title: Antimicrobial activity, beta-lactamase stability and beta-lactamase inhibition of cefotetan and other 7-alpha-methoxy beta-lactam antimicrobials.
abstract: The antimicrobial activity of three 7-alpha-methoxy beta-lactams were compared to cefoperazone and ceftriaxone. All had a similar spectrum of activity against the Enterobacteriaceae, except cefoxitin. Cefotetan was only slightly less active than moxalactam against the Enterobacter spp. Ceftriaxone was most effective on Neisserias, Haemophilus spp, nonenterococcal Streptococcus spp, and Acinetobacter spp. Cefoperazone generally inhibited more pseudomonads while all of the "cephamycins" showed activity against Bacteroides fragilis and B. thetaiotaomicron. Beta-lactamase hydrolysis studies of six substrates having pharmacologic serum half lives of greater than or equal to 2 hrs were performed by bioassay and automated procedures. Excellent correlations were found between methods up to 24 hrs. A "lag-phase" was observed for several drug/enzyme combinations before initiation of significant substrate hydrolysis. The 7-alpha-methoxy beta-lactams were routinely more stable to the six representative enzymes (Richmond-Sykes types I-V) than other "stable" cephalosporins. Substrate hydrolysis rates resulting in greater than 50% drug loss in less than or equal to 1 hr generally produced resistant in vitro test results. Cefotetan, cefoxitin, moxalactam, ceftriaxone, and dicloxacillin were potent inhibitors of Type I (P99) beta-lactamases. Moxalactam demonstrated significant inhibition and affinity for the Type V enzyme while cefoperazone uniquely possesses affinity (so-called inhibition) for all tested beta-lactamases. Cefotetan appears to be a promising, beta-lactam compound with some in vitro characteristics comparable to the 1-oxa-beta-lactams and alpha-methoxyimino cephalosporins.
mesh_terms: D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects* / Q000201:enzymology; D002438:Cefoperazone / Q000378:metabolism / Q000494:pharmacology; D002439:Cefotaxime / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D015313:Cefotetan; D002440:Cefoxitin / Q000378:metabolism / Q000494:pharmacology; D002443:Ceftriaxone; D002463:Cell Membrane Permeability / Q000187:drug effects; D002513:Cephamycins / Q000378:metabolism / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D009070:Moxalactam / Q000378:metabolism / Q000494:pharmacology; D001618:beta-Lactamases / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D002513:Cephamycins; D015313:Cefotetan; D002440:Cefoxitin; D002443:Ceftriaxone; D002438:Cefoperazone; D001618:beta-Lactamases; D002439:Cefotaxime; D009070:Moxalactam