INTERACTIONS OF B-LACTAMASES WITH SANFETRINEM (GV-104326) COMPARED TOTHOSE WITH IMIPENEM AND WITH ORAL BETA-LACTAMS

Sanfetrinem is a trinem beta-lactam which can be administered orally a s a hexatil ester. We examined whether its beta-lactamase interactions resembled those of the available carbapenems, i.e., stable to AmpC an d extended-spectrum beta-lactamases but labile to class B and function al group 2f enzymes. The comparator drugs were imipenem, oral cephalos porins, and amoxicillin. MICs were determined for beta-lactamase expre ssion variants, and hydrolysis was examined directly with representati ve enzymes. Sanfetrinem was a weak inducer of AmpC beta-lactamases bel ow the MIC and had slight lability, with a k(cat) of 0.00033 s(-1) for the Enterobacter cloacae enzyme, Its MICs for AmpC-derepressed E. clo acae and Citrobacter freundii were 4 to 8 mu g/ml, compared with MICs of 0.12 to 2 mu g/ml for AmpC-inducible and -basal strains; MICs for A mpC-derepressed Serratia marcescens and Morganella morganii were not r aised. Cefixime and cefpodoxime were more labile than sanfetrinem to t he E. cloacae AmpC enzyme, and AmpC-derepressed mutants showed much gr eater resistance; imipenem was more stable and retained full activity against derepressed mutants. Like imipenem, sanfetrinem was stable to TEM-1 and TEM-10 enzymes and retained full activity against isolates a nd transconjugants with various extended-spectrum TEM and SHV enzymes, whereas these organisms were resistant to cefixime and cefpodoxime, S anfetrinem, like imipenem and cefixime but unlike cefpodoxime, also re tained activity against Proteus vulgaris and Klebsiella oxytoca strain s that hyperproduced potent chromosomal class A beta-lactamases. Funct ional group 2f enzymes, including Sme-l, NMC-A, and an unnamed enzyme from Acinetobacter-spp., increased the sanfetrinem MICs by up to 64-fo ld. These enzymes also compromised the activities of imipenem and amox icillin but not those of the cephalosporins. The hydrolysis of sanfetr inem was examined with a purified Sme-l enzyme, and biphasic kinetics were found, Finally, zinc beta-lactamases, including LMP-I and the L1 enzyme of Stenotrophomonas maltophilia, conferred resistance to sanfet rinem and all other beta-lactams tested, and hydrolysis was confirmed with the IMP-1 enzyme, We conclude that sanfetrinem has beta-lactamase interactions similar to those of the available carbapenems except tha t it is a weaker inducer of AmpC types, with some tendency to select d erepressed mutants, unlike imipenem and meropenem.