Mechanisms of Resistance
The most important mechanism of resistance to β-lactam antibiotics is the production of specific enzymes (β-lactamases). These diverse enzymes bind to β-lactam antibiotics and the cyclic amide bonds of the β-lactam rings are hydrolyzed. The open ring forms of β-lactams cannot bind to their target sites and thus have no antimicrobial activity. The ester linkage of the residual β-lactamase acylenzyme complex is readily hydrolyzed by water, regenerating the active enzyme. These enzymes have been classified based on functional and structural characteristics.
Among Gram-positive cocci, the staphylococcal β-lactamases hydrolyze benzylpenicillin, ampicillin and related compounds, but are much less active against the antistaphylococcal penicillins and cephalosporins. Among Gram-negative bacilli the situation is complex, as these organisms produce many different β-lactamases with different spectra of activity. All β-lactam drugs, including the latest carbapenems, are degraded by some of these enzymes, many of which have recently evolved through stepwise mutations selected in patients treated with cephalosporins. Several of these β-lactamases are increasing in prevalence among Gram-negative pathogens in many parts of the world. The most widely dispersed are the group 2beextended-spectrum β-lactamases (ESBLs) that include those derived by mutational modifications from TEM and SHV enzymes as well as the CTX-M enzymes that originate from Kluyvera spp. ESBLs can hydrolyze most penicillins and all cephalosporins except the cephamycins. These enzymes are plasmid-mediated in Enterobacteriaceae, notably in Esch. coli isolates from both community and hospital settings, and K. pneumoniae strains from hospital epidemics in all continents. Another group of problematic β-lactamases is the group 1, which includes both the AmpC type, chromosomal, inducible cephalosporinases in Enterobacter, Serratia, Citrobacter and Pseudomonas aeruginosa and similar plasmid-mediated enzymes that are now spreading among Enterobacteriaceae such as Esch. coli and K. pneumoniae.13 Both hyperproduction of the chromosomal enzyme and high-copy number plasmid encoded enzymes are causing an increasing prevalence of resistance to all β-lactam drugs except some carbapenems. A third group of β-lactamases of emerging importance is the group 3 metalloenzymes that can hydrolyze all β-lactam drugs except monobactams. These β-lactamases, also called metallo-carbapenemases, include both diverse chromosomal enzymes found in aquatic bacteria such as Stenotrophomonas maltophilia and Aeromonas hydrophila and plasmid-mediated enzymes increasingly reported in clinical isolates of Ps. aeruginosa, Acinetobacter and Enterobacteriaceae in Asia, America and Europe. A group of β-lactamases that now constitute a major threat to available drug treatments is the class A, group 2f carbapenemases, of which KPC enzymes produced by K. pneumoniae have become widespread in parts of the USA and Europe.15 Likewise, many anaerobic bacteria also produce β-lactamases, and this is the major mechanism of β-lactam antibiotic resistance in this group.
