Correlation of Cerebral and Subcutaneous Glycerol in Severe Traumatic Brain Injury and Association with Tissue Damage.

BACKGROUND: This study is a substudy of a prospective consecutive double-blinded randomized study on the effect of prostacyclin in severe traumatic brain injury (sTBI). The aims of the present study were to investigate whether there was a correlation between brain and subcutaneous glycerol levels and whether the ratio of interstitial glycerol in the brain and subcutaneous tissue (glycerolbrain/sc) was associated with tissue damage in the brain, measured by using the Rotterdam score, S-100B, neuron-specific enolase (NSE), the Injury Severity Score (ISS), the Acute Physiology and Chronic Health Evaluation Score (APACHE II), and trauma type. A potential association with clinical outcome was explored. METHODS: Patients with sTBI aged 15-70 years presenting with a Glasgow Coma Scale Score ≤ 8 were included. Brain and subcutaneous adipose tissue glycerol levels were measured through microdialysis in 48 patients, of whom 42 had complete data for analysis. Brain tissue damage was also evaluated by using the Rotterdam classification of brain computed tomography scans and the biochemical biomarkers S-100B and NSE. RESULTS: In 60% of the patients, a positive relationship in glycerolbrain/sc was observed. Patients with a positive correlation of glycerolbrain/sc had slightly higher brain glycerol levels compared with the group with a negative correlation. There was no significant association between the computed tomography Rotterdam score and glycerolbrain/sc. S-100B and NSE were associated with the profile of glycerolbrain/sc. Our results cannot be explained by the general severity of the trauma as measured by using the Injury Severity Score or Acute Physiology and Chronic Health Evaluation Score. CONCLUSIONS: We have shown that peripheral glycerol may flux into the brain. This effect is associated with worse brain tissue damage. This flux complicates the interpretation of brain interstitial glycerol levels. We remind the clinicians that a damaged blood-brain barrier, as seen in sTBI, may alter the concentrations of various substances, including glycerol in the brain. Awareness of this is important in the interpretation of the data bedside as well in research.

A new microdialysis probe for continuous lactate measurement during fetal monitoring: Proof of concept in an animal model.

INTRODUCTION: Cardiotocography (CTG) is currently the most commonly used method for intrapartum fetal monitoring during labor. However, a high false-positive rate of fetal acidosis indicated by CTG leads to an increase in obstetric interventions. We developed a microdialysis probe that is integrated into a fetal scalp electrode allowing continuous measurement of lactate subcutaneously, thus giving instant information about the oxygenation status of the fetus. Our aim was to establish proof of concept in an animal model using a microdialysis probe to monitor lactate subcutaneously. MATERIAL AND METHODS: We performed an in vivo study in adult male wild-type Wistar rats. We modified electrodes used for CTG monitoring in human fetuses to incorporate a microdialysis membrane. Optimum flow rates for microdialysis were determined in vitro. For the in vivo experiment, a microdialysis probe was inserted into the skin on the back of the animal. De-oxygenation and acidosis were induced by lowering the inspiratory oxygen pressure. Oxygenation and heart rate were monitored. A jugular vein cannula was inserted to draw blood samples for analysis of lactate, pH, pco2 , and saturation. Lactate levels in dialysate were compared with plasma lactate levels. RESULTS: Baseline blood lactate levels were around 1 mmol/L. Upon de-oxygenation, oxygen saturation fell to below 40% for 1 h and blood lactate levels increased 2.5-fold. Correlation of dialysate lactate levels with plasma lactate levels was 0.89 resulting in an R2 of .78 in the corresponding linear regression. CONCLUSIONS: In this animal model, lactate levels in subcutaneous fluid collected by microdialysis closely reflected blood lactate levels upon transient de-oxygenation, indicating that our device is suitable for subcutaneous measurement of lactate. Microdialysis probe technology allows the measurement of multiple compounds in the dialysate, such as glucose, albumin, or inflammatory mediators, so this technique may offer the unique possibility to shed light on fetal physiology during the intrapartum period.

Design and Synthesis of an Activatable Photoacoustic Probe for Hypochlorous Acid.

