Pharmacodynamic Target Assessment and PK/PD Cutoff Determination for Gamithromycin Against Streptococcus suis in Piglets.
Pharmacodynamic Target Assessment and PK/PD Cutoff Determination for Gamithromycin Against Streptococcus suis in Piglets.
复制标题
加米霉素对抗仔猪猪链球菌的药效靶点评估和 PK/PD 截止值测定
DOI：
10.3389/fvets.2022.945632
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发表时间：
2022
影响因子：
3.2
通讯作者：
Zhou YF
中科院分区：
文献类型：
--
作者：
Wang RL;Liu P;Chen XF;Yao X;Liao XP;Liu YH;Sun J;Zhou YF
加米霉素是最近开发的一种长效氮杂环类抗生素，用于治疗猪呼吸道疾病。本研究评价了中国地区仔猪对猪链球菌2型的药代动力学/药效学(PK/PD)指标、PK/PD临界值和最佳给药方案。观察了伽米霉素对猪链球菌的短期抗生素后效应(PAEs)(0.5-2.6h)和PA-SMEs(2.4-7.7h)。血清基质极大地促进了猪链球菌细胞内对伽米霉素的摄取，从而有助于血清对其敏感性的增强作用，对猪链球菌的Mueller-Hinton肉汤(MHB)/血清最低抑菌浓度(MIC)比值为28.86。剂量-反应关系表明，浓度下面积(AUC)/MIC比率是与活性密切相关的预测PK/PD指数(R2>；0.93)。对于猪链球菌感染，在血清AUC 24小时/MIC靶点为17.9、49.1和166h时，达到净停滞、1-log10和2-log10杀灭效果。在目前的临床剂量为6 mg/kg时，伽米霉素PK/PD的临界值为8 mg/L。基于PK/PD的剂量评估表明，对于观察到的中国猪链球菌野生型MIC分布，有效治疗的最佳剂量方案为2.53 mg/kg，靶向达标率(≥)为90%。这些结果将有助于临床剂量优化研究的发展和建立伽米霉素治疗猪链球菌引起的猪呼吸道感染的临床转折点。
Gamithromycin is a long-acting azalide antibiotic that has been developed recently for the treatment of swine respiratory diseases. In this study, the pharmacokinetic/pharmacodynamic (PK/PD) targets, PK/PD cutoff, and optimum dosing regimen of gamithromycin were evaluated in piglets against Streptococcus suis in China, including a subset with capsular serotype 2. Short post-antibiotic effects (PAEs) (0.5–2.6 h) and PA-SMEs (2.4–7.7 h) were observed for gamithromycin against S. suis. The serum matrix dramatically facilitated the intracellular uptake of gamithromycin by S. suis strains, thus contributing to the potentiation effect of serum on their susceptibilities, with a Mueller-Hinton broth (MHB)/serum minimum inhibitory concentration (MIC) ratio of 28.86 for S. suis. Dose-response relationship demonstrated the area under the concentration (AUC)/MIC ratio to be the predictive PK/PD index closely linked to activity (R2 > 0.93). For S. suis infections, the net stasis, 1–log10, and 2–log10 kill effects were achieved at serum AUC24h/MIC targets of 17.9, 49.1, and 166 h, respectively. At the current clinical dose of 6.0 mg/kg, gamithromycin PK/PD cutoff value was determined to be 8 mg/L. A PK/PD-based dose assessment demonstrated that the optimum dose regimen of gamithromycin to achieve effective treatments for the observed wild-type MIC distribution of S. suis in China with a probability of target attainment (PTA) ≥ 90% was 2.53 mg/kg in this study. These results will aid in the development of clinical dose-optimization studies and the establishment of clinical breakpoints for gamithromycin in the treatment of swine respiratory infections due to S. suis.
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影响因子：
3.7
作者：
Chen C;Tang J;Dong W;Wang C;Feng Y;Wang J;Zheng F;Pan X;Liu D;Li M;Song Y;Zhu X;Sun H;Feng T;Guo Z;Ju A;Ge J;Dong Y;Sun W;Jiang Y;Wang J;Yan J;Yang H;Wang X;Gao GF;Yang R;Wang J;Yu J
通讯作者：
Yu J
影响因子：
3.2
作者：
Guo LL;Gao RY;Wang LH;Lin SJ;Fang BH;Zhao YD
通讯作者：
Zhao YD
影响因子：
5.2
作者：
Toutain PL;Bousquet-Mélou A;Damborg P;Ferran AA;Mevius D;Pelligand L;Veldman KT;Lees P
通讯作者：
Lees P
影响因子：
4.4
作者：
Watteyn, A.;Plessers, E.;Croubels, S.
通讯作者：
Croubels, S.
影响因子：
1.3
作者：
Lees, P.;Illambas, J.;Toutain, P. -L.
通讯作者：
Toutain, P. -L.