(1340) Impact of Vancomycin and Beta-Lactam Combinations on Renal Tubule Markers of Injury and Secretion

Introduction: The nephrotoxicity of combination piperacillin-tazobactam (PTZ) vs other beta-lactams (CEF/MEM) with vancomycin has been established in retrospective evaluations. There are no underpinned mechanisms for these observations, and a pseudo-toxicity hypothesis of competitive inhibition of creatinine secretion by PTZ into the tubule has been proposed. Limited data has evaluated these combinations on markers of tubular injury.

Methods: Secondary analysis of a prospective study evaluating the impact of beta-lactam concentrations on clinical outcomes in medical intensive care unit patients. Patients were included if vancomycin was concurrently administered with the beta-lactam. Two groups were identified: PTZ/VAN and CEF/MEM/VAN. Urinary biomarkers were measured daily up to five days following initiation of combination therapy. Primary outcome was the change in renal biomarkers NGAL, KIM-1, and TIMP-2/IGFBP-7, from baseline to peak. Secondary outcomes were serum creatinine defined AKI, and change in urine to serum creatinine (U:S) ratio over time in non-AKI patients to evaluate for tubular creatinine secretion inhibition.

Results: Eighteen patients met criteria with co-administration of vancomycin at the time of urinary biomarker collection for this analysis. Five patients (27%) received PTZ/VAN and 13 (72%) received CEF/MEM/VAN. Patients were male (60%), White (94%), with a median age of 59 years old. Baseline and treatment characteristics were comparable. There were no differences in the change in KIM-1: 0.01 ng/mL (0-0.01) PTZ/VAN vs 0 ng/mL (-0.03- 0.01) CEF/MEM/VAN; p=0.549; no differences in NGAL: 3.97 ng/mL (1-10.29) PTZ/VAN vs -1.41 ng/mL (-31.03- 6.28) CEF/MEM/VAN; p=0.301, and no differences in TIMP-2/IGFBP-7: 1.03 pg/mL (0.39-3.38) PTZ/VAN vs 0.05 pg/mL (-2.19- 0.47) CEF/MEM/VAN; p=0.085. Serum-creatinine defined AKI developed in 1 (20%) PTZ/VAN vs 2 (15%) CEF/MEM/VAN; p=0.814. U:S on D2 was numerically lower in the PTZ/VAN group 34 (10-60) versus the CEF/MEM/VAN group 59 (45-83); p=0.089.

Conclusions: The combination of PTZ/VAN was not associated with increased renal tubular injury. The U:S was almost doubled in the CEF/MEM/VAN group, possibly due to reduced creatinine secretion into the urine. These findings should be confirmed with additional investigations of tubular secretion.