NATURE AND RATE OF AMINOGLYCOSIDE RESISTA NCE MECHANISMS

Aminoglycoside resistance in Enterobacteriaceae is caused by aminoglyc oside-modifying enzymes that acetylate (AAC), adenylylate or phosphory late aminoglycoside, as well as by changes in the permeability to amin oglycosides. Early surveys in the United States and Europe showed that aminoglycoside resistance was mainly due to the occurrence of these m echanisms as single entities. The incidence of the different mechanism s paralleled the different usage of aminoglycosides in each country. S ingle mechanisms conferring gentamicin resistance accounted for most o f the aminoglycoside resistance in the United States and Europe.Recent ly the most frequently occurring resistance mechanisms have changed, b oth in Europe and in the United States. A trend toward complex combina tions of 2 or more aminoglycoside-modifying enzymes has been observed. These combinations often include AAC(6')-I, an enzyme that confers re sistance to tobramycin, netilmicin and amikacin but not gentamicin, an d they occur more frequently in geographical regions with historically high resistance to gentamicin. Isepamicin, a new aminoglycoside, has activity against strains that produce AAC(6')-I as well as against iso lates that produce gentamicin-modifying enzymes. Thus, it is active ag ainst strains producing a combination of these enzymes. The activity o f isepamicin and the resistance to amikacin may be related to differen ces at position 3('') of these two otherwise very similar aminoglycosi des. Amikacin may form a stable complex with AAC(6')-I enzymes via bin ding interactions at with primary amino groups at positions 3 and 3('' ). Isepamicin, which has a secondary amino group at position 3(''), ma y be able to interact only at position 3, and thus the enzyme-isepamic ine complexes are likely to be less stable.