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Antimicrobial Agents and Chemotherapy, July 2006, p. 2352-2360, Vol. 50, No. 7
0066-4804/06/$08.00+0     doi:10.1128/AAC.00073-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

In Vivo Survival of Teicoplanin-Resistant Staphylococcus aureus and Fitness Cost of Teicoplanin Resistance

N. McCallum,1*,{dagger} H. Karauzum,2,{dagger} R. Getzmann,2 M. Bischoff,1 P. Majcherczyk,3 B. Berger-Bächi,1 and R. Landmann2

Institute of Medical Microbiology, University of Zürich, Gloriastr. 32, 8006 Zürich, Switzerland,1 Division of Infectious Diseases, Department of Research, University Hospital, Basel, Switzerland,2 Department of Fundamental Microbiology, Bâtiment Biophore, Quartier UNIL-Sorge, University of Lausanne, 1015 Lausanne, Switzerland3

Received 10 January 2006/ Returned for modification 16 February 2006/ Accepted 11 April 2006

Glycopeptide resistance, in a set of in vitro step-selected teicoplanin-resistant mutants derived from susceptible Staphylococcus aureus SA113, was associated with slower growth, thickening of the bacterial cell wall, increased N-acetylglucosamine incorporation, and decreased hemolysis. Differential transcriptome analysis showed that as resistance increased, some virulence-associated genes became downregulated. In a mouse tissue cage infection model, an inoculum of 104 CFU of strain SA113 rapidly produced a high-bacterial-load infection, which triggered MIP-2 release, leukocyte infiltration, and reduced leukocyte viability. In contrast, with the same inoculum of the isogenic glycopeptide-resistant derivative NM67, CFU initially decreased, resulting in the elimination of the mutant in three out of seven cages. In the four cages in which NM67 survived, it partially regained wild-type characteristics, including thinning of the cell wall, reduced N-acetylglucosamine uptake, and increased hemolysis; however, the survivors also became teicoplanin hypersusceptible. The elimination of the teicoplanin-resistant mutants and selection of teicoplanin-hypersusceptible survivors in the tissue cages indicated that glycopeptide resistance imposes a fitness burden on S. aureus and is selected against in vivo, with restoration of fitness incurring the price of resistance loss.

* Corresponding author. Mailing address: Institute of Medical Microbiology, University of Zürich, 8006 Zurich, Switzerland. Phone: 41 44 634 2694. Fax: 41 44 634 4906. E-mail: mccallum{at}immv.unizh.ch.

{dagger} N.M. and H.K. contributed equally to this study.

Antimicrobial Agents and Chemotherapy, July 2006, p. 2352-2360, Vol. 50, No. 7
0066-4804/06/$08.00+0     doi:10.1128/AAC.00073-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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