From the Division of Infectious Diseases and Geographic Medicine, Tufts Medical Center and Tufts University School of Medicine, Boston (H.W.B.); the Department of Microbiology, Leeds Teaching Hospital and University of Leeds, Old Medical School, Leeds, United Kingdom (M.W.); Talbot Advisors, Anna Maria, FL (G.H.T.); Durata Therapeutics, Branford, CT (S.P., M.W.D.); and InClin, San Mateo, CA (A.F.D.).
N Engl J Med. 2014 Jun 5;370(23):2169-79. doi: 10.1056/NEJMoa1310480.
Dalbavancin, a lipoglycopeptide antibiotic agent that is active against gram-positive pathogens, has a long plasma half-life, allowing for once-weekly dosing. DISCOVER 1 and DISCOVER 2 were identically designed noninferiority trials of dalbavancin for the treatment of acute bacterial skin and skin-structure infection.
We randomly assigned patients to receive dalbavancin intravenously on days 1 and 8 or vancomycin intravenously for at least 3 days with the option to switch to oral linezolid to complete 10 to 14 days of therapy. The primary end point, early clinical response, required the cessation of spread of infection-related erythema and the absence of fever at 48 to 72 hours. Secondary end points at the end of therapy included clinical status and investigator's assessment of outcome.
Analysis of the primary end point showed noninferiority of dalbavancin in both DISCOVER 1 and DISCOVER 2. In the pooled analysis, 525 of 659 patients (79.7%) in the dalbavancin group and 521 of 653 (79.8%) in the vancomycin-linezolid group had an early clinical response indicating treatment success (weighted difference, -0.1 percentage point; 95% confidence interval, -4.5 to 4.2). The outcomes were similar in the analyses by study and the pooled analyses of clinical status at the end of therapy and the investigator's assessment of outcome. For patients infected with Staphylococcus aureus, including methicillin-resistant S. aureus, clinical success was seen in 90.6% of the patients treated with dalbavancin and 93.8% of those treated with vancomycin-linezolid. Adverse events and study days with an adverse event were less frequent in the dalbavancin group than in the vancomycin-linezolid group. The most common treatment-related adverse events in either group were nausea, diarrhea, and pruritus.
Once-weekly intravenous dalbavancin was not inferior to twice-daily intravenous vancomycin followed by oral linezolid for the treatment of acute bacterial skin and skin-structure infection. (Funded by Durata Therapeutics; DISCOVER 1 and DISCOVER 2 ClinicalTrials.gov numbers, NCT01339091 and NCT01431339.).
达巴万星是一种脂糖肽类抗生素，对革兰阳性病原体具有活性，其血浆半衰期较长，允许每周给药一次。DISCOVER 1 和 DISCOVER 2 是两项设计相同的达巴万星治疗急性细菌性皮肤和皮肤结构感染的非劣效性临床试验。
我们将患者随机分配至达巴万星静脉输注组（第 1 天和第 8 天）或万古霉素静脉输注组（至少 3 天，可选择转为口服利奈唑胺以完成 10 至 14 天的治疗）。主要终点为早期临床反应，要求感染性红斑扩散停止且 48 至 72 小时内无发热。治疗结束时的次要终点包括临床状态和研究者对结局的评估。
主要终点分析显示，在 DISCOVER 1 和 DISCOVER 2 中，达巴万星均不劣于万古霉素。汇总分析中，达巴万星组 659 例患者中的 525 例（79.7%）和万古霉素-利奈唑胺组 653 例患者中的 521 例（79.8%）出现早期临床反应，提示治疗成功（加权差值为-0.1%；95%置信区间，-4.5 至 4.2）。按研究和治疗结束时临床状态及研究者对结局评估的汇总分析，结局相似。对于金黄色葡萄球菌感染患者，包括耐甲氧西林金黄色葡萄球菌感染患者，达巴万星组的临床成功率为 90.6%，万古霉素-利奈唑胺组为 93.8%。达巴万星组不良事件及发生不良事件的天数少于万古霉素-利奈唑胺组。两组中最常见的治疗相关不良事件为恶心、腹泻和瘙痒。
每周一次静脉输注达巴万星与每日两次静脉输注万古霉素后口服利奈唑胺治疗急性细菌性皮肤和皮肤结构感染的效果相当。（由 Durata Therapeutics 资助；DISCOVER 1 和 DISCOVER 2 临床试验.gov 编号，NCT01339091 和 NCT01431339）。
