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Zusammenfassung Hintergrund Vor dem Hintergrund einer stetig zunehmenden Gesundheitsgefährdung durch multiresistente Erreger spielt neben der Bevölkerungsaufklärung, der Fachkenntnis und der Fortbildung der Ärztinnen und Ärzte auch deren Selbstsicherheit eine Schlüsselrolle in der klinischen Entscheidungsfindung. Ziel der Arbeit Die Analyse soll den Einfluss der Fachrichtung auf Unterschiede der Selbstsicherheit im Umgang mit Antibiotika und in der Selbsteinschätzung des eigenen Wissens untersuchen. Methodik Im Jahr 2015 wurden 1061 Ärztinnen und Ärzte der Fachrichtungen Innere Medizin, Allgemeinchirurgie, Gynäkologie und Urologie mithilfe des MR2 (Multiinstitutional Reconnaissance of practice with MultiResistant bacteria)-Surveys über ihre Einstellung und ihr Wissen zu Antibiotika und multiresistenten Erregern befragt. Ein ähnlicher Fragebogen wurde 2017 an 1268 Ärzte der Anästhesiologie versendet. Es wurden vier Fragen zur eigenen Sicherheit in der Anwendung von Antibiotika und elf Fragen zur Einschätzung des eigenen Wissens über multiresistente Erreger und rationale Antibiotikatherapie ausgewertet. Der Einfluss der Fachrichtung auf diese Items wurde mittels einer logistischen Regressionsanalyse, eines „chi square tests“ und des Kruskal-Wallis-Tests untersucht. Ergebnisse Die Rücklaufquoten betrugen 43 % (456/1061) und 56 % (705/1268). Im Jahr vor der Umfrage haben 44 % der Nicht-Anästhesisten und 57 % der Anästhesisten keine Fortbildung zu Inhalten des Antibiotic Stewardships besucht. Im Hinblick auf die Selbstsicherheit im Umgang mit Antibiotika zeigten sich Anästhesisten (Mittelwert ± Standardabweichung: 2,53±0,54) signifikant unsicherer als ihre Kollegen (Innere Medizin: 3,10±0,50; Chirurgie: 2,97±0,44; Gynäkologie: 3,12±0,42; Urologie: 3,15±0,44); dies gilt sowohl für die nicht-adjustierten (alle p Schlussfolgerungen Anästhesisten zeigten eine signifikant geringere Selbstsicherheit im Umgang mit Antibiotika als ihre Kollegen aus anderen Fachrichtungen. Fortbildungen zur rationalen Verordnung von Antibiotika waren mit einer höheren Handlungssicherheit assoziiert, so dass eine Verankerung in den jeweiligen Weiterbildungsinhalten zu diskutieren ist.

Objectives To assess plasma and tissue pharmacokinetics of cefazolin and metronidazole in obese patients undergoing bariatric surgery and non-obese patients undergoing intra-abdominal surgery. Patients and methods Fifteen obese and 15 non-obese patients received an IV short infusion of 2 g cefazolin and 0.5 g metronidazole for perioperative prophylaxis. Plasma and microdialysate from subcutaneous tissue were sampled until 8 h after dosing. Drug concentrations were determined by HPLC-UV. Pharmacokinetic parameters were calculated non-compartmentally. Results In obese patients (BMI 39.5–69.3 kg/m2) compared with non-obese patients (BMI 18.7–29.8 kg/m2), mean Cmax of total cefazolin in plasma was lower (115 versus 174 mg/L) and Vss was higher (19.4 versus 14.2 L). The mean differences in t½ (2.7 versus 2.4 h), CL (5.14 versus 4.63 L/h) and AUC∞ (402 versus 450 mg·h/L) were not significant. The influence of obesity on the pharmacokinetics of metronidazole was similar (Cmax 8.99 versus 14.7 mg/L, Vss 73.9 versus 51.8 L, t½ 11.9 versus 9.1 h, CL 4.62 versus 4.13 L/h, AUC∞ 116 versus 127 mg·h/L). Regarding interstitial fluid (ISF), mean concentrations of cefazolin remained >4 mg/L until 6 h in both groups, and those of metronidazole up to 8 h in the non-obese group. In obese patients, the mean ISF concentrations of metronidazole were between 3 and 3.5 mg/L throughout the measuring interval. Conclusions During the time of surgery, cefazolin concentrations in plasma and ISF of subcutaneous tissue were lower in obese patients, but not clinically relevant. Regarding metronidazole, the respective differences were higher, and may influence dosing of metronidazole for perioperative prophylaxis in obese patients.

