在大鼠模型和确认的细胞模型中，万古霉素和哌拉西林/他唑巴坦之间没有协同肾毒性。
Lack of synergistic nephrotoxicity between vancomycin and piperacillin/tazobactam in a rat model and a confirmatory cellular model.
机构信息
Department of Pharmacy Practice, Chicago College of Pharmacy, Midwestern University, Downers Grove, IL, USA.
Midwestern University, Chicago College of Pharmacy Pharmacometrics Center of Excellence, Downers Grove, IL, USA.
出版信息
J Antimicrob Chemother. 2020 May 1;75(5):1228-1236. doi: 10.1093/jac/dkz563.
BACKGROUND
Vancomycin and piperacillin/tazobactam are reported in clinical studies to increase acute kidney injury (AKI). However, no clinical study has demonstrated synergistic toxicity, only that serum creatinine increases.
OBJECTIVES
To clarify the potential for synergistic toxicity between vancomycin, piperacillin/tazobactam and vancomycin + piperacillin/tazobactam treatments by quantifying kidney injury in a translational rat model of AKI and using cell studies.
METHODS
(i) Male Sprague-Dawley rats (n = 32) received saline, vancomycin 150 mg/kg/day intravenously, piperacillin/tazobactam 1400 mg/kg/day intraperitoneally or vancomycin + piperacillin/tazobactam for 3 days. Urinary biomarkers and histopathology were analysed. (ii) Cellular injury was assessed in NRK-52E cells using alamarBlue®.
RESULTS
Urinary output increased from Day -1 to Day 1 with vancomycin but only after Day 2 for vancomycin + piperacillin/tazobactam-treated rats. Plasma creatinine was elevated from baseline with vancomycin by Day 2 and only by Day 4 for vancomycin + piperacillin/tazobactam. Urinary KIM-1 and clusterin were increased with vancomycin from Day 1 versus controls (P < 0.001) and only on Day 3 with vancomycin + piperacillin/tazobactam (P < 0.001, KIM-1; P < 0.05, clusterin). The histopathology injury score was elevated only in the vancomycin group when compared with piperacillin/tazobactam as a control (P = 0.04) and generally not so with vancomycin + piperacillin/tazobactam. In NRK-52E cells, vancomycin induced cell death with high doses (IC50 48.76 mg/mL) but piperacillin/tazobactam did not, and vancomycin + piperacillin/tazobactam was similar to vancomycin.
CONCLUSIONS
All groups treated with vancomycin demonstrated AKI; however, vancomycin + piperacillin/tazobactam was not worse than vancomycin. Histopathology suggested that piperacillin/tazobactam did not worsen vancomycin-induced AKI and may even be protective.
背景
万古霉素和哌拉西林/他唑巴坦在临床研究中被报道会增加急性肾损伤（AKI）。然而，没有临床研究表明存在协同毒性，只是血清肌酐升高。
目的
通过在 AKI 的翻译大鼠模型中定量评估肾损伤，并使用细胞研究来阐明万古霉素、哌拉西林/他唑巴坦和万古霉素+哌拉西林/他唑巴坦治疗之间协同毒性的可能性。
方法
（i）雄性 Sprague-Dawley 大鼠（n=32）接受生理盐水、万古霉素 150mg/kg/天静脉内、哌拉西林/他唑巴坦 1400mg/kg/天腹膜内或万古霉素+哌拉西林/他唑巴坦治疗 3 天。分析尿生物标志物和组织病理学。（ii）使用 alamarBlue®评估 NRK-52E 细胞中的细胞损伤。
结果
万古霉素治疗组大鼠的尿排量从第-1 天增加到第 1 天，但只有在第 2 天之后才增加；万古霉素+哌拉西林/他唑巴坦治疗组大鼠的血浆肌酐从第 2 天开始升高，仅在第 4 天升高。万古霉素治疗组大鼠的尿 KIM-1 和簇蛋白从第 1 天开始与对照组相比升高（P<0.001），仅在第 3 天万古霉素+哌拉西林/他唑巴坦治疗组升高（P<0.001，KIM-1；P<0.05，簇蛋白）。与哌拉西林/他唑巴坦作为对照相比，万古霉素组的组织病理学损伤评分仅升高（P=0.04），而万古霉素+哌拉西林/他唑巴坦组通常没有升高。在 NRK-52E 细胞中，高剂量的万古霉素（IC50 48.76mg/mL）诱导细胞死亡，但哌拉西林/他唑巴坦则没有，而且万古霉素+哌拉西林/他唑巴坦与万古霉素相似。
结论
所有接受万古霉素治疗的组均表现出 AKI；然而，万古霉素+哌拉西林/他唑巴坦并不比万古霉素更差。组织病理学提示哌拉西林/他唑巴坦不会加重万古霉素引起的 AKI，甚至可能具有保护作用。
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