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Antimicrobial Agents and Chemotherapy, April 2009, p. 1463-1467, Vol. 53, No. 4
0066-4804/09/$08.00+0     doi:10.1128/AAC.01307-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Relationship between Susceptibility to Daptomycin In Vitro and Activity In Vivo in a Rabbit Model of Aortic Valve Endocarditis{triangledown}

H. F. Chambers,1* L. Basuino,1 B. A. Diep,1 J. Steenbergen,2 S. Zhang,2 P. Tattevin,3 and J. Alder4

San Francisco General Hospital, University of California San Francisco, San Francisco, California,1 Cubist Pharmaceuticals, Lexington, Massachusetts,2 Pontchaillou University Hospital, Rennes, France,3 Bayer HealthCare, Monteville, New Jersey4

Received 30 September 2008/ Returned for modification 7 November 2008/ Accepted 15 January 2009

Daptomycin is approved for treatment of Staphylococcus aureus bacteremia and right-sided endocarditis. Increases in daptomycin MICs have been associated with failure. A rabbit model of aortic valve endocarditis was used to determine whether MIC correlates with activity in vivo and whether a higher daptomycin dose can improve efficacy. Two related clinical S. aureus strains, one with a daptomycin MIC of 0.5 µg/ml and the other with a MIC of 2 µg/ml, were used to establish aortic valve endocarditis in rabbits. Daptomycin was administered once a day for 4 days at 12 mg/kg of body weight or 18 mg/kg to simulate doses in humans of 6 mg/kg and 10 mg/kg, respectively. Endocardial vegetations, spleens, and kidneys were harvested and quantitatively cultured. The strain with a MIC of 2 µg/ml had a survival advantage over the strain with a MIC of 0.5 µg/ml with >100 times more organisms of the former in endocardial vegetations at the 12-mg/kg dose in a dual-infection model. Both the 12-mg/kg dose and the 18-mg/kg dose completely eradicated the strain with a MIC of 0.5 from vegetations, spleens, and kidneys. The 12-mg/kg dose was ineffective against the strain with a MIC of 2 in vegetations; the 18-mg/kg dose produced a reduction of 3 log10 units in CFU in vegetations compared to the controls, although in no rabbit were organisms completely eliminated. Increasing the dose of daptomycin may improve its efficacy for infections caused by strains with reduced daptomycin susceptibility.

* Corresponding author. Mailing address: University of California San Francisco, Division of Infectious Diseases-SFGH, Fourth Floor, Building 30, San Francisco General Hospital, 1001 Potrero Avenue, San Francisco, CA 94110. Phone: (415) 206-5437. Fax: (415) 648-8425. E-mail: hchambers{at}medsfgh.ucsf.edu

{triangledown} Published ahead of print on 26 January 2009.

Antimicrobial Agents and Chemotherapy, April 2009, p. 1463-1467, Vol. 53, No. 4
0066-4804/09/$08.00+0     doi:10.1128/AAC.01307-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Moise, P. A, Hershberger, E., Amodio-Groton, M. I, Lamp, K. C (2009). Safety and Clinical Outcomes when Utilizing High-Dose (>=8 mg/kg) Daptomycin Therapy. The Annals of Pharmacotherapy 43: 1211-1219 [Abstract] [Full Text]  


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