Interactions of meropenem with Class I chromosomal -lactamases

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Abstract
Most newer penicillins and cephalosporins are labile to the Class I β -lactamases that are inducible in Pseudomonas aeruginosa. Enterobacter spp., Citrobacter spp., Serratia spp. and indole-positive Proteeac, but fail to induce enzyme synthesis below the MIC. They remain active against the inducible strains but not against mutants (termed ‘stably derepressed’) that manufacture β -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. vulgar is. Nonetheless it remained equally active against inducible strains and their derepressed mutants, and was no more active against laboratory-derived β -lactamase basal mutants. It did not select derepressed mutants from β -lactamase-inducible populations. These data suggested great stability to Class I β -lactamases, and this deduction was confirmed by direct assays with purified β -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 β -lactamases.

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