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Antimicrobial Agents and Chemotherapy, January 2004, p. 63-68, Vol. 48, No. 1
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.1.63-68.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

In Vivo Pharmacodynamic Activity of Daptomycin

Nasia Safdar,1* David Andes,1 and W. A. Craig2

Department of Medicine, Section of Infectious Diseases, University of Wisconsin,1 Department of Medicine, Section of Clinical Pharmacology, William S. Middleton Memorial Veterans Affairs Hospital, Madison, Wisconsin2

Received 25 February 2003/ Returned for modification 16 July 2003/ Accepted 1 October 2003

Daptomycin is a lipopeptide antibiotic with activity against a wide range of gram-positive bacteria. We used the neutropenic murine thigh model to characterize the pharmacodynamics of daptomycin. ICR/Swiss mice were rendered neutropenic with cyclophosphamide; and the thigh muscles of the mice were infected with strains of Staphylococcus aureus, Streptococcus pneumoniae, and Enterococcus faecium. Animals were treated by subcutaneous injection of daptomycin at doses of 0.20 to 400 mg/kg of body weight/day divided into one, two, four, or eight doses over 24 h. Daptomycin exhibited linear pharmacokinetics, with an area under the concentration-time curve (AUC) from time zero to infinity/dose of 9.4 and a half-life of 0.9 to 1.4 h. The level of protein binding was 90%. Free daptomycin exhibited concentration-dependent killing and produced in vivo postantibiotic effects (PAEs) of 4.8 to 10.8 h. Nonlinear regression analysis was used to determine which pharmacokinetic (PK) or pharmacodynamic (PD) parameter was important for efficacy by using free drug concentrations. The peak concentration/MIC (peak/MIC) ratio and 24-h AUC/MIC ratio were the PK and PD parameters that best correlated with in vivo efficacy (R2 = 83 to 87% for peak/MIC and R2 = 86% for the AUC/MIC ratio, whereas R2 = 47 to 50% for the time that the concentration was greater than the MIC) against standard strains of S. aureus and S. pneumoniae. The peak/MIC ratios required for a bacteriostatic effect ranged from 12 to 36 for S. pneumoniae, 59 to 94 for S. aureus, and 0.14 to 0.25 for E. faecium. The AUC/MIC ratios needed for a bacteriostatic effect ranged from 75 to 237 for S. pneumoniae, 388 to 537 for S. aureus, and 0.94 to 1.67 for E. faecium. The free daptomycin concentrations needed to average from one to two times the MIC over 24 h to produce a bacteriostatic effect and two to four times the MIC over 24 h to produce greater than 99% killing. The long PAE and potent bactericidal activity make daptomycin an attractive option for the treatment of infections caused by gram-positive bacteria.

* Corresponding author. Mailing address: Division of Infectious Diseases, University of Wisconsin, Madison, 600 Highland Ave., Madison, WI 53792. Phone: (608) 263-1545. Fax: (608) 263-4464. E-mail: n.safdar{at}hosp.wisc.edu.

Antimicrobial Agents and Chemotherapy, January 2004, p. 63-68, Vol. 48, No. 1
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.1.63-68.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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