SAN FRANCISCO(EGMN) –A short course of therapy with torezolid phosphate cured virtually all patients with Staphylococcus aureus–based severe complicated skin and skin structure infections in a randomized, double-blind, phase II study.

A second-generation oxazolidinone related to linezolid, torezolid phosphate is a prodrug that can be given orally once per day, Dr. Philippe Prokocimer said in an interview. Dr. Prokocimer is medical director of Trius Therapeutics, the San Diego–based company that is developing the drug. He was one of the authors of the study, which was presented in a poster at the Interscience Conference on Antimicrobial Agents and Chemotherapy, sponsored by the American Society for Microbiology.

The study involved 192 patients with S. aureus infections who were randomized to receive 200 mg, 300 mg, or 400 mg of torezolid phosphate once a day for 5-7 days. All patients had severe complicated skin and skin structure infections (cSSSI, also called acute bacterial skin structure infections), defined as skin infections that were 5 cm or greater in diameter and/or included systemic signs of infection. Patients with uncomplicated disease or with infections requiring gram-negative coverage were excluded, as were immunocompromised patients and those who had used antibiotics for more than 24 hours within 96 hours of the start of the study.

The clinical outcomes were similar in all dosage groups. Of the patients whose lesions were microbiologically evaluable, 96% achieved a clinical cure, including 95.7% of the patients with methicillin-susceptible S. aureus infections and 96.9% of the patients with methicillin-resistant S. aureus infections.

Five of the patients in the study experienced serious adverse events, but only one of these could have been drug related – a case of acute cholecystitis in an obese 57-year-old woman 2 days after the end of therapy. All other treatment-emergent adverse events were mild or moderate, with nausea the most common (19% of patients). The investigators saw no clinically significant changes in QTc.

“The side effect profile is stellar,” Dr. Prokocimer said. “When we increase the dose, we don’t see a dose-related increase in the incidence of side effects.”

He noted that unlike linezolid, the 200-mg dose of torezolid phosphate had virtually no effects on patients’ lab values and showed no evidence of immunosuppression. The 200-mg dose will be the subject of two pivotal phase III studies, due to begin in 2010.

Each of those studies will enroll 500-600 patients, and the results will be available in 12-18 months. In one of the studies, patients will receive oral medication, and in the other they will start with intravenous medication, switching to oral dosing when possible. These trials will include only patients with cSSSI, but Dr. Prokocimer said that the company hopes to conduct other trials on torezolid phosphate in patients who have respiratory infections or bacteremia.

Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

旧金山(EGMN)—— 一项随机、双盲、II期试验显示，短疗程使用磷酸torezolid几乎治愈了所有金黄色葡萄球菌导致的重度复杂性皮肤和皮肤结构感染患者。

 

Philippe Prokocimer博士在采访中称，作为与利奈唑胺同类的第二代恶唑烷酮类抗生素，磷酸torezolid是一种前药，可口服给药，每日一次。Prokocimer博士是位于美国加州圣地亚哥的Trius Therapeutics公司的医学总监，该公司正在研发这种药物。Prokocimer博士是这项研究的作者之一，在美国微生物协会主办的抗微生物药物与化疗跨学科大会上以墙报形式报告了研究结果。

 

该研究纳入了192名金黄色葡萄球菌感染者，将其随机分组，分别服用200 mg、300 mg或400 mg磷酸torezolid，每日一次，连续服用5～7天。所有患者均患有重度复杂性皮肤和皮肤结构感染(cSSSI，也称为急性细菌性皮肤结构感染)，定义为直径大于或等于5 cm和/或出现了全身感染指征的皮肤感染。排除标准包括：非复杂性疾病或需要抗革兰氏阴性菌的抗生素治疗的感染、免疫缺陷患者以及试验开始前96h内使用抗生素超过24h。

 

所有剂量组的临床结果相似。在病灶可进行微生物评价的患者中，96%达到了临床治愈，其中95.7%的患者存在对甲氧西林敏感的金黄色葡萄球菌感染，96.9%存在对甲氧西林耐药的金黄色葡萄球菌感染。

 

在该试验中，5名患者出现了严重不良事件，但其中仅1例与药物相关，即1名57岁的肥胖女性患者在治疗结束后2天出现了急性胆囊炎。其他所有治疗引发不良事件均为轻度或中度，以恶心最为常见(19%的患者)。研究者没有发现任何有临床意义的QTc改变。

 

Prokocimer博士称，“该药的副作用呈零星分布，并且副作用的发生率并没有随着剂量的增加而上升。”

 

Prokocimer博士指出，与利奈唑胺不同，200 mg剂量的磷酸torezolid对患者的实验室检查结果几乎没有影响，也没有证据提示免疫抑制。计划于2010年开展的2项III期关键试验将以200 mg剂量为研究对象。

 

这2项试验将分别纳入500～600名患者，预计12～18个月后得出结果。其中一项将采用口服给药，另一项则计划先采用静脉给药，必要时再改为口服给药。这2项试验也将只纳入cSSSI患者，但Prokocimer博士表示，公司还计划在呼吸道感染或菌血症患者中开展针对磷酸torezolid的其他试验。

 
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