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There are different methods of artificial liver support for patients with acute liver dysfunction (ALD). However, CytoSorb (CS) might be a new approved option for those patients. Question of interest is whether the elimination performance of CS was comparable to that of advanced organ support (ADVOS). Patients, treated with CS (integrated into high-flux dialysis) or ADVOS and a total bilirubin > 10 mg/dl were included. Laboratory parameters were evaluated before starting therapy (d0) and 12–24 h thereafter (d1). The Wilcoxon-test with associated samples was used for statistical analysis. Thirty-nine patients (33 CS, 6 ADVOS) were included. The median bilirubin at d0 was 16.9 and 17.7 mg/dl and at d1 was 13.2 and 15.9 mg/dl, in the CS and ADVOS group, respectively. There was a significant bilirubin reduction as well in the CS group (p

Antibiotic dosing in intensive care patients is complex due to pharmacokinetic (PK) alterations. The aim of this article is to illustrate the role of therapeutic drug monitoring (TDM) and PK models to individualize antibiotic dosing.Guidelines and recommendations are discussed in the context of clinical practice and the prerequisites for routine TDM of different antibiotics are presented. In addition, the benefits and limitations of TDM are discussed. The advantages and disadvantages of TDM and PK models are described and the resulting future options are presented.In the clinical routine, the peak or trough concentrations of antibiotics in blood are measured depending on the antibiotic class. Prerequisites for a purposeful TDM are a coordinated blood sampling and a prompt reporting of findings. As target ranges are not uniformly defined following rules, dosage adjustments are difficult. The PK models offer a valid possibility to individualize the antibiotic therapy of intensive care patients. Areas of application are the calculation of the loading dose and the combination with TDM for treatment control. For whom and how often TDM is necessary and how it can best be combined with PK models or even replace them should be investigated in the future, in addition to evaluation of the optimal target area.The routine use of TDM for antibiotics in intensive care patients is only effective under the abovementioned conditions. By combination with PK models the treatment could be optimized in the future.HINTERGRUND UND ZIEL DER ARBEIT: Die Dosierung von Antibiotika ist bei IntensivpatientInnen aufgrund pharmakokinetischer (PK-)Veränderungen komplex. Das Ziel des Beitrags ist es, den Stellenwert von therapeutischem Drugmonitoring (TDM) und PK-Modellen bei der Dosierungsindividualisierung von Antibiotika zu zeigen.Hierfür werden Leitlinien und Empfehlungen im Kontext der klinischen Praxis erörtert und Voraussetzungen für ein routinemäßiges TDM der verschiedenen Antibiotika dargestellt. Zudem werden Nutzen und Limitationen des TDM erörtert. Die Vor- und Nachteile von TDM und PK-Modellen werden beschrieben und daraus resultierende Zukunftsoptionen präsentiert.In der klinischen Routine kann der Spitzen- oder Talspiegel von Antibiotika, abhängig von ihrer Klasse, im Blut gemessen werden. Voraussetzungen für ein zielführendes TDM sind eine koordinierte Blutentnahme und eine zeitnahe Befundmitteilung. Da Zielbereiche regelhaft nicht einheitlich definiert sind, gestalten sich Dosierungsanpassungen schwierig. Die PK-Modelle bieten eine valide Möglichkeit, die Antibiotikatherapie von IntensivpatientInnen zu individualisieren. Anwendungsbereiche sind die Kalkulation der initialen Antibiotikadosis, aber auch die Kombination mit TDM zur Therapiesteuerung. Für wen und wie oft ein TDM notwendig ist, und wie es mit PK-Modellen bestmöglich kombiniert oder durch diese sogar ersetzt werden kann, sollte neben der Evaluation des optimalen Zielbereichs zukünftig untersucht werden.Das routinemäßige TDM von Antibiotika bei IntensivpatientInnen ist nur unter oben genannten Voraussetzungen zielführend. Durch die Kombination mit PK-Modellen könnte die Therapie zukünftig optimiert werden.

