Global dissemination of beta-lactamases mediating resistance to cephalosporins and carbapenems.
While the main era of beta-lactam discovery programs is over, these agents continue to be the most widely prescribed antimicrobials in both community and hospital settings. This has led to considerable beta-lactam pressure on pathogens, resulting in a literal explosion of new beta-lactamase variants of existing enzyme classes. Recent advances in the molecular tools used to detect and characterize beta-lactamases and their genes has, in part, fueled the large increase in communications identifying novel beta-lactamases, particularly in Gram-negative bacilli. It now seems clear that the beta-lactams themselves have shaped the field of new enzymes, and the evolution of key amino acid substitutions around the active sites of beta-lactamases continues to drive resistance. Over 130 variants of TEM beta-lactamase now exist, and more are reported in the scientific literature each month. The most disturbing current trend is that many bla structural genes normally limited to the chromosome are now mobilized on plasmids and integrons, broadening the spread of resistance to include carbapenems and cephamycins. Furthermore, in some Enterobacteriaceae, concomitant loss of outer membrane porins act in concert with these transmissible beta-lactamase genes to confer resistance to the most potent beta-lactams and inhibitor combinations available. Continued reviews of the literature are necessary in order to keep abreast of the ingenuity with which bacteria are changing the current genetic landscape to confer resistance to this important class of antimicrobials.
Pfizer Global Research and Development, Department of Antimicrobials, Immunology and Cancer, Eastern Point Road, Groton, Connecticut 06340, USA. thomas_d_gootz@groton.pfizer.com.
Thomas D
TD
Gootz
D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001419:Bacteria / Q000187:drug effects* / Q000201:enzymology; D015780:Carbapenems / Q000494:pharmacology / Q000627:therapeutic use*; D002511:Cephalosporins / Q000494:pharmacology / Q000627:therapeutic use*; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D006801:Humans; D013329:Structure-Activity Relationship; D001618:beta-Lactamases / Q000145:classification / Q000235:genetics / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D015780:Carbapenems; D002511:Cephalosporins; D001618:beta-Lactamases