Comparative Pharmacodynamics of the New Oxazolidinone Tedizolid Phosphate and Linezolid in a Neutropenic Murine Staphylococcus aureus Pneumonia Model
Comparative Pharmacodynamics of the New Oxazolidinone Tedizolid Phosphate and Linezolid in a Neutropenic Murine Staphylococcus aureus Pneumonia Model
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DOI：
10.1128/aac.01303-12
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发表时间：
2012-11-01
影响因子：
4.9
通讯作者：
Andes, David R.
中科院分区：
文献类型：
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作者：
Lepak, Alexander J.;Marchillo, Karen;Andes, David R.
磷酸替地唑胺（TR-701）是一种新型恶唑烷酮前药（转化为活性形式替地唑胺[TR-700]），具有强效金黄色葡萄球菌活性。当前研究表征并比较了TR-701/TR-700和利奈唑胺对甲氧西林敏感性沙门氏菌的体内药代动力学/药效学（PD）特征。金黄色葡萄球菌（MSSA）和耐甲氧西林的S.金黄色葡萄球菌（MRSA）在血小板减少性鼠肺炎模型中的作用。两种药物的药代动力学特性在0.625至40 mg/kg体重的剂量范围内呈线性。利奈唑胺和TR-700的蛋白结合率分别为30%和85%。用11株S.金黄色葡萄球菌，包括MSSA和社区和医院获得性MRSA菌株。每12 h（q12 h）经口灌胃给予每种药物。利奈唑胺的给药方案范围为1.25 - 80 mg/kg/12 h，TR-701的给药方案范围为0.625 - 160 mg/kg/12 h。在治疗开始时，小鼠具有6.24 +/- 0.40 log（10）CFU/肺，在24小时内未治疗的动物中增加至7.92 +/- 1.02 log（10）CFU/肺。使用S形最大效应（E-max）模型确定与净停滞（静态剂量[SD]）和相对于治疗开始时负荷的1个对数单位微生物减少相关的抗菌剂暴露。利奈唑胺和TR-700的静态剂量药效学目标几乎相同，稳态下24 h内游离药物（非蛋白结合）浓度-时间曲线下面积除以MIC（AUC/MIC比）分别为19和20。1对数单位杀灭终点也相似，利奈唑胺为46.1，TR-700为34.6。MSSA和MRSA分离株的暴露目标也相当。这些剂量目标支持TR-701在MSSA和MRSA肺炎中的进一步临床试验检查。
Tedizolid phosphate (TR-701) is a novel oxazolidinone prodrug (converted to the active form tedizolid [TR-700]) with potent Staphylococcus aureus activity. The current studies characterized and compared the in vivo pharmacokinetic/pharmacodynamic (PD) characteristics of TR-701/TR-700 and linezolid against methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) in the neutropenic murine pneumonia model. The pharmacokinetic properties of both drugs were linear over a dose range of 0.625 to 40 mg/kg of body weight. Protein binding was 30% for linezolid and 85% for TR-700. Mice were infected with one of 11 isolates of S. aureus, including MSSA and community- and hospital-acquired MRSA strains. Each drug was administered by oral-gastric gavage every 12 h (q12h). The dosing regimens ranged from 1.25 to 80 mg/kg/12 h for linezolid and 0.625 to 160 mg/kg/12 h for TR-701. At the start of therapy, mice had 6.24 +/- 0.40 log(10) CFU/lungs, which increased to 7.92 +/- 1.02 log(10) CFU/lungs in untreated animals over a 24-h period. A sigmoid maximum-effect (E-max) model was used to determine the antimicrobial exposure associated with net stasis (static dose [SD]) and 1-log-unit reduction in organism relative to the burden at the start of therapy. The static dose pharmacodynamic targets for linezolid and TR-700 were nearly identical, at a free drug (non-protein-bound) area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC ratio) of 19 and 20, respectively. The 1-log-unit kill endpoints were also similar, at 46.1 for linezolid and 34.6 for TR-700. The exposure targets were also comparable for both MSSA and MRSA isolates. These dosing goals support further clinical trial examination of TR-701 in MSSA and MRSA pneumonia.