Alteration in Acute Kidney Injury Potential with the Combination of Vancomycin and Imipenem-Cilastatin/Relebactam or Piperacillin/Tazobactam in a Preclinical Model

Abstract

The risk of vancomycin (VAN)-associated acute kidney injury (AKI) may be altered with combination regimens. The specific AKI risk when VAN is combined with imipenem-cilastatin/relebactam (IMP-C/REL) or piperacillin/tazobactam (TZP) has not been clearly defined. We sought to quantify the dose-AKI relationships of VAN alone and in combination with TZP or IMP-C/REL. Male C57BL/6J mice (Charles River Laboratory) aged 10 to 12 weeks were dosed with study drug regimens in three stages. Stage 1 consisted of a VAN dose-ranging design (0 to 600 mg/kg daily) over a 7-day period to identify the VAN monotherapy dose-AKI relationship in the murine model. Stage 2 evaluated the approximate VAN dose eliciting 50% AKI response in stage 1 in combination with the highest human equivalent doses (HEDs) used in preclinical murine models (2.5 and 320 mg/kg daily for TZP and IMP-C/REL, respectively). Stage 3 tested these combinations with fractionated doses of TZP or IMP-C/REL administered at 6- and 12-h intervals. In these studies, AKI was defined with biomarkers (serum creatinine [SCr], blood urea nitrogen [BUN]) and with histopathological assessment by a treatment-blinded pathologist. VAN doses of 300 to 500 mg/kg daily reproducibly led to development of AKI within 4 days of dosing. Mice treated with VAN alone had a near doubling of their baseline SCr and BUN levels compared with mice treated with control, IMP-C/REL alone, or TZP alone. Both VAN+IMP-C/REL and VAN+TZP had significantly (P < 0.05) lower SCr and BUN values than VAN alone when dosed once daily. This nephroprotective effect was retained with VAN+IMP-C/REL but not VAN+TZP when IMP-C/REL and TZP were administered every 6 h. Biomarker results were concordant with histopathological findings. The VAN dose-AKI relationship can be attenuated with single daily HEDs of TZP or IMP-C/REL in mice. IMP-C/REL, but not TZP, retained a nephroprotective effect compared with VAN monotherapy when administered as fractionated doses.

Keywords: acute kidney injury; beta-lactams; carbapenems; glycopeptides; nephrotoxicity.