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

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.