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Antimicrobial Agents and Chemotherapy, September 2000, p. 2485-2491, Vol. 44, No. 9
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Concentration-Dependent Selection of Small Phenotypic Differences in TEM beta -Lactamase-Mediated Antibiotic Resistance

Maria-Cristina Negri,* Marc Lipsitch, Jesús Blázquez, Bruce R. Levin, and Fernando Baquero*

Department of Microbiology, Ramón y Cajal Hospital, National Institute of Health (INSALUD), 28034 Madrid, Spain, and Department of Biology, Emory University, Atlanta, Georgia 30322

Received 27 March 2000/Returned for modification 6 June 2000/Accepted 23 June 2000

In this paper, the first robust experimental evidence of in vitro and in vivo concentration-dependent selection of low-level antibiotic-resistant genetic variants is described. The work is based on the study of an asymmetric competition assay with pairs of isogenic Escherichia coli strains, differing only (apart from a neutral chromosomal marker) in a single amino acid replacement in a plasmid-mediated TEM-1 beta-lactamase enzyme, which results in the new TEM-12 beta-lactamase. The mixture was challenged by different antibiotic concentrations, both in vitro and in the animal model, and the selective process of the variant population was carefully monitored. A mathematical model was constructed to test the hypothesis that measured growth and killing rates of the individual TEM variants at different antibiotic concentrations could be used to predict quantitatively the strength of selection for TEM-12 observed in competition experiments at these different concentrations.

* Corresponding author. Mailing address: Department of Microbiology, Ramón y Cajal Hospital, National Institute of Health (INSALUD), Carretera Colmenar km 9,100, 28034-Madrid, Spain. Phone: (34)91 336 83 30. Fax: (34)91 336 88 09. E-mail for Fernando Baquero: fbaquero{at}hrc.insalud.es. E-mail for Maria-Cristina Negri: mnegri{at}hrc.insalud.es.

Antimicrobial Agents and Chemotherapy, September 2000, p. 2485-2491, Vol. 44, No. 9
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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