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An electronic survey on substance-induced epileptic crisis was conducted in order to investigate whether doctors, who recognise their own prescription errors, increase their therapeutic aggressiveness, resulting in a so-called "iatrogenicity cascade". Two pairs of clinical vignettes were constructed, in which a patient suffers from iatrogenic (original version) or non-iatrogenic (control version) epileptic crisis. Vignettes were randomised and sent to doctors at the University Hospital of Lausanne, Switzerland, at an interval of 3 weeks. The results of the present survey in the surveyed population of doctors suggest that inappropriate prescription does not increase therapeutic aggressiveness.

The antimicrobial spectrum of clarithromycin renders this antibiotic a frequently used option in the treatment of skin and soft-tissue infections. In most cases, these infections are caused by extracellularly proliferating microorganisms. Thus, clarithromycin concentrations achieved in the interstitial space are considered particularly important for clinical efficacy. In the present study, clarithromycin concentrations in plasma and interstitial-space fluid of subcutaneous adipose tissue and skeletal muscle of six healthy male volunteers were assessed by means of the microdialysis technique after oral single-dose administration of 250 mg and multiple doses of 500 mg of clarithromycin twice a day (b.i.d.). The ratios of the area under the concentration-time curve of free clarithromycin from 0 to 24 h calculated for a single dose of 250 mg ( f AUC 0-24 ) in interstitial-space fluid to the f AUC 0-24 in plasma were 0.29 ± 0.17 and 0.42 ± 0.18 for subcutis and skeletal muscle, respectively. For 500 mg of clarithromycin at the steady state (3 to 5 days of intake twice daily), the f AUC 0-24(b.i.d.) ratios at the steady state were 0.39 ± 0.04 and 0.41 ± 0.19 for subcutis and skeletal muscle, respectively. The half-life was around 2 h after a single dose but increased to approximately 4 h in plasma and tissues after repetitive clarithromycin administration. Based on subsequently performed pharmacokinetic-pharmacodynamic calculations, a dosing regimen of 500 mg b.i.d. may be ineffective in the treatment of soft-tissue infections caused by pathogens with a drug MIC higher than 0.125 mg/liter.

Conclusion: The present study investigated the usefulness of routinely employed scoring systems in predicting tissue penetration of antimicrobials. In addition, a novel, easy to use scoring system was designed for the estimation of tissue penetration of antimicrobials in patients with sepsis. Methods: Tissue pharmacokinetics were assessed in skeletal muscle and subcutaneous adipose tissue by use of the microdialysis technique in 34 patients with sepsis. Tissue penetration of antimicrobials was retrospectively determined by the ratios of the area under the concentration-time curves (AUC) in soft tissues (AUCtissue) to the AUC in plasma (AUCplasma). Mortality and sepsis scores currently used in intensive care were consecutively calculated and correlated with the AUCtissue: AUCplasma ratio. Single laboratory and clinical parameters showing the highest correlation with tissue penetration were identified and used in the novel Tissue Penetration Prediction Score (TPPS). Results: The currently used scoring systems Simplified Acute Physiology Scores 3 (r = −0.33, p = 0.006), Acute Physiology and Chronic Health Evaluation III (r = −0.27, p = 0.03) and Sepsis-Related (or Sequential) Organ Failure Assessment (r = −0.32, p = 0.01) showed significant overall correlations with tissue penetration. However, their predictive power for the concentrations of antimicrobials in muscle tissue was not satisfying. The parameters oxygen saturation, serum lactate concentration and the dose per time unit of norepinephrine (noradrenaline) administered showed the best correlation with tissue penetration and were used in the TPPS. Its overall correlation (r = −0.52, p = 0.000007) as well as correlations for the concentrations of antimicrobials in muscle (r = −0.46, p = 0.006) and adipose tissue (r = −0.59, p = 0.0003) were better than the currently used scoring systems. Conclusion: The TPPS may prove to be a powerful tool for the estimation of antimicrobial tissue penetration at the bedside in septic patients. This score may allow for adequate individual dose adjustment in septic patients. However, this needs to be verified in subsequent prospective clinical trials.

