Lack of synergistic nephrotoxicity between vancomycin and piperacillin/tazobactam in a rat model and a confirmatory cellular model

Abstract

Background Vancomycin and piperacillin/tazobactam are reported in clinical studies to increase acute kidney injury (AKI). However, no clinical study has demonstrated synergistic toxicity, only that serum creatinine increases. Objectives To clarify the potential for synergistic toxicity between vancomycin, piperacillin/tazobactam and vancomycin + piperacillin/tazobactam treatments by quantifying kidney injury in a translational rat model of AKI and using cell studies. Methods (i) Male Sprague–Dawley rats (n = 32) received saline, vancomycin 150 mg/kg/day intravenously, piperacillin/tazobactam 1400 mg/kg/day intraperitoneally or vancomycin + piperacillin/tazobactam for 3 days. Urinary biomarkers and histopathology were analysed. (ii) Cellular injury was assessed in NRK-52E cells using alamarBlue®. Results Urinary output increased from Day −1 to Day 1 with vancomycin but only after Day 2 for vancomycin + piperacillin/tazobactam-treated rats. Plasma creatinine was elevated from baseline with vancomycin by Day 2 and only by Day 4 for vancomycin + piperacillin/tazobactam. Urinary KIM-1 and clusterin were increased with vancomycin from Day 1 versus controls (P < 0.001) and only on Day 3 with vancomycin + piperacillin/tazobactam (P < 0.001, KIM-1; P < 0.05, clusterin). The histopathology injury score was elevated only in the vancomycin group when compared with piperacillin/tazobactam as a control (P = 0.04) and generally not so with vancomycin + piperacillin/tazobactam. In NRK-52E cells, vancomycin induced cell death with high doses (IC50 48.76 mg/mL) but piperacillin/tazobactam did not, and vancomycin + piperacillin/tazobactam was similar to vancomycin. Conclusions All groups treated with vancomycin demonstrated AKI; however, vancomycin + piperacillin/tazobactam was not worse than vancomycin. Histopathology suggested that piperacillin/tazobactam did not worsen vancomycin-induced AKI and may even be protective.

Nephrotoxicity from Vancomycin Combined with Piperacillin-Tazobactam: A Comprehensive Review

“…Despite the strong and consistent epidemiologic associations between VPT combination and AKI, our understanding of the pathogenesis of this phenomenon is still mainly based on hypotheses. It is intriguing that despite the numerous cohort studies and meta-analyses consistently reporting the VPT-AKI association, an animal experimental model did not show synergistic tubular toxicity of this drug combination [57], and histological correlations from human kidney biopsies are few. Only a few case reports described this phenomenon and its associated findings on kidney biopsy.…”

“…PT was associated with delayed renal recovery compared to other beta-lactams, with steady SCr decreases occurring during treatment with meropenem (or cefuroxime, in a less ill group), but delayed SCr decreases occurring only in the 5 days following cessation of PT therapy [83]. Taken together with the absence of synergistic experimental model tubular damage [57], a strong case for the pseudo-nephrotoxicity phenomenon may be made. Although interesting, pseudo-nephrotoxicity is unlikely to be the sole explanation for the consistently observed increased incidence of AKI in VPT-treated patients, which may alternatively be caused by true nephrotoxic injury (vancomycin-induced ATN, or allergic interstitial nephritis caused by vancomycin or piperacillin exposure) or septic AKI (hypoperfusion, inflammatory cytokines, postinfectious glomerulonephritis, etc.)…”

Of Rats and Men, a Translational Model to Understand Vancomycin Pharmacokinetic/Toxicodynamic relationships

“…We believe it was appropriate to use the AUC:KIM-1 data from the 24-hour rat studies in the exposure response analyses and link them to day 2 AUC:SCr VIKI endpoints in the human studies. We have observed in our model that KIM-1 increases on day 1 with vancomycin treatment and plateaus for several days in our more prolonged experiments (34). Thus, one day experiments appear sufficient to define the injury profile.…”

“…In particular, the availability of a reliable and accurate pre-clinical VIKI model will identify vancomycin dosing schemes associated with the lowest risk of VIKI, determine if ameliorating agents can minimize the risk of VIKI with vancomycin exposures required for efficacy, and assess populations in which vancomycin should be avoided (e.g., those receiving other nephrotoxic agents). Our group has utilized a pre-clinical rat model that describes the risk of VIKI as a function of the intensity of vancomycin exposure (9,31,34,39). While our model demonstrates that there is a clear relationship between vancomycin AUC and VIKI in rats, we have yet to determine if our model bridges to humans.…”

Effect of Local Delivery of Vancomycin and Tobramycin on Bone Regeneration

“…Local intrawound delivery of antibiotic powder after orthopedic surgery has been shown to reduce infection rates as much as 10‐fold 1 . This prophylactic method is better than intravenous and oral antibiotics, because of the adverse effects of systemic administration of antibiotics such as nephrotoxicity 4 . Furthermore, local delivery can reduce antibiotic resistance.…”