Piperacillin Exacerbates Vancomycin-Induced Toxicity in Renal Proximal Tubular Cells

Vancomycin (VCM) combined with piperacillin/tazobactam (PIPC/TAZ) is used as an empiric therapy in patients with severe infections, including sepsis. Recent research has found an increased incidence of acute kidney injury (AKI) in patients receiving combination therapy with these antibiotics. However, the pharmacological mechanism by which this combination worsens kidney function remains unclear. In this study, we investigated the direct cytotoxicity of VCM, PIPC, and TAZ on HK-2 cells and human renal proximal tubular epithelial cells (RPTEC). VCM, PIPC/TAZ, or PIPC significantly reduced cell viability in a concentration-dependent manner; the potency was in the order of VCM, PIPC/TAZ, and PIPC (IC₅₀ values were 1717, 2491, and 3020 μg/mL, respectively). The combined treatment with PIPC/TAZ or PIPC significantly enhanced the VCM-induced decrease in cell viability. Furthermore, PIPC/TAZ or PIPC increased lactate dehydrogenase leakage, indicating membrane cytotoxicity, whereas no such effect was observed with VCM or TAZ. VCM increased caspase-3/-7 activity, whereas PIPC did not. The VCM-induced increase in neutrophil gelatinase-associated lipocalin (NGAL) production was amplified by concomitant PIPC treatment. Synergistic effects were detected for both the cell viability and NGAL production, suggesting that the direct toxicity of PIPC to RPTEC was responsible for the increased AKI incidence in patients treated with VCM. Our results may contribute to a better understanding of how AKI is exacerbated, as well as provide tips for preventing AKI after VCM and PIPC/TAZ combined therapy.