The antibacterial effect of antibiotics is linked to the free drug concentration. This study investigated the applicability of an ultrafiltration method to determine free plasma concentrations of beta-lactam antibiotics in ICU patients.Eligible patients included adult ICU patients treated with ceftazidime (CAZ), meropenem (MEM), piperacillin (PIP)/tazobactam (TAZ), or flucloxacillin (FXN) by continuous infusion. Up to 2 arterial blood samples were drawn at steady state. Patients could be included more than once if they received another antibiotic. Free drug concentrations were determined by high-performance liquid chromatography with ultraviolet detection after ultrafiltration, using a method that maintained physiological conditions (pH 7.4/37°C). Total drug concentrations were determined to calculate the unbound fraction. In a post-hoc analysis, free concentrations were compared with the target value of 4× the epidemiological cut-off value (ECOFF) for Pseudomonas aeruginosa as a worst-case scenario for empirical therapy with CAZ, MEM or PIP/tazobactam and against methicillin-sensitive Staphylococcus aureus for targeted therapy with FXN.Fifty different antibiotic treatment periods in 38 patients were evaluated. The concentrations of the antibiotics showed a wide range because of the fixed dosing regimen in a mixed population with variable kidney function. The mean unbound fractions (fu) of CAZ, MEM, and PIP were 102.5%, 98.4%, and 95.7%, with interpatient variability of6%. The mean fu of FXN was 11.6%, with interpatient variability of 39%. It was observed that 2 of 12 free concentrations of CAZ, 1 of 40 concentrations of MEM, and 11 of 23 concentrations of PIP were below the applied target concentration of 4 × ECOFF for P. aeruginosa. All concentrations of FXN (9 samples from 6 patients) were8 × ECOFF for methicillin-sensitive Staphylococcus aureus.For therapeutic drug monitoring purposes, measuring total or free concentrations of CAZ, MEM, or PIP is seemingly adequate. For highly protein-bound beta-lactams such as FXN, free concentrations should be favored in ICU patients with prevalent hypoalbuminemia.

Pharmacokinetic/pharmacodynamic indices of anti-infective drugs should be referenced to free drug concentrations. In the present study, clindamycin, flucloxacillin and tedizolid have been determined in human plasma by HPLC-UV. The drugs were separated isocratically within 3-6 min on a C-18 column using mixtures of phosphate buffer-acetonitrile of pH 7.1-7.2. Sample treatment for the determination of total drug concentrations in plasma included extraction/back-extraction (clindamycin) or protein precipitation (flucloxacillin, tedizolid). The free drug concentrations were determined after ultrafiltration. An ultrafiltration device with a membrane consisting of regenerated cellulose proved to be suitable for all drugs. Maintaining a physiological pH was crucial for clindamycin, whereas maintaining body temperature was essential for tedizolid. The methods were applied to the analysis of total and free drug concentrations in clinical samples and were sufficiently sensitive for pharmacokinetic studies and therapeutic drug monitoring.

Tigecycline, a tetracycline derivative, shows atypical plasma protein binding behavior. The unbound fraction decreases with increasing concentration at therapeutic concentrations. Moreover, uncertainty exists about the magnitude of tigecyline's protein binding in man. Unbound fractions between 2.5% and 35% have been reported in plasma from healthy volunteers, and between 25% and 100% in patients, respectively. In the present study, the protein binding of tigecycline has been investigated by ultrafiltration using different experimental conditions. Whereas temperature had only a marginal influence, the unbound fraction at 0.3/3.0 mg/L was low at pH 8.2 (9.4%/1.9%) or in unbuffered pooled plasma (6.3%/1.2%), compared with plasma buffered with HEPES to pH 7.4 (65.9%/39.7%). In experiments with phosphate buffer and EDTA, the concentration dependency was markedly attenuated or abolished, which is compatible with a cooperative binding mechanism involving divalent cations such as calcium. The unbound fraction in clinical plasma samples from patients treated with tigecycline was determined to 66.3 ± 13.7% at concentrations0.3 mg/L compared with 41.3 ± 16.0% at1 to5 mg/L. To summarize, tigecycline appears to be only moderately bound to plasma proteins as determined by ultrafiltration, when a physiological pH is maintained.

Background Tigecycline is a vital antibiotic treatment option for infections caused by multiresistant bacteria in the intensive care unit (ICU). Acute kidney injury (AKI) is a common complication in the ICU requiring continuous renal replacement therapy (CRRT), but pharmacokinetic data for tigecycline in patients receiving CRRT are lacking. Methods Eleven patients mainly with intra-abdominal infections receiving either continuous veno-venous hemodialysis (CVVHD, n = 8) or hemodiafiltration (CVVHDF, n = 3) were enrolled, and plasma as well as effluent samples were collected according to a rich sampling schedule. Total and free tigecycline was determined by ultrafiltration and high-performance liquid chromatography (HPLC)-UV. Population pharmacokinetic modeling using NONMEM® 7.4 was used to determine the pharmacokinetic parameters as well as the clearance of CVVHD and CVVHDF. Pharmacokinetic/pharmacodynamic target attainment analyses were performed to explore the potential need for dose adjustments of tigecycline in CRRT. Results A two-compartment population pharmacokinetic (PK) model was suitable to simultaneously describe the plasma PK and effluent measurements of tigecycline. Tigecycline dialysability was high, as indicated by the high mean saturation coefficients of 0.79 and 0.90 for CVVHD and CVVHDF, respectively, and in range of the concentration-dependent unbound fraction of tigecycline (45–94%). However, the contribution of CRRT to tigecycline clearance (CL) was only moderate (CLCVVHD: 1.69 L/h, CLCVVHDF: 2.71 L/h) in comparison with CLbody (physiological part of the total clearance) of 18.3 L/h. Bilirubin was identified as a covariate on CLbody in our collective, reducing the observed interindividual variability on CLbody from 58.6% to 43.6%. The probability of target attainment under CRRT for abdominal infections was ≥ 0.88 for minimal inhibitory concentration (MIC) values ≤ 0.5 mg/L and similar to patients without AKI. Conclusions Despite high dialysability, dialysis clearance displayed only a minor contribution to tigecycline elimination, being in the range of renal elimination in patients without AKI. No dose adjustment of tigecycline seems necessary in CRRT. Trial registration EudraCT, 2012–005617-39. Registered on 7 August 2013.

