Aminoglycosides remain critical antibiotics in the armamentarium for serious Gram-negative bacterial infections despite their well-known risk for nephrotoxicity and ototoxicity. Aminoglycosides manifest their bactericidal activity by binding to the 30S ribosomal subunit which interferes with the initiation of protein synthesis. They are most commonly administered intravenously with peak serum concentrations occurring in 30 minutes. Aminoglycosides are excreted unchanged in the urine by glomerular filtration with an elimination half-life of 2-3 hours in patients with normal renal function. The incidence of aminoglycoside nephrotoxicity is 5-10%. Patient risk factors for aminoglycoside nephrotoxicity include advanced age, male gender, ascites, hypoalbuminemia, and leukemia. Medications such as clindamycin, vancomycin, piperacillin, cephalosporins, and angiotensin-converting enzyme inhibitors also increase the risk of nephrotoxicity when administered with aminoglycosides. Morphological changes seen in animals during aminoglycoside nephrotoxicity consist of epithelial cell damage confined to the S1 and S2 segments of the proximal tubule. The biochemical alterations that occur with aminoglycoside nephrotoxicity include decrements in the transport of organic base, ions, glucose, and low-molecular- weight proteins. The initial renal cortical binding sites for aminoglycosides are the acidic, anionic phospholipids found in the plasma membranes of the apical and basolateral surfaces of the proximal tubule cells. Once binding has occurred, aminoglycosides are transported across the apical or basolateral plasma membrane by receptor-mediated endocytosis via megalin. After endocytosis, the endosomes containing the aminoglycosides fuse with lysosomes. Once-daily aminoglycoside dosing in which a large loading dose of an aminoglycoside is given every 24-48 hours has been shown to maintain clinical efficacy and reduce the incidence of nephrotoxicity. Various interventions to prevent aminoglycoside nephrotoxicity have been proposed such as polyaspartic acid, superoxide dismutase, N-acetylcysteine, and melantonin. A congener of gentamicin has also been isolated that retains clinical efficacy, but does not cause nephrotoxicity. Until these interventions become adopted in clinical practice, however, clinicians must utilize established strategies to reduce the incidence of aminoglycoside-induced nephrotoxicity. These include selection of the least nephrotoxic aminoglycoside, correcting hypokalemia and hypomagnesemia, minimizing concomitant nephrotoxic medications, limiting the duration of therapy to 7-10 days, adjusting the dose of aminoglycoside for the level of renal function, and utilizing once-daily dosing of aminoglycoside when clinically appropriate.
|Original language||English (US)|
|Title of host publication||Renal Toxicology|
|Number of pages||18|
|State||Published - Aug 12 2010|
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