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Antimicrobial Agents and Chemotherapy, November 2008, p. 3941-3946, Vol. 52, No. 11
0066-4804/08/$08.00+0     doi:10.1128/AAC.00589-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

In Vivo Microdialysis Study of the Penetration of Daptomycin into Soft Tissues in Diabetic versus Healthy Volunteers{triangledown}

Aryun Kim,1 Larry A. Suecof,2,3 Christina A. Sutherland,1 Lihong Gao,4 Joseph L. Kuti,1 and David P. Nicolau1,5*

Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut,1 Connecticut Surgical Group, Hartford, Connecticut,2 Wound and Hyperbaric Medicine Center, Hartford Hospital, Hartford, Connecticut,3 Analytical Chemistry, Cubist Pharmaceuticals Inc., Lexington, Massachusetts,4 Division of Infectious Diseases, Hartford Hospital, Hartford, Connecticut5

Received 5 May 2008/ Returned for modification 16 June 2008/ Accepted 30 August 2008

Daptomycin is approved for the treatment of complicated skin and soft tissue infections, including diabetic wounds of the lower extremities, at a dose of 4 mg/kg of body weight once daily. For such localized tissue infections, drug concentrations in the interstitial space are an important determinant of successful therapy. In the diabetic population, peripheral arterial disease may limit antibiotic penetration into the target tissue. The objective of this study was to describe and compare the pharmacokinetic profiles of daptomycin in the interstitial fluid of soft tissues in diabetic and healthy volunteers by using in vivo microdialysis. Twelve subjects (six diabetic and six healthy) received a single 4-mg/kg dose of daptomycin intravenously. Samples of plasma and tissue were simultaneously collected over 24 h. Diabetic and healthy groups were matched in mean age (±10 years), gender ratio, mean weight (±10 kg), and creatinine clearance rate (±20 ml/min/1.73 m2). Pharmacokinetic parameters for plasma were similar between groups (P > 0.05). The mean peak drug concentrations ± standard deviations in tissue were 4.3 ± 3.3 µg/ml and 3.8 ± 1.4 µg/ml for diabetic and healthy subjects, respectively. The degree of tissue penetration, defined as the ratio of the area under the free drug concentration-time curve for tissue to that for plasma, was 0.93 ± 0.61 for diabetic subjects and 0.74 ± 0.09 for healthy subjects (P = 0.46). Daptomycin at 4 mg/kg penetrated well into the soft tissue, reaching concentrations approximately 70 to 90% of those of the free drug in plasma. Moreover, these free, bioactive concentrations in tissue exceeded the MICs for staphylococci and streptococci over the 24-h dosing interval.

* Corresponding author. Mailing address: Center for Anti-Infective Research and Development, Hartford Hospital, 80 Seymour St., Hartford, CT 06102. Phone: (860) 545-3941. Fax: (860) 545-3992. E-mail: dnicola{at}harthosp.org

{triangledown} Published ahead of print on 8 September 2008.

Antimicrobial Agents and Chemotherapy, November 2008, p. 3941-3946, Vol. 52, No. 11
0066-4804/08/$08.00+0     doi:10.1128/AAC.00589-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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