Continuous infusion of meropenem is a candidate strategy for optimization of its pharmacokinetic/pharmacodynamic profile. However, plasma concentrations are difficult to predict in critically ill patients. Steady-state concentrations of meropenem were determined prospectively during continuous infusion in 32 surgical ICU patients (aged 21-85 years, body weight 55-125 kg, APACHE II 5-29, measured creatinine clearance 22.7-297 mL/min). Urine was collected for the quantification of renal clearance of meropenem and creatinine. Cystatin C was measured as an additional marker of renal function. Population pharmacokinetic models were developed using NONMEM(®) , which described total meropenem clearance and its relationship with several estimates of renal function (measured creatinine clearance CLCR , Cockcroft-Gault formula CLCG , Hoek formula, 1/plasma creatinine, 1/plasma cystatin C) and other patient characteristics. Any estimate of renal function improved the model performance. The strongest association of clearance was found with CLCR (typical clearance = 11.3 L/h × [1 + 0.00932 × (CLCR - 80 mL/min)]), followed by 1/plasma cystatin C; CLCG was the least predictive covariate. Neither age, weight, nor sex was found to be significant. These models can be used to predict dosing requirements or meropenem concentrations during continuous infusion. The covariate CLCR offers the best predictive performance; if not available, cystatin C may provide a promising alternative to plasma creatinine.

Aims The aim of the present study was to assess the pharmacokinetics of total and unbound ceftriaxone in intensive care unit (ICU) patients and its protein binding characteristics.

The objective of this study was to provide a pharmacokinetic/pharmacodynamic (PK/PD) analysis of moxifloxacin in patients with diabetic foot infections (DFI). The plasma concentration-time courses were determined in 50 DFI patients on day 1 and 3 after intravenous moxifloxacin 400 mg once-daily. A two-compartment population pharmacokinetic model was developed, identifying as covariates total body weight on central and peripheral volume of distribution (V1, V2) and ideal body weight on clearance (CL), respectively. For a 70 kg patient V1 was 68.1 L (interindividual variability, CV: 27.4%), V2 44.6 L, and CL 12.1 L/h (25.6%). Simulations were performed to calculate the probability of target attainment (PTA) for Gram-positive and Gram-negative pathogens with fAUC/MIC targets of ≥30 and ≥100, respectively. PTA was 0.68-1 for susceptible (MIC ≤0.5 mg/L according to EUCAST) Gram-positive, but

Intra-abdominal infections (IAI) are an important cause of morbidity and are frequently associated with poor prognosis, particularly in high-risk patients. The cornerstones in the management of complicated IAIs are timely effective source control with appropriate antimicrobial therapy. Empiric antimicrobial therapy is important in the management of intra-abdominal infections and must be broad enough to cover all likely organisms because inappropriate initial antimicrobial therapy is associated with poor patient outcomes and the development of bacterial resistance. The overuse of antimicrobials is widely accepted as a major driver of some emerging infections (such as C. difficile), the selection of resistant pathogens in individual patients, and for the continued development of antimicrobial resistance globally. The growing emergence of multi-drug resistant organisms and the limited development of new agents available to counteract them have caused an impending crisis with alarming implications, especially with regards to Gram-negative bacteria. An international task force from 79 different countries has joined this project by sharing a document on the rational use of antimicrobials for patients with IAIs. The project has been termed AGORA (Antimicrobials: A Global Alliance for Optimizing their Rational Use in Intra-Abdominal Infections). The authors hope that AGORA, involving many of the world's leading experts, can actively raise awareness in health workers and can improve prescribing behavior in treating IAIs.

Antibiotika sind aus der Intensivmedizin nicht wegzudenken und mussen moglichst sinnvoll und rational eingesetzt werden. Fur den kritisch kranken Patienten kann die optimale Dosierung der antibiotischen Therapie entscheidend sein. Dafur mussen die Zusammenhange zwischen Pharmakokinetik (PK) und Pharmakodynamik (PD) bekannt sein und berucksichtigt werden. Praklinische Daten zeigten hier wesentliche Unterschiede zwischen verschiedenen Antibiotikaklassen, die zur Etablierung unterschiedlicher Dosierungsstrategien fuhrten, z. B. die hochdosierte Einmalgabe fur Aminoglykoside oder die verlangerte bzw. kontinuierliche Infusion von Betalactamen. Intensivpatienten mit krankheitsbedingten Veranderungen der PK-Parameter und Infektionen mit wenig empfindlichen Erregern konnen am ehesten von einer PK/PD-geleiteten Therapie profitieren.

