In vitro activities of the potent, broad-spectrum carbapenem MK-0826 (L-749,345) against broad-spectrum beta-lactamase- and extended-spectrum p-lactamase-producing Klebsiella pneumoniae and Escherichia coli clinical isolates

An important mechanism of bacterial resistance to beta-lactam antibiotics i s inactivation by beta-lactam-hydrolyzing enzymes (beta-lactamases). The ev olution of the extended-spectrum beta-lactamases (ESBLs) is associated with extensive use of beta-lactam antibiotics, particularly cephalosporins, and is a serious threat to therapeutic efficacy. ESBLs and broad-spectrum beta -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. pneumon iae and E. coli clinical isolates tested (MIC range, 0.008 to 0.12 mu g/ml) . In E. coli, this activity was associated with high-affinity binding to pe nicillin-binding proteins 2 and 3, When the inoculum level was increased 10 -fold, increasing the amount of beta-lactamase present, the MK-0826 MIC ran ge increased to 0.008 to 1 mu g/ml. By comparison, similar observations wer e made with meropenem while imipenem MICs were usually less affected. Not s urprisingly, MIC increases with noncarbapenem beta-lactams were generally s ubstantially greater, resulting in resistance in many cases. E. coli strain s that produce chromosomal (Bush group 1) beta-lactamase served as controls . All three carbapenems were subject to an inoculum effect with the majorit y of the BDSBL- and ESBL-producers but not the Bush group 1 strains, implyi ng some effect of the plasmid-borne enzymes on potency. Importantly, MK-082 6 MICs remained at or below 1 mu g/ml under all test conditions.