Choice of drug and dosage regimen. Two important risk factors for aminoglycoside nephrotoxicity.

Since the clinical use of aminoglycosides may be limited by the development of nephrotoxicity, it is important to be aware of those risk factors associated with a greater incidence of renal damage. Some of these factors are related to the drug and its administration and others are related to the patient's clinical condition. In the human kidney, the toxicity mechanism is very likely the same for all aminoglycosides, although the risk of nephrotoxicity increases for a given aminoglycoside as cortical concentrations increase. Kinetic studies in the rat demonstrated a nonlinear increase in renal cortical uptake of gentamicin and netilmicin, a linear relationship for tobramycin uptake, and a mixed kinetic pattern for amikacin, that is, saturation kinetics at low serum concentrations and a linear pattern at high serum levels. At comparable steady-state low serum levels, amikacin and tobramycin showed lower cortical concentrations than gentamicin or netilmicin, demonstrating a lower affinity for the uptake of amikacin and tobramycin in the rat. Since drug uptake kinetics determine the extent of cortical concentrations achieved, dosing strategies may affect cortical accumulation of aminoglycosides. Our kinetic data show that continuous infusions of low doses of gentamicin and amikacin resulted in higher cortical levels, but the differences between regimens were more remarkable for gentamicin than for amikacin. For tobramycin, however, cortical concentrations were similar regardless of the dosing strategy used. In addition, our data show that dosage regimens also determine cortical accumulation in humans. A second major determinant of nephrotoxicity is intrinsic toxicity. At therapeutic doses, gentamicin, tobramycin, netilmicin, and amikacin induce an early lysosomal phospholipidosis in the human kidney cortex comparable to that observed in animals treated with low doses of these drugs. However, animal and human studies have shown that amikacin induces significantly less lysosomal overloading than the other aminoglycosides with no loss of phospholipase A1 activity. Based on the examination of cortical drug levels and the detection of early biochemical and morphologic alterations induced by aminoglycosides, the data suggest that amikacin has less pronounced nephrotoxic effects than gentamicin, netilmicin, or tobramycin, when used in strictly comparable clinical conditions.