title: Interactions of ceftobiprole with beta-lactamases from molecular classes A to D.
abstract: The interactions of ceftobiprole with purified beta-lactamases from molecular classes A, B, C, and D were determined and compared with those of benzylpenicillin, cephaloridine, cefepime, and ceftazidime. Enzymes were selected from functional groups 1, 2a, 2b, 2be, 2d, 2e, and 3 to represent beta-lactamases from organisms within the antibacterial spectrum of ceftobiprole. Ceftobiprole was refractory to hydrolysis by the common staphylococcal PC1 beta-lactamase, the class A TEM-1 beta-lactamase, and the class C AmpC beta-lactamase but was labile to hydrolysis by class B, class D, and class A extended-spectrum beta-lactamases. Cefepime and ceftazidime followed similar patterns. In most cases, the hydrolytic stability of a substrate correlated with the MIC for the producing organism. Ceftobiprole and cefepime generally had lower MICs than ceftazidime for AmpC-producing organisms, particularly AmpC-overexpressing Enterobacter cloacae organisms. However, all three cephalosporins were hydrolyzed very slowly by AmpC cephalosporinases, suggesting that factors other than beta-lactamase stability contribute to lower ceftobiprole and cefepime MICs against many members of the family Enterobacteriaceae.
authors.affiliation: Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 1000 Route 202 South, Raritan, NJ 08869, USA. aqueenan@prdus.jnj.com
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Queenan
authors.forename: Wenchi
authors.initials: W
authors.lastname: Shang
authors.forename: Malgosia
authors.initials: M
authors.lastname: Kania
authors.forename: Malcolm G P
authors.initials: MG
authors.lastname: Page
authors.forename: Karen
authors.initials: K
authors.lastname: Bush
mesh_terms: D000900:Anti-Bacterial Agents / Q000378:metabolism*; D001419:Bacteria / Q000187:drug effects / Q000201:enzymology*; D000077723:Cefepime; D002442:Ceftazidime / Q000378:metabolism; D002511:Cephalosporins / Q000378:metabolism*; D006868:Hydrolysis; D007700:Kinetics; D008826:Microbial Sensitivity Tests; D013056:Spectrophotometry, Ultraviolet; D001618:beta-Lactamases / Q000145:classification / Q000302:isolation & purification / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; C443755:ceftobiprole; D000077723:Cefepime; D002442:Ceftazidime; D001618:beta-Lactamases