To determine unbound ertapenem concentrations in plasma and to describe the pharmacokinetics of unbound ertapenem in intensive care unit (ICU) patients.For assessing the influence of experimental conditions and for development of the ultrafiltration protocol, plasma from healthy volunteers was used. Concentrations of total and unbound ertapenem were determined by HPLC in 29 plasma samples from six ICU patients treated with 1 g of ertapenem once daily. The concentration-time courses were described by a one-compartment model. Ertapenem binding to albumin was assessed by Michaelis-Menten kinetics in solutions of human serum albumin, in plasma from healthy volunteers and in plasma from ICU patients.The unbound fraction (fu) of ertapenem was highly susceptible to pH and temperature during ultrafiltration and was ∼20% in plasma from healthy volunteers at clinically relevant concentrations. In ICU patients, fu was substantially higher (range 30.9%-53.6%). The unbound concentrations of ertapenem exceeded 2 mg/L for 72% (median; range 39%-100%) of the 24 h dosing interval and 0.25 mg/L for 100% (range 79%-100%). The number of binding sites per albumin molecule was 1.22 (95% CI 1.07-1.38) in plasma from healthy volunteers and 0.404 (95% CI 0.158-0.650) in samples from ICU patients.Determination of unbound ertapenem by ultrafiltration is susceptible to experimental conditions. When determined at physiological pH and temperature, fu of ertapenem is 2- to 4-fold higher than previously reported and even higher in ICU patients. Binding studies indicate that hypoalbuminaemia alone does not explain these differences. This issue should be further investigated for its clinical relevance.

Ultrafiltration is a rapid and convenient method to determine the free concentrations of drugs. In the present work, we aimed to develop an ultrafiltration method which is appropriate for routine determination of the free fraction of vancomycin and highly protein bound beta-lactams such as ertapenem, ceftriaxone and cefazolin in plasma from intensive care unit patients. Different filter types and experimental conditions (molecular weight cut-off, centrifugal force and time, pH, temperature) were evaluated and found to have influence on the result. In the final protocol, serum or plasma was buffered to pH 7.4-7.5, ultrafiltered at 1000×g at 37°C for 20min using Nanosep Omega 10K filters and subsequently analysed for the antibiotics by RP-HPLC with UV detection. The data from our investigation suggest to aim physiological conditions, i.e. 37°C and pH 7.4, and low to moderate relative centrifugal forces in order to get reliable results. With regard to the chromatographic separation, modulation of the pH in the range of 2.5-7.0 allows to determine several beta-lactams isocratically and/or to avoid interferences by co-administered drugs.

Objectives To assess the pharmacokinetics and tissue penetration of fosfomycin in obese and non-obese surgical patients. Methods Fifteen obese patients undergoing bariatric surgery and 15 non-obese patients undergoing major intra-abdominal surgery received an intravenous single short infusion of 8 g of fosfomycin. Fosfomycin concentrations were determined by LC-MS/MS in plasma and microdialysate from subcutaneous tissue up to 8 h after dosing. The pharmacokinetic analysis was performed in plasma and interstitial fluid (ISF) by non-compartmental methods. Results Thirteen obese patients (BMI 38–50 kg/m2) and 14 non-obese patients (BMI 0–29 kg/m2) were evaluable. The pharmacokinetics of fosfomycin in obese versus non-obese patients were characterized by lower peak plasma concentrations (468 ± 139 versus 594 ± 149 mg/L, P = 0.040) and higher V (24.4 ± 6.4 versus 19.0 ± 3.1 L, P = 0.010). The differences in AUC∞ were not significant (1275 ± 477 versus 1515 ± 352 mg·h/L, P = 0.16). The peak concentrations in subcutaneous tissue were reached rapidly and declined in parallel with the plasma concentrations. The drug exposure in tissue was nearly halved in obese compared with non-obese patients (AUC∞ 1052 ± 394 versus 1929 ± 725 mg·h/L, P = 0.0010). The tissue/plasma ratio (AUCISF/AUCplasma) was 0.86 ± 0.32 versus 1.27 ± 0.34 (P = 0.0047). Conclusions Whereas the pharmacokinetics of fosfomycin in plasma of surgical patients were only marginally different between obese and non-obese patients, the drug exposure in subcutaneous tissue was significantly lower in the obese patients.

After oral administration of 100 mg/kg b. w. (235.8 µmol/kg) salicortin to Wistar rats, peak serum concentrations of 1.43 mg/L (13.0 µM) catechol were detected after 0.5 h in addition to salicylic acid by HPLC-DAD after serum processing with β-glucuronidase and sulphatase. Both metabolites could also be detected in the serum of healthy volunteers following oral administration of a willow bark extract (Salicis cortex, Salix spec., Salicaceae) corresponding to 240 mg of salicin after processing with both enzymes. In humans, the cmax (1.46 mg/L, 13.3 µM) of catechol was reached after 1.2 h. The predominant phase-II metabolite in humans and rats was catechol sulphate, determined by HPLC analysis of serum samples processed with only one kind of enzyme. Without serum processing with glucuronidase and sulphatase, no unconjugated catechol could be detected in human and animal serum samples. As catechol is described as an anti-inflammatory compound, these results may contribute to the elucidation of the mechanism of the action of willow bark extract.

Published data on the unbound fraction of vancomycin in patient samples exhibit high variability. In the present study, a robust ultrafiltration method was developed and applied to 102 clinical samples from 22 intensive care unit patients who were treated with continuous infusion of vancomycin. A validated HPLC method was used for determination of total and unbound concentrations. The mean unbound fraction was 67.2% (standard deviation 7.5%, range 47.2-92.1%) and independent of total concentration of vancomycin or of albumin. The unbound fraction was significantly correlated (r = +0.67, P = .0009) with the renally filtered fraction (drug clearance/creatinine clearance), providing functional evidence for the validity of the measurements. Ultrafiltration proved to be susceptible to variations in the experimental conditions such as pH, temperature and centrifugal force. The measured unbound fraction increased from 60% at pH 6 to 100% at pH 9, from 57% at 4°C to 80% at 37°C, and was 76% at 1,000 g compared with 45% at 10,000 g. Lack of standardization may therefore partly explain the variable results reported in the literature.

