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Recent evidence suggests that among patients receiving vancomycin, receipt of concomitant piperacillin–tazobactam increases the risk of nephrotoxicity. Well-controlled, adequately powered studies comparing rates of acute kidney injury (AKI) among patients receiving vancomycin + piperacillin–tazobactam (VPT) compared to similar patients receiving vancomycin + cefepime (VC) are lacking. In this study we compared the incidence of AKI among patients receiving combination therapy with VPT to a matched group receiving VC.A retrospective, matched, cohort study was performed. Patients were eligible if they received combination therapy for ≥48 hours. Patients were excluded if their baseline serum creatinine was >1.2mg/dL or they were receiving renal replacement therapy. Patients receiving VC were matched to patients receiving VPT based on severity of illness, intensive care unit status, duration of combination therapy, vancomycin dose, and number of concomitant nephrotoxins. The primary outcome was the incidence of AKI. Multivariate modeling was performed using Cox proportional hazards.A total of 558 patients were included. AKI rates were significantly higher in the VPT group than the VC group (81/279 [29%] vs 31/279 [11%]). In multivariate analysis, therapy with VPT was an independent predictor for AKI (hazard ratio = 4.27; 95% confidence interval, 2.73–6.68). Among patients who developed AKI, the median onset was more rapid in the VPT group compared to the VC group (3 vs 5 days P =< .0001).The VPT combination was associated with both an increased AKI risk and a more rapid onset of AKI compared to the VC combination.