Background: NSAIDs are associated with a risk of lower GI bleeding and perforation similar to that seen in the upper GI tract. Being a pH-dependent phenomenon, the incidence of upper GI injury can be reduced by PPIs, which not only do not prevent NSAID-enteropathy, but might actually aggravate it. Several lines of evidence (both experimental and clinical) implicate commensal enterobacteria in the pathogenesis of NSAID-associated intestinal lesions and suggest that luminal bacteria represent a potential target for prevention and/or treatment. Aims: To evaluate the efficacy of a delayed-release formulation of rifaximin [Rifaximin-Extended Intestinal Release (EIR)], a poorly absorbed antibiotic with a broad spectrum of antibacterial activity (including Gram-positive and Gram-negative bacteria, both aerobes and anaerobes) in the prevention of NSAID-associated lesions, evaluated by videocapsule endoscopy (VCE). Methods: In this phase IIa study (EudraCT Number 2013000730-36), healthy volunteers were randomized to receive diclofenac SR 75 mg BID plus omeprazole 20 mg OD and either Rifaximin-EIR 800 mg or matching placebo BID for 14 days, in a double-blind fashion. VCE was performed at baseline and after treatment to assess intestinal injury. The primary endpoint of the study was the proportion of subjects developing at least one mucosal lesion, defined as erosion or ulcer, in the small bowel at final VCE. Secondary endpoints were the change from baseline to final VCE in the mean number of mucosal lesions (with and without hemorrhage) and the number of subjects with large erosions and/or ulcers at the end of treatment. Data from all randomized subjects, who received at least one dose of study medication and who successfully completed the final VCE, were analyzed. Safety data from all randomized subjects, who received at least one rifaximin dose, were also evaluated. Logistic regression analysis and McNemar Chi-Square test were used for "between groups" comparison of the primary and secondary endpoints. Results: 60 subjects (median age 26 years, 42% female) were randomized to rifaximin or placebo (30 per group). Findings concerning primary and secondary end-points are summarized in the enclosed Table. The number of adverse events observed after rifaximin (14/30) was not significant different from that seen after placebo (18/30). Conclusions: The efficacy on primary end-point fell just short off statistical significance, but went significant when sensitivity analysis, using age as covariate, was done. In addition, both secondary end-points were successfully reached in the study. As a consequence, this proof-of-concept study showed an overall protective effect of rifaximin on diclofenac-associated mucosal lesions. Support: This study was supported by Alfa Wassermann SpA, Bologna, Italy. Primary and Secondary End-points of the Study

Recent observations indicate that pharmacokinetics of beta-lactam antibiotics in the lung can be predicted by the use of concentration versus time profiles in peripheral soft tissues. If this observation is transferred to other classes of antimicrobials, measurement of antimicrobial concentrations in peripheral tissues would enable prediction of the pharmacokinetics of antimicrobials at the site of the respiratory tract infection. We set out to test the hypothesis that concentrations of the fluoroquinolone levofloxacin in the respiratory tract can be predicted on the basis of knowledge of its pharmacokinetics in peripheral soft tissues. After administration of a single intravenous dose of 500mg of levofloxacin, microdialysis was used to describe the concentration versus time profiles of levofloxacin in the interstitial space fluid of lung tissue of patients (n=5) undergoing elective lung surgery. These data were compared with the concentration versus time courses in the interstitial space fluid of skeletal muscle and subcutaneous adipose tissue of healthy volunteers (n=7). The median AUC(0-infinity) of free levofloxacin in lung (2267mg x min/L, 1980-2355) was about 2-fold and 1.5-fold lower compared with skeletal muscle (4381mg x min/L, range 1720-8195) and adipose tissue (3492mg x min/L, range 1323-6420) of healthy controls, respectively. Concentrations in the interstitial space fluid of the lung were descriptively lower compared with corresponding concentrations in peripheral soft tissues. This is in contrast to previous observations made for the class of beta-lactam antibiotics, and indicates that pharmacokinetics of levofloxacin derived from soft tissues may not be used uncritically for prediction of levofloxacin concentrations in the interstitium of the lung.

Objectives: Dosage recommendations for fosfomycin are available for haemodialysed patients but there are no data for patients undergoing continuous renal replacement therapy. Therefore, the present study was designed to determine the concentration-versus-time profile of fosfomycin in continuous venovenous haemofiltration (CVVH). Patients and methods: A total of 12 anuric intensive care patients (10 males and 2 females) with suspected or proven infection requiring parenteral antibiotic therapy were included in the study. All patients underwent CVVH. Blood samples were drawn from the arterial (input) and venous (output) line of the extracorporeal circuit after application of a single dose of 8 g of fosfomycin. Ultrafiltration samples were collected from the outlet of the ultrafiltrate compartment of the haemofilter. Fosfomycin in the samples was quantified by gas chromatography. Results: The peak serum concentration was 442.7 ± 124 mg/L at the arterial port. The trough serum level was 103.1 ± 36.6 mg/L at the arterial port after 720 min. The mean value of the area under the concentration-versus-time curve from 0 to 12 h (AUC 0-12 ) was 2159.4 ± 609.8 mg·h/L. Mean total removal of the drug was 76.7 ± 6.2%. The mean calculated clearance was 1.1 ± 0.2 L/h for CL HF . Mean CL tot was 6.4 ± 7.7 L/h. Conclusions: A regimen of 8.0 g of fosfomycin every 12 h, which is usually used in patients with intact renal function, should be an appropriate antimicrobial treatment for patients undergoing CVVH.

