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Antimicrobial Agents and Chemotherapy, July 2005, p. 2687-2692, Vol. 49, No. 7
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.7.2687-2692.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Reduced Susceptibility of Staphylococcus aureus to Vancomycin and Platelet Microbicidal Protein Correlates with Defective Autolysis and Loss of Accessory Gene Regulator (agr) Function

George Sakoulas,1 George M. Eliopoulos,2 Vance G. Fowler Jr.,3 Robert C. Moellering Jr.,2 Richard P. Novick,5 Natalie Lucindo,4 Michael R. Yeaman,4 and Arnold S. Bayer4*

Westchester Medical Center, New York Medical College, Valhalla, New York 10595,1 Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215,2 LA Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California 90502, and The Geffen School of Medicine at UCLA, Los Angeles, California 90024,3 Duke University Medical Center, Durham, North Carolina 27705,4 Skirball Institute, New York University School of Medicine, New York, New York 100165

Received 5 December 2004/ Returned for modification 31 January 2005/ Accepted 28 March 2005

Loss of agr function, vancomycin exposure, and abnormal autolysis have been linked with both development of the GISA phenotype and low-level resistance in vitro to thrombin-induced platelet microbicidal proteins (tPMPs). We examined the potential in vitro interrelationships among these parameters in well-characterized, isogenic laboratory-derived and clinical Staphylococcus aureus isolates. The laboratory-derived S. aureus strains included RN6607 (agrII-positive parent) and RN6607V (vancomycin-passaged variant; hetero-GISA), RN9120 (RN6607 agr::tetM; agr II knockout parent), RN9120V (vancomycin-passaged variant), and RN9120-GISA (vancomycin passaged, GISA). Two serial isolates from a vancomycin-treated patient with recalcitrant, methicillin-resistant S. aureus (MRSA) endocarditis were also studied: A5937 (agrII-positive initial isolate) and A5940 (agrII-defective/hetero-GISA isolate obtained after prolonged vancomycin administration). In vitro tPMP susceptibility phenotypes were assessed after exposure of strains to either 1 or 2 µg/ml. Triton X-100- and vancomycin-induced lysis profiles were determined spectrophotometrically. For agrII-intact strain RN6607, vancomycin exposure in vitro was associated with modest increases in vancomycin MICs and reduced killing by tPMP, but no change in lysis profiles. In contrast, vancomycin exposure of agrII-negative RN9120 yielded a hetero-GISA phenotype and was associated with defects in lysis and reduced in vitro killing by tPMP. In the clinical isolates, loss of agrII function during prolonged vancomycin therapy was accompanied by emergence of the hetero-GISA phenotype and reduced tPMP killing, with no significant change in lysis profiles. An association was identified between loss of agrII function and the emergence of hetero-GISA phenotype during either in vitro or in vivo vancomycin exposure. In vitro, these events were associated with defective lysis and reduced susceptibility to tPMP. The precise mechanism(s) underlying these findings is the subject of current investigations.

* Corresponding author. Mailing address: LA Biomedical Research Institute, St. John's Cardiovascular Research Center, 1124 West Carson St., Bldg. RB-2, Rm. 225, Torrance, CA 90502. Phone: (310) 222-6422. Fax: (310) 782-2016. E-mail: bayer{at}humc.edu.

Antimicrobial Agents and Chemotherapy, July 2005, p. 2687-2692, Vol. 49, No. 7
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.7.2687-2692.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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