PMID:12709336
| Citation |
Jamieson, CE, Lambert, PA and Simpson, IN (2003) In vitro and in vivo activities of AM-112, a novel oxapenem. Antimicrob. Agents Chemother. 47:1652-7 |
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| Abstract |
AM-112 [(1'R,5R,6R)-3-(4-amino-1,1-dimethyl-butyl)-6-(1'-hydroxyethyl)oxapenem-3-carboxylate] is a novel oxapenem compound which possesses potent beta-lactamase-inhibitory properties. Fifty-percent inhibitory concentrations (IC(50)s) of AM-112 for class A enzymes were between 0.16 and 2.24 micro M for three enzymes, compared to IC(50)s of 0.008 to 0.12 micro M for clavulanic acid. Against class C and class D enzymes, however, the activity of AM-112 was between 1,000- and 100,000-fold greater than that of clavulanic acid. AM-112 had affinity for the penicillin-binding proteins (PBPs) of Escherichia coli DC0, with PBP2 being inhibited by the lowest concentration of AM-112 tested, 0.1 micro g/ml. Ceftazidime was combined with AM-112 at 1:1 and 2:1 ratios in MIC determination studies against a panel of beta-lactamase-producing organisms. These studies demonstrated that AM-112 was effective at protecting ceftazidime against extended-spectrum beta-lactamase-producing strains and derepressed class C enzyme producers, reducing ceftazidime MICs by 16- and 2,048-fold. Similar results were obtained when AM-112 was combined with ceftriaxone, cefoperazone, or cefepime in a 1:2 ratio. Protection of ceftazidime with AM-112 was maintained against Enterobacter cloacae P99 and Klebsiella pneumoniae SHV-5 in a murine intraperitoneal sepsis model. The 50% effective dose of ceftazidime against E. cloacae P99 and K. pneumoniae SHV-5 was reduced from >100 and 160 mg/kg of body weight to 2 and 33.6 mg/kg, respectively, when it was combined with AM-112 at a 1:1 ratio. AM-112 demonstrates potential as a new beta-lactamase inhibitor. |
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| Keywords |
Animals; Bacterial Infections/drug therapy; Bacterial Proteins; Carrier Proteins/metabolism; Cephalosporins/pharmacology; Drug Therapy, Combination/pharmacology; Enzyme Inhibitors/pharmacology; Enzyme Inhibitors/therapeutic use; Hexosyltransferases; Lactams; Male; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Muramoylpentapeptide Carboxypeptidase/metabolism; Penicillin-Binding Proteins; Peptidyl Transferases; beta-Lactamases/antagonists & inhibitors; beta-Lactams/pharmacology; beta-Lactams/therapeutic use |
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