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 g/ml and 3.8 ؎ 1.4 g/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.Wound infections of the lower extremities frequently affect the diabetic population and are a significant cause of morbidity, hospitalization, and amputation (12). Gram-positive organisms, particularly Staphylococcus aureus, are the primary causative pathogens in these complicated skin infections. As the extent of antibiotic resistance has grown, the prevalence of methicillin-resistant S. aureus (MRSA) in skin and soft tissue infections (SSTI) has risen alarmingly, resulting in reports of worse outcomes for infections caused by MRSA than for infections caused by other bacteria (20).Anti-MRSA agents like daptomycin are increasingly in demand, particularly in light of recent queries regarding vancomycin's efficacy and continued utility (7). Daptomycin is approved for the treatment of complicated SSTI, including diabetic wound infections, at an intravenous dose of 4 mg/kg of body weight once daily (1, 13). While the pharmacokinetic profile of daptomycin in plasma has been reported previously, for localized tissue infections, drug concentrations in the interstitial space rather than those in plasma determine clinical outcomes. Moreover, diabetic patients also typically suffer from peripheral arterial disease (PAD), which may further limit antibiotic concentrations in infected tissues, as was shown previously for vancomyci...