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Antimicrobial Agents and Chemotherapy, May 2003, p. 1714-1718, Vol. 47, No. 5
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.5.1714-1718.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Efficacy of Daptomycin in Experimental Endocarditis Due to Methicillin-Resistant Staphylococcus aureus

George Sakoulas,1,2*{dagger} George M. Eliopoulos,1,2 Jeff Alder,3 and Claudie Thauvin- Eliopoulos1,2

Department of Medicine, Beth Israel Deaconess Medical Center,1 Harvard Medical School, Boston, Massachusetts 02215,2 Cubist Pharmaceuticals, Lexington, Massachusetts 024213

Received 14 May 2002/ Returned for modification 13 October 2002/ Accepted 30 December 2002

Methicillin-resistant Staphylococcus aureus is becoming increasingly prevalent as both a nosocomial and a community-acquired pathogen. Daptomycin, a lipopeptide antibiotic now in phase III clinical trials, is rapidly bactericidal in vitro against a range of gram-positive organisms, including methicillin-resistant S. aureus (MRSA). In this study, we compared the efficacy of daptomycin with that of vancomycin, each with or without rifampin, in a model of experimental aortic valve endocarditis due to MRSA. The infecting strain (MRSA strain 32) was susceptible to daptomycin (MIC = 1 µg/ml), vancomycin (MIC = 0.5 µg/ml), and rifampin (MIC = 0.5 µg/ml). Daptomycin was administered at 25 or 40 mg/kg q24h (q24h) by subcutaneous injection in an attempt to simulate human doses of 4 and 6 mg/kg q24h, respectively. Vancomycin was given at 150 mg/kg q24h by continuous intravenous infusion. Rifampin was given at 25 mg/kg by intramuscular injection q24h. Treatment was started 6 h postinoculation and continued for 4.5 days. Outcome was assessed by counting the residual viable bacteria in vegetations. The mean peak daptomycin levels in serum at 2 h after subcutaneous administration of 25 and 40 mg/kg were 64 and 91 µg/ml, respectively. Daptomycin was undetectable in serum at 24 h. The total exposure was comparable to that achieved clinically in humans receiving the drug. Bacterial counts (mean log10 number of CFU per gram ± the standard deviation) in untreated controls reached 10.6 ± 0.8. In treated rats, bacterial counts were as follows: vancomycin, 7.1 ± 2.5; daptomycin at 25 mg/kg, 5.5 ± 1.7; daptomycin at 40 mg/kg, 4.2 ± 1.5. The difference between daptomycin at 40 mg/kg and vancomycin at 150 mg/kg was statistically significant (P = 0.004). In the study of combination therapy, vegetation bacterial counts were as follows: daptomycin at 40 mg/kg, 4.6 ± 1.6; rifampin, 3.6 ± 1.3; vancomycin plus rifampin, 3.3 ± 1.1; daptomycin plus rifampin, 2.9 ± 0.8. The difference between daptomycin and daptomycin plus rifampin was statistically significant (P = 0.006). These results support the continued evaluation of daptomycin for serious MRSA infections, including infective endocarditis.

* Corresponding author. Present address: Infectious Disease-Crystal Run Healthcare, 155 Crystal Run Rd., Middletown, N.Y. 10941. Phone: (845) 703-6999. Fax: (845) 361-1156. E-mail: gsakoulas{at}crystalrunhealthcare.com.

Antimicrobial Agents and Chemotherapy, May 2003, p. 1714-1718, Vol. 47, No. 5
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.5.1714-1718.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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