氟苯尼考对猪链球菌的药动学-药效学同步模型研究

Florfenicol (FF) is one of the common drugs used for treating swine streptococcus disease for its advantages of strong antibacterial activity, quick absorption and rapid accumulation in the lung tissue of pigs. But improper use of this antibiotic may lead to treatment failure and antimicrobial drug resistance. This work focused on the inter-relationships of the dynamic process of FF concentration in lung tissue fluid and its antibacterial effect against streptococcus suis (S. suis). It also reflects the relationship of drug, bacteria and animals by the method of pharmacokinetic-pharmacodynamic (PK-PD) model to design a dosage regimen for FF in clinical application. In this study, the minimal inhibitory concentration (MIC) of FF against 100 strains of S. suis isolates from swine will be determined following Clinical and Laboratory Standards Institute (CLSI) guidance to screening the clinical pathogenic strains; the PK properties of FF will be determined in lung tissue fluid of swine by using the electronic bronchoscope together with the detection of urea nitrogen and HPLC method ; the ex vivo PD of FF against S. suis will be investigated in lung tissue fluid and to establish a PK-PD model of FF in swine streptococcus by WinNonlin software. The model validation of the dosage regimen will be executed in infected animal finally. Through this study, it will lay a theoretic foundation of FF for rational use in clinical therapy.

氟苯尼考因其抗菌活性强，给药吸收快，肺部药物浓度高等优点是目前治疗猪链球菌病的常用药物，但临床给药方案的不合理往往导致治疗效果不理想且极易导致耐药性的产生。本项目拟利用药动学-药效学(PK-PD)同步模型研究氟苯尼考在猪肺部动态变化过程及其抗猪链球菌的相互关系，为其制定科学合理的临床给药方案。本研究通过对100株临床分离的猪链球菌进行敏感性试验并筛选敏感致病菌，应用电子纤维支气管镜收集肺泡灌洗液结合尿素氮的检测和高效液相分析的方法建立氟苯尼考在敏感致病菌感染猪体内的肺部药动学，并取肺部组织液进行半体内的药效学研究，在此基础上采用WinNonlin软件建立氟苯尼考的PK-PD同步模型并制定其合理的临床给药方案，最后通过耐药致病菌和敏感致病菌感染健康猪开展PK-PD同步模型的验证试验。本研究将为临床科学合理使用氟苯尼考治疗猪链球菌病提供理论依据，也有助于降低氟苯尼考耐药性的产生。

抗菌药物的细菌耐药性日趋严重，与临床不合理使用有直接关系。药动学-药效学(PK-PD)同步模型综合药物体内过程、菌株与宿主三者相互关系与作用规律，对制定防耐药给药方案具有重要指导意义。为此，本项目开展了氟苯尼考对猪链球菌以及多西环素对副猪嗜血杆菌的PK-PD模型研究，为延长临床使用寿命提供帮助。传统药动学大多基于健康动物，这与临床患病动物存在较大的生理与病理差异。所以，本项目进行了替米考星、多西环素、氟苯尼考等猪细菌性呼吸道致病菌常用防治药物在患病模型下的药动学研究，为优化临床给药剂量提供理论依据。再有，猪链球菌等致病菌大多定植于呼吸道黏液中，血清/血浆中的药物浓度并不能很好的关联抑菌效应，为此，本项目开展了氟苯尼考在猪肺泡灌洗液中的药动学，为进一步优化氟苯尼考防治猪细菌性疾病提供理论参考。最后，氟苯尼考、替米考星水溶性极差、给药副作用大、体内代谢快，临床频繁给药等，不仅给动物造成了不利的应激反应，还加大了兽医工作者劳动强度。因此，我们利用了纳米载体技术研制了氟苯尼考与替米考星复方固体脂质纳米粒，在发挥药物间协同作用的同时，避免使用有机溶剂，增加了用药的安全性，延长了药物体内滞留时间，获得了明显的缓释效应，为优化临床疾病防治效应提供技术借鉴。