IGNITE4: Results of a Phase 3, Randomized, Multicenter, Prospective Trial of Eravacycline vs Meropenem in the Treatment of Complicated Intraabdominal Infections
IGNITE4: Results of a Phase 3, Randomized, Multicenter, Prospective Trial of Eravacycline vs Meropenem in the Treatment of Complicated Intraabdominal Infections
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DOI：
10.1093/cid/ciy1029
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发表时间：
2019-09-15
影响因子：
11.8
通讯作者：
Tsai, Larry
中科院分区：
文献类型：
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作者：
Solomkin, Joseph S.;Gardovskis, Janis;Tsai, Larry
背景引起复杂性腹腔内感染（cIAI）的病原体中抗菌药物耐药性的增加支持了新抗菌药物的开发。埃拉环素是氟环素家族的新成员，对包括超广谱β-内酰胺酶（ESBL）和碳青霉烯类耐药肠杆菌科在内的多重耐药菌具有活性。IGNITE 4是一项前瞻性、随机、双盲试验。cIAI住院患者接受埃拉霉素1 mg/kg每12小时或美罗培南1 g每8小时静脉注射4-14天。主要目的是使用12.5%的NI界值证明微生物学意向治疗人群中治愈验证访视（治疗开始后25-31天）时临床治愈率的统计学非劣效性（NI）。微生物学结果和安全性也进行了评价。在主要终点方面，埃拉环素非劣效于美罗培南（177/195 [90.8%] vs 187/205 [91.2%];差异，-0.5%; 95%置信区间[CI]，-6.3至5.3），超过了预先规定的界值。次要终点包括改良ITT人群的临床治愈率（231/250 [92.4%] vs 228/249 [91.6%];差异，0.8; 95% CI，-4.1，5.8）和临床可评价人群（218/225 [96.9%] vs 222/231 [96.1%];（差异，0.8; 95% CI-2.9，4.5）。在产ESBL肠杆菌科患者中，埃拉环素组和美罗培南组的临床治愈率分别为87.5%（14/16）和84.6%（11/13）。Eravacycline在该类药物中的不良事件发生率相对较低，分别有不到5%、4%和3%的患者发生恶心、呕吐和腹泻。在cIAI成人患者中，包括耐药病原体引起的感染，eravacycline治疗不劣于美罗培南。
Background. Increasing antimicrobial resistance among pathogens that cause complicated intraabdominal infections (cIAIs) supports the development of new antimicrobials. Eravacycline, a novel member of the fluorocycline family, is active against multi-drug-resistant bacteria including extended-spectrum beta-lactamase (ESBL) and carbapenem-resistant Enterobacteriaceae.Methods. IGNITE4 was a prospective, randomized, double-blind trial. Hospitalized patients with cIAI received either eravacy-cline 1 mg/kg every 12 hours or meropenem 1 g every 8 hours intravenously for 4-14 days. The primary objective was to demonstrate statistical noninferiority (NI) in clinical cure rates at the test-of-cure visit (25-31 days from start of therapy) in the microbiological intent-to-treat population using a NI margin of 12.5%. Microbiological outcomes and safety were also evaluated.Results. Eravacycline was noninferior to meropenem in the primary endpoint (177/195 [90.8%] vs 187/205 [91.2%]; difference, -0.5%; 95% confidence interval [CI], -6.3 to 5.3), exceeding the prespecified margin. Secondary endpoints included clinical cure rates in the modified ITT population (231/250 [92.4%] vs 228/249 [91.6%]; difference, 0.8; 95% CI, -4.1, 5.8) and the clinically evaluable population (218/225 [96.9%] vs 222/231 [96.1%]; (difference, 0.8; 95% CI -2.9, 4.5). In patients with ESBL-producing Enterobacteriaceae, clinical cure rates were 87.5% (14/16) and 84.6% (11/13) in the eravacycline and meropenem groups, respectively. Eravacycline had relatively low rates of adverse events for a drug of this class, with less than 5%, 4%, and 3% of patients experiencing nausea, vomiting, and diarrhea, respectively.Conclusions. Treatment with eravacycline was noninferior to meropenem in adult patients with cIAI, including infections caused by resistant pathogens.