Photoacoustic (PA) imaging is a novel imaging modality that combines the high contrast of optical imaging and the deep tissue penetration of ultrasound. PA imaging contrast agents targeting various biological phenomena have been reported, but the development of activatable PA probes, which show a PA signal only in the presence of target molecules, remains challenging in spite of their potential usefulness for real-time PA imaging of specific biomolecules in vivo. To establish a simple design strategy for activatable PA probes, we first designed and synthesized a silicon-rhodamine based near-infrared nonfluorescent dye, wsSiNQ660 (water-soluble SiNQ660), as a scaffold and demonstrated that it offers a high conversion efficiency from light to ultrasound compared to typical near-infrared fluorescent dyes. Importantly, absorption off/on strategies previously established for rhodamine-based fluorescent probes are also applicable to this nonfluorescent dye scaffold. We validated this approach by synthesizing an activatable PA probe for hypochlorous acid (HOCl) and confirmed that it enables three-dimensional imaging of HOCl in mouse subcutis.

Fast and sensitive HPLC/UV method for cefazolin quantification in plasma and subcutaneous tissue microdialysate of humans and rodents applied to pharmacokinetic studies in obese individuals.

Antimicrobial prophylactic dosing of morbidly obese patients may differ from normal weighted individuals owing to alterations in drug tissue distribution. Drug subcutaneous tissue distribution can be investigated by microdialysis patients and animals. The need for cefazolin prophylactic dose adjustment in obese patients remains under discussion. The paper describes the validation of an HPLC-UV method for cefazolin quantification in plasma and microdialysate samples from clinical and pre-clinical studies. A C18 column with an isocratic mobile phase was used for drug separation, with detection at 272 nm. Total and unbound cefazolin lower limit of quantitation was 5 µg/mL in human plasma, 2 µg/mL in rat plasma, and 0.5 and 0.025 µg/mL in human and rat microdialysate samples, respectively. The maximum intra- and inter-day imprecisions were 10.7 and 8.1%, respectively. The inaccuracy was <9.7%. The limit of quantitation imprecision and inaccuracy were < 15%. Cefazolin stability in the experimental conditions was confirmed. Cefazolin plasma concentrations and subcutaneous tissue penetration were determined by microdialysis in morbidly obese patients (2 g i.v. bolus) and diet-induced obese rats (30 mg/kg i.v. bolus) using the method. This method has the main advantages of easy plasma clean-up and practicability and has proven to be useful in cefazolin clinical and pre-clinical pharmacokinetic investigations.

Superficial Solitary Fibrous Tumor: A Series of 26 Cases.

While superficial (cutaneous/subcutaneous) solitary fibrous tumor (SFT) have been described, definitive diagnosis is difficult due to overlapping features with other tumors. We describe the largest series to date of superficial SFT. For inclusion, SFT had to arise in dermis or subcutis. Twenty-six cases were identified. Patients ranged from 16 to 80 years (mean, 47 y) with a marked female predominance (19 F; 7 M). Tumors involved the head (11), thigh (7), back (3), shoulder (2), upper arm (1), ankle (1), and great toe (1). Mean size was 2.9 cm (range, 1.0 to 7.0 cm). The majority (n=19) had typical histologic features (cellular SFT) with irregular fascicles of spindled cells, staghorn-like blood vessels, and variable amounts of collagen. Necrosis was evident in 3 cases (all <25%). Mitotic activity ranged from 0 to 10 mitotic figures/10 high-power fields (mean, 2 mitotic figures/10 high-power fields). Seventeen of the 18 were positive for STAT6, whereas 21/22 expressed CD34. All were low risk (23/23) by proposed criteria (Demicco and colleagues), including 2 cases with malignant histology. Three could not be risk stratified due to lack of information on tumor size. Follow-up, available on 7 cases, showed no recurrence/metastasis (mean follow-up, 100 mo; range, 2 to 241 mo). Cutaneous SFT are more common in women and most often involve the head. They are usually low risk by proposed criteria and appear to behave in an indolent manner, though larger studies are needed to confirm this. Recognition that SFT may present as a superficial mass will avoid misclassification as other CD34-positive neoplasms that frequently arise in the skin and subcutaneous tissue.