The concentration-time profile of linezolid varies considerably in critically ill patients. Question of interest is, if the site of infection influences linezolid serum concentrations.68 critically ill patients, treated with linezolid, were included. The concentration-time-profile for linezolid was determined using maximum a-posteriori predictions. A trough concentration (CThe indications for linezolid therapy were in descending order: peritonitis (38.2%), pneumonia (25.0%), infectious acute respiratory distress syndrome (ARDS) (19.1%), and other non-pulmonary infection (17.7%). 27.2 and 7.9% of CLinezolid serum concentrations are reduced in patients with pulmonary infections. Future studies should investigate if other linezolid thresholds are needed in those patients due to linezolid pooling in patients´ lung.

Background Galactomannan antigen (GM) testing is widely used in the diagnosis of invasive aspergillosis (IA). Digestive enzymes play an important role in enzyme substitution therapy in exocrine pancreatic insufficiency. As digestive enzymes of fungal origin like Nortase contain enzymes from Aspergillus, a false-positive result of the test might be possible because of cross-reacting antigens of the cell wall of the producing fungi. We, therefore, asked whether the administration of fungal enzymes is a relevant cause of false-positive GM antigen test results. Methods Patients with a positive GM antigen test between January 2016 and April 2020 were included in the evaluation and divided into two groups: group 1—Nortase-therapy, group 2—no Nortase-therapy. In addition, dissolved Nortase samples were analyzed in vitro for GM and β-1,3-D-glucan. For statistical analysis, the chi-squared and Mann‒Whitney U tests were used. Results Sixty-five patients were included in this evaluation (30 patients receiving Nortase and 35 patients not receiving Nortase). The overall false positivity rate of GM testing was 43.1%. Notably, false-positive results were detected significantly more often in the Nortase group (73.3%) than in the control group (17.1%, p Conclusions Our data demonstrate that the administration of digestive enzymes of fungal origin like Nortase leads to a significantly higher rate of false-positive GM test results compared to that in patients without digestive enzyme treatment.

This case-control study investigated the long-term evolution of multidrug-resistant bacteria (MDRB) over a 5-year period associated with the use of selective oropharyngeal decontamination (SOD) in the intensive care unit (ICU). In addition, effects on health care-associated infections and ICU mortality were analysed.We investigated patients undergoing mechanical ventilation 48 h in 11 adult ICUs located at 3 campuses of a university hospital. Administrative, clinical, and microbiological data which were routinely recorded electronically served as the basis. We analysed differences in the rates and incidence densities (ID, cases per 1000 patient-days) of MDRB associated with SOD use in all patients and stratified by patient origin (outpatient or inpatient). After propensity score matching, health-care infections and ICU mortality were compared.5034 patients were eligible for the study. 1694 patients were not given SOD. There were no differences in the incidence density of MDRB when SOD was used, except for more vancomycin-resistant Enterococcus faecium (0.72/1000 days vs. 0.31/1000 days, p 0.01), and fewer ESBL-producing Klebsiella pneumoniae (0.22/1000 days vs. 0.56/1000 days, p 0.01). After propensity score matching, SOD was associated with lower incidence rates of ventilator-associated pneumonia and death in the ICU but not with ICU-acquired bacteremia or urinary tract infection.Comparisons of the ICU-acquired MDRB over a 5-year period revealed no differences in incidence density, except for lower rate of ESBL-producing Klebsiella pneumoniae and higher rate of vancomycin-resistant Enterococcus faecium with SOD. Incidence rates of ventilator-associated pneumonia and death in the ICU were lower in patients receiving SOD.

