In Vitro Activities of the Potent, Broad-Spectrum Carbapenem MK-0826 (L-749,345) against Broad-Spectrum β-Lactamase-and Extended-Spectrum β-Lactamase-Producing Klebsiella pneumoniae and Escherichia coli Clinical Isolates

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Abstract
An important mechanism of bacterial resistance to β-lactam antibiotics is inactivation by β-lactam-hydrolyzing enzymes (β-lactamases). The evolution of the extended-spectrum β-lactamases (ESBLs) is associated with extensive use of β-lactam antibiotics, particularly cephalosporins, and is a serious threat to therapeutic efficacy. ESBLs and broad-spectrum β-lactamases (BDSBLs) are plasmid-mediated class A enzymes produced by gram-negative pathogens, principally Escherichia coli and Klebsiella pneumoniae . MK-0826 was highly potent against all ESBL- and BDSBL-producing K. pneumoniae and E. coli clinical isolates tested (MIC range, 0.008 to 0.12 μg/ml). In E. coli , this activity was associated with high-affinity binding to penicillin-binding proteins 2 and 3. When the inoculum level was increased 10-fold, increasing the amount of β-lactamase present, the MK-0826 MIC range increased to 0.008 to 1 μg/ml. By comparison, similar observations were made with meropenem while imipenem MICs were usually less affected. Not surprisingly, MIC increases with noncarbapenem β-lactams were generally substantially greater, resulting in resistance in many cases. E. coli strains that produce chromosomal (Bush group 1) β-lactamase served as controls. All three carbapenems were subject to an inoculum effect with the majority of the BDSBL- and ESBL-producers but not the Bush group 1 strains, implying some effect of the plasmid-borne enzymes on potency. Importantly, MK-0826 MICs remained at or below 1 μg/ml under all test conditions.

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