Dunne Michael W, Aronin Steven I, Das Anita F, Akinapelli Karthik, Breen Jeanne D, Zelasky Michael T, Puttagunta Sailaja
Bill and Melinda Gates Medical Research Institute, Cambridge, MA, USA.
Iterum Therapeutics, Old Saybrook, CT, USA.
Clin Microbiol Infect. 2025 Mar;31(3):396-401. doi: 10.1016/j.cmi.2024.10.025. Epub 2024 Nov 2.
To demonstrate the non-inferiority of intravenous (IV) sulopenem to IV ertapenem, each followed by an oral regimen, in adults with complicated intra-abdominal infections (cIAI).
Hospitalized adults with cIAI were randomly assigned to 5 days of IV sulopenem followed by oral sulopenem etzadroxil/probenecid twice daily or 5 days of IV ertapenem followed by oral ciprofloxacin/metronidazole or amoxicillin-clavulanate depending on baseline pathogen susceptibility. The target treatment duration was 7-10 days. The primary (FDA [Food and Drug Administration]-specified) endpoint was clinical response at day 28 (test-of-cure) in the micro-modified intent-to-treat (micro-MITT) population.
A total of 674 patients were randomly assigned. The two treatment arms were well balanced. Escherichia coli (395 patients) and Bacteroides fragilis (111 patients) were the most frequently isolated pathogens. Clinical success rates in the micro-MITT population were 81.9% (204/249) for sulopenem-treated patients and 87.9% (233/265) for ertapenem-treated patients. The lower bound of the CI for the treatment difference of the primary endpoint was below the pre-specified non-inferiority margin of -10.0 (treatment difference -6.0%, 95% CI, [-12.2 to 0.2]). In all other analysis populations, the lower limit of the 95% CI was above -10.0. Treatment-emergent adverse events (all, 26.0% [87/335] vs. 23.4% [78/333]; related, 6.0% [20/335] vs. 5.1% [17/333]) were similar for sulopenem and ertapenem, respectively. Most events were mild to moderate in severity. There were more serious adverse events in the sulopenem arm (7.5% [25/335] vs. 3.6% [12/333]), only two of which were considered possibly drug-related.
Sulopenem IV followed by oral sulopenem etzadroxil/probenecid was not non-inferior to ertapenem followed by oral step-down in treating cIAI in the micro-MITT population. This finding should be interpreted in the context of country regulations, as endpoint timing, primary analysis population and non-inferiority margin may vary regionally. Both IV and oral sulopenem were well-tolerated; the oral formulation allowed patients with resistant pathogens to step-down from IV therapy.
在患有复杂性腹腔内感染（cIAI）的成人患者中，证明静脉注射舒洛培南与静脉注射厄他培南（随后均采用口服给药方案）相比的非劣效性。
将住院的cIAI成人患者随机分配，一组接受5天静脉注射舒洛培南治疗，随后每日两次口服舒洛培南依扎曲沙/丙磺舒；另一组接受5天静脉注射厄他培南治疗，随后根据基线病原体敏感性口服环丙沙星/甲硝唑或阿莫西林-克拉维酸。目标治疗疗程为7 - 10天。主要（美国食品药品监督管理局指定）终点是微改良意向性治疗（micro-MITT）人群中第28天（治愈试验）的临床反应。
共674例患者被随机分配。两个治疗组平衡良好。大肠埃希菌（395例患者）和脆弱拟杆菌（111例患者）是最常分离出的病原体。舒洛培南治疗患者在micro-MITT人群中的临床成功率为81.9%（204/249），厄他培南治疗患者为87.9%（233/265）。主要终点治疗差异的置信区间下限低于预先设定的非劣效界值-10.0（治疗差异-6.0%，95%置信区间，[-12.2至0.2]）。在所有其他分析人群中，95%置信区间下限高于-10.0。舒洛培南和厄他培南的治疗中出现的不良事件（全部，分别为26.0%[87/335]对23.4%[78/333]；相关的，分别为6.0%[20/335]对5.1%[17/333]）相似。大多数事件严重程度为轻至中度。舒洛培南组有更多严重不良事件（7.5%[25/335]对3.6%[12/333]），其中只有两例被认为可能与药物相关。
在micro-MITT人群中治疗cIAI时，静脉注射舒洛培南随后口服舒洛培南依扎曲沙/丙磺舒并不非劣效于静脉注射厄他培南随后口服降阶梯治疗。这一发现应结合国家法规来解释，因为终点时间、主要分析人群和非劣效界值可能因地区而异。静脉注射和口服舒洛培南耐受性均良好；口服制剂允许耐药病原体患者从静脉治疗转换为口服治疗。
