intermittent dosing regimens, of which total daily dose ranged from 25 to 4800 μg per mouse and dosage intervals included 8, 12 or 24 h. The sigmoid Emax model of inhibitory effect was employed for PK/PD modeling. The results of PK/PD integration of Cefquinome against S. aureus suggested that the percentage of duration that drug concentration exceeded the minimal inhibitory concentration (%T>MIC) and the ratio of area under time-concentration curve over MIC (AUC/MIC) are important indexes to evaluate the antibacterial activity. The PK/PD parameters of %T>MIC and AUC0-24/MIC were 35.98% and 137.43 h to obtain a 1.8 logCFU/gland reduction of bacterial colony counts in vivo, against S. aureus strains with Cefquinome MIC of 0.5μg/ml.

  • in vivo pharmacokinetics pharmacodynamics of Cefquinome in an experimental mouse model of staphylococcus aureus mastitis following intramammary infusion
    PLOS ONE, 2016
    Co-Authors: Yufeng Zhou, Jian Sun, Mei-ren Chen, Gui-lin Qiao, Xiao-ping Liao, Yahong Liu
    Abstract:

    Staphylococcus aureus remains the major cause of morbidity of bovine mastitis worldwide leading to massive economic losses. Cefquinome is a fourth generation cephalosporin, which preserves susceptibility and antibacterial activity against S. aureus. This work aims to study the pharmacokinetic (PK) and pharmacodynamic (PD) modeling following intramammary administration of Cefquinome against S. aureus mastitis. The mouse model of S. aureus mastitis was developed for the PK/PD experiments. The plasma PK characteristics after intramammary injection of Cefquinome at various single doses of 25, 50, 100, 200, 400 μg per gland (both fourth pairs of glands: L4 and R4) were calculated using one-compartment and first-order absorption model. PD study was investigated based on twenty-one intermittent dosing regimens, of which total daily dose ranged from 25 to 4800 μg per mouse and dosage intervals included 8, 12 or 24 h. The sigmoid Emax model of inhibitory effect was employed for PK/PD modeling. The results of PK/PD integration of Cefquinome against S. aureus suggested that the percentage of duration that drug concentration exceeded the minimal inhibitory concentration (%T>MIC) and the ratio of area under time-concentration curve over MIC (AUC/MIC) are important indexes to evaluate the antibacterial activity. The PK/PD parameters of %T>MIC and AUC0-24/MIC were 35.98% and 137.43 h to obtain a 1.8 logCFU/gland reduction of bacterial colony counts in vivo, against S. aureus strains with Cefquinome MIC of 0.5μg/ml.

  • pharmacokinetic pharmacodynamic correlation of Cefquinome against experimental catheter associated biofilm infection due to staphylococcus aureus
    Frontiers in Microbiology, 2016
    Co-Authors: Yufeng Zhou, Jian Sun, Wei Shi, Mengting Tao, Yan Q Xiong, Yahong Liu
    Abstract:

    Biofilm formations play an important role in Staphylococcus aureus pathogenesis and contribute to antibiotic treatment failures in biofilm-associated infections. The aim of this study was to evaluate the pharmacokinetic/pharmacodynamic (PK/PD) profiles of Cefquinome against an experimental catheter-related biofilm model due to S. aureus, including three clinical isolates and one non-clinical isolate. The minimal inhibitory concentration (MIC), minimal biofilm inhibitory concentration (MBIC), biofilm bactericidal concentration (BBC), minimal biofilm eradication concentration (MBEC) and biofilm prevention concentration (BPC) and in vitro time-kill curves of Cefquinome were studied in both planktonic and biofilm cells of study S. aureus strains. The in vivo post-antibiotic effects (PAEs), PK profiles and efficacy of Cefquinome were performed in the catheter-related biofilm infection model in murine. A sigmoid E max model was utilized to determine the PK/PD index that best described the dose-response profiles in the model. The MICs and MBICs of Cefquinome for the four S. aureus strains were 0.5 and 16 μg/mL, respectively. The BBCs (32-64 μg/mL) and MBECs (64-256 μg/mL) of these study strains were much higher than their corresponding BPC values (1-2 μg/mL). Cefquinome showed time-dependent killing both on planktonic and biofilm cells, but produced much shorter PAEs in biofilm infections. The best-correlated PK/PD parameters of Cefquinome for planktonic and biofilm cells were the duration of time that the free drug level exceeded the MIC (fT > MIC, R (2) = 96.2%) and the MBIC (fT > MBIC, R (2) = 94.7%), respectively. In addition, the AUC24h/MBIC of Cefquinome also significantly correlated with the anti-biofilm outcome in this model (R (2) = 93.1%). The values of AUC24h/MBIC for biofilm-static and 1-log10-unit biofilm-cidal activity were 22.8 and 35.6 h; respectively. These results indicate that the PK/PD profiles of Cefquinome could be used as valuable guidance for effective dosing regimens treating S. aureus biofilm-related infections.

