Department of Medicine, Duke University School of Medicine, 310 Trent Drive, Durham, NC 27710, USA.
Department of Medical Microbiology, Leeds Teaching Hospitals & University of Leeds, Leeds, UK.
Int J Antimicrob Agents. 2019 Jun;53(6):830-837. doi: 10.1016/j.ijantimicag.2019.01.016. Epub 2019 Feb 1.
This post-hoc analysis compared the pharmacokinetics and clinical outcomes of ceftaroline fosamil 600 mg every 12 (q12h) versus every 8 hours (q8h) in patients with acute bacterial skin and skin-structure infection (ABSSSI) and signs of sepsis. Clinical outcomes at test-of-cure in patients with ABSSSI and systemic inflammatory signs/systemic inflammatory response syndrome (SIRS) as well as ceftaroline minimum inhibitory concentrations (MICs) against baseline pathogens were compared between the COVERS trial (ceftaroline fosamil 600 mg q8h, 2-h infusion) and the CANVAS 1 and 2 trials (ceftaroline fosamil 600 mg q12h, 1-h infusion). Ceftaroline exposure among patients in COVERS with or without markers of sepsis was compared using population pharmacokinetic modelling. In COVERS, 62% (312/506) and 41% (208/506) of ceftaroline fosamil-treated patients had ≥1 systemic inflammatory sign or SIRS, respectively, compared with 55% (378/693) and 22% (155/693), respectively, in the CANVAS trials. Clinical cure rates for the modified intent-to-treat population in COVERS and CANVAS were similar for ceftaroline fosamil-treated patients with ≥1 sign of sepsis [82% (255/312) and 85% (335/394)] and for those with SIRS [84% (168/199) and 85% (131/155)]. Ceftaroline MIC distributions were similar across trials. Sepsis did not affect predicted individual steady-state ceftaroline exposure. Clinical cure rates in patients with ≥1 systemic inflammatory sign or SIRS were comparable for both ceftaroline fosamil dosage regimens. Pathogen susceptibilities to ceftaroline were similar across trials. Ceftaroline exposure was not affected by disease severity. Ceftaroline fosamil 600 mg q12h is a robust dosage regimen for most ABSSSI patients with sepsis [ClinicalTrials.gov ID: NCT01499277, NCT00424190, NCT00423657].
本事后分析比较了 600 毫克头孢洛林酯前体药物每 12 小时（q12h）与每 8 小时（q8h）给药方案治疗急性细菌性皮肤和皮肤结构感染（ABSSSI）合并脓毒症体征患者的药代动力学和临床结局。比较了 ABSSSI 患者和全身炎症体征/全身炎症反应综合征（SIRS）患者的治愈期临床结局以及基线病原体的头孢洛林最低抑菌浓度（MIC），这些患者来自 COVERS 试验（头孢洛林酯前体药物 600 毫克 q8h，2 小时输注）和 CANVAS1 与 2 试验（头孢洛林酯前体药物 600 毫克 q12h，1 小时输注）。使用群体药代动力学模型比较 COVERS 中伴有或不伴有脓毒症标志物患者的头孢洛林暴露情况。在 COVERS 中，分别有 62%（312/506）和 41%（208/506）接受头孢洛林酯前体药物治疗的患者存在至少 1 项全身炎症体征或 SIRS，而在 CANVAS 试验中这一比例分别为 55%（378/693）和 22%（155/693）。在 COVERS 和 CANVAS 的改良意向治疗人群中，对于存在≥1 项脓毒症体征的头孢洛林酯前体药物治疗患者，临床治愈率相似[82%（255/312）和 85%（335/394）]，对于存在 SIRS 的患者，临床治愈率相似[84%（168/199）和 85%（131/155）]。各个试验中头孢洛林 MIC 分布相似。脓毒症并未影响预测的个体稳态头孢洛林暴露量。存在≥1 项全身炎症体征或 SIRS 的患者，两种头孢洛林酯前体药物剂量方案的临床治愈率相当。不同试验中病原体对头孢洛林的敏感性相似。疾病严重程度未影响头孢洛林的暴露量。头孢洛林酯前体药物 600 毫克 q12h 是治疗大多数伴有脓毒症的 ABSSSI 患者的有效剂量方案[临床试验注册编号：NCT01499277、NCT00424190、NCT00423657]。
