title: Mechanisms of resistance to beta-lactam antibiotics.
abstract: The use of new beta-lactam antibiotics has led to selection of novel forms of resistance. Newer-generation cephalosporins, ureidopenicillins and monobactams, but not carbapenems (e.g. imipenem), are labile to Class I chromosomal beta-lactamases and tend to select mutants of E. cloacae and P. aeruginosa that constitutively synthesize high levels of these enzymes. Selection occurs more rarely with Serratia, Citrobacter and indole positive protease. Third-generation cephalosporins and monobactams, but not carbapenems and cephamycins, are inactivated by a range of new variants of the well-known TEM and SHV-1 plasmid-mediated beta-lactamases. These variants have arisen by spontaneous mutation and differ only marginally in amino-acid sequence from their parent enzymes. Already prevalent in France, their potential for spread is a major concern. Outer membrane impermeability is another source of resistance to beta-lactams in Gram-negative bacteria. Rare in enterobacteria, it is more important in P. aeruginosa, where broad and narrow spectrum forms can arise via mutation. The narrow spectrum form involves loss of the D2 outer membrane protein and gives resistance to carbapenems but not other beta-lactams. The broad spectrum form, of unknown mechanism, simultaneously affects many beta-lactam and unrelated (e.g. quinolone) drugs, but not imipenem. Target (penicillin-binding protein) insensitivity also can mediate resistance, most notably in MRSA. Unlike the mechanisms described above, this affects all beta-lactams, including carbapenems as well as penicillins and cephalosporins.
authors.affiliation: Department of Medical Microbiology, London Hospital Medical College, U.K.
authors.forename: D M
authors.initials: DM
authors.lastname: Livermore
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects* / Q000201:enzymology; D004352:Drug Resistance, Microbial; D001618:beta-Lactamases / Q000378:metabolism*; D047090:beta-Lactams
chemical_list: D000900:Anti-Bacterial Agents; D047090:beta-Lactams; D001618:beta-Lactamases