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The activity of the three two-drug combinations of sulfamethoxazole (SMX), trimethoprim (TMP), and polymyxin B (PB) against 52 clinical isolates of gram-negative bacilli was studied by a “checkerboard” agar dilution method. The organisms studied included strains of Enterobacterspp., Klebsiella pneumoniae, Serratia marcescens, Providence, Proteus, and Pseudomonas aeruginosa. The majority of these isolates were resistant to at least two of the three agents used in the combined studies and to the most commonly used antimicrobials. The TMP-PB combination demonstrated enhanced activity more frequently than the other two-drug combinations, showing synergism or addition in 85% of the combined studies; indifference or antagonism was also observed least frequently with TMP-PB. The great majority (83%) of Enterobacter-Klebsiella-Serratiaisolates were susceptible to enhanced activity of all combinations. Proteus-Providenceisolates were frequently susceptible (63%), but combined activity was indifferent or antagonistic against 60% of P. aeruginosa. Twelve isolates were selected for “killing-curve” assays in which an inoculum was incubated with SMX, TMP, and PB individually and in various two- and three-drug combinations. Surviving bacteria were counted at timed intervals over 24 h of incubation. The triple combination (SMX-TMP-PB) was synergistic against 9 of 12 isolates, whereas TMP-PB and SMX-PB showed synergism against 5 and 3 isolates, respectively. These data suggest that, although TMP-PB will often show enhanced activity against the gram-negative bacilli studied here, optimal antibacterial activity will be demonstrated when the three-drug combination is used.

The activity of sulfamethoxazole (SMX), trimethoprim (TMP), and the combination of the two was determined against a variety of anaerobic bacteria. Brucella agar was somewhat inhibitory for SMX and TMP but activity was good and equivalent in Diagnostic Sensitivity Test Agar (Oxoid) and Mueller-Hinton agar and the latter was selected for use in these studies. Agar dilution susceptibility tests showed that 95 of 98 anaerobic isolates were resistant to =100 µg of SMX per ml and 85 were resistant to =6.25 µg of TMP per ml. “Checkerboard” agar dilution studies of combined activity showed that 66 of 72 isolates were resistant to = (100 µg of SMX per ml + 6.25 µg of TMP per ml) and only six isolates were susceptible to the synergistic activity of the combination. The majority of 32 isolates tested by the disk diffusion method were also resistant to SMX and TMP individually and to the combination 25-µg disk. Correlation between agar dilution minimal inhibitory concentration and disk zone size results was in general good for individual agents. Four Bacteroides fragilisisolates were inhibited by the combination 25-µg disk but were resistant to SMX + TMP by agar dilution “checkerboard.” This discrepancy may have been due to different incubation periods since disk results also showed resistance when read after 48 h (as is done with agar dilution) rather than the standard 24 h for disk tests. These studies suggest that SMX and TMP, either individually or in combination, are not active against the great majority of anaerobic bacteria.