Huang Zilong, Wu Yuzhi, Zhou Zichong, Xia Xirui, Gu Xiaoyan, Cai Qinren, Shen Xiangguang, Yang Hong, Ding Huanzhong
Guangdong Key Laboratory for Veterinary Drug Development and Safety Evaluation, South China Agricultural University, Guangzhou, China.
Technical Center for Inspection and Quarantine, Zhuhai Entry-Exit Inspection and Quarantine Bureau, Zhuhai, China.
Front Pharmacol. 2019 Jun 12;10:670. doi: 10.3389/fphar.2019.00670. eCollection 2019.
is the major pathogen causing chronic respiratory disease in chickens. In the present study, we successfully established a one-compartment open model with first-order absorption to determine the relationship between tilmicosin pharmacokinetic and pharmacodynamic (PK/PD) indices and in . The aim was to simulate the PK/PD of tilmicosin against in lung tissues. The results of static time-killing curves at constant drug concentrations [0-64 minimum inhibitory concentration (MIC)] showed that the amount of was reduced to the limit of detection after 36 h when the drug concentration exceeded 1 MIC, with a maximum kill rate of 0.53 h. In dynamic time-killing studies, tilmicosin produced a maximum antimycoplasmal effect of 6.38 Log CFU/ml reduction over 120 h. The area under the concentration-time curve over 24 h divided by the MIC (AUC/MIC) was the best PK/PD parameter to predict the antimicrobial activity of tilmicosin against [R = 0.87, compared with 0.49 for the cumulative time that the concentration exceeds the MIC (%T > MIC)]. Therefore, tilmicosin showed concentration-dependent activity. Seven strains (M1-M7) with decreased susceptibility to tilmicosin were isolated from seven dose groups. These strains of had acquired resistance to erythromycin as well as to tylosin. However, no change in susceptibility to amikacin and doxycycline was observed in these strains. Gene mutation analysis was performed on the basis of annotated single nucleotide polymorphisms using the genome of strain S6 as the reference. For strain M5, a G495T mutation occurred in domain II of the 23S gene. In strain M3, resistance was associated with a T854A mutation in domain II of the 23S gene and a G2799A mutation in domain V of 23S . To the best of our knowledge, these tilmicosin resistance-associated mutations in have not been reported. In conclusion, tilmicosin shows excellent effectiveness and concentration-dependent characteristics against strain S6 . Additionally, these results will be used to provide a reference to design the optimal dosage regimen for tilmicosin in infection and to minimize the emergence of resistant bacteria.
是引起鸡慢性呼吸道疾病的主要病原体。在本研究中，我们成功建立了一个具有一级吸收的单室开放模型，以确定替米考星药代动力学和药效学（PK/PD）指标之间的关系以及在……中的情况。目的是模拟替米考星在肺组织中对……的PK/PD。在恒定药物浓度[0 - 64最低抑菌浓度（MIC）]下的静态时间杀菌曲线结果表明，当药物浓度超过1 MIC时，36小时后……的数量减少到检测限，最大杀灭率为0.53小时。在动态时间杀菌研究中，替米考星在120小时内产生了最大6.38 Log CFU/ml的抗支原体效果。24小时浓度 - 时间曲线下面积除以MIC（AUC/MIC）是预测替米考星对……抗菌活性的最佳PK/PD参数[R = 0.87，相比之下浓度超过MIC的累积时间（%T > MIC）为0.49]。因此，替米考星表现出浓度依赖性活性。从七个剂量组中分离出七株对替米考星敏感性降低的……菌株（M1 - M7）。这些……菌株对红霉素以及泰乐菌素均获得了耐药性。然而，在这些菌株中未观察到对阿米卡星和多西环素敏感性的变化。以菌株S6的基因组为参考，基于注释的单核苷酸多态性进行基因突变分析。对于菌株M5，在23S……基因的结构域II中发生了G495T突变。在菌株M3中，耐药性与23S……基因结构域II中的T854A突变以及23S……结构域V中的G2799A突变有关。据我们所知，这些在……中与替米考星耐药相关的突变尚未见报道。总之，替米考星对……菌株S6表现出优异的有效性和浓度依赖性特征。此外，这些结果将为设计替米考星在……感染中的最佳给药方案以及尽量减少耐药菌的出现提供参考。
