COMPARISON OF METHODOLOGIES FOR SYNERGISM TESTING OF DRUG-COMBINATIONS AGAINST RESISTANT STRAINS OF PSEUDOMONAS-AERUGINOSA

The purpose of this study was to determine if synergism was maintained for various combinations of p-lactams with an aminoglycoside against four clinical strains and one laboratory strain of Pseudomonas aerugin osa which were resistant, according to the MICs, to the beta-lactams a nd/or aminoglycoside, The results from both the checkerboard and killi ng curve methodologies were compared. The laboratory strain (ATCC 2785 3) was manipulated in vitro by serial passage onto agar containing inc reasing concentrations of each antibiotic to select for resistance. On e clinical isolate (R61) was also serially passed to raise the MIC of piperacillin from 128 to 1,024 mu g/ml. The fractional inhibitory conc entration indices for all isolates indicated indifference for all comb ination therapies, with values ranging from 0.6 to 3. In contrast, kil ling curve results for all isolates demonstrated synergism with drug c oncentrations at either one-fourth or one-half the MIC for each organi sm. The MIC of piperacillin for the laboratory-manipulated clinical is olate R61 was 1,024 mu g/ml, and synergism was still observed with con centrations of one-half the MIC of piperacillin and amikacin, For clin ical isolate R166, which was beta-lactam and tobramycin resistant, syn ergism continued to be demonstrated with concentrations of tobramycin (1/16 MIC) in combination with piperacillin and cefepime at 1/2 the MI G. The results of this study indicate that against P. aeruginosa, syne rgism is observed in spite of resistance to beta-lactams and/or aminog lycosides. Synergism appears to be maintained even at very high MICs ( piperacillin, 1,024 mu g/ml; tobramycin, 128 mu g/ml) with drug concen trations within achievable therapeutic ranges, With current definition s of synergism there was a complete lack of correlation between the re sults obtained by the checkerboard and killing curve methodologies, wi th the fractional inhibitory concentration indices showing indifferenc e and killing curves resulting in synergism, The methodologies and def initions of synergism or antagonism are variable and not standardized and should be reevaluated.