Gwendolyn M Pais1,2, Jiajun Liu1,2, Sean N Avedissian1,2, Danielle Hiner3, Theodoros Xanthos4, Athanasios Chalkias5, Ernesto d'Aloja6, Emanuela Locci6, Annette Gilchrist2,7, Walter C Prozialeck8, Nathaniel J Rhodes1,2, Thomas P Lodise9, Julie C Fitzgerald10, Kevin J Downes11,12, Athena F Zuppa10, Marc H Scheetz1,2,8. 1. Department of Pharmacy Practice, Chicago College of Pharmacy, Midwestern University, Downers Grove, IL, USA. 2. Midwestern University, Chicago College of Pharmacy Pharmacometrics Center of Excellence, Downers Grove, IL, USA. 3. Chicago College of Pharmacy, Midwestern University, Downers Grove, IL, USA. 4. School of Medicine, European University Cyprus, Nicosia, Cyprus. 5. Department of Anesthesiology, University of Thessaly, Larisa, Greece. 6. Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy. 7. Department of Pharmaceutical Sciences, Chicago College of Pharmacy, Midwestern University, Downers Grove, IL, USA. 8. Department of Pharmacology, College of Graduate Studies, Midwestern University, Downers Grove, IL, USA. 9. Department of Pharmacy Practice, Albany College of Pharmacy and Health Sciences, Albany, NY, USA. 10. Division of Critical Care, Department of Anesthesiology and Critical Care, The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. 11. Division of Infectious Diseases, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. 12. Department of Pediatrics, The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
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.
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: Jack Chang; Gwendolyn M Pais; Kimberly Valdez; Sylwia Marianski; Erin F Barreto; Marc H Scheetz Journal: Antimicrob Agents Chemother Date: 2022-01-10 Impact factor: 5.938
Authors: J D Workum; C Kramers; E Kolwijck; J A Schouten; S N de Wildt; R J Brüggemann Journal: J Antimicrob Chemother Date: 2021-01-01 Impact factor: 5.790
Authors: Marc H Scheetz; Gwendolyn M Pais; Thomas P Lodise; Steven Y C Tong; Joshua S Davis; J Nicholas O'Donnell; Jiajun Liu; Michael Neely; Walter C Prozialeck; Peter C Lamar; Nathaniel J Rhodes; Thomas Holland; Sean N Avedissian Journal: Antimicrob Agents Chemother Date: 2021-08-02 Impact factor: 5.191