Combinations of three antimicrobial agents (II): Enhancement of the in vitro combined effect of cefoperazone plus amikacin by addition of sulbactam

We compared the in vitro combined effect of sulbactam/cefoperazone (SBT/CPZ=1:1) plus amikacin (AMK) against a total of 160 strains of clinical isolates of eight different species with that of CPZ plus AMK. The in vitro combined effect was determined by a checkerboard broth dilution method using the Dynatech MIC-2000 system. The FIC index, mean MIC values of SBT/CPZ, or CPZ in combination with varying concentrations of AMK, and the enhancement of combined effect index (ECE index) were then determined and expressed in terms of the geometrical mean. The ECE index was defined as the ratio of the area under the MIC curve of SBT/CPZ, or CPZ in combination with two different combinations of AMK. The combination of CPZ and AMK was found to be remarkably synergistic against all the species except S. aureus, as shown by a mean FIC index of 0.46. Also, a remarkable synergistic combined effect (mean FIC index of 0.48) was found between SBT/CPZ and AMK against all the species. Although the FIC indices of the above two combination regimens were almost the same, the addition of SBT reduced the MICs of CPZ. The area under the MIC curve of SBT/CPZ combined with AMK thus became smaller than that of CPZ plus AMK. Namely, the ECE index of SBT in combination with CPZ plus AMK was 0.34 against S. aureus, 0.47 against E. coli, 0.65 against K. pneumoniae, 0.26 against E. cloacae, 0.35 against S. marcescens, 0.87 against P. mirabilis, 0.81 against M. morganii, and 0.35 against P. aeruginosa. In addition, enhancement of the in vitro combined effect by the addition of SBT was remarkable against β-lactamase-producing strains. The above results suggest that the combination of SBT with CPZ plus AMK is useful in the treatment of severe infections, especially those caused by β-lactamase-producing strains.