Flucloxacillin worsens while imipenem–cilastatin protects against vancomycin-induced kidney injury in a translational rat model

Abstract

Background and Purpose: Vancomycin is one of the most common clinical antibiotics, 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. 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, but after the first dose only in the vancomycin group. In the vancomycin + flucloxacillin group, urinary KIM-1 increased on all days compared with vancomycin. In the vancomycin + imipenem–cilastatin group, urinary KIM-1 was decreased on Days 1 and 2 compared with vancomycin. Similar trends were observed for clusterin. More vancomycin accumulated in the kidney with vancomycin + flucloxacillin compared with vancomycin and vancomycin + imipenem–cilastatin. The accumulation of vancomycin in the kidney tissue correlated with increasing urinary KIM-1. Conclusions and Implications: Vancomycin + flucloxacillin caused more kidney injury compared with vancomycin alone and vancomycin + imipenem–cilastatin in a translational rat model. The combination of vancomycin + imipenem–cilastatin was nephroprotective.