Lack of synergistic nephrotoxicity between vancomycin and piperacillin/tazobactam in a rat model and a confirmatory cellular model. (3rd February 2020)

• Record Type: Journal Article
• Authors: Pais, Gwendolyn M; Liu, Jiajun; Avedissian, Sean N; Hiner, Danielle; Xanthos, Theodoros; Chalkias, Athanasios; d'Aloja, Ernesto; Locci, Emanuela; Gilchrist, Annette; Prozialeck, Walter C; Rhodes, Nathaniel J; Lodise, Thomas P; Fitzgerald, Julie C; Downes, Kevin J; Zuppa, Athena F; Scheetz, Marc H
• Is Part Of: Journal of antimicrobial chemotherapy. Volume 75:Number 5(2020)
• Page Start: 1228
• Page End: 1236
• Publication Date: 2020-02-03
• Subjects: Anti-infective agents -- Periodicals; Chemotherapy -- Periodicals; 615.58
• DOI: 10.1093/jac/dkz563
• Languages: English
• ISSNs: 0305-7453

Abstract

Abstract: 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.