【作者】 张旭；

【导师】 王大菊；

【作者基本信息】 华中农业大学 ， 基础兽医学， 2005， 硕士

【摘要】 氟苯尼考是动物专用氯霉素类广谱抗菌药物,其抗菌活性明显优于氯霉素和甲砜霉素,对耐氯霉素和甲砜霉素的病原菌特别敏感,其临床应用日趋广泛。研究氟苯尼考的体外和体内PAE（Post-antibiotic effect,PAE）及药物动力学,旨在为其临床合理应用提供科学依据。 本研究测定了9种抗菌药物对禽多杀性巴氏杆菌（Pasteurella multocida 462 C 48-11）体外抗菌活性及氟苯尼考对禽多杀性巴氏杆菌的体外PAE、抗菌药后亚抑菌浓度效应（Post-antibiotic sub-MIC effect,PA-SME）、抗菌药亚抑菌浓度效应（Sub-MIC effect,SME）。并建立鸡皮下组织笼感染模型,以体外接触药物法研究了氟苯尼考对禽多杀性巴氏杆菌的体内PAE。通过探讨肉鸡内服氟苯尼考后的药物动力学特征,结合体内和体外PAE,设计氟苯尼考治疗禽巴氏杆菌病的给药方案。 采用试管二倍稀释法测定的氨苄西林、阿莫西林、卡那霉素、土霉素、多西环素、甲砜霉素、氟苯尼考、替米考星、诺氟沙星对禽多杀性巴氏杆菌的MIC依次为:0.125、0.125、2、128、32、8、0.5、2和0.125μg/mL。 以菌落计数法测定氟苯尼考对禽多杀性巴氏杆菌的PAE、PA-SME和SME,其范围分别为0.18～5.87h、1.66～24.2h和0.05～1.31h。药物浓度、细菌接种量及药物与细菌接触时间是影响PAE的重要因素。研究表明,在2～8MIC浓度范围内,PAE与药物浓度和接触时间呈正相关,与细菌接种量呈负相关。PA-SME受诱导PAE的药物浓度及亚抑菌药物浓度（Sub-MIC）的影响,提示临床上氟苯尼考可能具有比体外更长的体内PAE。 通过建立鸡皮下组织笼感染模型测定氟苯尼考的体内PAE,氟苯尼考以4MIC和8MIC浓度分别与禽多杀性巴氏杆菌接触1h,测定的体内PAE分别为1.20h和1.48h,同时测定的体外PAE为0.93h和1.17h。表明,氟苯尼考体内PAE长于体外PAE。 肉鸡单剂量（30mg/kg）内服氟苯尼考后,血药经时过程符合一级吸收一室开放模型,其方程为C=4.7804(e^-0.1096t-e^-2.5858t)。主要药物动力学参数为:t_1/2Ka0.28±0.07h、t_1/2Ke6.42±0.83h、t_max1.32±0.26h、C_max 3.96±0.42μg/mL、AUC 42.41±7.50（μg/mL）h。表明,氟苯尼考在鸡体内吸收快,消除相对缓慢。 由氟苯尼考对禽多杀性巴氏杆菌的体外抗菌活牲,结合药物动力学参数及体内和体外PAE,提出鸡内服氟苯尼考的给药方案为1日1次,维持剂量30mg/kg b.w.。更多还原

【Abstract】 Florfenicol, a fluorinated analogue of thiamphenicol and chloramphenicol, is a synthetic, broad-spectrum antibiotic specially for veterinary use. Its structural modification confers advantages in antibacterial activity, particularly against pathogenic bacteria resistant to thiamphenicol and chloramphenicol. For its widely used in the future, PAE and pharmacokmetics of florfenicol were studied.The antibacterial activity of 9 kinds of antimicrobial agents against Pasteurella multocida （462 C48-11） in vitro was studied. And the post-antibiotic effects （PAEs）, post-antibiotic Sub-MIC effects （PA-SMEs） and Sub-MIC effects （SMEs） of florfenicol against P. multocida were observed. The infected tissue cage models, for determining PAEs in vivo of florfenicol, had been developed in chickens. Florfenicol was orally administed to investigate its pharmacokinetic characteristics by using bioassay.Minimal inhibitory concentration （MIC） of Ampicillin, Amoxicillin, Kanamycin, Oxytetracycline, Doxycycline, Thiamphenical, Florfenicol, Tilmicosin, Norfloxacin against P. multocida was detected by the two-fold dilution method in vitro. The results showed that MICs were 0.125, 0.125, 2, 128, 32, 8, 0.5, 2 and 0.125μg/mL, respectively.Florfenicol was exposured to P. multocida for 1 to 2h and removed, the viable bacteria were counted according to its growth on agar plate. PAEs, PA-SMEs and SMEs of florfenicol ranged from 0.18 to 5.87h, from 1.66h to 24.2h and from 0.05 to 1.31h. The results showed that PAEs were positively related to the drug concentrations in 2-8MIC and the time exposure to the bacteria, but negetively to the inoculum size. The results of florfenicol demonstrated that PA-SMEs were longer than PAEs in the same inducement concentration.The infected tissue cage model, developed by implanting two plastic tissue cages in chicken’s subcutaneous tissue, was used to determine PAEs of florfenicol against P. multocida in vivo after the exposure to the drug in vitro for lh. The results showed that PAEs of 4MIC and 8MIC were 1.20 and 1.48h in vivo, 0.93 and 1.17h in vitro, respectively.The pharmacokinetics showed that the concentration course of florfenicol in serum following its oral administration （30mg/kg） in chicken can be described by one-compartment open model with first-order absorption. The equation was shown below: C=4.7804（e⁰.1096t-e^-2.5858t）. The primary parameters were as follows: t₁/2Ka 0.28±0.07h, 6.42±0.83h, tmax 1.32±0.26h, Cmax 3.96±0.42ug/mL, AUC 42.41 ±7.50 （μg/mL）h.The results showed that florfenicol is can be absorbed quickly, the elimination half life is long.Binding the pharmacokinetic characteristics of florfenicol following its oral administration and the PAE in vitro and in vivo, the ideal dosage regime is suggested that chicken can take florfenicol once daily with oral administration of 30mg/kg b.w..更多还原