In vivo measurement of concentrations of drugs and endogenous substances at the site of action has become a primary focus of research. In this context the minimal invasive microdialysis (MD) technique has been increasingly employed for the determination of pharmacokinetics in lung. Although lung MD is frequently employed to investigate various drugs and endogenous substances, the majority of lung MD studies were performed to determine the pharmacokinetic profile of antimicrobials that can be related to the importance of respiratory tract infections. For the lower respiratory tract various methods, such as surgical collection of whole lung tissue and bonchoalveolar lavage (BAL), are currently available for the determination of pharmacokinetics of antimicrobials. Head-to-head comparison of pharmacokinetics of antibiotics in lung revealed high differences between MD and conventional methods. MD might be regarded as a more advantageous approach because of its higher anatomical resolution and the ability to obtain dynamic time-vs-concentration profiles within one subject. However, due to ethical objections lung MD is limited to animals or patients undergoing elective thoracic surgery. From these studies it was speculated that the concentrations in healthy lung tissue may be predicted reasonably by the measurement of concentrations in skeletal muscle tissue. However, until now this was only demonstrated for beta-lactam antibiotics and needs to be confirmed for other classes of antimicrobials. In conclusion, the present review shows that MD is a promising method for the determination of antimicrobials in the lung, but might also be applicable for measuring a wide range of other drugs and for the investigation of metabolism in the lower respiratory tract.

Because many drugs possess an intracellular site of action, the knowledge of intracellular concentration-time profiles is desirable. In the present study, PET, which measures total (i.e., intracellular, extracellular, and intravascular) concentrations of radiolabeled drugs in tissue, and microdialysis, which determines unbound drug concentrations in the extracellular space fluid of tissue, were combined to describe the intracellular pharmacokinetics of a model compound--that is, the (18)F-labeled antibiotic (18)F-ciprofloxacin--in vivo in humans.Ten healthy male volunteers received a mixture of 687 +/- 50 MBq of (18)F-ciprofloxacin and 200 mg of unlabeled ciprofloxacin as an intravenous bolus infusion over 10 min. The pharmacokinetics of ciprofloxacin in skeletal muscle tissue were assessed by means of combined PET and in vivo microdialysis for 5 h after drug administration. A 3-compartment pharmacokinetic model was fitted to the tissue concentration-time profiles of ciprofloxacin measured by PET to estimate the rate constants of ciprofloxacin uptake and transport.In muscle tissue, mean total and extracellular peak concentration (C(max)) values of ciprofloxacin of 1.8 +/- 0.4 microg/mL and 0.7 +/- 0.2 microg/mL were attained at 95 +/- 34 min and 48 +/- 20 min after drug administration, respectively. The extracellular-to-intracellular exchange appeared to be very fast, with an estimated rate constant k(3) of 1.69 +/- 0.25 min(-1). An intracellular-to-extracellular concentration ratio (C(intra)/C(extra)) of 3.2 +/- 0.8 was reached at 110 min after injection and followed by sustained intracellular retention of the antibiotic for the remainder of the experiment. The predicted extracellular concentration-time profiles from the compartmental modeling were in good agreement with the measured microdialysis data.The results obtained in the present study were in accordance with previous in vitro data describing cellular ciprofloxacin uptake and retention. The presently used PET/microdialysis combination might be useful during research and development of new drugs, for which knowledge of intracellular concentrations is of interest.

