bli-489 and Bacterial-Infections

The novel bicyclic penem inhibitor BLI-489 has demonstrated activity as an inhibitor of class A, C, and D beta-lactamases. To determine the combination of piperacillin and BLI-489 to be used in susceptibility testing that would most accurately identify susceptible and resistant isolates, a predictor panel of beta-lactamase-producing bacteria was utilized to determine the reliability of the combination of piperacillin-BLI-489 at a constant inhibitor concentration of 2 or 4 microg/ml and at ratios of 1:1, 2:1, 4:1, and 8:1. There were a number of strains that would be falsely reported as susceptible or intermediate if tested with the ratios of 1:1 and 2:1, whereas the constant concentration of 2 microg/ml of BLI-489 and the ratio of 8:1 had a tendency to overpredict resistance. Similar MICs were obtained with piperacillin-BLI-489 in a 4:1 ratio and when BLI-489 was held constant at 4 microg/ml. Based on these results, an in vitro testing methodology employing a constant concentration of 4 microg/ml BLI-489 was used to evaluate the combination of piperacillin-BLI-489 against a larger panel of recently identified clinical isolates. Approximately 55% of all of the enteric bacilli tested were nonsusceptible to piperacillin alone (MIC > or = 32 microg/ml). However, 92% of these piperacillin nonsusceptible strains were inhibited by < or =16 microg/ml piperacillin-BLI-489; in contrast, only 66% were inhibited by < or =16 microg/ml piperacillin-tazobactam. The combination of piperacillin-BLI-489 also demonstrated improved activity compared to that of piperacillin-tazobactam against the problematic extended-spectrum beta-lactamase- and AmpC-expressing strains.

Topics: Anti-Bacterial Agents; Bacteria; Bacterial Infections; beta-Lactamase Inhibitors; Drug Combinations; Enzyme Inhibitors; Humans; Lactams; Microbial Sensitivity Tests; Piperacillin

The in vivo efficacy of piperacillin in combination with the penem inhibitor BLI-489 was determined using acute lethal systemic infections in mice. On the basis of preliminary results with various ratios, a dosing ratio of 8:1 was found to be optimal for retention of enhanced efficacy. Piperacillin-BLI-489 dosed at an 8:1 ratio was efficacious against murine infections caused by class A (including extended-spectrum beta-lactamases), class C (AmpC), and class D beta-lactamase-expressing pathogens.

Topics: Animals; Anti-Bacterial Agents; Bacterial Infections; beta-Lactamase Inhibitors; Disease Models, Animal; Drug Therapy, Combination; Female; Lactams; Mice; Piperacillin