Department of Clinical Pharmacy, Institute of Pharmacy, University of Hamburg, Hamburg, Germany.
Institute for Medical Microbiology, Virology and Hygiene, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
J Antimicrob Chemother. 2022 Aug 25;77(9):2470-2478. doi: 10.1093/jac/dkac183.
Tedizolid is a novel oxazolidinone antibiotic. Considering the higher antibacterial effect in immunocompetent compared with immunosuppressed animals, it is not recommended in immunocompromised patients.
In this study, we assessed the 'pure' pharmacokinetic-pharmacodynamic (PKPD) relationship for tedizolid against Enterococcus in the hollow-fibre infection model (HFIM).
Unbound plasma concentration time profiles (200-5000 mg/day IV) were simulated in the HFIM over 120 h against an Enterococcus faecalis strain and two clinical isolates of Enterococcus faecium (VRE-vanB and VRE-vanA). Next, a PKPD model describing tedizolid efficacy against bacterial isolates was developed. A population PK model was linked to the developed PKPD model and utilized to predict the bacterial kinetics in plasma and in target tissues [adipose, muscle, epithelial lining fluid (ELF) and sputum] over 120 h of therapy.
The PKPD model adequately described the bacterial kill kinetics for all bacterial populations. At the human recommended dose of 200 mg/day, bacterial growth was predicted in plasma and all tissues, except for ELF. Bacteriostasis was observed only at a higher dose of 1200 mg/day over 120 h. An fAUC/MIC of 80 related to stasis over 120 h. Subpopulations resistant to 3 × MIC were amplified in plasma and target tissues, except for ELF, at doses of 200-800 mg/day.
The human dose of 200 mg/day was insufficient to suppress bacterial growth in the HFIM, indicating that further components contribute to the clinical effect of tedizolid. This study supports the warning/precaution for tedizolid to limit its use in immunocompromised patients.
替加环素是一种新型噁唑烷酮类抗生素。鉴于其在免疫功能正常动物中的抗菌效果更高，因此不建议在免疫功能低下的患者中使用。
在本研究中，我们评估了替加环素在中空纤维感染模型（HFIM）中针对肠球菌的“纯”药代动力学-药效学（PKPD）关系。
在 HFIM 中模拟了 120 小时内替加环素（200-5000mg/天 IV）针对粪肠球菌菌株和两株临床分离屎肠球菌（VRE-vanB 和 VRE-vanA）的游离血浆浓度时间曲线。接下来，开发了一个描述替加环素对细菌分离株疗效的 PKPD 模型。将群体 PK 模型与开发的 PKPD 模型相链接，并利用该模型预测治疗 120 小时内替加环素在血浆和目标组织（脂肪、肌肉、上皮衬里液（ELF）和痰）中的细菌动力学。
PKPD 模型充分描述了所有细菌群体的细菌杀灭动力学。在推荐的 200mg/天的人体剂量下，预测在血浆和所有组织中均会发生细菌生长，除了 ELF 外。仅在 1200mg/天的较高剂量下观察到 120 小时的抑菌作用。fAUC/MIC 为 80 与 120 小时的抑制有关。在 200-800mg/天的剂量下，在血浆和靶组织中（除了 ELF 外），对 3×MIC 耐药的亚群被扩增。
200mg/天的人体剂量不足以抑制 HFIM 中的细菌生长，这表明替加环素的临床疗效还有其他因素。本研究支持了替加环素的警告/谨慎使用，以限制其在免疫功能低下患者中的应用。
