Nephrotoxicity of Gentamicin and Vancomycin Given Alone and in Combination as Determined by Enzymuria and Cortical Antibiotic Levels in Rats

Abstract

The purpose of this study was to compare the nephrotoxicity of gentamicin and vancomycin alone and in combination. Thirty-two male Sprague-Dawley rats were randomized into 4 groups of 8 animals. Each group received 200mg/kg gentamicin (G) i.m., or 300 mg/kg vancomycin (V) i.v., or an association of 200 mg/kg gentamicin + 300 mg/kg vancomycin (i.m. and i.v., respectively), or 0.9% NaCl solution i.m. and i.v. (controls). To determine AAP, GGT, and NAG enzyme excretions, urine samples were taken over 24-h periods before and after the start of the experiment. A single renal cortical sample was obtained at necropsy for quantitation of antibiotic levels. No significant modifications of urinary excretions of creatinine and enzymuria were noted during the 24-h period before each drug administration or in controls. AAP, GGT, and NAG excretions were significantly increased after G and G + V injections (p < 0.001), whereas only AAP and GGT were statistically higher in rats receiving V (p < 0.05). NAG elimination (mean +/- SD) was higher in G + V (16.0 +/- 0.2 IU/mmol creatinine/24 h; p < 0.001) than g (8.8 +/- 0.6) or V (1.7 +/- 0.2). Surprisingly, mean vancomycin cortical levels decreased in the combination (827 +/- 131 vs. 1964 +/- 23 micrograms/g for V alone; p < 0.001), whereas gentamicin concentration was unchanged (826 +/- 66 vs. 839 +/- 28 micrograms/g for G alone). Determination of enzymuria allowed the nephrotoxicity of the antibiotics to be graded in the following order: vancomycin + gentamicin > gentamicin > vancomycin.

Prognostic Value of Tubular Proteinuria and Enzymuria in Nonoliguric Acute Tubular Necrosis

“…Possibly, early peak urinary excretion of enzymes was missed because ATN patients were not included in the study at the time of the insult that caused the proximal tubular injury, but with some time delay, as is common in clinical practice. This could be important because enzymuria was demonstrated to occur more rapidly after renal injury than tubular proteinuria (21,23,25,27 ). Additionally, urinary excretion of enzymes is markedly diuresis dependent (45 ).…”

Vancomycin-Associated Acute Kidney Injury with a Steep Rise in Serum Creatinine

“…This concern was validated by a reduction in vancomycin-associated (VA) acute kidney injury (AKI) that followed a technological improvement in the fermentation process, which led to a 95% level of product purity by 1985 [1-3]. Subsequently, most reports of AKI associated with vancomycin were described in the context of concomitant administration of other known nephrotoxic drugs, such as aminoglycosides [4, 5]. In addition, because vancomycin is cleared by the kidneys, studies reporting association of high vancomycin trough levels with AKI have been difficult to interpret when the precise timing of the kidney injury and the high vancomycin trough levels cannot be clearly determined [6-8].…”

Nephrotoxicity due to Combination Antibiotic Therapy with Vancomycin and Aminoglycosides in Septic Critically Ill Patients

“…albumin and different low-molecular-weight proteins [4,10] , and of different tubular enzymes [4,10,12] , e.g. alanine aminopeptidase and ␥ -glutamyltransferase (GGT) specifi c for brush border damage of proximal tubular cells [15] , N-acetyl-␤ -D -glucosaminidase (NAG) specifi c for lysosomal damage [10,12] and lactate dehydrogenase (LDH), which is a cytosolic enzyme [12] . Still debated is whether the concurrent administration of vancomycin and aminoglycosides increases the risk of nephrotoxicity due to either drug [4-7, 9, 10] .…”