  • Pharmacokinetics and bioavailability of Cefquinome in healthy ducks.
    American journal of veterinary research, 2011
    Co-Authors: Liguo Yuan, Jian Sun, Rui Wang, Lihua Sun, Lixiang Zhu, Xianyang Luo, Binghu Fang, Yahong Liu
    Abstract:

    To determine pharmacokinetics and bioavailability of Cefquinome administered IV, IM, or PO to healthy ducks. Thirty-six 2-month-old Muscovy ducks. Ducks were randomly assigned to 3 groups of 12 birds each for a single IV, IM, or PO administration at a dose of 5 mg/kg. Blood samples were collected before and at various intervals after each administration. Cefquinome concentration was determined by use of high-performance liquid chromatography at 268 nm with a UV detector, and pharmacokinetics were analyzed. The disposition of Cefquinome following IV or IM administration was best described by a 2-compartment model. After IV administration, mean ± SD elimination halflife was 1.57 ± 0.06 hours, clearance value was 0.22 ± 0.02 L/kg·h, and apparent volume of distribution at steady state was 0.41 ± 0.04 L/kg. After IM administration, elimination half-life was 1.79 ± 0.13 hours, peak concentration time was 0.38 ± 0.06 hours, peak drug concentration was 9.38 ± 1.61 μg/mL, and absolute mean ± SD bioavailability was 93.28 ± 13.89%. No Cefquinome was detected in plasma after PO administration. Results indicated that Cefquinome was absorbed quickly and had excellent bioavailability after IM administration, but absorption after PO administration was poor.

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  • Correlation of PK/PD Indices with Resistance Selection for Cefquinome against Staphylococcus aureus in an In Vitro Model
    Frontiers in Microbiology, 2016
    Co-Authors: Baoyi Feng, Zhenling Zeng, Dawei Yang, Bingxu Zhang, Huanzhong Ding
    Abstract:

    Cefquinome is a fourth-generation Cephalosporin approved for use in animals exclusively. The objective of this study was to explore the relationship of Cefquinome pharmacokinetic/pharmacodynamic (PK/PD) indices with resistance selection of Staphylococcus aureus ATCC25923 in an in vitro model. Six dosing regiments of Cefquinome at an interval of 24 h for three consecutive times were simulated, resulting in maximum concentrations (Cmax) from 1/2 MIC to 16 MIC and half-lives (t1/2β) of 3 and 6 h, respectively. The in vitro sensitivity of S. aureus was monitored by bacterial susceptibility and dynamic time-kill curve experiments over the six Cefquinome concentrations. The correlation between changes in bacterial susceptibility (MIC72/MIC0) and the percentage of time within mutant selection window (MSW) versus dosing interval (TMSW %) was subjected to Gaussian function and regression analysis. The results favored the consensus that time above MIC (T>MIC) was recognized as an important PK/PD parameter of cephalosporins for antibacterial efficiency. Cefquinome reached the maximum killing effect when T>MIC% attained approximately 40%~60%. The subsequent correlation analysis demonstrated that resistant S. aureus ATCC25923 was easy to occur when TMSW% attained an index of about 20% with t1/2β of 3 h after multiple dosing, and 40% with t1/2β of 6 h after multiple dosing.

  • in vivo activity of Cefquinome against escherichia coli in the thighs of neutropenic mice
    Antimicrobial Agents and Chemotherapy, 2014
    Co-Authors: Chaoping Liang, Jufeng Li, Qi Xin-shan, Jing Wang, Zhenling Zeng
    Abstract:

    Cefquinome is a cephalosporin with broad-spectrum antibacterial activity, including activity against enteric Gram-negative bacilli such as Escherichia coli. We utilized a neutropenic mouse model of colibacillosis to examine the pharmacodynamic (PD) characteristics of Cefquinome, as measured by organism number in homogenized thigh cultures after 24 h of therapy. Serum drug levels following 4-fold-escalating single doses of Cefquinome were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The pharmacokinetic (PK) properties of Cefquinome were linear over a dose range of 10 to 640 mg/kg of body weight. Serum half-lives ranged from 0.29 to 0.32 h. Dose fractionation studies over a 24-h dose range of 2.5 to 320 mg/kg were conducted every 3, 6, 12, or 24 h. Nonlinear regression analysis was used to determine which pharmacodynamic parameter best correlated with efficacy. The free percentage of the dosing interval that the serum levels exceed the MIC (fT>MIC) was the PK-PD index that best correlated with efficacy (R2 = 73% for E. coli, compared with 13% for the maximum concentration of the free drug in serum [fCmax]/MIC and 45% for the free-drug area under the concentration-time curve from 0 to 24 h [fAUC0-24]/MIC). Subsequently, we employed a similar dosing strategy by using 4-fold-increasing total Cefquinome doses administered every 4 h to treat animals infected with four additional E. coli isolates. A sigmoid maximum-effect (Emax) model was used to estimate the magnitudes of the %fT>MIC associated with net bacterial stasis, a 1-log10 CFU reduction from baseline, and a 2-log10 CFU reduction from baseline; the corresponding values were 28.01% ± 2.27%, 37.23% ± 4.05%, and 51.69% ± 9.72%. The potent bactericidal activity makes Cefquinome an attractive option for the treatment of infections caused by E. coli.