Background:Standard doses of linezolid may not be suitable for all patient groups. Intensive care unit (ICU) patients in particular may be at risk of inadequate concentrations. This study investigated variability of drug exposure and its potential sources in this population.Methods:Plasma concentrations of linezolid were determined by high-performance liquid chromatography in a convenience sample of 20 ICU patients treated with intravenous linezolid 600 mg twice daily. Ultrafiltration applying physiological conditions (pH 7.4/37 degrees C) was used to determine the unbound fraction. Individual pharmacokinetic (PK) parameters were estimated by population PK modeling. As measures of exposure to linezolid, area under the concentration-time curve (AUC) and trough concentrations (C-min) were calculated and compared with published therapeutic ranges (AUC 200-400 mg*h/L, C-min 2-10 mg/L). Coadministered inhibitors or inducers of cytochrome P450 and/or P-glycoprotein were noted.Results:Data from 18 patients were included into the PK evaluation. Drug exposure was highly variable (median, range: AUC 185, 48-618 mg*h/L, calculated C-min 2.92, 0.0062-18.9 mg/L), and only a minority of patients had values within the target ranges (6 and 7, respectively). AUC and C-min were linearly correlated (R = 0.98), and classification of patients (underexposed/within therapeutic range/overexposed) according to AUC or C-min was concordant in 15 cases. Coadministration of inhibitors was associated with a trend to higher drug exposure, whereas 3 patients treated with levothyroxine showed exceedingly low drug exposure (AUC approximate to 60 mg*h/L, C-min

Intra-abdominal infections (IAI) are an important cause of morbidity and are frequently associated with poor prognosis, particularly in high-risk patients. The cornerstones in the management of complicated IAIs are timely effective source control with appropriate antimicrobial therapy. Empiric antimicrobial therapy is important in the management of intra-abdominal infections and must be broad enough to cover all likely organisms because inappropriate initial antimicrobial therapy is associated with poor patient outcomes and the development of bacterial resistance. The overuse of antimicrobials is widely accepted as a major driver of some emerging infections (such as C. difficile), the selection of resistant pathogens in individual patients, and for the continued development of antimicrobial resistance globally. The growing emergence of multi-drug resistant organisms and the limited development of new agents available to counteract them have caused an impending crisis with alarming implications, especially with regards to Gram-negative bacteria. An international task force from 79 different countries has joined this project by sharing a document on the rational use of antimicrobials for patients with IAIs. The project has been termed AGORA (Antimicrobials: A Global Alliance for Optimizing their Rational Use in Intra-Abdominal Infections). The authors hope that AGORA, involving many of the world's leading experts, can actively raise awareness in health workers and can improve prescribing behavior in treating IAIs., 0, SCOPUS: ar.j, info:eu-repo/semantics/published

Objectives: To assess the pharmacokinetics of moxifloxacin in morbidly obese patients. Methods: Twelve morbidly obese patients (2 male/10 female, age 25‐61 years, weight 98 ‐166 kg, body mass index 43.0‐ 58.2 kg/m 2 ) scheduled for gastric bypass surgery were treated with 400 mg of moxifloxacin orally once daily for 3 days and with 400 mg of moxifloxacin intravenously on day 4 (day of surgery). Pharmacokinetic analysis was performed on day 1 and day 4. Specimens of small intestine, greater omentum and subcutaneous adipose tissue were collected intraoperatively 1.8 ‐3.7 h after moxifloxacin infusion. Moxifloxacin concentrations were determined by HPLC. Results: The plasma pharmacokinetics (mean+SD) was comparable to historical data in normal-weight subjects. Oral bioavailability was 79.6%+11.5%. After intravenous administration, plasma clearance was 9.6+2.0 L/h, volume of distribution was 165+30 L and area under the curve was 43.7+11.8 mg.h/L. Linear regression analysis showed the volume of distribution to be better correlated with ideal body weight, lean body weight, fat-free mass or height (R 2 ¼0.60 ‐0.67, P ¼ 0.001‐0.003) than with total body weight (R 2 ¼ 0.46, P ¼ 0.015). Whereas mean tissue concentrations in small intestine (6.99+2.34 mg/kg) were twice the concomitant plasma concentrations, the concentrations in greater omentum (0.801+0.168 mg/kg) or subcutaneous fat (0.638+0.180 mg/kg) were only one-quarter of those. Conclusions: The pharmacokinetics of moxifloxacin is not significantly affected by morbid obesity. No dose adjustment seems to be necessary in this particular population.

