Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA.
Achaogen, Inc., South San Francisco, California, USA.
Antimicrob Agents Chemother. 2019 Sep 23;63(10). doi: 10.1128/AAC.00148-19. Print 2019 Oct.
Plazomicin is a new FDA-approved aminoglycoside antibiotic for complicated urinary tract infections (cUTI). In the product labeling, trough-based therapeutic drug management (TDM) is recommended for cUTI patients with renal impairment to prevent elevated trough concentrations associated with serum creatinine increases of ≥0.5 mg/dl above baseline. Herein, the utility of the Hartford nomogram to prevent plazomicin trough concentrations exceeding the TDM trough of 3 μg/ml and optimize the area under the curve (AUC) was assessed. The AUC reference range was defined as the 5th to 95th percentile AUC observed in the phase 3 cUTI trial (EPIC) (121 to 368 μg · h/ml). Observed 10-h plazomicin concentrations from patients in EPIC ( = 281) were plotted on the nomogram to determine an eligible dosing interval (every 24 h [q24h], q36h, q48h). Based on creatinine clearance (CLcr), a 15- or 10-mg/kg of body weight dose was simulated with the nomogram-derived interval. The nomogram recommended an extended interval (q36h and q48h) in 31% of patients. Compared with the 15 mg/kg q24h regimen received by patients with CLcr of ≥60 ml/min in EPIC, the nomogram-derived interval reduced the proportion of patients with troughs of ≥3 μg/ml (q36h, 27% versus 0%, = 0.021; q48h, 57% versus 0%, = 0.002) while significantly increasing the number of patients within the AUC range. Compared with the 8 to 12 mg/kg q24h regimen (received by patients with CLcr of >30 to 59 ml/min in EPIC), the nomogram-derived interval significantly reduced the proportion of troughs of ≥3μg/ml in the q48h cohort (72% versus 0%, < 0.001) while maintaining a similar proportion of patients in the AUC range. Simulated application of the Hartford nomogram optimized plazomicin exposures in patients with cUTI while reducing troughs to <3 μg/ml.
泊沙康唑是一种新的美国食品和药物管理局批准的氨基糖苷类抗生素，用于治疗复杂尿路感染（cUTI）。在产品标签中，建议对有肾损伤的 cUTI 患者进行基于谷浓度的治疗药物监测（TDM），以预防与血清肌酐升高≥0.5 mg/dl 相关的谷浓度升高。本文评估了哈特福德列线图在预防泊沙康唑谷浓度超过 TDM 谷值 3μg/ml 和优化曲线下面积（AUC）方面的应用。AUC 参考范围定义为 3 期 cUTI 试验（EPIC）中观察到的第 5 至 95 百分位 AUC（121 至 368μg·h/ml）。EPIC 中（n=281）患者的 10 小时泊沙康唑实测浓度被绘制在列线图上，以确定合适的给药间隔（每 24 小时[q24h]、q36h、q48h）。根据肌酐清除率（CLcr），用列线图计算的间隔模拟 15 或 10mg/kg 体重剂量。列线图建议在 31%的患者中延长间隔（q36h 和 q48h）。与 EPIC 中 CLcr≥60ml/min 的患者接受的 15mg/kg q24h 方案相比，列线图衍生的间隔降低了谷浓度≥3μg/ml 的患者比例（q36h，27%比 0%，=0.021；q48h，57%比 0%，=0.002），同时显著增加了 AUC 范围内的患者数量。与 8 至 12mg/kg q24h 方案（EPIC 中 CLcr>30 至 59ml/min 的患者接受）相比，列线图衍生的间隔显著降低了 q48h 组谷浓度≥3μg/ml 的比例（72%比 0%，<0.001），同时保持 AUC 范围内相似比例的患者。模拟应用哈特福德列线图优化了 cUTI 患者的泊沙康唑暴露量，同时将谷浓度降低至<3μg/ml。