The present study tested the ability of linezolid to penetrate soft tissues in healthy volunteers. Ten healthy volunteers were subjected to linezolid drug intake at a dose of 600 mg twice a day for 3 to 5 days. The first dose was administered intravenously. All following doses were self-administered orally. The tissue penetration of linezolid was assessed by use of in vivo microdialysis. In the single-dose experiments the ratios of the area under the concentration-time curve from 0 to 8 h (AUC 0-8 ) for tissue to the AUC 0-8 for free plasma were 1.4 ± 0.3 (mean ± standard deviation) and 1.3 ± 0.4 for subcutaneous adipose and muscle tissue, respectively. After multiple doses, the corresponding mean ratios were 0.9 ± 0.2 and 1.0 ± 0.5, respectively. The ratios of the AUC from 0 to 24 h (AUC 0-24 ) for free linezolid in tissues to the MIC were between 50 and 100 for target pathogens with MICs between 2 and 4 mg/liter. In conclusion, the present study showed that linezolid penetrates rapidly into the interstitial space fluid of subcutaneous adipose and skeletal muscle tissues in healthy volunteers. On the basis of pharmacokinetic-pharmacodynamic calculations, we suggest that linezolid concentrations in soft tissues can be considered sufficient to inhibit the growth of many clinically relevant bacteria.

A high-performance liquid chromatography method for the quantitative determination of telithromycin in biological fluids is described. The method is suitable for plasma and microdialysates from the interstitial space fluid of skeletal muscle and subcutaneous adipose tissue. Plasma samples were deproteinised with trichloroacetic acid and neutralised with sodium hydroxide. Microdialysates were analysed without further preparation step. Telithromycin was separated isocratically on a reverse-phase column using acetonitrile-0.03 M ammonium acetate, pH 5.2 (43:57, v/v) at a flow rate of 0.8 mlmin(-1), and fluorescence detection (excitation 263 nm, emission 460 nm). The calibration curve was linear from 0.01 to 5 microgml(-1). Within- and between-day imprecision and inaccuracy was < or =10%. The limits of quantification were 0.02 and 0.015 microgml(-1) for plasma and microdialysates, respectively. Since telithromycin is decomposed in aqueous solution at ambient temperature, it is strongly recommended to store samples frozen at -80 degrees C, to maintain the temperature at 4 degrees C during all preparation steps, and to analyse samples within 120 min after thawing.

By use of microdialysis we assessed the concentrations of telithromycin in muscle and adipose tissue to test its ability to penetrate soft tissues. The ratios of the area under the concentration-versus-time curve from 0 to 24 h to the MIC indicated that free concentrations of telithromycin in tissue and plasma might be effective against Streptococcus pyogenes but not against staphylococci and human and animal bite pathogens.

Plasma protein binding (PPB) is known to impair the antimicrobial activity of beta-lactams, but its impact on the activity of other classes of antimicrobials such as fluoroquinolones is controversial. This study was undertaken to investigate the effect of PPB on bacterial killing by selected antibiotics and moxifloxacin, which served as a model compound for the class of fluoroquinolones.Bacterial time-killing curves were employed in the absence and presence of physiological albumin concentrations (40 g/L). Moxifloxacin, ampicillin and oxacillin were investigated. Fosfomycin, a non-protein bound antibiotic was used for comparison. Simulations were carried out by employing concentrations of antibiotics of one-fourth of the minimal inhibitory concentration (MIC), equal to the MIC and four-fold the MIC of one select bacterial strain (Staphylococcus aureus ATCC 29213). To correlate bacterial killing to the extent of PPB, bacterial time-killing curves were plotted using the calculated free and the total drug concentration.Bacterial killing by fosfomycin was not affected by the addition of albumin. The antimicrobial activity of oxacillin and ampicillin was reduced in the presence of albumin as expected by the calculation of the free fraction of these antibiotics. Adding albumin to moxifloxacin resulted in a significant decrease in bacterial killing of more than 1 log10 cfu/mL after a period of 8 h when the moxifloxacin concentration was equal to the respective MIC.Our data confirm the view that albumin substantially impairs the antimicrobial activity of antibiotics including moxifloxacin, a member of the class of fluoroquinolones.

