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

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 CS7BL/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.

Automated summary

In mouse experiments, the dose of vancomycin (VAN) was found to be associated with the development of acute kidney injury (AKI). The risk of AKI can be reduced by combining VAN with piperacillin/tazobactam (TZP) or imipenem-cilastatin/relebactam (IMP-C/REL).