The potential for discovery and development of improved aminoglycosides.

ABSTRACT

Following the development of amikacin, pharmaceutical companies made intensive efforts to find even more potent and broader-spectrum aminoglycosides. This effort was justifiable in view of the fact that over the preceding decade, these agents, because of their unique properties, had proven to be the primary weapons in the therapeutic armamentarium for the treatment of seriously ill patients. Since the toxicities associated with the aminoglycosides were beginning to limit their use in general medicine, researchers ultimately shifted their emphasis from probing for higher-potency, broader-spectrum agents to finding those with a reduced potential for toxicity. This article addresses the issue of whether superior aminoglycoside derivatives will reach the marketplace in the future. A comparison is made of several key properties of virtually all aminoglycosides that have reached an advanced preclinical development stage, gone into the clinic, or been registered for commercial use over the past 10 years. The following parameters are used for comparisons with already marketed aminoglycosides antibacterial potency, as measured by relative minimum inhibitory concentrations for 50 percent of the strains tested, against wild-type Pseudomonas aeruginosa; degree of resistance to inactivation by microbial enzymes; and potential for toxicity utilizing comparative acute intravenous lethal doses for 50 percent of the population in mice, values that appear to predict the maximum recommended daily doses in man. An assessment of a number of compounds, including three structurally related to gentamicin, two to sisomicin, two to kanamycin A, three to kanamycin B, and two to fortimicin, revealed that none had overall properties superior to those already being utilized commercially. In no case did a compound prove to be less toxic, and in many instances, the antibacterial potency of the newer agents was lower than that exhibited by the older aminoglycosides. Some increase in resistance to inactivating enzymes was seen, but only BB-K 311 proved refractory to more enzymes than did amikacin. In view of this and the fact that no new agents of promise have moved into the development stage during the past five years, it seems safe to say that the current armamentarium of aminoglycosides is all that will be available for use in the foreseeable future.