Aims The present study addressed the ability of levofloxacin to penetrate into subcutaneous adipose tissues in patients with soft tissue infection. Methods Tissue concentrations of levofloxacin in inflamed and healthy subcutaneous adipose tissue were measured in six patients by microdialysis after administration of a single intravenous dose of 500 mg. Levofloxacin was assayed by high-performance liquid chromatography. Results The mean concentration vs time profile of free levofloxacin in plasma was identical to that in inflamed and healthy tissues. The ratios of the mean area under the free levofloxacin concentration vs time curve from 0 to 10 h (AUC(0,10 h)) in tissue to that in plasma were 1.2 ± 1.0 for inflamed and 1.1 ± 0.6 for healthy subcutaneous adipose tissue (mean ± SD). The mean difference in the ratio of the AUCtissue : AUCplasma for inflamed and healthy tissue was 0.09 (95% confidence interval −0.58, 0.759, P > 0.05). Interindividual variability in tissue penetration was high, as indicated by a coefficient of variation of approximately 82% for AUCtissue : AUCplasma ratios. Conclusions The penetration of levofloxacin into tissue appears to be unaffected by local inflammation. Our plasma and tissue data suggest that an intravenous dose of 500 mg levofloxacin provides effective antibacterial concentrations at the target site. However, in treatment resistant patients, tissue concentrations may be sub-therapeutic.

The present study was performed to test the ability of fosfomycin to penetrate into the CSF of neurointensive care patients with ventriculostomy-associated ventriculitis.Six patients requiring neurointensive care monitoring, including extraventricular drainage due to secondary obstructive hydrocephalus, were enrolled into the study. All patients received 8 g of fosfomycin intravenously three times a day over a period of at least 5 days. Concentrations of fosfomycin in the CSF and plasma were measured after single-dose administration and at steady state.Mean values of the fosfomycin area under the time-concentration curves for the dosing interval of 8 h (AUC(8)) were 929 +/- 280 and 225 +/- 131 mg.h/L for plasma and CSF after single-dose administration, respectively (P0.03). The ratios of the AUC(8) for CSF to the AUC(8) for plasma were 0.23 +/- 0.07 after a single dose and 0.27 +/- 0.08 following multiple doses (P0.05, not significant). Additional in vitro experiments have shown that fosfomycin exerts non-concentration-dependent microbial growth inhibition. At steady state, the time above MIC (tMIC) values were 98%, 92% and 61% for pathogens with MIC values of 8, 16 and 32 mg/L, respectively.The present pharmacokinetic study indicates that 8 g of fosfomycin three times per day should provide sufficient antimicrobial concentrations in the CSF for the overall treatment period. Thus, the co-administration of fosfomycin could be useful for the treatment of ventriculitis caused by susceptible pathogens.

Because of fatal cases of rhabdomyolysis the HMG-CoA-reductase inhibitor cerivastatin had to be withdrawn from the global market in 2001. The high frequency and severity of cerivastatin-associated rhabdomyolysis caused concerns about the safety of the entire class of HMG-CoA-reductase inhibitors (statins). Still, the frequency of deadly incidents of rhabdomyolysis with cerivastatin was 16 to 80 times higher than with other statins. This seems to be due to a combination of several pharmacokinetic and pharmacodynamic characteristics of cerivastatin. Cerivastatin shows the highest oral bioavailability within its class. Interactions with other drugs like gemfibrocil may cause further elevation of cerivastatin plasma levels, thereby leading to higher frequencies of side effects in peripheral organs. With approximately 1 pM cerivastatin shows the lowest IC50 for inhibition of HMG-CoA-reductase of all statins. The combination of high systemic drug levels and high intrinsic activity potentially leads to apoptosis and energy-depletion of skeletal-muscle cells. Therefore cerivastatin-associated fatal rhabdomyolysis seems to be based on specific pharmacokinetic and pharmacodynamic properties of cerivastatin, and is not a general characteristic of all members of this drug-class. The experiences with cerivastatin support the importance of clinical studies even about well established drugs, and underline the relevance of precise reporting of adverse events by each physician.

We employed an in-vivo pharmacokinetic/in-vitro pharmacodynamic method to simulate bacterial killing in plasma and the interstitium of skeletal muscle tissue after intravenous administration of 2 g of cefpirome and 8 g of fosfomycin alone and in combination to patients with sepsis. Interstitial antimicrobial concentrations were determined by use of in-vivo microdialysis. CFU/ ml of Staphylococcus aureus (ATCC 29213) and Pseudomonas aeruginosa (clinical isolate) decreased by approximately 2 log10 for plasma and muscle tissue 6 h after cefpirome and fosfomycin administration compared with the baseline, respectively. The simulation of plasma and tissue pharmacokinetics for the combined administration of these antibiotics resulted in complete eradication of S. aureus within 5 h after drug exposure. No bacterial re-growth occurred in any of the simulations within 6 h. The invitro simulation of in-vivo plasma and tissue pharmacokinetics of cefpirome and fosfomycin has shown that both antimicrobial agents kill S. aureus and P. aeruginosa strains effectively after single dose administration. This effect was most pronounced by the combined use of these antimicrobial agents. Therefore, this data corroborates antimicrobial strategies of simultaneous administration of cefpirome and fosfomycin in patients with severe soft tissue infection. # 2003 Elsevier Science B.V. and the International Society of Chemotherapy. All rights reserved.

