Toxicity, of aminoglycosides

Williams, P.D., Hottendorf, G.H. and Bennett, D.B. (1986a). Inhibition of renal membrane binding and nephrotoxicity of aminoglycosides. J. Pharmacol. Exp. Ther. 237 919-925. Williams, P.D., Laska, D.A. and Hottendorf, G.H. (1986b). Comparative toxicity of aminoglycoside antibiotics in cell cultures derived from human and pig kidney. In Vitro Toxicol. 1 23-32. 

The toxicity of aminoglycosides in the kidney and other organs is concentration-dependent. Antibiotics such as kanamycin and gentamycin have their half-lives doubled in elderly patients. The elderly commonly suffer from osteoarthritis and (less commonly) rheumatoid arthritis. NSAIDs must be carefully used in geriatric patients, as they cause GI toxicity. For example, aspirin causes GI irritation... 

Mattie H, Craig WA, Pechere JC. Determinants of efficacy and toxicity of aminoglycosides. J Antimicrob Chemother 1989 24(3) 281-93. 

A few other fluorinated kanamycins, including 5-deoxy-5-epi-fluoroamikacin, 5-deoxy-5-ep(-fluoroarbekacin, and their related analogs, have been prepared to study the fluorination-toxicity relationship. In contrast to the low toxicities of the 5-fluoro derivatives [121], these epi-fluoro compounds showed acute toxicity values identical to those of arbekacin and amikacin [122]. This indicates the importance of stereo-electronic effects of the fluoro group at position 5 of the 2-deoxystreptomine moiety in toxicity of aminoglycoside antibiotics. 

Many attempts have been made to reduce the toxicity of aminoglycosides. The combination of D-glucaro-6-lactam decrease the nephrotoxicity The application of 2,3-dimercaptopropanol during the therapy reduces the ototoxicity. 

Fujisawa KL, Hoshiya T, Kawaguchi H (1974) Aminoglycoside antiobiotics. Vn. Acute toxicity of aminoglycoside antibiotics. J Antibiot 27 677-681... 

Resistance to drug toxic effects has also been observed in children. The incidence of aminoglycoside toxicity has been reported to be much lower in infants and children than in adults [39,48]. Diminished tissue sensitivity has been suggested as an explanation. 

A major clinical distinction between the effects on the inner ear and the kidney is the fact that the renal effects are reversible while the effects on the inner ear are irreversible, leading to permanent loss of balance or auditory function. Furthermore, renal insults can more easily be monitored and thereby largely prevented, while monitoring of impending auditory or vestibular damage is not always possible. Ototoxic side effects frequently develop after cessation of aminoglycoside treatment, sometimes delayed by weeks. This review will therefore focus on the ototoxic side effects as a major unresolved issue in aminoglycoside toxicity. 

Figure 9.2. Mechanisms of aminoglycoside toxicity. This schematic representation summarizes the principles of aminoglycoside toxicity discussed in the text. Treatment with the drugs leads to the formation of reactive oxygen species through a redox-active complex with iron and unsaturated fatty acid or by triggering superoxide production by way of NADPH oxidase. An excess of reactive oxygen species, not balanced by intracellular antioxidant systems, will cause an oxidative imbalance potentially severe enough to initiate cell death pathways. Augmenting cellular defenses by antioxidant therapy can reverse the imbalance and restore homeostasis to protect the cell.

The aminoglycosides decrease the fidelity of translation by binding to the 30S subunit of the ribosome. This permits the formation of the peptide initiation complex but prohibits any subsequent addition of amino acids to the peptide. This effect is due to the inhibition of polymerization as well as to the failure of tRNA and mRNA codon recognition. Aminoglycosides are ototoxic (i.e., may produce partial deafness), damaging the auditory nerve. Kanamycin is less toxic. Since aminoglycosides are concentrated in the kidney, they may occasionally cause kidney damage. 

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