Aminoglycosides : Activity and resistance

Aminoglycosides are highly potent, broad-spectrum antibiotics with many desirable properties for the treatment of life-threatening infections. Their history begins in 1944 with streptomycin and was thereafter marked by the successive introduction of a series of milestone compounds (kanamycin, gentamicin, and tobramycin) which definitively established the usefulness of this class of antibiotics for the treatment of gram-negative bacillary infections. In the 1970s, the semisynthetic aminoglycosides dibekacin, amikacin, and netilmicin demonstrated the possibility of obtaining compounds which were active against strains that had developed resistance mechanisms towards earlier aminoglycosides as well as displaying distinct toxicological profiles. Since then, however, the pace of development of new aminoglycosides has markedly slowed down. Conversely, we have witnessed a period of extensive basic and clinical research which has made us view these drugs very differently from what was commonly accepted when they were first introduced in the clinic. We attempt to present and discuss these developments, not to ascertain whether there is a likelihood that new molecules or effective means to avoid bacterial resistance and drug-induced toxicity will eventually reach the clinical arena, but to foster continuing research on aminoglycosides and to make the clinician aware of the pertinent progress made in this area. The present paper is focused on activity and resistance, whereas the companion review deals with nephrotoxicity (ototoxicity has been reviewed earlier in this journal). In both reviews, we did not attempt to be exhaustive in any of these domains, and the material presented has been selected on the basis of its interest in terms of new concepts or because it deals directly with the design of new aminoglycosides or an improved use of the available agents.