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Antimicrobial Agents and Chemotherapy, February 2009, p. 370-384, Vol. 53, No. 2
0066-4804/09/$08.00+0     doi:10.1128/AAC.01047-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Establishment of In Vitro Susceptibility Testing Methodologies and Comparative Activities of Piperacillin in Combination with the Penem β-Lactamase Inhibitor BLI-489 {triangledown}

Peter J. Petersen,1* C. Hal Jones,1 Aranapakam M. Venkatesan,2 Tarek S. Mansour,2 Steven J. Projan,3,{dagger} and Patricia A. Bradford1

Infectious Disease Research, Chemical Sciences,1 Wyeth Research, Pearl River, New York,2 Biological Technologies Wyeth Research, Cambridge, Massachusetts3

Received 4 August 2008/ Returned for modification 13 September 2008/ Accepted 29 October 2008

The novel bicyclic penem inhibitor BLI-489 has demonstrated activity as an inhibitor of class A, C, and D β-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 β-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 µg/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 µg/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 µg/ml. Based on these results, an in vitro testing methodology employing a constant concentration of 4 µg/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 µg/ml). However, 92% of these piperacillin nonsusceptible strains were inhibited by ≤16 µg/ml piperacillin-BLI-489; in contrast, only 66% were inhibited by ≤16 µg/ml piperacillin-tazobactam. The combination of piperacillin-BLI-489 also demonstrated improved activity compared to that of piperacillin-tazobactam against the problematic extended-spectrum β-lactamase- and AmpC-expressing strains.

* Corresponding author. Mailing address: Infectious Disease Research, Wyeth Research, Bldg. 200, Rm. 3301, 401 N. Middletown Rd., Pearl River, NY 10965. Phone: (845) 602-3070. Fax: (845) 602-5671. E-mail: petersp{at}wyeth.com

{triangledown} Published ahead of print on 10 November 2008.

{dagger} Present address: Novartis Institutes for Biomedical Research, Cambridge, MA.

Antimicrobial Agents and Chemotherapy, February 2009, p. 370-384, Vol. 53, No. 2
0066-4804/09/$08.00+0     doi:10.1128/AAC.01047-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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