Side effects of aminoglycosides on the kidney, ear and balance in cystic fibrosis

Abstract

Aminoglycoside antibiotics are a central component of the treatment of pulmonary exacerbations of cystic fibrosis (CF) and slow the decline in lung function which ultimately causes the death of most patients. The prognosis of CF has improved, and thus side effects of treatments have become increasingly important. Observational studies suggest that the morbidity from side effects of aminoglycosides is disturbingly common, and that aggressive treatment may lead to more side effects. This review of the current literature on side effects of aminoglycosides considers the pathophysiological mechanisms, epidemiology and risk factors, investigation of side effects and preventative strategies. Treatments which have shown early promise are identified and areas of future research are discussed.

Figure 1

Potential cellular mechanism of toxicity. This diagram summarises the major themes of the literature, much of which is in vitro work and so has to be interpreted as a model. Gentamicin enters the tubular cell via the multiligand receptor megalin (shown in blue) and then uptake is via a clatharin-coated pit. Gentamicin passes in a retrograde manner via the lysosomes, Golgi and endoplasmic reticulum into the cytoplasm where it forms complexes with iron which catalyse the formation of reactive oxygen species (ROS). In the lysosomes, gentamicin causes release of the pro-apoptotic cathepsins and, in the endoplasmic reticulum, gentamicin causes release of the pro-apoptotic stress protein von Hippel–Lindau binding protein 1 (VBP1). Cytosolic gentamicin either directly or indirectly (via ROS) causes the release of cytochrome C from the mitochondria, a key step in apoptosis. ROS cause an increase in the gene expression of oxidative stress-inducible genes, stress-inducible chaperones and oxido-reductive enzymes. Gentamicin may have intracellular effects without entry to the cell. It can cause a rapid increase in intracellular Ca²⁺ and an early increase in the anti-apoptosis and pro-proliferative signals Akt and Erk; this may be mediated by the membrane Ca²⁺ receptor CaR (shown in purple).

Figure 2

Effects of saturable uptake on kidney cortical accumulation in single daily versus three times daily dosing. In three times daily dosing (shown in red), all of the area under the curve (AUC; red shaded area) contributes to the uptake of the aminoglycoside into the kidney cortex. However, above a certain threshold (indicated by the arrow), the receptor-mediated uptake of the aminoglycoside is saturated and serum concentrations above this level do not contribute to the uptake of aminoglycoside into the renal cortex. As this threshold is exceeded in single daily dosing (shown in green), a proportion of the single daily dose AUC does not contribute to renal uptake. Thus, the area below this threshold contributes to renal uptake (the green area in single daily dosing). As the green area is smaller than the red area, the renal uptake in single daily dosing is thought to be lower than with the three times daily dosing regimen.