马波沙星与头孢喹肟半体内和休内药动药效学同步模型研究

In the present study, the pharmacokinetic properties of marbofloxacin and cefquinome in serum, inflamed tissue cage fluid (exudate), and noninflamed tissue cage fluid (transudate) will be characterized by using a tissue cage model，and the in vitro and ex vivo activities of marbofloxacin and cefquinome in serum, exudate, and transudate against a pathogenic strain of Pasteurella multocida (P. multocida) will be studied，thus，the ex vivo PK-PD model will be established. In addition, in vitro antimicrobial activity of marbofloxacin and cefquinome against staphylococcus aurous will be determined, and the in vivo activity of marbofloxacin and cefquinome of different dosage regimens against Staphylococcus aureus and the pharmacokinetic properties of the two drugs in mouse will be studied by using a neutropenic murine thigh model. Then, the in vivo PK-PD model will be developed. With those models, the clinical dosage regimen of marbofloxacin and cefquinome against corresponding pathogenic bacterium will be optimized to make the aims of veterinary clinical treatment not only to cure the clinical symptoms but also to eradicate the pathogens in the infection sites to prevent the selective enrichment growth of single-step mutation drug-resistant bacteria group, those will prolong the clinical service lives of new antibacterial drugs only used in the animals and can help to prevent the animal pathogenic bacteria to produce resistance and spread it to human pathogens, which can reduce the risk of threats to human healths.

本项目在建立组织笼模型的基础上，研究马波沙星和头孢喹肟在牛血清、组织液及炎症渗出液中的药动学（PK）特征，测定这两种药物在三种体液中对多杀性巴氏杆菌的体外及半体内抗菌活性，从而建立半体内PK-PD（药效学）同步模型；本研究拟测定这些药物对金黄色葡萄球菌的体外抗菌活性，在建立免疫抑制小鼠大腿感染模型的基础上，研究这些药物在小鼠体内的PK特征，测定这两种药物的不同给药方案对金黄色葡萄球菌的体内抗菌活性，建立体内PK-PD同步模型。本项目通过建立马波沙星和头孢喹肟半体内和体内PK-PD同步模型优化两种药物对多杀性巴氏杆菌和金黄色葡萄球菌的给药方案，使兽医临床治疗的目的不只是局限于临床症状上的治愈，同时还要根除感染部位的病原菌，防止突变耐药菌群的选择性富集生长，有助于延长动物专用抗菌新药在兽医临床的使用寿命，也有助于避免动物病原菌产生耐药性并传播给人类病原菌，减少威胁人类健康的风险。

兽用抗菌药物的长期大量使用，导致了日益严重的细菌耐药性问题，严重威胁到人类健康。近年来，开展药动学（PK）-药效学（PD）模型研究，优化给药方案，是防止和控制耐药性问题的根本途径和最重要的环节。本项目开展了马波沙星和头孢喹肟半体内和体内PK-PD模型研究，首先建立了牛组织笼模型，开展了马波沙星和头孢喹肟对多杀性巴氏杆菌的半体内PK-PD模型研究，采用inhibitory sigmoid Emax model对半体内抗菌效应与PK/PD指数进行拟合，研究结果表明，AUC24h/MIC的相关性较强，马波沙星在血清、组织液和炎症渗出液清除细菌所需的值分别为124.67h，112.33h和117.08h，头孢喹肟在血清、组织液和炎症渗出液达到99%抗菌效应所需的值分别为117.08h，124.90h和116.78h。然后，开展了马波沙星在多杀性巴氏杆菌感染牛体内的PK-PD模型研究，采用inhibitory sigmoid Emax model对体内抗菌效应与PK/PD指数进行拟合，研究结果表明，AUC24h/MIC或者AUC24h/MBC相关性较强，下降1个log所需的值分别为18.60h和4.67h，下降3个log所需的值分别为50.65h和12.89h。接着，建立了免疫抑制小鼠大腿感染模型，开展头孢喹肟在金黄色葡萄球菌感染小鼠体内的PK-PD模型研究，采用inhibitory sigmoid Emax model对体内抗菌效应与PK/PD指数进行拟合，研究结果表明，%fT>MIC）的相关性较强（R2 = 86%），达到静态效应、0.5-log 和 1-log 杀菌效应所需的值分别为30.28% ~ 36.84%、34.38 % ~ 46.70% 和43.50% ~ 54.02%。最后，建立了小鼠肺部感染模型，开展马波沙星在多杀性巴氏杆菌感染小鼠体内的PK-PD模型研究，采用inhibitory sigmoid Emax model对体内抗菌效应与PK/PD指数进行拟合，研究结果表明，fAUC24h/MIC的相关性较强（R2=83%），达到静态效应、下降2-log和3-log杀菌效应所需的值分别为40.84h，139.34h和278.08h。上述研究为马波沙星和头孢喹肟的合理用药提供科学依据。