Interactions of meropenem with class I chromosomal beta-lactamases

Abstract

Most newer penicillins and cephalosporins are labile to the Class I beta-lactamases that are inducible in Pseudomonas aeruginosa. Enterobacter spp., Citrobacter spp., Serratia spp. and indole-positive Proteeae, but fail to induce enzyme synthesis below the MIC. They remain active against the inducible strains but not against mutants (termed 'stably depressed') that manufacture beta-lactamase copiously without induction. Such mutants are segregated at high frequency and may be selected during therapy, sometimes causing clinical failure. Meropenem induced Class I enzymes weakly below the MIC in Ps. aeruginosa, Ent. cloacae, C. freundii, Ser. marcescens, Morganella morganii and Pr. vulgaris. Nonetheless it remained equally active against inducible strains and their derepressed mutants, and was no more active against laboratory-derived beta-lactamase basal mutants. It did not select derepressed mutants from beta-lactamase-inducible populations. These data suggested great stability to Class I beta-lactamases, and this deduction was confirmed by direct assays with purified beta-lactamases. Initial hydrolysis rates ranged from 0.9-10.0 drug molecules hydrolysed/enzyme molecule/minute but these values declined by 80-90% before 5% of the antibiotic had been hydrolysed, indicating that the carbapenem could deactivate the enzymes. Deactivation was reversible, full activity being restored once the meropenem was removed. These results suggest that meropenem, like imipenem and various experimental penems, may overcome the resistance problems presented by Class I beta-lactamases.