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Antimicrobial Agents and Chemotherapy, December 2007, p. 4255-4260, Vol. 51, No. 12
0066-4804/07/$08.00+0     doi:10.1128/AAC.00824-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Bactericidal Action of Daptomycin against Stationary-Phase and Nondividing Staphylococcus aureus Cells{triangledown}

Carmela T. M. Mascio,* Jeff D. Alder, and Jared A. Silverman

Cubist Pharmaceuticals, Inc., Lexington, Massachusetts

Received 25 June 2007/ Returned for modification 27 July 2007/ Accepted 30 September 2007

Most antibiotics with bactericidal activity require that the bacteria be actively dividing to produce rapid killing. However, in many infections, such as endocarditis, prosthetic joint infections, and infected embedded catheters, the bacteria divide slowly or not at all. Daptomycin is a lipopeptide antibiotic with a distinct mechanism of action that targets the cytoplasmic membrane of gram-positive organisms, including Staphylococcus aureus. Daptomycin is rapidly bactericidal against exponentially growing bacteria (a 3-log reduction in 60 min). The objectives of this study were to determine if daptomycin is bactericidal against nondividing S. aureus and to quantify the extent of the bactericidal activity. In high-inoculum methicillin-sensitive S. aureus cultures in stationary phase (1010 CFU/ml), daptomycin displayed concentration-dependent bactericidal activity, requiring 32 µg/ml to achieve a 3-log reduction. In a study comparing several antibiotics at 100 µg/ml, daptomycin demonstrated faster bactericidal activity than nafcillin, ciprofloxacin, gentamicin, and vancomycin. In experiments where bacterial cell growth was halted by the metabolic inhibitor carbonyl cyanide m-chlorophenylhydrazone or erythromycin, daptomycin (10 µg/ml) achieved the bactericidal end point (a 3-log reduction) within 2 h. In contrast, ciprofloxacin (10 µg/ml) did not produce bactericidal activity. Daptomycin (2 µg/ml) remained bactericidal against cold-arrested S. aureus, which was protected from the actions of ciprofloxacin and nafcillin. The data presented here suggest that, in contrast to that of other classes of antibiotics, the bactericidal activity of daptomycin does not require cell division or active metabolism, most likely as a consequence of its direct action on the bacterial membrane.

* Corresponding author. Mailing address: Cubist Pharmaceuticals, Inc., 65 Hayden Avenue, Lexington, MA 02421. Phone: (781) 860-8525. Fax: (781) 861-1164. E-mail: carmela.mascio{at}cubist.com

{triangledown} Published ahead of print on 8 October 2007.

Antimicrobial Agents and Chemotherapy, December 2007, p. 4255-4260, Vol. 51, No. 12
0066-4804/07/$08.00+0     doi:10.1128/AAC.00824-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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