title: Consecutive mutations leading to the emergence in vivo of imipenem resistance in a clinical strain of Enterobacter aerogenes.
abstract: Three consecutive isolates of Enterobacter aerogenes were obtained from the blood cultures of a hospitalised patient who was receiving antibiotic therapy. The initial isolate possessed an inducible cephalosporinase and was susceptible to third-generation cephalosporins. After ceftazidime treatment, a second isolate resistant to this antibiotic and characterised by stable overproduction of the chromosomal beta-lactamase was obtained, and therapy was altered to a new combination which included imipenem. During this course of treatment, a strain of E. aerogenes was isolated that was resistant to virtually all beta-lactam agents including imipenem. Comparison of biotypes and ribotyping profiles indicated that the three isolates were probably derived from a single strain which had undergone several mutations during antibiotic exposure. Examination of outer-membrane protein (OMP) preparations and lipopolysaccharide (LPS) profiles showed that the imipenem-resistant isolate lacked a major OMP and high molecular mass LPS. Furthermore, this isolate displayed reduced permeability to cephaloridine compared with the initial isolate. The introduction of a plasmid carrying a wild-type ampD allele prevented cephalosporinase production and restored beta-lactam susceptibility in the imipenem-resistant isolate. It was concluded that stable derepression of class-I beta-lactamase production and reduced permeability are both required for expression of imipenem resistance in E. aerogenes, and that previous exposure to cephalosporins may encourage the emergence of such strains.
authors.affiliation: Department of Bacteriology, Hellenic Pasteur Institute, Athens, Greece.
authors.forename: L S
authors.initials: LS
authors.lastname: Tzouvelekis
authors.forename: E
authors.initials: E
authors.lastname: Tzelepi
authors.forename: M E
authors.initials: ME
authors.lastname: Kaufmann
authors.forename: A F
authors.initials: AF
authors.lastname: Mentis
mesh_terms: D000368:Aged; D001425:Bacterial Outer Membrane Proteins / Q000032:analysis; D002463:Cell Membrane Permeability; D002511:Cephalosporins / Q000494:pharmacology / Q000627:therapeutic use; D004352:Drug Resistance, Microbial / Q000235:genetics; D004754:Enterobacter / Q000145:classification / Q000187:drug effects / Q000235:genetics*; D004756:Enterobacteriaceae Infections / Q000188:drug therapy / Q000382:microbiology*; D006801:Humans; D015378:Imipenem / Q000494:pharmacology* / Q000627:therapeutic use; D009154:Mutation; D001618:beta-Lactamases / Q000096:biosynthesis
chemical_list: D001425:Bacterial Outer Membrane Proteins; D002511:Cephalosporins; D015378:Imipenem; D001618:beta-Lactamases