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Antimicrobial Agents and Chemotherapy, January 2008, p. 269-278, Vol. 52, No. 1
0066-4804/08/$08.00+0     doi:10.1128/AAC.00719-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Failures in Clinical Treatment of Staphylococcus aureus Infection with Daptomycin Are Associated with Alterations in Surface Charge, Membrane Phospholipid Asymmetry, and Drug Binding{triangledown}

Tiffanny Jones,1 Michael R. Yeaman,1,2,3 George Sakoulas,4 Soo-Jin Yang,1 Richard A. Proctor,5 Hans-Georg Sahl,6 Jacques Schrenzel,7 Yan Q. Xiong,1,2,3 and Arnold S. Bayer1,2,3*

Los Angeles Biomedical Research Institute, Torrance, California,1 Department of Medicine, Division of Infectious Diseases, Harbor-UCLA Medical Center, Torrance, California,2 Geffen School of Medicine at UCLA, Los Angeles, California,3 Department of Medicine/Infectious Diseases, New York Medical College, Valhalla, New York,4 Departments of Microbiology, Immunology and Medicine, University of Wisconsin, Madison, Wisconsin,5 Department of Medical Microbiology and Immunology, University of Bonn, Bonn, Germany,6 Department of Internal Medicine, University Hospitals, Geneva, Switzerland7

Received 4 June 2007/ Returned for modification 5 August 2007/ Accepted 11 October 2007

Increasingly frequent reports have described the in vivo loss of daptomycin susceptibility in association with clinical treatment failures. The mechanism(s) of daptomycin resistance is not well understood. We studied an isogenic set of Staphylococcus aureus isolates from the bloodstream of a daptomycin-treated patient with recalcitrant endocarditis in which serial strains exhibited decreasing susceptibility to daptomycin. Since daptomycin is a membrane-targeting lipopeptide, we compared a number of membrane parameters in the initial blood isolate (parental) with those in subsequent daptomycin-resistant strains obtained during treatment. In comparison to the parental strain, resistant isolates demonstrated (i) enhanced membrane fluidity, (ii) increased translocation of the positively charged phospholipid lysyl-phosphotidylglycerol to the outer membrane leaflet, (iii) increased net positive surface charge (P < 0.05 versus the parental strain), (iv) reduced susceptibility to daptomycin-induced depolarization, permeabilization, and autolysis (P < 0.05 versus the parental strain), (v) significantly lower surface binding of daptomycin (P < 0.05 versus the parental strain), and (vi) increased cross-resistance to the cationic antimicrobial host defense peptides human neutrophil peptide 1 (hNP-1) and thrombin-induced platelet microbicidal protein 1 (tPMP-1). These data link distinct changes in membrane structure and function with in vivo development of daptomycin resistance in S. aureus. Moreover, the cross-resistance to hNP-1 and tPMP-1 may also impact the capacity of these daptomycin-resistant organisms to be cleared from sites of infection, particularly endovascular foci.

* Corresponding author. Mailing address: LA Biomedical Research Institute at Harbor-UCLA, 1124 West Carson Street, Bldg. RB2, Room 225, Torrance, CA 90502. Phone: (310) 222-6422. Fax: (310) 782-2016. E-mail: bayer{at}humc.edu

{triangledown} Published ahead of print on 22 October 2007.

Antimicrobial Agents and Chemotherapy, January 2008, p. 269-278, Vol. 52, No. 1
0066-4804/08/$08.00+0     doi:10.1128/AAC.00719-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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