Establishment Of In Vitro Susceptibility Testing Methodologies And Comparative Activities Of Piperacillin In Combination With The Penem Beta-Lactamase Inhibitor Bli-489

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-lactamaseproducing bacteria was utilized to determine the reliability of the combination of piperacillin-BLI-489 at a constant inhibitor concentration of 2 or 4 mu g/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 mu g/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 mu g/ml. Based on these results, an in vitro testing methodology employing a constant concentration of 4 mu g/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 >= 32 mu g/ml). However, 92% of these piperacillin nonsusceptible strains were inhibited by <= 16 mu g/ml piperacillin-BLI-489; in contrast, only 66% were inhibited by <= 16 mu g/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.