Mineral Depositions of Calcifying Skin Disorders are Predominantly Composed of Carbonate Apatite.

Subcutaneous calcifications can lead to complications, including pain, inflammation, ulceration and immobilization. Studies on the pathophysiology of mineral compositions and effective treatment modalities are limited. We therefore studied 14 patients with subcutaneous calcifications. Mineral material was collected and analysed by Fourier transform infrared spectrometry. Blood analyses were run to evaluate systemic alterations of mineral metabolism. Carbonate apatite (CAP) was found to be the single constituent in the majority of patients (n = 9, 64.3%), 3 cases (21.4%) had a composition of CAP and calcium oxalate dihydrate and one case had a combination of CAP and magnesium ammonium phosphate, whereas CAP was the major component in all 4 cases. Only one case showed predominantly calcium oxalate. Thus, CAP was found to be the only or predominant component in most cases of subcutaneous calcifications. Chemical analyses of the mineral compositions may aid in the development of new treatment regimes to improve the solubility of mineral components and to decrease extraosseous calcifications.

Plasma, subcutaneous tissue and bone concentrations of ceftiofur sodium after regional limb perfusion in horses.

REASONS FOR PERFORMING STUDY: Regional limb perfusion (RLP) is an effective treatment option for injuries and infections of the distal limb in horses. Using ceftiofur sodium in RLP has been studied due to its superior spectrum of Gram-positive organisms compared to aminoglycosides, but it is not known if this antimicrobial drug adequately penetrates subcutaneous tissue and bone. OBJECTIVE: To determine the concentration of ceftiofur in plasma, subcutaneous tissue and bone in horses after RLP. STUDY DESIGN: Experimental prospective study. METHODS: Six healthy horses were used in this study. Under standing sedation, an Esmarch tourniquet was applied to both proximal metacarpi and RLP was performed in each forelimb by injecting either ceftiofur sodium (experimental limb) or saline (control limb) i.v. in the lateral palmar digital vein. The experimental limb was injected with 2 g ceftiofur diluted to 60 mL with sterile saline. The control limb was injected with 60 mL of sterile saline. The tourniquet was left in place for 30 min post injection. Plasma, subcutaneous tissue and cortical bone samples were collected immediately after tourniquet removal (0.5 h), 12 and 24 h post injection. Ceftiofur concentrations and its active metabolite desfuroylceftiofur were analysed using high performance liquid chromatography-tandem mass spectrometry and the results were compared between control and experimental limbs using a Wilcoxon signed rank test. RESULTS: The median plasma concentrations were greater than the minimum inhibitory concentration (MIC) for common pathogens (1 µg/mL) at 0 and 12 h post RLP. The median subcutaneous tissue concentrations were greater than MIC (1 µg/g) at all 3 time points in the experimental limb. The median bone concentration was above MIC (1 µg/g) at time 0 in the experimental limb but was below MIC at 12 and 24 h in the experimental limb. CONCLUSIONS: Ceftiofur administration via RLP maintained plasma concentrations above MIC for 12 h. Subcutaneous tissue concentrations above MIC were maintained for 24 h. Bone concentrations were only above MIC immediately after tourniquet removal. Further research is needed to evaluate ceftiofur administration via RLP and its implications in disease states.

Tissue pharmacokinetics of telavancin in healthy volunteers: a microdialysis study.

