氨曲南/阿维巴坦治疗住院成人复杂腹腔感染的药代动力学和安全性：来自 REJUVENATE 研究的结果。,Journal of Antimicrobial Chemotherapy

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氨曲南/阿维巴坦治疗住院成人复杂腹腔感染的药代动力学和安全性：来自 REJUVENATE 研究的结果。
Journal of Antimicrobial Chemotherapy ( IF 3.9 ) Pub Date : 2020-03-01 , DOI: 10.1093/jac/dkz497
Oliver A Cornely ₁ , José M Cisneros ₂ , Julian Torre-Cisneros ₃ , María Jesús Rodríguez-Hernández ₂ , Luis Tallón-Aguilar ₄ , Esther Calbo ₅ , Juan P Horcajada ₆ , Christian Queckenberg ₁ , Ulrike Zettelmeyer ₁ , Dorothee Arenz ₁ , Clara M Rosso-Fernández ₂ , Silvia Jiménez-Jorge ₂ , Guy Turner ₇ , Susan Raber ₈ , Seamus O'Brien ₇ , Alison Luckey ₇ ,

Affiliation

目的研究单环内酰胺/β-内酰胺酶抑制剂联合氨曲南/阿维巴坦在复杂腹腔感染 (cIAI) 患者中的药代动力学 (PK) 和安全性（主要目标）和疗效（次要目标）。方法这项 2a 期开放标签、多中心研究 (NCT02655419; EudraCT 2015-002726-39) 将患有 cIAI 的成年人纳入连续队列，进行 5-14 天的治疗。队列 1 患者接受 500/137 毫克（30 分钟输注）的氨曲南/阿维巴坦负荷剂量，然后每 6 小时接受 1500/410 毫克（3 小时输注）的维持剂量；队列 2 接受 500/167 mg（30 分钟输注），然后是 1500/500 mg（3 小时输注）q6h。队列 3 是高剂量方案暴露的延伸。针对 31-50 mL/min 的肌酐清除率调整剂量（队列 2 + 3）。所有患者均接受静脉注射甲硝唑 500 mg q8h。评估了PK、安全性和有效性。结果 34 名患者（队列 1，n = 16；队列 2 + 3，n = 18）包括改良 ITT（MITT）人群。队列 2 + 3 中氨曲南和 avibactam 的平均暴露量与预期在 >90% 的患者中实现联合 PK/药效学目标的暴露量一致。各组之间的不良事件 (AE) 相似。最常见的 AE 是肝酶升高 [n = 9 (26.5%)] 和腹泻 [n = 5 (14.7%)]。治愈测试访视的总体临床治愈率为 20/34 (58.8%) (MITT) 和 14/23 (60.9%) (微生物-MITT 人群)。结论观察到的 AE 与已知的氨曲南单一疗法的安全性特征一致，没有发现新的安全问题。

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Pharmacokinetics and safety of aztreonam/avibactam for the treatment of complicated intra-abdominal infections in hospitalized adults: results from the REJUVENATE study.

OBJECTIVES To investigate pharmacokinetics (PK) and safety (primary objectives) and efficacy (secondary objective) of the investigational monobactam/β-lactamase inhibitor combination aztreonam/avibactam in patients with complicated intra-abdominal infection (cIAI). METHODS This Phase 2a open-label, multicentre study (NCT02655419; EudraCT 2015-002726-39) enrolled adults with cIAI into sequential cohorts for 5-14 days treatment. Cohort 1 patients received an aztreonam/avibactam loading dose of 500/137 mg (30 min infusion), followed by maintenance doses of 1500/410 mg (3 h infusions) q6h; Cohort 2 received 500/167 mg (30 min infusion), followed by 1500/500 mg (3 h infusions) q6h. Cohort 3 was an extension of exposure at the higher dose regimen. Doses were adjusted for creatinine clearance of 31-50 mL/min (Cohorts 2 + 3). All patients received IV metronidazole 500 mg q8h. PK, safety and efficacy were assessed. RESULTS Thirty-four patients (Cohort 1, n = 16; Cohorts 2 + 3, n = 18) comprised the modified ITT (MITT) population. Mean exposures of aztreonam and avibactam in Cohorts 2 + 3 were consistent with those predicted to achieve joint PK/pharmacodynamic target attainment in >90% patients. Adverse events (AEs) were similar between cohorts. The most common AEs were hepatic enzyme increases [n = 9 (26.5%)] and diarrhoea [n = 5 (14.7%)]. Clinical cure rates at the test-of-cure visit overall were 20/34 (58.8%) (MITT) and 14/23 (60.9%) (microbiological-MITT population). CONCLUSIONS Observed AEs were consistent with the known safety profile of aztreonam monotherapy, with no new safety concerns identified. These data support selection of the aztreonam/avibactam 500/167 mg (30 min infusion) loading dose and 1500/500 mg (3 h infusions) maintenance dose q6h regimen, in patients with creatinine clearance >50 mL/min, for the Phase 3 development programme.

更新日期：2020-03-01

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