Combined vancomycin and piperacillin-tazobactam treatment is not associated with worsening renal function when assessed using plasma cystatin C
Dr. Miano is a Critical Care Pharmacist at the Hospital of the University of Pennsylvania and an Instructor of Epidemiology at the Perelman School of Medicine. He is an elected fellow of the American College of Critical Care Medicine, an International Editor of the British Journal of Clinical Pharmacology, and an Associate Editor of BMC Pharmacology and Toxicology. Dr. Miano’s research leverages electronic health record data to study drug safety and comparative effectiveness in the critically ill population. His work seeks to understand drug effect heterogeneity and quantify the impacts of variable response on outcomes. Areas of emphasis include drug associated acute kidney injury and drug-drug interactions.
Rationale: Although dozens of studies have associated combined vancomycin+piperacillin-tazobactam treatment (VN+PT) with increased acute kidney injury (AKI) risk, the mechanism of this drug-drug interaction remains unknown. AKI is defined based on changes in serum creatinine. VN and PT are substrates for kidney creatinine transporters, suggesting that creatinine defined AKI might be an artifact of altered creatinine transport. We tested this hypothesis by contrasting changes in creatinine with changes in cystatin C (Cys-C), a well-validated alternative marker of kidney function.
Methods: We performed a cohort study of patients with sepsis who were treated with VN+PT or VN+cefepime (CP), an active comparator. Changes in kidney function were evaluated by: 1) percentage change in Cys-C and creatinine from baseline to 48 hours; 2) creatinine-defined AKI at the end of therapy; and 3) renal replacement therapy (RRT) at the end of therapy.
Results: 534 patients were included (VN+PT n=241, VN+CP n=293), of whom 99 had Cys-C measurements (VN+PT n=42, VN+CP n=57). VN+PT was associated with a higher incidence of creatinine-defined AKI: 42.3% vs 30.4% (adjusted-RR 1.34 [CI95 1.08-1.67]); and a higher percentage increase of creatinine at 48 hours: 26.9% vs 1.9% (adjusted-difference 22.3% [-0.6-45.1]). In contrast, VN+PT was not associated with a change in Cys-C at 48 hours: 8.2% vs 11.0% (adjusted-difference -4.0% [-23.3-15.2]), or the need for RRT.
Conclusion: The discordant associations between VN+PT treatment and changes of creatinine versus Cys-C suggest that combined use of these cornerstone antibiotics may not be associated with worsening kidney function in critically ill patients with sepsis.
Keywordsacute kidney injury; nephrotoxicity; antibiotics; sepsis; drug-drug interactions
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