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

Abstract

Background: This 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. Objectives: To quantify the dose-AKI relationships of VAN alone and in combination with TZP or imipenem-cilastatin/relebactam (IMP-C/REL). Methods: Ten to twelve week old male C57BL/6J mice (Charles River Laboratory) were dosed with study drug regimens in three stages. Stage 1 consisted of a VAN dose-ranging design (0-600 mg/kg/day) 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 (HED) used in pre-clinical murine models (2.5 g/kg/day of TZP, 320 mg/kg/day of IMP-C/REL). Stage 3 tested these combinations with fractionated doses of TZP or IMP-C/REL administered at 6- and 12-hour intervals. In these studies, AKI was defined both by biomarkers (serum creatinine [SCr], blood urea nitrogen [BUN]) and histopathological assessment by a treatment-blinded pathologist. Results: VAN doses of 300 to 500 mg/kg/day 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 compared to 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 compared to 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 hours. Biomarker results were concordant with histopathologic findings. Conclusions: 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 to VAN monotherapy when administered as fractionated doses.

Association of vancomycin plus piperacillin–tazobactam with early changes in creatinine versus cystatin C in critically ill adults: a prospective cohort study

“…Our findings of isolated increases in creatinine that were not matched by changes in either Cys-C or BUN are consistent with this hypothesized mechanism. Our findings are also consistent with animal studies suggesting that PT does not enhance VN toxicity [6,[8][9][10], with some suggesting that PT may actually reduce VN nephrotoxicity. A caveat to the animal models is that, beyond demonstrating no adverse effect on kidney function, some have also shown that VN + PT does not increase creatinine concentrations [8,9].…”

“…Our findings are also consistent with animal studies suggesting that PT does not enhance VN toxicity [ 6 , 8 – 10 ], with some suggesting that PT may actually reduce VN nephrotoxicity. A caveat to the animal models is that, beyond demonstrating no adverse effect on kidney function, some have also shown that VN + PT does not increase creatinine concentrations [ 8 , 9 ]. Nevertheless, regardless of mechanism, the data raise doubt that PT enhances VN-mediated nephrotoxicity.…”

“…In contrast, there is little evidence linking PT to nephrotoxicity, other than rare cases of acute interstitial nephritis [7]. Moreover, animal models have failed to demonstrate synergistic toxicity [6,[8][9][10], with some suggesting that PT may actually reduce VN nephrotoxicity [8][9][10].…”

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

“…Even less is known about agents that can prevent kidney injury due to vancomycin. Imipenem-cilastatin/relebactam has been shown to decrease serum creatinine of mice that received vancomycin (He, Souza, Matvekas, Crass, & Pai, 2021) with similar findings reported in retrospective clinical studies (Hakeam, AlAnazi, Mansour, AlFudail, & AlMarzouq, 2019).…”

Glomerular function and urinary biomarker changes between vancomycin and vancomycin plus piperacillin-tazobactam in a translational rat model

“…kidney injury molecule-1 [KIM-1], clusterin, and osteopontin (OPN)) and histopathology (15). In these models, results conflicted with retrospective human studies; additive nephrotoxicity associated with VAN+TZP was not observed in animal studies (15,16). KIM-1 was identified as the most relevant urinary biomarker in animal studies for vancomycin induced kidney injury, correlating with GFR changes and end-organ histopathologic damage at proximal tubule (15,(17)(18)(19).…”