The randomized, double-blind, phase 3 ASPECT-NP trial evaluated the efficacy of 3 g of ceftolozane/tazobactam (C/T) versus 1 g of meropenem infused every 8 h for 8 to 14 days for treatment of adults with hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia (VABP). We assessed the probability of target attainment and compared efficacy outcomes from ASPECT-NP in participants with augmented renal clearance (ARC) versus those with normal renal function. Baseline renal function was categorized as normal renal function (creatinine clearance 80–130 mL/min) or ARC (creatinine clearance > 130 mL/min). Population pharmacokinetic models informed Monte Carlo simulations to assess probability of target attainment in plasma and pulmonary epithelial lining fluid. Outcomes included 28-day all-cause mortality and clinical cure and per-participant microbiologic cure rates at the test-of-cure visit. A > 99% and > 80% probability of target attainment was demonstrated for ceftolozane and tazobactam, respectively, in simulated plasma and epithelial lining fluid. Within treatment arms, 28-day all-cause mortality rates in participants with normal renal function (C/T, n = 131; meropenem, n = 123) and ARC (C/T, n = 96; meropenem, n = 113) were comparable (data comparisons presented as rate; treatment difference [95% CI]) (C/T: normal renal function, 17.6%; ARC, 17.7%; 0.2 [− 9.6 to 10.6]; meropenem: normal renal function, 20.3%; ARC, 17.7%; − 2.6 [− 12.6 to 7.5]). Clinical cure rates at test-of-cure were also comparable across renal function groups within treatment arms (C/T: normal renal function, 57.3%; ARC, 59.4%; − 2.1 [− 14.8 to 10.8]; meropenem: normal renal function, 59.3%; ARC, 57.5%; 1.8 [− 10.6 to 14.2]). Per-participant microbiologic cure rates at test-of-cure were consistent across renal function groups within treatment arms (C/T: normal renal function, 72.2% [n/N = 70/97]; ARC, 71.4% [n/N = 55/77]; 0.7 [− 12.4 to 14.2]; meropenem: normal renal function, 75.0% [n/N = 66/88]; ARC, 70.0% [n/N = 49/70]; 5.0 [− 8.7 to 19.0]). C/T and meropenem resulted in 28-day all-cause mortality, clinical cure, and microbiologic cure rates that were comparable between participants with ARC or normal renal function. In conjunction with high probability of target attainment, these results confirm that C/T (3 g) every 8 h is appropriate in patients with HABP/VABP and ARC. Trial registration ClinicalTrials.gov identifier: NCT02070757, registered February 25, 2014; EudraCT: 2012-002862-11.

中文翻译：

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在随机 3 期 ASPECT-NP 试验中增加肾脏清除率的参与者中，头孢洛扎/他唑巴坦达到目标的可能性和结果

随机、双盲、3 期 ASPECT-NP 试验评估了 3 g 头孢唑烷/他唑巴坦 (C/T) 与每 8 小时输注 1 g 美罗培南的疗效，持续 8 至 14 天治疗成人医院获得性细菌性肺炎 (HABP) 或呼吸机相关细菌性肺炎 (VABP)。我们评估了达到目标的可能性，并比较了 ASPECT-NP 在肾清除率增加 (ARC) 与肾功能正常的参与者中的疗效结果。基线肾功能分为正常肾功能（肌酐清除率 80–130 mL/min）或 ARC（肌酐清除率 > 130 mL/min）。群体药代动力学模型为 Monte Carlo 模拟提供了信息，以评估血浆和肺上皮内衬液中达到目标的可能性。结果包括 28 天全因死亡率和临床治愈率，以及治愈测试访视时每位参与者的微生物学治愈率。在模拟血浆和上皮内衬液中，头孢洛扎和他唑巴坦分别有 > 99% 和 > 80% 的目标实现概率。在治疗组中，肾功能正常（C/T，n = 131；美罗培南，n = 123）和 ARC（C/T，n = 96；美罗培南，n = 113）参与者的 28 天全因死亡率具有可比性（数据比较表示为比率；治疗差异 [95% CI]）（C/T：肾功能正常，17.6%；ARC，17.7%；0.2 [− 9.6 至 10.6]；美罗培南：肾功能正常，20.3% ；ARC，17.7%；- 2.6 [- 12.6 至 7.5]）。治疗组内各肾功能组的治愈测试临床治愈率也相当（C/T：肾功能正常，57.3%；ARC，59.4%；− 2.1 [− 14.8 至 10.8]；美罗培南：肾功能正常，59.3%；ARC，57.5%；1.8 [- 10.6 到 14.2])。治疗组内各肾功能组在治愈测试中每位参与者的微生物学治愈率一致（C/T：肾功能正常，72.2% [n/N = 70/97]；ARC，71.4% [n/N] = 55/77]；0.7 [− 12.4 至 14.2]；美罗培南：肾功能正常，75.0% [n/N = 66/88]；ARC，70.0% [n/N = 49/70]；5.0 [− 8.7到 19.0]）。C/T 和美罗培南导致的 28 天全因死亡率、临床治愈率和微生物学治愈率在 ARC 或肾功能正常的参与者之间具有可比性。结合达到目标的高概率，这些结果证实每 8 小时 C/T (3 g) 对 HABP/VABP 和 ARC 患者是合适的。试验注册 ClinicalTrials.gov 标识符：NCT02070757，2 月 25 日注册，2014; EudraCT：2012-002862-11。