To characterize the potential of ciprofloxacin penetration into human soft tissues following intravenous (i.v.) and oral (p.o.) administration, we measured the free ciprofloxacin concentrations in interstitial space fluid of skeletal muscle and subcutaneous adipose tissue by microdialysis. In addition, ciprofloxacin concentrations were measured in cantharis-induced skin blisters, saliva, and capillary plasma and were compared to the total concentrations in venous plasma. Furthermore, a pharmacodynamic in vitro model was used to simulate in vivo pharmacokinetics in bacterial culture. Eight healthy volunteers received ciprofloxacin in an open randomized crossover fashion either as a single i.v. infusion of 400 mg over 60 min or as a single p.o. dose of 500 mg. For both tissues the mean areas under the concentration-time curves (AUCs) for interstitial space fluid (AUC interstitial fluid s) were significantly lower than the corresponding AUC plasma s, with AUC interstitial fluid /AUC plasma ratios ranging from 0.38 to 0.68. For skeletal muscle, the AUC interstitial fluid was significantly higher after administration of 400 mg i.v. than after administration of 500 mg p.o., with a ratio of the AUC after p.o. administration/AUC after i.v. administration of 0.64. The ratio of the concentration in skeletal muscle/concentration in plasma increased over the entire observation period, implying that ciprofloxacin concentrations were not at steady state. The ratio of the concentration in skin blister fluid/concentration in plasma reached values above 4, indicating a preferential penetration of ciprofloxacin into inflamed lesions. The concentrations in saliva and capillary blood were similar to the corresponding total levels in plasma. In vitro both in vivo ciprofloxacin concentration-time profiles were equally effective against select bacterial strains. In conclusion, single-dose administration of two bioequivalent dosage forms of ciprofloxacin might lead to differences in target site pharmacokinetics. These differences, however, are not related to a difference in target site pharmacodynamics.

Echinococcosis is caused by the ingestion of eggs of the dog tapeworm or fox tapeworm belonging to the genus Echinococcus . E. granulosus causes considerable human morbidity and mortality, with the highest prevalence in rural areas because of close co-habitation of humans, animal intermediate hosts, and final hosts. Oncospheres migrate after ingestion to different organs and form cysts most commonly located in the liver (60–70%) and lungs (20%). Other localizations of cysts, including the kidney, spleen, muscles, bone, pancreas, central nervous system, and soft tissue, have been described but are less common. 1–3 Treatment recommendations for E. granulosus cysts include long-term therapy with albendazole alone or in combination with praziquantel, percutaneous drainage, and surgical removal of the lesions. 4–6 Albendazole is a benzimidazole derivative and is highly active against echinococcal protoscolices. However, the in vivo therapeutic response is limited by its low and erratic bioavailability. 7–10 Nevertheless albendazole is the most commonly used drug for pre- and post-operative anthelminthic treatment and continued suppressive therapy of inoperable hydatid cysts. 11 On the background of its variable absorption, the penetration of albendazole and its active metabolite albendazole sulphoxide into cysts is of major importance for adequate in vivo activity. Whereas limited data are available for Echinococcus cysts of the liver, little is known about the intra-cystic concentrations of albendazole in patients treated for echinococcal cysts located in other organs than the liver. In this study, we aimed to assess the ability of albendazole and its active metabolite albendazole sulphoxide to penetrate into E. granulosus cysts of two patients with nonliver cysts. A 60-year-old women of Turkish origin (Patient A) residing in Austria for > 5 years was diagnosed with a painless tumor on the left thigh, which became noticeable after voluntary weight loss of 25 kg. The second patient (Patient B), a 30-yearold Turkish citizen, presented at the hospital with progressive cough, night sweats, and dyspnea. Inflammation markers were increased in both patients, with C-reactive protein at 8.7 and 2.4 mg/dL for Patients A and B, respectively (normal range, < 1 mg/dL). Marked eosinophilia was recorded (550 and 3,020/µL blood for Patients A and B, respectively ) in differential blood count, and serologic investigation by enzyme-linked immunosorbent assay and Western blot confirmed the diagnosis of E. granulosus infection. Computer tomography and magnetic resonance imaging showed a cystic lesion in the proximal Musculus satorius of 7.5 cm diameter in Patient A. Patient B had a distinctive pleural effusion on the right side of the lung with transgression of the diaphragm. Following current treatment recommendations, patients were prescribed 400 mg albendazole to be taken twice daily with a fatty meal for 5 and 4 days before surgical removal, respectively. 12

