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Antimicrobial Agents and Chemotherapy, November 2003, p. 3561-3566, Vol. 47, No. 11
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.11.3561-3566.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Analysis of Daptomycin Efficacy and Breakpoint Standards in a Murine Model of Enterococcus faecalis and Enterococcus faecium Renal Infection

Jeff Alder,1* Tongchaun Li,1 Donghui Yu,1 Larry Morton,1 Jared Silverman,1 Xi-Xian Zhang,1 Ian Critchley,2 and Grace Thorne1

Cubist Pharmaceuticals, Inc., Lexington, Massachusetts,1 Focus Technologies, Herndon, Virginia2

Received 14 January 2003/ Returned for modification 5 May 2003/ Accepted 18 August 2003

Daptomycin efficacy against clinical isolates of Enterococcus faecalis, Enterococcus faecium, and a lab-derived daptomycin-resistant isolate of E. faecalis was investigated in a mouse model of renal infection. The daptomycin MICs against these enterococci ranged from 0.5 to 50 µg/ml. The objective of this study was to determine the relationship between the MICs of drugs against E. faecalis and E. faecium and the level of daptomycin exposure needed to evaluate the drug's efficacy. Correlating the required therapeutic exposures of mice with the exposures achieved clinically allowed us to project enterococcal breakpoint values. Mice pretreated with carrageenan were infected intravenously with 3 x 108 to 4 x 108 CFU of E. faecalis or E. faecium. Daptomycin (5 to 50 mg of drug/kg of body weight) or saline control was administered 4 h postinfection and continued once daily for 2 days (three total doses). On day 4, infected kidneys were harvested, homogenized, and dilution plated. Efficacy was defined as a >=2-log10 (99%) reduction in bacterial burden in infected kidneys. At clinically relevant dosages and exposures (area under the curve, 400 to 600 µg · hr/ml), daptomycin demonstrated similar and marked efficacy against all clinical enterococcal isolates tested. Daptomycin achieved efficacy with comparable doses against both vancomycin-sensitive (MIC, <=4 µg/ml) and -resistant enterococcal strains tested. Efficacy was also established against the lab-derived daptomycin-resistant E. faecalis isolate. In this murine renal infection model, clinically relevant exposures of daptomycin were effective against E. faecalis and E. faecium strains for which MICs were <=8 µg/ml. These murine efficacy data for daptomycin, along with surveillance data and human pharmacokinetic exposures achieved, suggest a breakpoint concentration value of <=8 µg/ml (susceptible) and >=16 µg/ml (resistant) for daptomycin against E. faecium and E. faecalis.

* Corresponding author. Mailing address: Department of Microbiology and Pharmacology, Cubist Pharmaceuticals, Inc., 65 Hayden Ave., Lexington, MA 02421. Phone: (781) 860-8303. Fax: (781) 861-0566. E-mail: jalder{at}cubist.com.

Antimicrobial Agents and Chemotherapy, November 2003, p. 3561-3566, Vol. 47, No. 11
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.11.3561-3566.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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