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.

Article Details

Citation

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
DrugTargetKindOrganismPharmacological ActionActions
ErtapenemD-alanyl-D-alanine carboxypeptidase DacBProteinEscherichia coli (strain K12)
Yes
Inhibitor
Details
ErtapenemD-alanyl-D-alanine carboxypeptidase DacCProteinEscherichia coli (strain K12)
Yes
Inhibitor
Details
ErtapenemPenicillin-binding protein 1AProteinEscherichia coli (strain K12)
Yes
Inhibitor
Details
ErtapenemPenicillin-binding protein 1BProteinEscherichia coli (strain K12)
Yes
Inhibitor
Details
ErtapenemPenicillin-binding protein 2ProteinHaemophilus influenzae (strain ATCC 51907 / DSM 11121 / KW20 / Rd)
Yes
Inhibitor
Details
ErtapenemPenicillin-binding protein 2ProteinEscherichia coli (strain K12)
Yes
Inhibitor
Details
ErtapenemPeptidoglycan synthase FtsIProteinHaemophilus influenzae (strain ATCC 51907 / DSM 11121 / KW20 / Rd)
Yes
Inhibitor
Details
ErtapenemPeptidoglycan synthase FtsIProteinEscherichia coli (strain K12)
Yes
Inhibitor
Details