BACKGROUND: Telavancin is a novel lipoglycoprotein antibiotic with MRSA activity. To date, tissue pharmacokinetics (PK) and plasma protein binding of the drug are insufficiently described. OBJECTIVES: To investigate tissue PK and plasma protein binding of telavancin in healthy volunteers. METHODS: Eight male healthy subjects received a single dose of 10 mg/kg of body weight of telavancin as an intravenous infusion over 1 h. At defined timepoints before and up to 24 h after treatment, total telavancin concentrations were measured in plasma. Additionally, unbound telavancin levels were determined in plasma, muscle and subcutis by means of microdialysis. RESULTS: Key PK parameters of total telavancin in plasma were in good agreement with previously described values. Mean ±â€ŠSD Cmax and calculated AUC0-24 of free telavancin in plasma were 13.8 ±â€Š7.8 mg/L and 82.9 ±â€Š34.3 mg·h/L, respectively. Unbound drug levels in plasma ranged from 13.2% to 24.8% of corresponding total telavancin. Mean ±â€ŠSD Cmax and AUC0-24 of unbound telavancin were 4.3 ±â€Š1.5 mg/L and 61.5 ±â€Š27.1 mg·h/L for muscle and 3.4 ±â€Š1.8 and 50.0 ±â€Š29.8 mg·h/L for subcutis, respectively. Relevant PK/pharmacodynamic indices were calculated for total and unbound drug. CONCLUSIONS: This study provides important information on soft tissue PK and plasma protein binding of telavancin in healthy volunteers. Unbound plasma concentrations above levels assumed from previously available data and sustained free drug exposure in soft tissues support the current mode of administration.

Single- and Repeated-Dose Pharmacokinetics of Ceftaroline in Plasma and Soft Tissues of Healthy Volunteers for Two Different Dosing Regimens of Ceftaroline Fosamil.

Ceftaroline fosamil (CPT-F) is currently approved for use for the treatment of complicated skin and soft tissue infections and community-acquired pneumonia at 600 mg twice daily (q12h), but other dosing regimens are under evaluation. To date, very limited data on the soft tissue pharmacokinetics (PK) of the active compound, ceftaroline (CPT), are available. CPT concentrations in the plasma, muscle, and subcutis of 12 male healthy volunteers were measured by microdialysis after single and repeated intravenous administration of 600 mg CPT-F q12h or three times daily (q8h) in two groups of 6 subjects each. Relevant PK and PK/pharmacodynamic (PD) parameters were calculated and compared between groups. In plasma, the area under the concentration-time curve (AUC) from 0 to 24 h for total CPT and the cumulative percentage of the dosing interval during which the free drug concentrations exceeded the MIC (fTMIC) for unbound CPT for the currently established threshold of 1 mg/liter were significantly higher in the group receiving CPT-F q8h. Exposure to free drug in soft tissues was higher in the group receiving CPT-F q8h, but high interindividual variability in relevant PK parameters was observed. The mean ratios of the AUC from time zero to the end of the dosing interval (AUC0-τ) for free CPT in soft tissues and the AUC0-τ for the calculated free fraction in plasma at steady state ranged from 0.66 to 0.75. Administration of CPT-F q8h led to higher levels of drug exposure in all investigated compartments. When MIC values above 1 mg/liter were assumed, the calculated fTMIC after dosing q12h was markedly lower than that after dosing q8h. The clinical implications of these differences are discussed in light of recently completed clinical phase III and PK/PD studies.

Influence of implantation on the electrochemical properties of smooth and porous TiN coatings for stimulation electrodes.

OBJECTIVE: To determine whether changes in electrochemical properties of porous titanium nitride (TiN) electrodes as a function of time after implantation are different from those of smooth TiN electrodes. APPROACH: Eight smooth and 8 porous TiN coated electrodes were implanted in 8 rats. Before implantation, voltage transients, cyclic voltammograms and impedance spectra were recorded in phosphate buffered saline (PBS). After implantation, these measurements were done weekly to investigate how smooth and porous electrodes were affected by implantation. MAIN RESULTS: The electrode capacitance of the porous TiN electrodes decreased more than the capacitance of the smooth electrodes due to acute implantation under fast measurement conditions (such as stimulation pulses). This indicates that protein adhesion presents a greater diffusion limitation for counter-ions for the porous than for the smooth electrodes. The changes in electrochemical properties during the implanted period were similar for smooth and porous TiN electrodes, indicating that cell adhesion poses a similar diffusion limitation for smooth and porous electrodes. SIGNIFICANCE: This knowledge can be used to optimize the porous structure of the TiN film, so that the effect of protein adhesion on the electrochemical properties is diminished. Alternatively, an additional coating could be applied on the porous TiN that would prevent or minimize protein adhesion.

