title: Establishment of in vitro susceptibility testing methodologies and comparative activities of piperacillin in combination with the penem {beta}-lactamase inhibitor BLI-489.
abstract: 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.
authors.affiliation: Infectious Disease Research, Wyeth Research, Pearl River, NY 10965, USA. petersp@wyeth.com
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Petersen
authors.forename: C Hal
authors.initials: CH
authors.lastname: Jones
authors.forename: Aranapakam M
authors.initials: AM
authors.lastname: Venkatesan
authors.forename: Tarek S
authors.initials: TS
authors.lastname: Mansour
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Projan
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Bradford
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects; D001424:Bacterial Infections / Q000382:microbiology; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007769:Lactams / Q000494:pharmacology; D008826:Microbial Sensitivity Tests / Q000379:methods*; D010878:Piperacillin / Q000494:pharmacology*; D065093:beta-Lactamase Inhibitors
chemical_list: D000900:Anti-Bacterial Agents; C539934:BLI-489; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D007769:Lactams; D065093:beta-Lactamase Inhibitors; D010878:Piperacillin