7.13.9 Prevention

Given the clinical severity of the toxicities associated with aminoglycosides, a great deal of research has been devoted to the discovery of agents that can prevent these sequelae. The polyamino acids, poly-l-aspartic acid (PAA) and poly-l-glutamic acid (PGA), are a group of compounds that have been shown to be efficacious at preventing aminoglycoside nephrotoxicity without impairing antimicrobial activity (Ali 2003; Beauchamp et al. 1990; Josepovitz et al. 1982; Kishore et al. 1990a, 1992; Mingeot-Leclercq and Tulkens 1999; Ramsammy et al. 1989; Williams et al. 1986). Unlike the aminoglycosides, PAA and PGA are polyanions. In their seminal research, Williams et al. (1986) showed that PAA and PGA markedly inhibit gentamicin binding at the renal brush border. Researchers initially believed that the mechanism of action of the polyamines was aminoglycoside binding inhibition (Josepovitz et al. 1982; Williams et al. 1986). This specific mechanism would suggest that renal cortical concentrations of aminoglycosides would be attenuated in PAA-treated animals. However, Gilbert et al. (1989) were able to show that PAA actually enhanced the renal cortical uptake of gentamicin. PAA-treated rats had renal cortical gentamicin levels 10 times that of controls. Subsequent research corroborated these findings (Beauchamp et al. 1990; Swan et al. 1992). Working independently, research by Beauchamp et al. (1990) and Kishore et al. (1992) revealed that PAA reduced lysosomal enlargement, myeloid body deposition, and phospholipidosis in rats given gentamicin (Bartal et al. 2003). Kishore et al. (1990b) also demonstrated that PAA binds gentamicin optimally at pH 5.4, which is equal to the intralysosomal pH. In addition, they revealed that PAA displaces gentamicin from negatively charged lysosomes. As a result of this body of research, our understanding of the mechanism of action of polyamines profoundly expanded. This research also possibly helped to explain the apparent paradox of increased renal cortical concentrations of aminoglycosides seen with PAA treatment. Researchers now postulate that PAA confers renal protection by binding to gentamicin directly or by displacing it from negatively charged lysosomes, thus preventing the development of lysosomal phospholipidosis (Kishore et al. 1990b).

ROS have long been implicated as possible instigators of aminoglycoside nephrotoxicity. As a result, multiple antioxidant agents have been investigated as candidate compounds for nephrotoxicity prevention. Some of the potential antioxidant agents investigated include deferrioxamine, methimazole, vitamin E, vitamin C, and selenium (Ali 1995, 2003; Ben-Ismail et al. 1994). Each of these agents was shown to be effective in preventing gentamicin nephrotoxicity. Other proven agents were superoxide dismutase, dimethyl sulfoxide (DMSO), lipoic acid, N-acetylcysteine, and melatonin (Ali 2003; Ali and Bashir 1996; Ali and Mousa 2001; Mazzon et al. 2001; Ozbek et al. 2000; Reiter et al. 2002; Sandya et al. 2005). Interestingly, agents that would not be expected to exhibit antioxidant properties, such as the beta blocker carvedilol and the antihyperlipidemic probucol, were also shown to be effective in preventing free radical-mediated gentamicin nephrotoxicity (Kumar et al. 2000a,b).

Ethylene Diamine Tetraacetate Acid Tetrasodium Salt (EDTA-4Na)

Calcium has been shown to be an efficacious prophylactic agent in aminoglycoside nephrotoxicity. In animal studies, Bennett et al. (1982) demonstrated that dietary calcium loading in rats given gentamicin delayed the onset and reduced the magnitude of nephrotoxicity. This was corroborated in subsequent work by Quarum et al. (1984) and Humes et al. (1982a), who also showed that dietary calcium supplements moderated gentamicin-induced nephrotoxicity. Calcium appears to prevent critical gentamicin–membrane interactions within the renal tubular cell (Humes et al. 1982).

Despite the clinical promise of these various agents in preventing aminoglycoside nephrotoxicity, they have yet to be adopted as the standard of care in the clinical setting. However, recent discoveries may make these potential preventative compounds unnecessary. A congener of gentamicin has been isolated that retains its antimicrobial activity yet lacks the typical nephrotoxic liability of the commercially available forms. Commercially available gentamicin is a heterogeneous compound composed of four different gentamicin congeners, C₁, C_1a, C₂, and C_2a. Each of these congeners differs in its propensity to cause nephrotoxicity (Sandoval et al. 2006). Early research by Kohlhepp et al. 1984, which evaluated the C₁, C_1a, and C₂ congeners, initially attributed the nephrotoxicity of gentamicin to the C₂ congener (Kohlhepp et al. 1984). However, this work was hindered by the limitations of high-pressure liquid chromatography (HPLC) technology at that time and likely cross-contamination of their C₂ sample with C_2a. Later research by Sandoval et al. 2006 showed that the C_2a was actually responsible for the renal cellular toxicity. More compelling, though, Sandoval et al. 2006 found that the C₂ congener not only caused minimal renal cellular toxicity, but also retained its antimicrobial activity. Using elegant immunofluorescent techniques, Sandoval et al. 2006 showed that the C₂ congener did not induce the intracellular trafficking abnormalities of the Golgi complex and lysosomes that were observed with the cytotoxic congeners and native gentamicin. The dependable activity of aminoglycosides coupled with the emergence of multidrug-resistant Gram-negative pathogens makes the clinical potential of a nonnephrotoxic aminoglycoside quite apparent.

Until the prophylactic interventions or the C₂ gentamicin congener becomes adopted in practice, clinicians must utilize established strategies to reduce the incidence of aminoglycoside-induced nephrotoxicity. The selection of the least nephrotoxic aminoglycoside when clinically possible is imperative. Other strategies shown to be beneficial include correcting hypokalemia and hypomagnesemia, minimizing concomitant nephrotoxic medications, adjusting the dose of aminoglycoside for the level of renal function, and limiting the duration of therapy to 7–10 days (Guo and Nzerue 2002; Humes 1988; Martin 2003). Finally, ODA programs should be considered in appropriate patients as an effective and less toxic alternative to conventional aminoglycoside dosing regimens (Baciewicz et al. 2003; Bailey et al. 1997; Ferriols-Lisart and Alos-Alminana 1996; Guo and Nzerue 2002; Hatala et al. 1996; Martin 2003; Munckhof et al. 1996).