Overproduced -Lactamase and the Outer-membrane Barrier as Resistance Factors in Serratia marcescens Highly Resistant to -Lactamase-stable -Lactam Antibiotics

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Abstract
In a clinical isolate of Serratia marcescens different states of low and high resistance to different .beta.-lactam antibiotics considered to be .beta.-lactamase-stable, viz. cefotaxime, ceftizoxime, ceftazidime, aztreonam, cefoxitin and imipenem, were found to be connected with the presence of constitutively overproduced, chromosomally encoded .beta.-lactamase at concentrations in the bacterial periplasm of 0.4 and 0.9 nM, respectively. All the antibiotics were degraded by the .beta.-lactamase. However, kinetic constants varied widely: Km from 92 to 0.012 .mu.M, and kcat from 3.4 to 2 .times. 10-4 s-1. The relative contributions to resistance by the functioning of periplasmic .beta.-lactmase, resynthesis of this enzyme, and limitation of antibiotic penetration by the bacterial outer membrane were analysed by computer simulations according to steady-state and non-steady-state models of interactions in the periplasm. Results for cefotaxime, ceftizoxime, ceftazidime, aztreonam and latamoxef revealed overproduced .beta.-lactamase as the sole cause of the state of low resistance while antibiotic permeability was the same as in non-resistant S. marcescens strains. In contrast, high resistance was due to .beta.-lactamase action and decreased permeability of antibiotics. For resistance to aztreonam, only, immobilization of the antibiotic as covalent acyl-enzyme by newly synthesized .beta.-lactamase was essential. For cefoxitin, ampicillin and imipenem the analyses indicated that additional resistance factors may play a role, e.g. induction of .beta.-lactamase.