In vitro release studies of insulin from lipid implants in solution and in a hydrogel matrix mimicking the subcutis.

Widely accepted in vitro methodologies for sustained release parenteral drug formulations remain to be established. Hydrogels have been proposed as a release matrix more closely resembling the in vivo conditions for formulations intended for subcutaneous administration. The perspective of the current work was to investigate the feasibility of developing UV imaging-based in vitro methods enabling visualization and characterization of drug release and transport of protein therapeutics intended for subcutaneous administration. Specifically, the objectives were to prepare lipid implants providing sustained release of the model protein insulin and investigate the release into 0.5% (w/v) agarose hydrogels, pH7.40, using UV imaging- and a gel sampling-based release testing method. These results were compared to insulin release into well agitated buffer solution. Irrespective of the applied in vitro release method, the insulin release from Sterotex implants with a drug load of 20% (w/w) was faster as compared to the release from implants with a load of 10% (w/w), most likely due to the higher porosity of the implants with increasing drug load. Insulin release from 10% (w/w) implants into agitated solution was faster as compared to release into agarose hydrogel. This was ascribed to the additional mass transfer resistance provided by the agarose hydrogel. Interestingly, the release profiles of insulin from implants with an initial drug load of 20% (w/w) obtained by the three in vitro methods were relatively similar. The gel-based methods, in particular UV imaging, enable monitoring local drug concentrations in the vicinity of the implant over time thereby facilitating assessment of, e.g., sink conditions. The study highlights that the selection of the in vitro release method should take into account various factors including mass transport, drug stability, data analysis and simplicity of the methodology.

Robust PBPK/PD-Based Model Predictive Control of Blood Glucose.

GOAL: Automated glucose control (AGC) has not yet reached the point where it can be applied clinically [3]. Challenges are accuracy of subcutaneous (SC) glucose sensors, physiological lag times, and both inter- and intraindividual variability. To address above issues, we developed a novel scheme for MPC that can be applied to AGC. RESULTS: An individualizable generic whole-body physiology-based pharmacokinetic and dynamics (PBPK/PD) model of the glucose, insulin, and glucagon metabolism has been used as the predictive kernel. The high level of mechanistic detail represented by the model takes full advantage of the potential of MPC and may make long-term prediction possible as it captures at least some relevant sources of variability [4]. Robustness against uncertainties was increased by a control cascade relying on proportional-integrative derivative-based offset control. The performance of this AGC scheme was evaluated in silico and retrospectively using data from clinical trials. This analysis revealed that our approach handles sensor noise with a MARD of 10%-14%, and model uncertainties and disturbances. CONCLUSION: The results suggest that PBPK/PD models are well suited for MPC in a glucose control setting, and that their predictive power in combination with the integrated database-driven (a priori individualizable) model framework will help overcome current challenges in the development of AGC systems. SIGNIFICANCE: This study provides a new, generic, and robust mechanistic approach to AGC using a PBPK platform with extensive a priori (database) knowledge for individualization.

Simple, Rapid Mycobacterium ulcerans Disease Diagnosis from Clinical Samples by Fluorescence of Mycolactone on Thin Layer Chromatography.

INTRODUCTION: Mycobacterium ulcerans infection, known as Buruli ulcer, is a disease of the skin and subcutaneous tissues which is an important but neglected tropical disease with its major impact in rural parts of West and Central Africa where facilities for diagnosis and management are poorly developed. We evaluated fluorescent thin layer chromatography (f-TLC) for detection of mycolactone in the laboratory using samples from patients with Buruli ulcer and patients with similar lesions that gave a negative result on PCR for the IS2404 repeat sequence of M. ulcerans. METHODOLOGY/PRINCIPAL FINDINGS: Mycolactone and DNA extracts from fine needle aspiration (FNA), swabs and biopsy specimen were used to determine the sensitivity and specificity of f-TLC when compared with PCR for the IS2404. For 71 IS2404 PCR positive and 28 PCR negative samples the sensitivity was 73.2% and specificity of 85.7% for f-TLC. The sensitivity was similar for swabs (73%), FNAs (75%) and biopsies (70%). CONCLUSIONS: We have shown that mycolactone can be detected from M. ulcerans infected skin tissue by f-TLC technique. The technique is simple, easy to perform and read with minimal costs. In this study it was undertaken by a member of the group from each endemic country. It is a potentially implementable tool at the district level after evaluation in larger field studies.

