THE CHANGING NATURE OF AMINOGLYCOSIDE RESISTANCE MECHANISMS AND THE ROLE OF ISEPAMICIN - A NEW BROAD-SPECTRUM AMINOGLYCOSIDE

Aminoglycoside resistance mechanisms from recent studies(1,2) were com pared with those found in earlier studies in the USA (3-5) and Europe (6-8) for three pathogen groups. Among Citrobacter-Enterobacter-Klebsi ella, four single mechanisms (AAC(3)-II, AAC(3)-I, ANT(2'')-I and AAC( 6')-I) were found in all studies, but the most recent studies showed a significant increase in combinations of AAC(6')-I with the other comm on mechanisms. Since AAC(6')-I confers resistance to tobramycin, netil micin and amikacin, combinations of it with the other gentamicin modif ying enzymes conferred broad-spectrum resistance to all clinically ava ilable aminoglycosides except isepamicin. Similar changes occurred in Escherichia-Morganella-Proteus-Salmonella-Shigella except that the fre quency of combinations was much lower and two additional single mechan isms - AAC(3)-IV and permeability - were also found frequently. Among aminoglycoside-resistant Pseudomonas, three mechanisms, AAC(6')-II, AN T(2'')-I and permeability, were always common and remained common.(1,2 ,9) However, combinations of the three mechanisms with each other and with other mechanisms were more common in the recent surveys. Differen t genes which produce differ ent proteins with the same aminoglycoside -modifying activity are now known. The results of hybridisation studie s with two dnc(3)-I, 2 aac(6')-II and 4 aac(6')-I gene probes are pres ented. The most commonly occurring genes were: aac(3)-Ia, aac(3)-IIa, aac(6')-IIa, aac(6')-Ib and, in Serratia, aac(6')-Ic. The activity of isepamicin against amikacin resistant strains which produce AAC(6')-I can be related to differences in the structure of these two similar am inoglycosides at Position 3''. Amikacin may form a stable complex with AAC(6')-I enzymes via binding interactions at Position 3 and 3''. Ise pamicin, which has a secondary amino group at Position 3'', may only b e able to interact at Position 3 and enzyme-isepamicin complexes are l ikely to be less stable.