Antagonistic effect of penicillin-amikacin combinations against enterococci

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Abstract
Amikacin has been shown to antagonize the bactericidal effect of penicillin against strains of Streptococcus faecalis which produce aminoglycoside 3'-phosphotransferase. The mechanism by which this phenomenon occurs was studied with an enzyme-producing strain (8436) and an enzyme-negative strain (8436c) derived by curing the former with novobiocin. Combinations of amikacin with beta-lactam antibiotics were antagonistic against strain 8436 but synergistic against strain 8436c. Against strain 8436 penicillin-amikacin combinations resulted in levels of killing comparable to those seen with high concentrations of penicillin (500 micrograms/ml), which were less bactericidal than lower concentrations of penicillin. No antagonism was observed between amikacin and non-beta-lactam cell wall-active drugs or between penicillin and kanamycin or neomycin, both of which are substrates for the enzyme. At concentrations near the MIC, amikacin was bactericidal against strain 8436c but bacteriostatic against strain 8436 (MIC, 250 micrograms/ml; MBC, 2,000 micrograms/ml). Neither penicillin nor phosphorylated amikacin affected the inhibition of ribosomal protein synthesis by amikacin in a cell-free system. Although antagonism of killing by amikacin in enzyme-positive strains was specific for combinations which included beta-lactam antibiotics, amikacin did not influence the binding of [3H]penicillin to penicillin-binding proteins in isolated bacterial cell membranes or in intact cells and did not detectably affect the autolytic system of cells exposed to penicillin. Antagonism of beta-lactam activity by a bacteriostatic effect of amikacin against the enzyme-producing strain is the most likely explanation for this phenomenon.