Automated On-Line Microdialysis Sampling Coupled with HPLC for Synchronous Determination of Puerarin in Subcutaneous Tissue and Plasma Following Topical Administration.

BACKGROUND: Studies on transdermal administration have shown that puerarin can permeate rat skin rapidly with long-term drug delivery, but there are no reports demonstrating whether topical use of puerarin can provide a steady plasma concentration to produce therapeutic effects. The aim of the study is to evaluate the percutaneous penetration and plasma concentration of puerarin after transdermal administration in experimental rats. METHODS: The skin and plasma concentration of puerarin was quantified by microdialysis, and the recovery was determined by retrodialysis. Puerarin microdialysate concentrations were measured by on-line high-performance liquid chromatography (HPLC). Puerarin release from gels was determined by analysis of the amount of remaining drug after dermal application to hairless skin. RESULTS: The average recoveries of puerarin in the skin and plasma over an 8-hour period were 31.49% and 15.5%. Puerarin was rapidly absorbed with transdermal administration, with the C(max) values of 30.64 µg/mL and 3.53 µg/mL, the AUC0 t-values of 11.60 and 1.48 µg/mL per minute, for skin and plasma, respectively. CONCLUSIONS: The results indicate that the automated on-line microdialysis technique can be used to detect the skin and plasma pharmacokinetics of puerarin and that the use of skin gel can provide an effective means of puerarin administration.

Population Pharmacokinetics and Target Attainment of Meropenem in Plasma and Tissue of Morbidly Obese Patients after Laparoscopic Intraperitoneal Surgery.

Meropenem serves as a clinically important, broad-spectrum antibiotic. While meropenem is commonly used in obese patients, its pharmacokinetics in this patient group is not well known. Our aim was to characterize the population pharmacokinetics and target attainment in plasma, subcutaneous tissue, and peritoneal fluid for meropenem in morbidly obese patients. Four doses of 1g meropenem were given as 15-min infusions every 8 h to five morbidly obese patients (body mass index [BMI], 47.6 to 62.3 kg/m(2)). After the fourth dose, serial meropenem concentrations were determined in plasma and, via microdialysis, in subcutaneous tissue and peritoneal fluid. All concentrations were analyzed simultaneously via population modeling, and target attainment probabilities predicted via Monte Carlo simulations using the target of unbound meropenem concentrations above the MIC for at least 40% of the dosing interval. For patients with 53 kg fat-free mass, total clearance was 18.7 liters/h and volume of distribution at steady state was 27.6 liters. The concentrations in subcutaneous tissue and peritoneal fluid largely paralleled those in plasma (equilibration half-life, <30 min). The area under the curve (AUC) in subcutaneous tissue divided by the plasma AUC had a mean of 0.721. For peritoneal fluid, this AUC ratio had a mean of 0.943. Target attainment probabilities were >90% after 1 g meropenem every 8 h as a 15-min infusion for MICs of up to 2 mg/liter in plasma and peritoneal fluid and 0.5 mg/liter in subcutaneous tissue. Meropenem pharmacokinetics in plasma and peritoneal fluid of obese patients was predictable, but subcutaneous tissue penetration varied greatly. (This study has been registered at ClinicalTrials.gov under registration no. NCT01407965.).

Fibrous hamartoma of infancy: a clinical pathological analysis of seventeen cases.

