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Flucloxacillin worsens while imipenem-cilastatin protects against vancomycin induced kidney injury in a translational rat model
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  • Gwendolyn Pais,
  • Sylwia Marianski,
  • Kimberly Valdez,
  • Renz Paulo Melicor,
  • Jiajun Liu,
  • Roxane Rohani,
  • Jack Chang,
  • Steven Tong,
  • Joshua Davis,
  • Marc Scheetz
Gwendolyn Pais
Midwestern University - Downers Grove Campus
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Sylwia Marianski
Midwestern University - Downers Grove Campus
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Kimberly Valdez
Midwestern University - Downers Grove Campus
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Renz Paulo Melicor
Midwestern University - Downers Grove Campus
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Jiajun Liu
FDA
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Roxane Rohani
Midwestern University - Downers Grove Campus
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Jack Chang
Midwestern University - Downers Grove Campus
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Steven Tong
The Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity
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Joshua Davis
The University of Newcastle Hunter Medical Research Institute
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Marc Scheetz
Midwestern University - Downers Grove Campus

Corresponding Author:mschee@midwestern.edu

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Abstract

Background and Purpose Vancomycin is one of the most common antibiotics administered in the hospital setting, yet acute kidney injury is a major limiting factor. Common combinations of antibiotics with vancomycin have been reported to worsen and improve vancomycin-induced kidney injury. We aimed to study the impact of flucloxacillin and imipenem-cilastatin on kidney injury when combined with vancomycin in our translational rat model. Experimental Approach Male Sprague-Dawley rats received allometrically scaled (1) vancomycin (2) flucloxacillin, (3) vancomycin+flucloxacillin, (4) vancomycin+imipenem-cilastatin, or (5) saline for 4 days. Vancomycin was administered intravenously and flucloxacillin or imipenem-cilastatin were administered intraperitoneally. Kidney injury was evaluated via drug accumulation and urinary biomarkers including urinary output, kidney injury molecule-1 (KIM-1), clusterin, and osteopontin. Relationships between vancomycin accumulation in the kidney and urinary kidney injury biomarkers were explored. Key Results Urinary output increased every study day for vancomycin+flucloxacillin; whereas in the vancomycin group it was elevated after the first dose only. In the vancomycin+flucloxacillin group, urinary KIM-1/24h increased on all days compared to vancomycin. In the vancomycin+imipenem-cilastatin group, urinary KIM-1/24h was decreased on days 1 and 2 compared to vancomycin. Similar trends were observed for clusterin. More vancomycin accumulated in the kidney with vancomycin+flucloxacillin compared to vancomycin and vancomycin+imipenem-cilastatin. The accumulation of vancomycin in the kidney tissue correlated with increasing urinary KIM-1 (4-parameter Hill Slope, R2=0.7985). Conclusion and Implications Vancomycin+flucloxacillin caused more kidney injury compared to vancomycin alone and vancomycin+imipenem-cilastatin in a translational rat model as determined by multiple kidney injury biomarkers. The combination of vancomycin+imipenem-cilastatin was nephroprotective.
17 Jan 2023Submitted to British Journal of Pharmacology
17 Jan 2023Submission Checks Completed
17 Jan 2023Assigned to Editor
17 Jan 2023Review(s) Completed, Editorial Evaluation Pending
03 Feb 2023Reviewer(s) Assigned
16 Apr 2023Editorial Decision: Revise Minor
26 May 20231st Revision Received
31 May 2023Submission Checks Completed
31 May 2023Assigned to Editor
31 May 2023Review(s) Completed, Editorial Evaluation Pending
05 Jun 2023Reviewer(s) Assigned
13 Jul 2023Editorial Decision: Revise Minor
11 Aug 20232nd Revision Received
12 Aug 2023Review(s) Completed, Editorial Evaluation Pending
12 Aug 2023Submission Checks Completed
12 Aug 2023Assigned to Editor
28 Aug 2023Editorial Decision: Accept