  • Pharmacodynamics of Cefquinome in a neutropenic mouse thigh model of Staphylococcus aureus infection.
    Antimicrobial agents and chemotherapy, 2014
    Co-Authors: Jing Wang, Chaoping Liang, Qi Xin-shan, Huanzhong Ding, Zhenling Zeng
    Abstract:

    Cefquinome is a cephalosporin with broad-spectrum antibacterial activity, including activity against Staphylococcus aureus. The objective of our study was to examine the in vivo activity of Cefquinome against S. aureus strains by using a neutropenic mouse thigh infection model. Cefquinome kinetics and protein binding in infected neutropenic mice were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). In vivo postantibiotic effects (PAEs) were determined after a dose of 100 mg/kg of body weight in mice infected with S. aureus strain ATCC 29213. The animals were treated by subcutaneous injection of Cefquinome at doses of 2.5 to 320 mg/kg of body weight per day divided into 1, 2, 3, 6, or 12 doses over 24 h. Cefquinome exhibited time-dependent killing and produced in vivo PAEs at 2.9 h. The percentage of time that serum concentrations were above the MIC (%T>MIC) was the pharmacokinetic-pharmacodynamic (PK-PD) index that best described the efficacy of Cefquinome. Subsequently, we employed a similar dosing strategy by using increasing total Cefquinome doses that increased 4-fold and were administered every 4 h to treat animals infected with six additional S. aureus isolates. A sigmoid maximum effect (Emax) model was used to estimate the magnitudes of the ratios of the %T that the free-drug serum concentration exceeded the MIC (%T>fMIC) associated with net bacterial stasis, a 0.5-log10 CFU reduction from baseline, and a 1-log10 CFU reduction from baseline; the respective values were 30.28 to 36.84%, 34.38 to 46.70%, and 43.50 to 54.01%. The clear PAEs and potent bactericidal activity make Cefquinome an attractive option for the treatment of infections caused by S. aureus.

  • Pharmacokinetics and Residues of Cefquinome in Milk of Lactating Chinese Dairy Cows After Intramammary Administration
    Journal of Integrative Agriculture, 2014
    Co-Authors: Lin Wang, Zhenling Zeng, Fan Yang, Bo Yuan, Jian-hua Shu, Huanzhong Ding
    Abstract:

    Abstract The purpose of the study was to investigate the pharmacokinetics of Cefquinome in plasma and milk samples of lactating Chinese Holstein following a single intramammary administration into one quarter at the dose of 75 mg. Residue depletion of Cefquinome in milk administrated at one quarter following three consecutive infusions at the same dose were also carried out. Cefquinome concentrations in plasma and milk were determined by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method. A non-compartmental analysis was used to obtain the pharmacokinetic parameters of Cefquinome. Following the single treatment, Cefquinome wasn't detected in any of the plasma samples. The concentration of Cefquinome in milk reached peaked values (C max ) of (599.00±322.00) μg mL −1 at 2 h after administration (T max ), elimination half-life (t 1/2λz ) was (4.63±0.26) h, area under the concentration-time curve (AUC 0-∞ ) was (4890.19±1906.98) μg mL −1 h, and mean residence time (MRT) was (6.03±2.27) h. In residue depletion study, Cefquinome concentrations in 5 out of 6 milk samples at 72 h were lower than the maximum residue limit fixed by the European regulatory agency (20 μg kg −1 for Cefquinome) and Cefquinome still could be detected in milk of treated quarters at 120 h post-treatment. The maximum concentration (C max ) of Cefquinome in milk from treated quarters was (486.50±262.92) μg mL −1 and arrived at 6 h after administration (T max ), elimination half-life (t 1/2λz ) was (6.30±0.76) h, area under the concentration-time curve (AUC 0-∞ ) was (44747.79±11434.43) μg mL −1 h, and mean residence time (MRT) was (10.09±1.40) h. This study showed that Cefquinome has the feature of poor penetration into blood and was eliminated quickly from milk in lactating cows after intramammary administration.