Urinary biomarker and histopathological evaluation of vancomycin and piperacillin-tazobactam nephrotoxicity in comparison with vancomycin in a rat model and a confirmatory cellular model

Abstract

word count: 294 34 2 | Page Abstract: 35Introduction: Vancomycin and piperacillin tazobactam (VAN+TZP) are two of the most 36 commonly utilized antibiotics in the hospital setting and are reported in clinical studies to 37 increase acute kidney injury (AKI). However, no clinical study has demonstrated that synergistic 38 toxicity occurs, only that serum creatinine (SCr) increases with VAN+TZP. The purpose of this 39 study was to assess biologic plausibility by quantifying kidney injury between VAN, TZP, and 40 VAN+TZP treatments using a translational rat model of AKI and rat kidney epithelial cell studies. 41 Methods: (i) Male Sprague-Dawley rats (n=32) received either saline, VAN 150 mg/kg/day 42 intravenously, TZP 1400 mg/kg/day via intraperitoneal injection, or VAN+TZP. Animals were 43 placed in metabolic cages pre-study and on drug dosing days 1-3. Urinary biomarkers and 44 histopathology were analyzed. (ii) Cellular injury of VAN+TZP was assessed in serum-deprived 45 rat kidney cells (NRK-52E) using an alamarBlue® viability assay. Cells were incubated with 46 antibiotics VAN, TZP, cefepime, and gentamicin alone or combined with the same drugs plus 47 VAN 1 mg/mL. 48Results: In the VAN-treated rats, urinary KIM-1 and clusterin were increased on days 1, 2, and 3 49 compared to controls (P<0.001). Elevations were seen only after 3 days of treatment with 50 VAN+TZP (P<0.001 KIM-1, P<0.05 clusterin). Histopathology was only elevated in the VAN 51 group when compared to TZP as a control (P=0.04). Results were consistent across biomarkers 52and histopathology suggesting that adding TZP did not worsen VAN induced AKI and may even 53 be protective. In NRK-52E cells, VAN alone caused moderate cell death with high doses (IC50 54 48.76 mg/mL). TZP alone did not cause cellular death under the same conditions. VAN+TZP 55 was not different from VAN alone in NRK-52E cells (P>0.2). 56Conclusions: VAN+TZP does not cause more kidney injury than VAN alone in a rat model of 57 VIKI or in rat kidney epithelial cells. 58 59 3 | Page

Short Versus Extended Duration Vancomycin and Piperacillin/Tazobactam and the Incidence of Acute Kidney Injury in Noncritically Ill Patients

“…25,32,34,35 Furthermore, bench research using rat models has failed to demonstrate a histopathological or alternative to SCr biomarker (eg, urinary kidney injury molecule (KIM)-1 and clusterin) difference in AKI between the combination of vancomycin and pipercillin/tazobactam versus vancomycin alone. 36 Pais and colleagues hypothesize that competition for secretion or reabsorption of SCr with vancomycin and piperacillin/tazobactam may falsely increase SCr without truly affecting renal function, similar to sulfamethoxazole-trimethoprim. 36 Using a more specific measure or using a combination of methods may help determine true kidney damage versus measurement or detection errors.…”

“…36 Pais and colleagues hypothesize that competition for secretion or reabsorption of SCr with vancomycin and piperacillin/tazobactam may falsely increase SCr without truly affecting renal function, similar to sulfamethoxazole-trimethoprim. 36 Using a more specific measure or using a combination of methods may help determine true kidney damage versus measurement or detection errors. However, more studies are needed using novel kidney biomarkers and clinicians should continue to consider adjusting antibiotic therapy in patients who develop AKI using SCr measurements while receiving VPT.…”

Utilizing the Patient Care Process to Minimize the Risk of Vancomycin-Associated Nephrotoxicity

“…There are also clinical data suggesting that the addition of piperacillin-tazobactam to vancomycin lowers dialysis rates even in the face of increased rates of AKI as measured by increases in serum creatinine [29]. Data from a benchtop animal study suggest that the concomitant use of piperacillin/tazobactam may delay the increase in kidney injury molecule-1 (KIM-1) in animals receiving vancomycin [34]. Therefore, piperacillin-tazobactam may be renal-protective even though it increases serum creatinine.…”