Background Recently, differences in development of bacterial resistance were observed for macrolides with short and long elimination half life. Although one might speculate that this observation is to be explained by prolonged subinhibitory concentrations at the site of bacterial dwelling, the pharmacokinetic (PK) confirmation of this theory is missing. Thus we set out to compare PK of azithromycin and erythromycin in plasma, polymorphonuclear leukocytes (PML) and interstitial space fluid (ISF) of soft tissues.

Background Positron emission tomography (PET) with the radiolabelled substrate of the multidrug efflux transporter Pglycoprotein (P-gp) (R)-[C]verapamil (VPM) can be used to assess P-gp function at the blood-brain barrier (BBB). We have shown in rats that performing VPM PET scans after half-maximum inhibition of P-gp with the third-generation P-gp inhibitor tariquidar (TQD) is more sensitive for detecting regional differences in cerebral P-gp function than VPM baseline scans [1]. In order to translate this concept to humans a detailed understanding of the dose-response relationship of TQD for inhibition of P-gp at the human BBB is required.

Here, we report on the outcome of the 2nd International Danube Symposium on advanced biomarker development that was held in Vienna, Austria, in early 2018. During the meeting, cross-speciality participants assessed critical aspects of non-invasive, quantitative biomarker development in view of the need to expand our understanding of disease mechanisms and the definition of appropriate strategies both for molecular diagnostics and personalised therapies. More specifically, panelists addressed the main topics, including the current status of disease characterisation by means of non-invasive imaging, histopathology and liquid biopsies as well as strategies of gaining new understanding of disease formation, modulation and plasticity to large-scale molecular imaging as well as integrative multi-platform approaches. Highlights of the 2018 meeting included dedicated sessions on non-invasive disease characterisation, development of disease and therapeutic tailored biomarkers, standardisation and quality measures in biospecimens, new therapeutic approaches and socio-economic challenges of biomarker developments. The scientific programme was accompanied by a roundtable discussion on identification and implementation of sustainable strategies to address the educational needs in the rapidly evolving field of molecular diagnostics. The central theme that emanated from the 2nd Donau Symposium was the importance of the conceptualisation and implementation of a convergent approach towards a disease characterisation beyond lesion-counting “lumpology” for a cost-effective and patient-centric diagnosis, therapy planning, guidance and monitoring. This involves a judicious choice of diagnostic means, the adoption of clinical decision support systems and, above all, a new way of communication involving all stakeholders across modalities and specialities. Moreover, complex diseases require a comprehensive diagnosis by converging parameters from different disciplines, which will finally yield to a precise therapeutic guidance and outcome prediction. While it is attractive to focus on technical advances alone, it is important to develop a patient-centric approach, thus asking “What can we do with our expertise to help patients?” ISSN:1860-2002 ISSN:1536-1632

Results At incision performed 158 ± 112 min after administration, cefpirome concentrations in abscess ranged from below the limit of quantification to 47 mg/L (8.4 ± 14.1 mg/L), and moxifloxacin concentrations ranged from below the limit of quantification to 9.2 mg/L (1.9 ± 3.4 mg/L). Relative to plasma, abscess concentrations of moxifloxacin were significantly higher than of cefpirome (p = 0.037). Inhibitory concentrations of both antibiotics reported for abscess-relevant bacterial species were reached in several, but not in all abscess observations. Antibiotic abscess penetration could not be adequately explained considering covariates such as pH of abscess fluid, or the ratio of surface area to volume of abscesses, linked to plasma pharmacokinetics.