The aim of the present study was to assess the pharmacokinetics of total and unbound ceftriaxone in intensive care unit (ICU) patients and its protein binding characteristics.Twenty patients (m/f 15/5, age 25-86 years, body weight 60-121 kg, APACHE II 7-40, estimated glomerular filtration rate 19-157 ml min(-1) , albumin 11.7-30.1 g l(-1) , total bilirubin0.1-36.1 mg dl(-1) ) treated with intravenous ceftriaxone were recruited from two ICUs. Timed plasma samples were obtained using an opportunistic study protocol. Ceftriaxone concentrations were determined by high-performance liquid chromatography; unbound concentrations were determined after ultrafiltration using a new method which maintains physiological pH and temperature. The pharmacokinetics was described by a one-compartment model, the protein-binding characteristics by Michaelis-Menten kinetics.For total drug, the volume of distribution was 20.2 l (median; interquartile range 15.6-24.5 l), the half-life 14.5 h (10.0-25.5 h) and the clearance 0.96 l h(-1) (0.55-1.28 l h(-1) ). The clearance of unbound drug was 1.91 l h(-1) (1.46-6.20 l h(-1) ) and linearly correlated with estimated glomerular filtration rate (slope 0.85, y-intercept 0.24 l h(-1) , r(2) = 0.70). The unbound fraction was higher in ICU patients (33.0%; 20.2-44.5%) than reported in healthy volunteers, particularly when renal impairment or severe hyperbilirubinaemia was present. In all patients, unbound concentrations during treatment with ceftriaxone 2 g once daily remained above the EUCAST susceptibility breakpoint (≤1 mg l(-1) ) throughout the whole dosing interval.Protein binding of ceftriaxone is reduced and variable in ICU patients due to hypoalbuminaemia, but also to altered binding characteristics. Despite these changes, the pharmacokinetics of unbound ceftriaxone is governed by renal function. For patients with normal or reduced renal function, standard doses are sufficient.

Background In ICU patients, glomerular filtration is often impaired, but also supraphysiological values are observed (“augmented renal clearance”, >130 mL/min/1.73 m2). Renally eliminated drugs (e.g. many antibiotics) must be adjusted accordingly, which requires a quantitative measure of renal function throughout all the range of clinically encountered values. Estimation from plasma creatinine is standard, but cystatin C may be a valuable alternative. Methods This was a secondary analysis of renal function parameters in 100 ICU patients from two pharmacokinetic studies on vancomycin and betalactam antibiotics. Estimated clearance values obtained by the Cockcroft-Gault formula (eCLCG), the CKD-EPI formula (eCLCKD-EPI) or the cystatin C based Hoek formula (eCLHoek) were compared with the measured endogenous creatinine clearance (CLCR). Agreement of values was assessed by modified Bland-Altman plots and by calculating bias (median error) and precision (median absolute error). Sensitivity and specificity of estimates to identify patients with reduced (130 mL/min/1.73 m2) CLCR were calculated. Results The CLCR was well distributed from highly compromised to supraphysiological values (median 73.2, range 16.8-234 mL/min/1.73 m2), even when plasma creatinine was not elevated (≤0.8 mg/dL for women, ≤1.1 mg/dL for men). Bias and precision were +13.5 mL/min/1.73 m2 and ±18.5 mL/min/1.73 m2 for eCLCG, +7.59 and ±16.8 mL/min/1.73 m2 for eCLCKD-EPI, and -4.15 and ±12.9 mL/min/1.73 m2 for eCLHoek, respectively, with eCLHoek being more precise than the other two (p

I read with interest the report by Lodise and colleagues on the penetration of meropenem into the epithelial lining fluid (ELF) of 17 patients with ventilator-associated pneumonia (VAP) (6). Briefly, they report a median penetration rate of meropenem into ELF of 25.4%, but Monte Carlo simulations predict an enormous variability (25th to 75th percentiles, 9.0 to 70.14%; 10th to 90th percentiles, 3.7 to 178%), which would leave many patients with insufficient drug exposure at the site of infection and thus possibly a poor clinical outcome. Like the authors themselves, I am somewhat surprised by the huge magnitude of variability of ELF penetration reported in this study, which exceeds by far the variability in the cited studies on the ELF penetration of piperacillin (median, 42%; interquartile range [IQR], 32 to 63.5%), ertapenem (median, 32%; IQR, 28 to 46%), ceftazidime (mean standard deviation [SD], 20.6 8.9%), and cefepime (mean concentration SD, 13.5 3.3 mg/liter in plasma and 14.1 2.8 mg/liter in ELF), all reported by Boselli et al. in patients with VAP or severe nosocomial pneumonia (1–4). Whereas it is of course possible that ELF penetration of meropenem is actually more variable, I suggest an explanation based on the macropharmacokinetic properties and the employed sampling strategy. In the cases of piperacillin, ceftazidime, and cefepime, steady-state concentrations (CSS) were determined during continuous infusion. With this method, it is impossible to describe the time course of ELF penetration but very simple to determine the area under the concentration-time curve (AUC steady-state concentration time) and thus the total drug exposure. As for ertapenem, the half-life of abou t8hm ay still permit the assumption that simultaneous concentrations in serum and ELF are close to equilibrium and representative of total penetration. In the present study, meropenem was given as an intermittent infusion (0.5 or 3 h) every 8 h. Given its short half-life (1 to 2 h), equilibrium between ELF and plasma is unlikely at any given time point, and only comparison of AUCs, as described by the authors, is valid. However, due to the practical limitations of ELF sampling, only one specimen was obtained per patient, and the full concentration-time course and AUC in ELF was estimated from this single concentration.

