The epidemiology of beta-lactamases.

Chromosomally mediated species-specific beta-lactamases, as well as plasmid-mediated beta-lactamases, contribute to bacterial resistance to beta-lactam antibiotics. Chromosomally mediated enzymes confer primary resistance to some drugs and secondary resistance, by mutation to over-production of the enzyme. By far the most prevalent and most important of the, more than thirty, described plasmid-mediated beta-lactamases are those of the TEM group. They can be found in nearly all Gram-negative bacterial species of clinical importance. Furthermore these enzymes have changed their specificity by mutation so that recently described TEM enzymes hydrolyse even third generation cephalosporins. Although there is no change in the quantity of these enzymes, as far as the percentage of producer strains in any species is concerned, there has been a change in quality. The enzymes are further distributed to new species and hydrolyse more so-called 'stable' beta-lactam compounds.

Beta-lactam antibiotics and selection of resistance: speculation on the evolution of R-plasmids.

In this paper we describe two genetic mechanisms which are responsible for the development of resistance to third-generation cephalosporins. One is a plasmid-mediated mechanism involving a mutation in the SHV-1-gene towards the production of the beta-lactamase SHV-2 which has increased affinity for these antibiotics. The other is chromosomally mediated and occurs at high frequency by mutation of inducible beta-lactamase-genes, leading to derepressed production of the enzyme. Together with other examples of resistance genes these two mechanisms lead us to a hypothesis about the evolution of beta-lactamase producing bacteria.

Evolution of plasmid-coded resistance to broad-spectrum cephalosporins.

A clinical isolate of Klebsiella ozaenae with transferable resistance to broad-spectrum cephalosporins produces a beta-lactamase determined by plasmid pBP60. The beta-lactamase had the same isoelectric point as SHV-1 (7.6). From heteroduplex analysis, an extensive homology between the two bla genes could be deduced; therefore, the new beta-lactamase was designated SHV-2. Enzymatic studies revealed that SHV-2 was able to hydrolyze broad-spectrum cephalosporins due to an increased affinity of these compounds for the enzyme. The assumption that SHV-2 is a natural mutant of SHV-1 was strongly supported by the isolation of a laboratory mutant of SHV-1 that showed activities similar to those of SHV-2.