Staphylococcus aureus and other Gram-positive organisms, including methicillin-resistant S. aureus, continue to be the predominant pathogens associated with diabetic foot infections. Consequently, linezolid is often used to treat these infections. The purpose of the current study was to describe the pharmacokinetic profile and determine the level of penetration of linezolid into healthy thigh tissue and infected wound tissue of the same extremity in 9 diabetic patients with chronic lower limb infections by use of in vivo microdialysis. Hourly plasma and dialysate samples were obtained over a 12-h dosing interval following 3 to 4 doses of linezolid (600 mg intravenously every 12 h). Plasma protein binding was also assessed at 1, 6, and 12 h postdose. The means ؎ standard deviations (SD) for the maximum concentration in serum (C max ), the volume of distribution at terminal phase (V z ), and the half-life (t 1/2 ) for linezolid in plasma were 11.99 ؎ 3.67 g/ml,

Tissue penetration of systemic antibiotics is an important consideration for positive outcomes in diabetic patients. Herein we describe the exposure profile and penetration of tigecycline in the interstitial fluid of wound margins versus that of uninfected thigh tissue in 8 adult diabetic patients intravenously (IV) administered 100 mg and then 50 mg of tigecycline twice daily for 3 to 5 doses. Prior to administration of the first dose, 2 microdialysis catheters were inserted into the subcutaneous tissue, the first within 10 cm of the wound margin and the second in the thigh of the same extremity. Samples for determination of plasma and tissue concentrations were simultaneously collected over 12 h under steady-state conditions. Tissue concentrations were corrected for percent in vivo recovery by the retrodialysis technique. Plasma samples were also collected for determination of protein binding at 1, 6, and 12 h postdose for each patient. Protein binding data were corrected using a fitted polynomial equation. The mean patient weight was 95.1 kg (range, 63.6 to 149.2 kg), the mean patient age was 63.5 ؎ 9.4 years, and 75% of the patients were males. The mean values for the plasma, thigh, and wound free area under the concentration-time curve from 0 to 24 h (fAUC 0-24 ) were 2.65 ؎ 0.33, 2.52 ؎ 1.15, and 2.60 ؎ 1.02 g ⅐ h/ml, respectively. Protein binding was nonlinear, with the percentage of free drug increasing with decreasing serum concentrations. Exposure values for thigh tissue and wound tissue were similar (P ‫؍‬ 0.986). Mean steady-state tissue concentrations for the thigh and wound were similar at 0.12 ؎ 0.02 g/ml, and clearance from the tissues appeared similar to that from plasma. Tissue penetration ratios (tissue fAUC/plasma fAUC) were 99% in the thigh and 100% in the wound (P ‫؍‬ 0.964). Tigecycline penetrated equally well into wound and uninfected tissue of the same extremity.

c Cefazolin, a first-generation cephalosporin with activity against methicillin-susceptible Staphylococcus aureus and streptococci, is often used to treat lower limb infections caused by these pathogens. Antimicrobial penetration is often limited in these patients due to compromised vasculature. Therefore, we sought to evaluate the exposure profile of cefazolin in serum and tissue in patients with lower limb infections. An in vivo microdialysis catheter was inserted into the tissue near the margin of the wound and constantly perfused with lactated Ringer's solution. Steady-state serum and tissue samples were simultaneously collected over a dosing interval. Serum protein binding was also assessed. Serum concentrations were analyzed by noncompartmental analysis. Tissue concentrations were corrected for percent in vivo recovery by using the retrodialysis technique. Seven patients with a mean weight of 95.45 ؎ 18.51 kg and a mean age of 54 ؎ 19 years were enrolled. Six patients received 1 g every 8 h, and one patient received 2 g every 24 h due to acute kidney injury. The free area under the curve from 0 to 8 h (fAUC 0 -8 ) values for serum and wound were 48.0 ؎ 18.66 and 56.35 ؎ 41.17 g · h/ml, respectively, for the patients receiving 1 g every 8 h. The fAUC 0 -24 values for serum and wound were 1,326.1 and 253.9 g · h/ml, respectively, for the single patient receiving 2 g every 24 h. The mean tissue penetration ratio (tissue/serum fAUC ratio) was 1.06. These data suggest that the amount of time that free-drug concentrations remain above the MIC (fT>MIC) for cefazolin in wound tissue is adequate to treat patients with lower limb infections.

Herein, we present pharmacokinetic and tissue penetration data for oral tedizolid in hospitalized patients with diabetic foot infections (DFI) compared with healthy volunteers. Participants received oral tedizolid phosphate 200 mg every 24 h for 3 doses to achieve steady state. A microdialysis catheter was inserted into the subcutaneous tissue near the margin of the wound for patients or into thigh tissue of volunteers. Following the third dose, 12 blood and 14 dialysate fluid samples were collected over 24 h to characterize tedizolid concentrations in plasma and interstitial extracellular fluid of soft tissue. Mean ± standard deviation (SD) tedizolid pharmacokinetic parameters in plasma for patients compared with volunteers, respectively, were as follows: maximum concentration (), 1.5 ± 0.5 versus 2.7 ± 1.1 mg/liter ( = 0.005); time to () (median [range]), 5.9 (1.2 to 8.0) versus 2.5 (2.0 to 3.0 h) ( = 0.003); half-life (t), 9.1 ± 3.6 versus 8.9 ± 2.2 h ( = 0.932); and plasma area under the concentration-time curve for the dosing interval (AUC ), 18.5 ± 9.7 versus 28.7 ± 9.6 mg · h/liter ( = 0.004). The tissue area under the concentration-time curve (AUC ) for the dosing interval was 3.4 ± 1.5 versus 5.2 ± 1.6 mg · h/liter ( = 0.075). Tissue penetration median (range) was 1.1 (0.3 to 1.6) versus 0.8 (0.7 to 1.0) ( = 0.351). Despite lower plasma and delayed values for patients with DFI relative to healthy volunteers, the penetration into and exposure to tissue were similar. Based on available pharmacodynamic thresholds for tedizolid, the plasma and tissue exposures using the oral 200 mg once-daily regimen are suitable for further study in treatment of DFI.

These data suggest that against MRSA with minimum inhibitory concentrations of 1 μg/mL or less, vancomycin achieved blood pharmacodynamic targets required for the likelihood of success. Reduced concentrations may contribute to poor outcomes and the development of resistance. As other literature suggests, alternative agents may be needed when the pathogen of interest has a minimum inhibitory concentration greater than 1 μg/mL.