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Antimicrobial Agents and Chemotherapy, May 2003, p. 1652-1657, Vol. 47, No. 5
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.5.1652-1657.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

In Vitro and In Vivo Activities of AM-112, a Novel Oxapenem

Conor E. Jamieson,1* Peter A. Lambert,1 and Iain N. Simpson2

Life and Health Sciences, Aston University, Birmingham,1 Micron Research, Cambridge, United Kingdom2

Received 3 June 2002/ Returned for modification 17 November 2002/ Accepted 4 February 2003

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 ß-lactamase-inhibitory properties. Fifty-percent inhibitory concentrations (IC50s) of AM-112 for class A enzymes were between 0.16 and 2.24 µM for three enzymes, compared to IC50s of 0.008 to 0.12 µM 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 µg/ml. Ceftazidime was combined with AM-112 at 1:1 and 2:1 ratios in MIC determination studies against a panel of ß-lactamase-producing organisms. These studies demonstrated that AM-112 was effective at protecting ceftazidime against extended-spectrum ß-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 ß-lactamase inhibitor.

* Corresponding author. Present address: Department of Microbiology, City Hospital, Birmingham, B18 7QH, United Kingdom. Phone: 44 121 554 3801, ext. 5536. Fax: 44 121 551 7763. E-mail: conor.jamieson{at}swbh.nhs.uk.

Antimicrobial Agents and Chemotherapy, May 2003, p. 1652-1657, Vol. 47, No. 5
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.5.1652-1657.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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