The present in vitro study set out to determine for the first time the continuous venovenous hemofiltration (CVVH) clearance of the novel lipopetide antibiotic, daptomycin, from human whole blood. Factors influencing daptomycin sieving and membrane adsorption were investigated in an in vitro setting. A recirculation model was established and daptomycin was added to the simulated blood circuit at different concentrations and in different solvent systems. The concentration of daptomycin over time in the modelled blood compartment and in ultrafiltrate was measured by HPLC. Mean sieving coefficients (SCs) of daptomycin over time were 1 ± 0.05, 0.3 ± 0.02 and 0.4 ± 0.03 in Ringer lactate, Ringer lactate containing human albumin and plasma, respectively. The CVVH clearance of daptomycin from whole blood exceeded the physiological clearance in an individual with normal renal function. Adsorption of daptomycin to synthetic surfaces proved moderate, resulting in loss of around 20% of the initial dose at 1 hour after the start of CVVH. Since mean SCs of daptomycin in protein-containing media were higher than the free fraction in plasma, our results suggest that besides protein binding, unknown factors such as intracellular drug partitioning influence sieving of daptomycin during hemofiltration. Due to the high in vitro CVVH clearance of daptomycin we determined from human whole blood, we recommend monitoring of daptomycin concentrations in patients undergoing hemofiltration. from 13th Scientific Symposium of the Austrian Pharmacological Society (APHAR). Joint Meeting with the Austrian Society of Toxicology (ASTOX) and the Hungarian Society for Experimental and Clinical Pharmacology (MFT) Vienna, Austria. 22–24 November 2007

Methods Time-kill curves of daptomycin, doripenem, linezolid, moxifloxacin, and tigecycline were determined for Staphylococcus aureus ATCC 29213 and of colistin, doripenem and moxifloxacin for a clinical isolate of Pseudomonas aeruginosa at concentrations above or equal to the respective MICs. All experiments were performed over 24 h in Mueller-Hinton broth (MHB) and in MHB enriched with porcine surfactant at a concentration of 1 mg/mL (MHBsurf).

Methods Urine obtained from healthy volunteers was pooled and sterile filtered. Microdilution tests were performed with Escherichia coli ATCC 25922 in MHB and human urine. The pH of urine was adjusted to values ranging from 5 to 8. For simulating different glucose levels in urine of diabetic patients, urine was adjusted to glucose levels of 100 and 1000 mg/dL. Bacterial growth in different media was investigated by growth curves. Results obtained from MIC testing were confirmed by use of bacterial killing curves. Klebsiella oxytoca ATCC 700324 was used to investigate transferability of finding to other strains. Each experiment was performed 5 times.

Background The pan-European VACCELERATE network aims to implement the first transnational harmonized and sustainable vaccine trial Volunteer Registry, being a single entry point for potential volunteers of large-scale vaccine trials across Europe. This work exhibits a set of harmonized vaccine trial–related educational and promotional tools for the general public, designed and disseminated by the pan-European VACCELERATE network. Objective This study primarily aimed to design and develop a standard toolkit to increase positive attitudes and access to trustworthy information for better access and increased recruitment to vaccine trials for the public. More specifically, the produced tools are focused on inclusiveness and equity, and are targeting different population groups, including underserved ones, as potential volunteers for the VACCELERATE Volunteer Registry (older individuals, migrants, children, and adolescents). The promotional and educational material is aligned with the main objectives of the Volunteer Registry to increase public literacy and awareness regarding vaccine-related clinical research or trials and trial participation, including informed consent and legal issues, side effects, and frequently asked questions regarding vaccine trial design. Methods Tools were developed per the aims and principles of the VACCELERATE project, focusing on trial inclusiveness and equity, and are adjusted to local country-wise requirements to improve public health communication. The produced tools are selected based on the cognitive theory, inclusiveness, and equity of differently aged and underrepresented groups, and standardized material from several official trustworthy sources (eg, COVID-19 Vaccines Global Access; the European Centre for Disease Prevention and Control; the European Patients’ Academy on Therapeutic Innovation; Gavi, the Vaccine Alliance; and the World Health Organization). A team of multidisciplinary specialists (infectious diseases, vaccine research, medicine, and education) edited and reviewed the subtitles and scripts of the educational videos, extended brochures, interactive cards, and puzzles. Graphic designers selected the color palette, audio settings, and dubbing for the video story-tales and implemented QR codes. Results This study presents the first set of harmonized promotional and educational materials and tools (ie, educational cards, educational and promotional videos, extended brochures, flyers, posters, and puzzles) for vaccine clinical research (eg, COVID-19 vaccines). These tools inform the public about possible benefits and disadvantages of trial participation and build confidence among participants about the safety and efficacy of COVID-19 vaccines and the health care system. This material has been translated into several languages and is intended to be freely and easily accessible to facilitate dissemination among VACCELERATE network participant countries and the European and global scientific, industrial, and public community. Conclusions The produced material could help fill knowledge gaps of health care personnel, providing the appropriate future patient education for vaccine trials, and tackling vaccine hesitancy and parents’ concerns for potential participation of children in vaccine trials.