In vivo analysis of structure-activity relationships among four aminoglycosides: Gentamicin, netilmicin, 1-N HAPA gentamicin B and amikacin

Structure-activity relationships for gentamicin, netilmicin, amikacin, and 1-N HAPA gentamicin B were compared in treatment of mice lethally infected with a variety of Enterobacteriaceae. The relative activity of the antibiotics against non-enzyme producing strains was analyzed as an indicator of intrinsic potency determined primarily by the basic aminoglycoside ring structure. Activity against strains producing two types of aminoglycoside-inactivating enzymes was analyzed on the basis of ring structure modifications affecting susceptibility to enzyme inactivation. Results of protection tests with strains possessing no enzyme activity generally correlated with structure-activity relationships previously determined in vitro. The two 'gentamicin-like' antibiotics, gentamicin and netilmicin, had a greater intrinsic potency than the two 'kanamycin-like' antibiotics, amikacin and 1-N HAPA gentamicin B. In vitro results were less predictive of in vivo potency in tests with strains producing aminoglycoside-inactivating enzymes. Although these latter organisms all initially appeared susceptible to the four antibiotics in vitro, rapid emergence of resistance in vivo was observed in several instances. The therapeutic efficacy against these strains, however, was related to specific aminoglycoside ring structure modifications affecting the susceptibility of the drugs to inactivating enzymes. The 'kanamycin-like' drugs, amikacin and 1-N HAPA gentamicin B, were more active than gentamicin and netilmicin against AAC (2') producing strains while gentamicin alone was most effective against AAC (6') producing strains.