To discuss the clinical and pathological features, differential diagnosis and prognosis of fibrous hamartoma of infancy (FHI), seventeen FHI specimens were analyzed with H&E staining and strepavidin peroxidase (SP) immunohistochemistry to detect distinguishing tissue markers. The long-term outcomes of select cases were also obtained. Among the 17 patients (13 males, 4 females, average age 16 months), FHI manifested as a subcutaneous painless mass, primarily on the back of the neck, the upper arms and buttocks. One recurrence was noted among six follow-up cases. The tumors consisted of three main components: fibrous connective tissue; mature fat; and undifferentiated mesenchymal tissue. Immunohistochemistry revealed that fibrous connective tissue was positive for SMA and actin, mature fat tissue was positive for S-100 protein, and undifferentiated mesenchymal tissue was positive for CD34 and was partially positive for actin and SMA. The tumors were negative for desmin, NSE, bcl-2, ß-catenin and Ki-67. In brief, FHI is a benign, fibroblastic/myofibroblastic proliferative lesion. Defined histologic features of FHI as presented here would distinguish FHI from similar invasive tumors including infant fibromatosis, calcifying aponeurotic fibroma, fibrous fatty tumor and embryonal rhabdomyosarcoma. Once clearly identified, FHI is curable with complete resection.

Influence of sustained low-efficiency diafiltration (SLED-f) on interstitial fluid concentrations of fluconazole in a critically ill patient: Use of microdialysis.

Acute kidney injury is a common complication in critically ill patients, and hybrid techniques including sustained low-efficiency dialysis/diafiltration (SLED-f) are being increasingly utilised in intensive care units. Most fungal infections occur in the interstitial fluid (ISF) of tissues and successful treatment of a fungal infection relies on the ability of an antifungal agent to achieve adequate concentrations at the site of infection. Tissue distribution of antimicrobials is impaired in critically ill patients owing to a variety of disease-related physiological changes, e.g. sepsis. Fluconazole is a widely used antifungal agent used to treat Candida spp. infections in critically ill patients. The implications for ISF concentrations of enhanced elimination during renal replacement therapy have not yet been reported for fluconazole. The aim of this single-patient case report was to describe the influence of SLED-f on subcutaneous (SC) ISF concentrations of fluconazole and the implications for achieving pharmacokinetic/pharmacodynamic targets. Serial blood and ISF samples were collected at pre- and post-filter ports within the SLED-f circuit and subcutaneously inserted microdialysis probe, respectively. Fluconazole concentrations were measured using a validated chromatography method. The SC ISF-to-plasma partition coefficient of fluconazole in this patient was 0.91, indicating rapid equilibrium. SC ISF fluconazole concentrations consistently decreased after initiating SLED-f. The majority of the fluconazole was eliminated from the SC ISF as a result of redistribution. Considering the extensive tissue re-distribution of fluconazole and observed elimination from tissue compartments, higher doses may be required to treat deep-seated fungal infections.

Vancomycin serum concentrations do not adequately predict tissue exposure in diabetic patients with mild to moderate limb infections.

OBJECTIVES: Vancomycin is a common treatment for complicated skin and skin structure infections (cSSSIs) caused by MRSA. This analysis aimed to understand the variability of vancomycin tissue exposure at the site of infection. METHODS: Vancomycin serum and interstitial tissue fluid concentration data for nine patients with cSSSI and normal renal function were derived from an in vivo microdialysis study. Using Pmetrics, the non-parametric population modelling package for R, we co-modelled serum and tissue concentration data. A 5000-patient Monte Carlo simulation was conducted for 1 g of vancomycin every 12 h and every 8 h to calculate the penetration distribution (AUCtissue/fAUCserum) and probability of target attainment (PTA) at an fAUC/MIC target of ≥200 in tissue fluid. RESULTS: A three-compartment model fitted the data best. The mean (SD) and median penetration ratios into tissue of the simulated population were 1.91 (4.56) and 0.85, respectively, which were consistent with observed values in the original patients. PTAs for 1 g of vancomycin every 12 h and every 8 h in tissue fluid were 39.6% and 56.6% at an MIC of 1 mg/L. Serum trough concentrations (R(2) = 0.06) and serum AUC exposure (R(2) = 0.002) were poor predictors of vancomycin AUC tissue exposure. CONCLUSIONS: Standard dosages of vancomycin provide a low likelihood of obtaining target pharmacodynamic exposure in the tissue of a lower limb infection. This low likelihood is due to wide variability in vancomycin penetration in the interstitial tissue fluid, which could not be predicted by serum concentrations.