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Journal of Clinical Microbiology, January 2003, p. 5-14, Vol. 41, No. 1
0095-1137/03/$08.00+0     DOI: 10.1128/JCM.41.1.5-14.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Cell Wall Thickening Is a Common Feature of Vancomycin Resistance in Staphylococcus aureus

Longzhu Cui,1 Xiaoxue Ma,1 Katsuhiro Sato,2 Keiko Okuma,1 Fred C. Tenover,3 Elsa M. Mamizuka,4 Curtis G. Gemmell,5 Mi-Na Kim,6 Marie-Cecile Ploy,7 N. El Solh,8 Vivian Ferraz,9 and Keiichi Hiramatsu1*

Department of Bacteriology,1 Electron Microscopy Center, Faculty of Medicine, Juntendo University, Bunkyo-ku, Tokyo 113-8421, Japan,2 Division of Health Care Quality Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia,3 School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil,4 Department of Bacteriology, Medical School, University of Glasgow Royal Infirmary, Glasgow, United Kingdom,5 Department of Clinical Pathology, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Korea,6 Department de Bacteriology, Virology, Hygiene, CHU Dupuytren, 87042 Limoges,7 French National Reference Centre for Staphylococci, Unite of Staphylocoques, Institute Pasteur, 75724 Paris Cedex 15, France,8 Department of Clinical Microbiology and Infectious Diseases, South African Institute for Medical Research and University of the Witwatersrand, Johannesburg, South Africa9

Received 17 May 2002/ Returned for modification 21 June 2002/ Accepted 10 October 2002

We have previously shown that a thickened cell wall is responsible for the vancomycin resistance of vancomycin-resistant Staphylococcus aureus (VRSA) (equivalent to vancomycin-intermediate S. aureus and glycopeptide-intermediate S. aureus) strain Mu50 (L. Cui, H. Murakami, K. Kuwahara-Arai, H. Hanaki, and K. Hiramatsu, Antimicrob. Agents Chemother. 44:2276-2285, 2000). However, the mechanism of vancomycin resistance in other VRSA strains remained unclear. In this study, 16 clinical VRSA strains from seven countries were subjected to serial daily passage in drug-free medium. After 10 to 84 days of passage in the nonselective medium, passage-derived strains with decreased MICs of vancomycin (MIC, <4 mg/liter) were obtained. However, all of the passage-derived strains except one (15 of 16) still possessed subpopulations that were resistant to vancomycin as judged by population analysis, and vancomycin-resistant mutant strains were selected from the passage-derived strains by one-step vancomycin selection with a frequency of 4.25 x 10-6 to 1.64 x 10-3. The data indicated that vancomycin-resistant cells are frequently generated from the passage-derived strains even after vancomycin selective pressure is lifted. Cell wall thicknesses and MICs of glycopeptides (vancomycin and teicoplanin) and beta-lactams (imipenem and oxacillin) were determined for a total of 48 strains, including 15 sets of three strains: the clinical VRSA strain, the passage-derived strain, and the vancomycin-resistant mutant strain obtained from the passage-derived strain. No simple correlation between glycopeptide and beta-lactam MICs was seen, while significant correlations between MICs of vancomycin and teicoplanin (r = 0.679; P < 0.001) and between MICs of imipenem and oxacillin (r = 0.787; P < 0.001) were recognized. Moreover, all of the VRSA strains had significantly thickened cell walls, which became thinner with the loss of vancomycin resistance during drug-free passages and again became thick in the resistant mutant strains. The data showed that cell wall thickness had high correlation with the MICs of the two glycopeptides (correlation coefficients, 0.908 for vancomycin and 0.655 for teicoplanin) but not with those of the beta-lactam antibiotics tested. These results together with coupled changes of cell wall thickness and vancomycin MICs in 16 isogenic sets of strains indicate that thickening of the cell wall is a common phenotype of clinical VRSA strains and may be a phenotypic determinant for vancomycin resistance in S. aureus.

* Corresponding author. Mailing address: Department of Bacteriology, Faculty of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. Phone: (03)-5802-1041. Fax: (03)-5684-7830. E-mail: hiram{at}med.juntendo.ac.jp.

Journal of Clinical Microbiology, January 2003, p. 5-14, Vol. 41, No. 1
0095-1137/03/$08.00+0     DOI: 10.1128/JCM.41.1.5-14.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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