An in vitro comparison of the early synergistic interaction between amikacin and each of six IT-lactam antibiotics was made by using time-kill curves against 48 multiply resistant members of the family Enterobacteriaceae. Overall, these six combinations demonstrated early synergism (x2 logs of increased kill after 7 h of incubation) against the 48 strains on 74% (range, 67 to 85%) of occasions; cefotaxime-amikacin and piperacilin-amikacin were the most efficacious combinations. Antagonism was not observed with any of the combinations against any of the 48 Enterobacteriaceae strains tested.Combination therapy with an aminoglycoside plus a semisynthetic penicillin or cephalosporin commonly is used in the treatment of life-threatening infections caused by gramnegative bacilli, especially in the immunocompromised patient (1, 16). These antibiotic combinations, shown to be synergistic both in vivo (1, 11) and in vitro (7-9), are used in place of single-drug therapy with the aim of obtaining increased therapeutic efficacy as well as reducing the likelihood of emergence of resistance among infecting gramnegative bacilli (5,18).In a prior investigation with timne-kill curves to evaluate the early synergistic interaction between gentamicin or amikacin and three ,-lactams against 48 members of the family Enterobacteriaceae, we demonstrated that amikacin ih combination with carbenicillin, ticarcillin, or piperacillin produced early synergism against 46% of the strains, whereas gentamicin in combination with these same P-lactams exhibited early synergism against only 28% of the strains (4). Of the P-lactams studied previously, piperacillin in combination with either amikacin or gentamicin demonstrated early synergism against 71% of the strains, whereas carbenicillin plus amikacin or gentamicin and ticarcillin plus amikacin or gentamicin produced early synergism against 16 (14).Susceptibility testing. Antimicrobial susceptibility testing was performed by the agar dilution method (19). Serial twofold dilutions of the respective antibiotics were incorporated into Mueller-Hinton agar, and an inoculum of 1 organisms per ml was delivered onto each plate with a Steers replicator (Craft Machine, Inc., Chester, Pa.). The MIC was defined as the lowest concentration of antibiotic producing no visible growth after 18 h of incubation at 37°C.Ahtibiotic synergism. The synergistic interaction between amikacin and each of the six P-lactam drugs was evaluated by time-kill curves during 7 h of incubation, as described previously (4). The following concentrations of antibiotics in the flasks were selected to be at or below the MIC for each drug and within a clinically achievable range (10, 17) for each drug: <125 ,ug/ml for piperacillin, -62 ,ug/ml for each of the cephalosporins, and s8 ,ug/ml for amikacin. A starting inoculum of 105 organisms per ml was prepared by appropriate dilutiod of an overnight broth culture and added to each flask (final volume, 20 ml of Mueller-Hinton broth). The culture flasks were incubated without agitation at 37...