In vitro activities of the potent, broad-spectrum carbapenem MK-0826 (L-749,345) against broad-spectrum beta-lactamase-and extended-spectrum beta-lactamase-producing Klebsiella pneumoniae and Escherichia coli clinical isolates.
An important mechanism of bacterial resistance to beta-lactam antibiotics is inactivation by beta-lactam-hydrolyzing enzymes (beta-lactamases). The evolution 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. pneumoniae and E. coli clinical isolates tested (MIC range, 0.008 to 0.12 microgram/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 beta-lactamase present, the MK-0826 MIC range increased to 0.008 to 1 microgram/ml. By comparison, similar observations were made with meropenem while imipenem MICs were usually less affected. Not surprisingly, MIC increases with noncarbapenem beta-lactams were generally substantially greater, resulting in resistance in many cases. E. coli strains that produce chromosomal (Bush group 1) beta-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 microgram/ml under all test conditions.
Kohler
J
J
Departments of Infectious Diseases, Merck Research Laboratories, Rahway, New Jersey 07065-0900, USA. joyce_kohler@merck.com
Dorso
K L
KL
Young
K
K
Hammond
G G
GG
Rosen
H
H
Kropp
H
H
Silver
L L
LL
D015780:Carbapenems / Q000494:pharmacology*; D018550:Cephalosporin Resistance; D004926:Escherichia coli / Q000187:drug effects* / Q000201:enzymology; D007711:Klebsiella pneumoniae / Q000187:drug effects* / Q000201:enzymology; D008826:Microbial Sensitivity Tests; D001618:beta-Lactamases / Q000378:metabolism
D015780:Carbapenems; C108047:L 749345; C118072:MK 826; D001618:beta-Lactamases