All members of the aminoglycoside group of antimicrobics have a six-member aminocyclitol ring with attached amino sugars. The individual agents differ in terms of the exact ring structure and the number and nature of the amino sugar residues. Aminoglycosides are active against a wide range of bacteria, but only those organisms that are able to trans-port them into the cell by a mechanism that involves oxidative phosphorylation. Thus, they have little or no activity against strict anaerobes or facultative organisms that metab-olize only fermentatively (eg, streptococci). It appears highly probable that aminoglyco-side activity against facultative organisms is similarly reduced in vivo when the oxidation – reduction potential is low.
Once inside bacterial cells, aminoglycosides inhibit protein synthesis by binding to the bacterial ribosomes either directly or by involving other proteins. This binding desta-bilizes the ribosomes, blocks initiation complexes, and thus prevents elongation of polypeptide chains. The agents may also cause distortion of the site of attachment of mRNA, mistranslation of codons, and failure to produce the correct amino acid sequence in proteins. The first aminoglycoside, streptomycin, is bound to the 30S ribosomal sub-unit, but the newer and more active aminoglycosides bind to multiple sites on both 30S and 50S subunits. This gives the newer agents broader spectrum and less susceptibility to resistance due to binding site mutation.
Eukaryotic ribosomes are resistant to aminoglycosides, and the antimicrobics are not actively transported into eukaryotic cells. These properties account for their selective tox-icity and also explain their ineffectiveness against intracellular bacteria such as Rickettsia and Chlamydia.
Gentamicin and tobramycin are the major aminoglycosides; they have an extendedspectrum, which includes staphylococci; Enterobacteriaceae; and of particular impor-tance, P. aeruginosa.Streptomycin and amikacin are now primarily used in combination with other antimicrobics in the therapy of tuberculosis and other mycobacterial diseases. Neomycin, the most toxic aminoglycoside, is used in topical preparations and as an oralpreparation before certain types of intestinal surgery, because it is poorly absorbed.
All of the aminoglycosides are toxic to the vestibular and auditory branches of the eighth cranial nerve to varying degrees; this damage can lead to complete and irreversible loss of hearing and balance. These agents may also be toxic to the kidneys. It is often essential to monitor blood levels during therapy to ensure adequate yet nontoxic doses, especially when renal impairment diminishes excretion of the drug. For example, blood levels of gentamicin should be below 10 μg/mL to avoid nephrotoxicity, but many strains of P. aeruginosa require 2 to 4 μg/mL for inhibition.
The clinical value of the aminoglycosides is a consequence of their rapid bactericidal effect, their broad spectrum, the slow development of resistance to the agents now most often used, and their action against Pseudomonas strains that resist many other antimicro-bics. They cause fewer disturbances of the normal flora than most other broad-spectrum antimicrobics, probably because of their lack of activity against the predominantly anaer-obic flora of the bowel, and because they are only used parenterally for systemic infec-tions. The β-lactam antibiotics often act synergistically with the aminoglycosides, most likely because their action on the cell wall facilitates aminoglycoside penetration into the bacterial cell. This effect is most pronounced with organisms such as streptococci and en-terococci, which lack the metabolic pathways required to transport aminoglycosides to their interior.