To systematically assess the impact of pharmacodynamic interactions when adding either linezolid or vancomycin to meropenem on the antibacterial activity against methicillin-susceptible Staphylococcus aureus (MSSA). These regimens are frequently used in empiric therapy when risk factors for MRSA are present, but MSSA will often turn out as pathogen.Checkerboard and time-kill curve studies were performed against three strains of MSSA covering clinically relevant concentrations of all antibiotics. We newly elaborated a response surface analysis (RSA) to quantify the extent of the pharmacodynamic interactions.The most prominent result was that linezolid fully antagonised the rapid (4-6 h) bactericidal effect of meropenem against MSSA to bacteriostasis at clinically relevant concentrations of both drugs. This interaction was invisible in the conventional checkerboard analysis (insensitive turbidity threshold). RSA quantified a 1.5-3.2 log10-fold higher bacterial load compared to expected additivity for linezolid and meropenem. Vancomycin and meropenem interacted partly synergistic (subinhibitory) or additive (inhibitory combinations) being bactericidal after 24 h.Standard doses of linezolid and meropenem will provide inhibitory concentrations and thus pharmacodynamic antagonism throughout the whole dosing interval for MSSA. Further data is required to assess the clinical significance of this interaction.

It has recently been shown in a bioassay guided fractionation of a Willow bark extract (Salicis cortex, Salix spec., Salicaceae) that not the isolated compound salicortin itself but its degradation product catechol was responsible for an anti-inflammatory effect in vitro. To investigate if this in vitro effect has impact on the in vivo situation, a pharmacokinetic study was performed in humans with eight healthy volunteers. After oral administration of a Willow bark extract corresponding to 240 mg salicin, venous blood samples were taken up to 24 hours, and serum was analyzed by HPLC-DAD after processing with glucuronidase and sulfatase. Mean peak concentrations of 13.3µM catechol were observed after 1.2 hours. No free catechol could be detected without enzyme processing and the predominant phase-II-metabolite was catechol sulfate. To exclude that the detected catechol in the human serum samples was not solely absorbed as a genuine compound of the Willow bark extract, pure salicortin 100 mg/kg b.w. was orally administered to Wistar rats. In this study, catechol could definitely be proved as a metabolite of salicortin in serum with a cmax of 13.0µM after 0.5h. These findings indicate that not salicortin per se but rather catechol, which is one of its active metabolites reported in the literature to have anti-inflammatory properties, contributes towards the overall ant-inflammatory and analgesic efficacy of Willow bark.

Published data on the unbound fraction of vancomycin in patient samples exhibit high variability. In the present study, a robust ultrafiltration method was developed and applied to 102 clinical samples from 22 intensive care unit patients who were treated with continuous infusion of vancomycin. A validated HPLC method was used for determination of total and unbound concentrations. The mean unbound fraction was 67.2% (standard deviation 7.5%, range 47.2-92.1%) and independent of total concentration of vancomycin or of albumin. The unbound fraction was significantly correlated (r = +0.67, P = .0009) with the renally filtered fraction (drug clearance/creatinine clearance), providing functional evidence for the validity of the measurements. Ultrafiltration proved to be susceptible to variations in the experimental conditions such as pH, temperature and centrifugal force. The measured unbound fraction increased from 60% at pH 6 to 100% at pH 9, from 57% at 4°C to 80% at 37°C, and was 76% at 1,000 g compared with 45% at 10,000 g. Lack of standardization may therefore partly explain the variable results reported in the literature.

OBJECTIVES: To describe the plasma concentration-time profile of moxifloxacin after intravenous and enteral administration in intensive care unit (ICU) patients and to provide a pharmacodynamic (PD) evaluation with regard to pneumonia. PATIENTS AND METHODS: Twenty-five adult patients from a cardiothoracic/mixed surgical ICU were enrolled. Moxifloxacin was given as a standard dose (400 mg once daily). Therapy was successfully switched to enteral administration on day 5 in 16 patients. A rich data sampling schedule was performed after intravenous (day 4) and enteral (day 8) administration. Moxifloxacin concentrations were analysed by HPLC. A population pharmacokinetic (PK) model was developed using NONMEM VII. Simulated concentration-time profiles were evaluated for their probability of attaining PK/PD target values relevant for community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP). RESULTS: A linear-elimination two-compartment model described the data adequately. Parameter estimates (coefficient of variation of inter-individual variability) were: absorption rate constant, 1.09/h (135%); enteral bioavailability, 76% (20.0%); central volume of distribution, 55.6 L; peripheral volume of distribution, 59.6 L (15.3%); inter-compartmental clearance, 47.7 L/h; and clearance, 11.3 L/h (23.7%). Both intravenously and enterally administered standard-dose moxifloxacin reliably attained the PK/PD target values for pathogens with MICs ≤0.25 mg/L for CAP and ≤0.125 mg/L for HAP. CONCLUSIONS: Drug exposure to moxifloxacin in ICU patients was more variable than in healthy volunteers. The standard dosing provides sufficient drug exposure for treatment of CAP but for HAP it does so only when a highly susceptible pathogen is present. Intravenous/enteral sequential therapy may be considered for cautiously selected cases in ICU patients.

In 2 crossover studies, 12 healthy volunteers (6 male/6 female) received a single oral dose of mycophenolate mofetil (MMF) 1000 mg or an equimolar dose of enteric-coated mycophenolate sodium (EC-MPS) 720 mg fasting with and without coadministered omeprazole 20 mg bid. The plasma concentrations of mycophenolic acid (MPA) and of the inactive metabolite mycophenolic acid glucuronide (MPA-G) were measured by high-performance liquid chromatography (HPLC). In addition, dissolution of MMF 500 mg or EC-MPS 360 mg tablets was determined using an USP paddle apparatus in aqueous buffer of pH 1 to 7. The bioavailability of MPA following administration of MMF or EC-MPS was similar except for the time to peak concentration, which was longer in the EC-MPS group. Concomitant treatment with omeprazole lowered significantly C(max) and AUC(12h) of MPA following administration of MMF. The pharmacokinetics of EC-MPS was not affected. Dissolution of MMF in aqueous buffer decreased dramatically at pH above 4.5. The EC-MPS tablet was stable up to pH 5. Above, EC-MPS was quantitatively disintegrated and MPS quantitatively dissolved. There is strong evidence that impaired absorption of MMF with concomitant proton pump inhibitors is due to incomplete dissolution of MMF in the stomach at elevated pH.

