In vivo microdialysis study of the penetration of daptomycin into soft tissues in diabetic versus healthy volunteers.
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 m(2)). 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 microg/ml and 3.8 +/- 1.4 microg/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.
Kim
Aryun
A
Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut 06102, USA.
Suecof
Larry A
LA
Sutherland
Christina A
CA
Gao
Lihong
L
Kuti
Joseph L
JL
Nicolau
David P
DP
D000328:Adult; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016022:Case-Control Studies; D017576:Daptomycin / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D048909:Diabetes Complications / Q000188:drug therapy* / Q000378:metabolism*; D045604:Extracellular Fluid / Q000378:metabolism; D005260:Female; D006801:Humans; D007866:Leg; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus; D017551:Microdialysis; D008875:Middle Aged; D018461:Soft Tissue Infections / Q000150:complications* / Q000188:drug therapy* / Q000378:metabolism; D013203:Staphylococcal Infections / Q000150:complications / Q000188:drug therapy / Q000378:metabolism
D000900:Anti-Bacterial Agents; D017576:Daptomycin
Circulation. 2006 Mar 21;113(11):e463-654
16549646
Antimicrob Agents Chemother. 1992 Feb;36(2):318-25
1318678
Clin Infect Dis. 2004 Oct 1;39(7):885-910
15472838
J Antimicrob Chemother. 2007 Oct;60(4):819-23
17673476
Antimicrob Agents Chemother. 2003 Apr;47(4):1318-23
12654665
Antimicrob Agents Chemother. 2004 Jan;48(1):63-8
14693519
Antimicrob Agents Chemother. 2002 Jan;46(1):31-3
11751107
Clin Infect Dis. 2004 Jun 15;38(12):1673-81
15227611
Antimicrob Agents Chemother. 2006 Nov;50(11):3529-34
17065618
Expert Opin Investig Drugs. 2004 Sep;13(9):1159-69
15330747
Antimicrob Agents Chemother. 2006 Apr;50(4):1372-5
16569854
Antimicrob Agents Chemother. 2005 Jun;49(6):2367-71
15917535
Antimicrob Agents Chemother. 1996 Dec;40(12):2703-9
9124826
Diabetes Res Clin Pract. 2008 Jun;80(3):344-51
18291550
BMJ. 2002 Mar 9;324(7337):588-91
11884326
Nephron. 1976;16(1):31-41
1244564
J Clin Pharmacol. 2008 Mar;48(3):351-64
18285620
J Antimicrob Chemother. 2005 Feb;55(2):240-5
15659542
Clin Infect Dis. 2007 Jun 15;44(12):1543-8
17516396
Diagn Microbiol Infect Dis. 2008 Jun;61(2):235-9
18314293