Putative mechanisms of action of the aminoglycosides. Normal protein synthesis is shown in the top panel. At least 3 aminoglycoside effects have been described, as shown in the bottom panel: block of formation of the initiation complex; miscoding of amino acids in the emerging peptide chain due to misreading of the mRNA; and block of translocation on mRNA. Block of movement of the ribosome may occur after the formation of a single initiation complex, resulting in an mRNA chain with only a single ribosome on it, a so-called monosome.

Mechanisms of Resistance

Streptococci, including Streptococcus pneumoniae, and enterococci are relatively resistant to gentamicin and most other aminoglycosides owing to failure of the drugs to penetrate into the cell. However, the primary mechanism of resistance to aminoglycosides, especially in gram-negative bacteria, involves the plasmid-mediated formation of inactivating enzymes. These enzymes are group transferases that catalyze the acetylation of amine functions and the transfer of phosphoryl or adenylyl groups to the oxygen atoms of hydroxyl groups on the aminoglycoside. Individual aminoglycosides have varying susceptibilities to such enzymes. For example, transferases produced by enterococci can inactivate amikacin, gentamicin, and tobramycin but not streptomycin. However, amikacin is often resistant to many enzymes that inactivate gentamicin and tobramycin. In addition, resistance to streptomycin, which is common, appears to be due to changes in the ribosomal binding site.

Clinical Uses

The main differences among the individual aminoglycosides lie in their activities against specific organisms, particularly gram-negative rods. Gentamicin, tobramycin, and amikacin are important drugs for the treatment of serious infections caused by aerobic gram-negative bacteria, including Escherichia coli and Enterobacter, Klebsiella, Proteus, Providencia, Pseudomonas, and Serratia species. These aminoglycosides also have activity against strains of Haemophilus influenzae, Moraxella catarrhalis, and Shigella species, although they are not drugs of choice for infections caused by these organisms. In most cases, aminoglycosides are used in combination with a beta-lactam antibiotic. When used alone, aminoglycosides are not reliably effective in the treatment of infections caused by gram-positive cocci. Antibacterial synergy may occur when aminoglycosides are used in combination with cell wall synthesis inhibitors. Examples include their combined use with penicillins in the treatment of pseudomonal, listerial, and enterococcal infections.

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