Lack of synergistic nephrotoxicity between vancomycin and piperacillin/tazobactam in a rat model and a confirmatory cellular model.

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.

• Authors: Gwendolyn M Pais, Jiajun Liu, Sean N Avedissian, Danielle Hiner, Theodoros Xanthos, Athanasios Chalkias, Ernesto d'Aloja, Emanuela Locci, Annette Gilchrist, Walter C Prozialeck, Nathaniel J Rhodes, Thomas P Lodise, Julie C Fitzgerald, Kevin J Downes, Athena F Zuppa, Marc H Scheetz
• Journal: The Journal of antimicrobial chemotherapy (J Antimicrob Chemother) Vol. 75 Issue 5 Pg. 1228-1236 (05 01 2020) ISSN: 1460-2091 [Electronic] England
• PMID: 32011685 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: [email protected].

Chemical References

• Anti-Bacterial Agents
• Piperacillin, Tazobactam Drug Combination
• Vancomycin
• Penicillanic Acid
• Piperacillin

Topics

• Acute Kidney Injury (chemically induced)
• Animals
• Anti-Bacterial Agents (toxicity)
• Drug Therapy, Combination
• Male
• Penicillanic Acid (toxicity)
• Piperacillin (toxicity)
• Piperacillin, Tazobactam Drug Combination (toxicity)
• Rats
• Rats, Sprague-Dawley
• Retrospective Studies
• Vancomycin (toxicity)