The ability of fluconazole to penetrate into ventilated, healthy and inflamed lung tissue in a model of severe sepsis in rats.

BACKGROUND/AIMS: We measured the extracellular concentrations of fluconazole in lung tissue of septic and healthy rats. METHODS: A single intravenous dose of 6 mg/kg total body weight of fluconazole was administered intravenously to rats following insertion of microdialysis probes into lung tissue. Another probe was inserted into skeletal muscle and served as control. RESULTS: The mean peak concentration (C(max)), time to C(max), area under the concentration-versus-time curve from 0 to 6 h (fAUC(0-6)) and area under the concentration-versus-time curve from 0 to ∞ of unbound fluconazole for healthy lung were 11.0 ± 2.3 mg/l, 1.9 ± 1.5 h, 47.4 ± 8.6 mg·h/l and 233.7 ± 121.1 mg·h/l, respectively. The corresponding values for inflamed lung were 11.8 ± 1.7 mg/l, 1.5 ± 0.0 h, 52.9 ± 6.2 mg·h/l and 212.6 ± 79.7 mg·h/l, respectively. The mean apparent terminal elimination half-lives of fluconazole ranged from 12.3 to 22.4 h between compartments. The ratios of the fAUC(0-6) for lung to the fAUC(0-6) for plasma were 1.38 ± 0.39 and 1.32 ± 0.04 for healthy and inflamed lung, respectively. CONCLUSION: We provide evidence that free fluconazole levels in plasma, the extracellular space fluid of lung tissue and skeletal muscle are almost superimposable during inflammatory and normal conditions.

Soft tissue and bone penetration abilities of daptomycin in diabetic patients with bacterial foot infections.

OBJECTIVES: In the attempt to overcome increasing glycopeptide- and methicillin-resistant soft tissue infections, daptomycin is presently considered as an attractive alternative to the class of glycopeptides. However, daptomycin dosing and its ability to penetrate into inflamed target tissues are still a matter of controversy. Thus, in the present investigation, we set out to evaluate daptomycin's ability to penetrate into inflamed subcutaneous adipose tissue and bone in diabetic patients presenting with severe bacterial foot infection. PATIENTS AND METHODS: The microdialysis technique was utilized to collect interstitial space fluid from inflamed subcutaneous adipose tissue and metatarsal bone. Plasma and unaffected subcutaneous adipose tissue served as reference compartments. Serial sampling of specimens at steady-state was performed from 0 to 8 h post-dose in five patients (Group A) and from 8 to 16 h after study drug administration in another group of four patients (Group B). In all subjects, daptomycin was administered intravenously once daily at a dosage of 6 mg/kg body weight for 4 consecutive days at minimum. RESULTS: Equilibrium between free tissue and plasma concentrations was achieved approximately 2 h post-infusion. Under steady-state conditions, the degree of tissue penetration was assessed by the calculation of the ratio of free (f) AUC of daptomycin in plasma to the fAUC in tissues. The mean ratios of the fAUC0-16 tissue to the fAUC0-16 plasma were 1.44, 0.98 and 1.08 for healthy tissue, inflamed subcutaneous adipose tissue and bone, respectively. The corresponding ratios of the fAUCs from 0 to 24 h were 1.54, 1.06 and 1.17, respectively. CONCLUSIONS: With the reservation that pharmacokinetic-pharmacodynamic targets for daptomycin in tissues are currently not established, we conclude that daptomycin given at intravenous doses of 6 mg/kg body weight once daily may be considered an effective treatment regimen in diabetic patients suffering from bacterial foot infection and osteomyelitis.

High fosfomycin concentrations in bone and peripheral soft tissue in diabetic patients presenting with bacterial foot infection.

OBJECTIVES: Appropriate antimicrobial therapy and surgical intervention may be required in diabetic patients presenting with severe bacterial foot infection. Methicillin-resistant Staphylococcus aureus (MRSA) agents such as fosfomycin are increasingly in demand because of recent concern regarding vancomycin and daptomycin efficacy and constant use. Intravenous fosfomycin is approved for the therapy of severe soft tissue infections and is highly active against methicillin-susceptible S. aureus and MRSA. in the present study we investigated fosfomycin's ability to penetrate bone tissue in diabetic patients suffering from severe bacterial foot infection. PATIENTS AND METHODS: The well established microdialysis technique was utilized to determine fosfomycin concentrations in metatarsal bone in nine patients scheduled for partial bone resection due to bacterial foot infection and osteomyelitis. Plasma and unaffected subcutaneous adipose tissue served as reference compartments. RESULTS: After a single intravenous dose of approximately 100 mg of fosfomycin per kg of body weight, the mean C(max), T(max) and AUC(0-6) for bone were 96.4 mg/L, 3.9 h and 330.0 mg x h/L, respectively. The degree of tissue penetration as determined by the ratios of the AUC(0-6) for bone to plasma and for subcutaneous adipose tissue to plasma were 0.43 +/- 0.04 and 0.76 +/- 0.05, respectively. CONCLUSIONS: On the basis of relevant pharmacokinetic-pharmacodynamic indices, it seems that fosfomycin is an effective antibiotic for the treatment of deep-seated diabetic foot infections with osseous matrix involvement.

Rapid and sensitive determination of the antibiotic linezolid in low plasma volumes by high-performance liquid chromatography.

A rapid and sensitive method for the determination of linezolid by high-performance liquid chromatography (HPLC) with UV detection (251 nm) is presented. Linezolid is an important antibiotic against severe infections caused by multi-resistant bacterial pathogens. Scientific efforts continue investigating its effectiveness in different conditions and patient populations including children and newborns. Because plasma samples in a pediatric setting or from animal models are usually collected in low volumes, there is a necessity for a reliable and precise analytical method that is reliable and precise even at sample volumes below 50 microL. The presented method is suitable for plasma sample volumes of 20 microL and can be performed with basic HPLC equipment. Linezolid is extracted from plasma with 10% methanol-90% dichloromethane at neutral conditions and separated isocratically on a microbore ODS column using ammonium acetate buffer (pH 4.4, 0.5%, w/v) and acetonitrile (84:16, v/v) as the eluent. The method exerts linearity from 0.05-40 mg/L and meets commonly accepted specifications regarding accuracy and precision.

Linezolid concentrations in infected soft tissue and bone following repetitive doses in diabetic patients with bacterial foot infections.

The present study aimed at assessing unbound extracellular concentrations of linezolid in inflamed soft tissue and bone of diabetic patients suffering from severe bacterial foot infections. Linezolid was administered intravenously twice daily at a dosage of 600 mg. At steady-state conditions, the microdialysis technique was utilised to sample serially interstitial space fluid from inflamed subcutaneous adipose tissue and metatarsal bone from 0-8h post dose in three representative patients. Mean peak concentrations of free linezolid in plasma, healthy subcutis, inflamed subcutis and cancellous bone were 16.6+/-3.0, 15.5+/-2.5, 15.8+/-2.8 and 15.1+/-4.1mg/L, respectively. The degree of tissue penetration as expressed by the ratio of the area under the concentration-time curve of free linezolid from 0-12h (fAUC(0-12)) in tissue to the fAUC(0-12) in plasma was 1.32+/-0.09, 1.12+/-0.22 and 1.09+/-0.11 for healthy subcutis, inflamed subcutis and bone, respectively. Based on currently available pharmacokinetic/pharmacodynamic targets, we conclude that linezolid administered at 600 mg twice daily may be considered an effective treatment in diabetic patients suffering from bacterial foot infection complicated by osteomyelitis.