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Antimicrobial Agents and Chemotherapy, March 2001, p. 845-851, Vol. 45, No. 3
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.3.845-851.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Pharmacodynamics of Daptomycin in a Murine Thigh Model of Staphylococcus aureus Infection

Arnold Louie,1,2,* Pamela Kaw,1 Weiguo Liu,1 Nelson Jumbe,1 Michael H. Miller,1,2 and George L. Drusano2,3

Divisions of Infectious Diseases1 and Clinical Pharmacology,3 Albany Medical College, and the Clinical Research Institute of Albany Medical College and Wadsworth Center, New York State Department of Health,2 Albany, New York 12208

Received 22 February 2000/Returned for modification 4 July 2000/Accepted 23 December 2000

Daptomycin is a lipopeptide antibiotic with activity against gram-positive bacteria, including Staphylococcus aureus. We defined the pharmacodynamic parameters that determine the activity of daptomycin for S. aureus using in vitro methods and the Craig (W. A. Craig, J. Redington, and S. C. Ebert, J. Antimicrob. Chemother. 27[Suppl. C]:29-40, 1991) neutropenic mouse thigh infection model. In Mueller-Hinton broth, the MICs for three S. aureus isolates were 0.1 to 0.2 µg/ml. In mouse serum, the MICs were 1.0 µg/ml. The protein binding of daptomycin was 90 to 92.5% in mouse serum. Single-dose intraperitoneal (i.p.) pharmacokinetic studies with infected mice showed a linear relationship between dose versus the maximum concentration of drug in serum and dose versus the area under the concentration-time curve (AUC). The serum half-life of daptomycin in infected mice was approximately 1.8 h. In single-dose, dose-ranging studies using mice, daptomycin showed a dose-response effect described by an inhibitory sigmoid Emax (maximum effect) curve (r = 0.974; P 0.001). The density of S. aureus in untreated controls was 8.26 log10 CFU/g, and the Emax was 3.97 log10 CFU/g. The 50% effective dose (ED50) was 3.7 mg/kg of body weight i.p. and the stasis dose was 7.1 mg/kg. Dose fractionation studies at schedules of Q6h, Q12h, and Q24h, for total 24-h ED30, ED60, and ED80 doses of 2.5, 5.6, and 15 mg/kg i.p., showed no difference in effect at each total 24-h dose level by schedule, indicating that the AUC/MIC ratio is the dynamically linked variable.

* Corresponding author. Mailing address: Division of Infectious Diseases, Mail Code-49, Albany Medical College, 47 New Scotland Ave., Albany, NY 12208. Phone: (518) 262-6548. Fax: (518) 262-6727. E-mail: LouieA{at}mail.amc.edu.

Antimicrobial Agents and Chemotherapy, March 2001, p. 845-851, Vol. 45, No. 3
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.3.845-851.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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