Abstract
Sulbactam/Cefoperazone (SBT/CPZ) have been used in clinical infusion at ratios of 1:1 and 1:2 in Japan and U.S.A., respectively. After an administration of these drugs as a 1:1 parenteral formulation, the ratio of levels of CPZ and SBT in blood was 1:1/4 to 1:1/5 for 1 to 2 hours, whereas the ratio of free, unbound drug levels was 1:1.4 to 1:1.5. In urine these drugs were excreted at a ratio between 1:1 and 1:4 during 6 hours after the infusion. Antimicrobial interaction studies using various combinations of CPZ and SBT were performed to obtain information with respect to the effect of SBT on the antimicrobial activity of CPZ in vivo and the most appropriate ratio of these drugs for the in vitro test system.
Antimicrobial activities were determined using the agar dilution method and the disk diffusion susceptibility test. SBT increased the activity of CPZ against various clinical isolates tested except Enterococcus faecalis. CPZ-SBT at a fixed ratio of 1:1/5 significantly increased the antimicrobial activity of CPZ, resulting in decreases in MIC values and increases in disk inhibitory zone diameters. These drugs at ratios 1:1 to 1:3 maximized the synergistic enhancement of the activity. Therefore, a fixed ratio between 1:1/5 and 1:1 would be appropriate for the in vitro antimicrobial test system using either the agar dilution method or the disk susceptibility test.
Based on pharmacokinetic data for CPZ and SBT, results of the present study on antimicrobial activity would support that the parenteral formulation of CPZ-SBT at the fixed ratios of 1:1 and 2:1 for the intravenous infusion used in Japan and U.S.A., respectively, are appropriate.
The effect of SBT on the activity of CPZ was more marked against clinical isolates with greater production abilities of β-lactamase than against those with less production abilities. SBT/CPZ, however, exerted a synergistic effect against methicillin-resistant Staphylococcus aureus without β-lactamase production.
The MIC80 of SBT/CPZ (1:1) against various clinical isolates with 106 CFU/ml inoculum size were as follows: S. aureus 12.5 μg/ml, Staphylococcus epidermidis 3.13 μg/ml, and E. faecalis 50 μg/ml. Those of Gram-negative bacilli were: Escherichia coli 0.20 μg/ml, Klebsiella pneumoniae 0.20 μg/ml, Proteus mirabilis 0.78 μg/ml, Proteus vulgaris 0.78 μg/ml, Pseudomonas aeruginosa 12.5 μg/ml, Serratia marcescens 25 μg/ml, Enterobacter spp. 3.13 μg/ml, Citrobacter spp. 12.5 μg/ml and Acinetobacter spp. 0.78 μg/ml.