Vancomycin (VAN) dosing requires adjustment to renal function, which is often estimated using the Cockcroft-Gault formula; however, its precision is poor in Intensive Care Unit (ICU) patients. VAN clearance (CL(Van)) during continuous infusion was prospectively determined in 25 ICU patients [14 male, 11 female; age range 31-82 years; body mass index (BMI) 16.5-41.5 kg/m²; Acute Physiology and Chronic Health Evaluation (APACHE) II score at admission 8-36; creatinine clearance 25-195 mL/min] and its correlation with measured creatinine clearance (CL(Crea)), estimated creatinine clearance using the Cockcroft-Gault formula (CL(CG)) and estimated glomerular filtration rate according to Hoek's formula based on serum cystatin C (GFR(Hoek)) was investigated. The correlation between CL(Van) and CL(Crea) was very good (r²=0.88), but it was rather poor with CL(CG) (r² = 0.37) and was acceptable with GFR(Hoek) (r² = 0.70). For VAN dose adjustments in ICU patients, determination of cystatin C may be an interesting and practical alternative to measured CL(Crea), whereas the Cockcroft-Gault formula should be used with caution.

This chapter discusses effects of inflammatory mediators such as interleukins, tumor necrosis factor, interferons, and others on the sympathetic or parasympathetic nervous system. This includes inflammatory mediator-induced alterations at central autonomic control centers, of sympathetic and parasympathetic ganglia, of nerves and autonomic receptors, of neurotransmitter secretion from nerve terminals, of neurotransmitter receptor signaling, of peripheral neurotransmitter effects without exact localization of the site of action, of chromaffin cells, and of enzymes responsible for adrenergic or cholinergic neurotransmitter production. Although this chapter cannot be complete, it clearly demonstrates a close interaction between these inflammatory mediators and altered function of the autonomic nervous system. Particularly, the sympathetic nervous system is affected in many different ways which, in general, lead to an increase of the sympathetic nervous tone but to a loss of sympathetic innervation in inflamed tissue. At present, it is not known how inflammatory mediators exactly influence the autonomic nervous system in chronic inflammatory diseases. It is likely that this influence may lead to autonomic neuropathy and also to autonomic nervous hyper-reflexia with many deleterious consequences such as sympathetic overdrive, hypertension, arteriosclerosis, metabolic disturbances, and others. Furthermore, long-loop anti-inflammatory feedback effects of the autonomic nervous system may be altered under such circumstances, the consequences of which remain to be elucidated.

Using a spleen slice microsuperfusion technique in mice, we have previously characterized the role of norepinephrine (NE) and other neurotransmitters for sympathetic modulation of IL-6 and TNF secretion of splenic macrophages. Since experiments in spleen slices do not reflect the situation of an entire perfused organ, we investigated sympathetic modulation of lipopolysaccharide (LPS)-induced secretion of IL-6 and TNF in perfusion experiments of rat spleen. In an organ bath, perfusion was performed in explanted whole spleens, and catecholamines and cytokines were measured by HPLC and ELISA, respectively. Release of NE depended on stimulation frequency (maximum at 10 Hz). Apart from NE, perfusates also contained significant amounts of dopamine and epinephrine. Furthermore, perfusate epinephrine levels correlated positively with perfusate NE levels (RRank=0.750, p

Background Secondary peritonitis requires surgical source control and adequate antimicrobial treatment. Antimicrobial regimens are usually selected according to local susceptibility data of individual pathogens against single agents, but this neglects both the polymicrobial nature of the infection and the use of combination therapy. We analysed the probability of common regimens to cover all relevant pathogens isolated in one patient (“spectrum adequacy rate”, SAR) in a real-life data set. Methods Data from 242 patients with secondary peritonitis (88 community acquired, 154 postoperative cases) treated in our IMCU/ICU were obtained retrospectively. The relative frequency of pathogens, resistance rates and the SAR were analysed using the free software R. Results Enterococci were isolated in 47.1 % of all patients, followed by Escherichia coli (42.6 %), other enterobacteriaceae (33.1 %), anaerobes (29.8 %) and Candida spp. (28.9 %). Resistance patterns were consistent with general surveillance data from our hospital. The susceptibility rates and SAR were lower in postoperative than in community acquired cases. The following regimens yielded a SAR > 95 % when enterobacteriaceae only were considered: piperacillin/tazobactam + gentamicin, cefotaxim (only for community acquired cases), cefotaxim + gentamicin, meropenem, tigecycline + gentamicin or tigecycline + ciprofloxaxin. When enterococci were also considered, all betalactam based regimens required combination with vancomycin or linezolid for a SAR > 95 %, whereas TGC based regimens were not compromised. As for Candida spp., the SAR of fluconazole was 81.9–87.5 %. Conclusions This study demonstrates a rational approach to assess the adequacy of antimicrobial regimens in secondary peritonitis, which may help to adjust local guidelines or to select candidate regimens for clinical studies.