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.
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Kohler J, Dorso KL, Young K, Hammond GG, Rosen H, Kropp H, Silver LL
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.
Antimicrob Agents Chemother. 1999 May;43(5):1170-6.
- PubMed ID
- 10223931 [ View in PubMed]
- Abstract
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.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Ertapenem D-alanyl-D-alanine carboxypeptidase DacB Protein Escherichia coli (strain K12) YesInhibitorDetails Ertapenem D-alanyl-D-alanine carboxypeptidase DacC Protein Escherichia coli (strain K12) YesInhibitorDetails Ertapenem Penicillin-binding protein 1A Protein Escherichia coli (strain K12) YesInhibitorDetails Ertapenem Penicillin-binding protein 1B Protein Escherichia coli (strain K12) YesInhibitorDetails Ertapenem Penicillin-binding protein 2 Protein Haemophilus influenzae (strain ATCC 51907 / DSM 11121 / KW20 / Rd) YesInhibitorDetails Ertapenem Penicillin-binding protein 2 Protein Escherichia coli (strain K12) YesInhibitorDetails Ertapenem Peptidoglycan synthase FtsI Protein Haemophilus influenzae (strain ATCC 51907 / DSM 11121 / KW20 / Rd) YesInhibitorDetails Ertapenem Peptidoglycan synthase FtsI Protein Escherichia coli (strain K12) YesInhibitorDetails