Time-kill studies and synergy testing of broad-spectrum antibiotics against blood culture isolates

Time-kill studies and synergy testing were performed with blood culture isolates from 80 patients with septicemia. Ten isolates each of Escherichia coli, Proteus mirabilis, indole-positive Proteus, Klebsiella pneumoniae, Enterobacter cloacae, Pseudomonas aeruginosa, Staphylococcus aureus, and coagulase-negative staphylococci were included. The isolates were tested against netilmicin, piperacillin, cefoxitin, cefuroxime, and cefotaxime, alone and in different combinations. Cefotaxime was the most active agent against Enterobacteriaceae, whereas netilmicin was the most active agent against P. aeruginosa and staphylococci. The most active antibiotic combinations were netilmicin-cefotaxime and netilmicin-piperacillin, where a synergistic activity was observed in 68 and 61%, respectively. The highest synergistic activity was against Enterobacteriaceae, but the netilmicin-cefotaxime combination also acted synergistically against more than half of the S. aureus isolates. A relatively low synergistic activity was noted against P. aeruginosa. No case of antagonism was observed. Subinhibitory concentrations of netilmicin, in combination with a greater than or equal to MIC concentration of one of the tested beta-lactam antibiotics, significantly improved the killing of the isolates. Netilmicin exerted a more rapid and pronounced bacterial reduction than the beta-lactam antibiotics tested.