Meropenem is one of the most frequently used antibiotics to treat life-threatening infections in critically ill patients. This study aimed to develop a meropenem dosing algorithm for the treatment of Gram-negative infections based on intensive care unit (ICU)-specific resistance data. Antimicrobial susceptibility testing of Gram-negative bacteria obtained from critically ill patients was carried out from 2016 to 2020 at a tertiary care hospital. Based on the observed MIC distribution, stochastic simulations (n = 1,000) of an evaluated pharmacokinetic meropenem model, and a defined pharmacokinetic/pharmacodynamic target (100%T(>4×MIC) while minimum concentrations were 90% was considered adequate. The observed MIC distribution significantly differed from the EUCAST database. Based on the 6,520 MIC values included, a three-level dosing algorithm was developed. If the pathogen causing the infection is unknown (level 1), known (level 2), known to be neither Pseudomonas aeruginosa nor Acinetobacter baumannii, or classified as susceptible (level 3), a continuous infusion of 1.5 g daily reached sufficient target attainment independent of renal function. In all other cases, dosing needs to be adjusted based on renal function. ICU-specific susceptibility data should be assessed regularly and integrated into dosing decisions. The presented workflow may serve as a blueprint for other antimicrobial settings.

Pneumonia is one of the most common infections in intensive care patients, and it is often treated with beta-lactam antibiotics. Even if therapeutic drug monitoring in blood is available, it is unclear whether sufficient concentrations are reached at the target site: the lung. The present study was initiated to fill this knowledge gap. Various compartments from 10 patients' explanted lungs were subjected to laboratory analysis. Meropenem was quantified in serum, bronchoalveolar lavage (BAL) fluid, microdialysate, and homogenized lung tissue with isotope dilution liquid chromatography tandem mass spectrometry (ID-LC-MS/MS). BAL fluid represents diluted epithelial lining fluid (ELF), and microdialysate represents interstitial fluid (IF). Differences between target site and blood concentrations were investigated. The median meropenem concentration in blood, ELF, IF, and tissue were 26.8, 18.0, 12.1, and 9.1 mg/liter, respectively. A total of 37.5% of the target site ELF and IF meropenem concentrations were below the clinical EUCAST breakpoint of 8 mg/liter. The median ELF/serum quotient was 61.8% (interquartile range [IQR], 24.8% to 87.6%), the median IF/serum quotient was 35.4% (IQR, 23.8% to 54.3%), and the median tissue/serum quotient was 34.2% (IQR, 28.3% to 38.2%). We observed a substantial interindividual variability between the blood and the compartments (ELF and IF), whereas the intraindividual variability was relatively low. Target site measurement in different lung compartments was feasible and successfully applied in a clinical setting. A relevant amount of 37.5% of the target site concentrations were below the clinical EUCAST breakpoint, indicating subtherapeutic dosing in high-risk patients receiving perioperative antibiotic prophylaxis in lung transplantation. (This study has been registered at ClinicalTrials.gov under identifier NCT03970265.).

The aim of this study was to investigate optimal loading doses prior to continuous infusion of meropenem in critically ill patients. A previously published and successfully evaluated pharmacokinetic model of critically ill patients was used for stochastic simulations of virtual patients. Maintenance doses administered as continuous infusion of 1.5–6 g/24 h with preceding loading doses (administered as 30 min infusion) of 0.15–2 g were investigated. In addition to the examination of the influence of individual covariates, a best-case and worst-case scenario were simulated. Dosing regimens were considered adequate if the 5th percentile of the concentration–time profile did not drop at any time below four times the S/I breakpoint (= 2 mg/L) of Pseudomonas aeruginosa according to the EUCAST definition. Low albumin concentrations, high body weight and high creatinine clearances increased the required loading dose. A maximum loading dose of 0.33 g resulted in sufficient plasma concentrations when only one covariate showed extreme values. If all three covariates showed extreme values (= worst-case scenario), a loading dose of 0.5 g was necessary. Higher loading doses did not lead to further improvements of target attainment. We recommend the administration of a loading dose of 0.5 g meropenem over 30 min immediately followed by continuous infusion.

BACKGROUND Posaconazole and itraconazole are commonly used for systemic antifungal prophylaxis after lung transplantation. The aim of this study on critically ill lung transplant recipients was to assess the rate of adequate plasma concentrations and the frequency of fungal-induced transitions from antifungal prophylaxis to therapy after the administration of either posaconazole or itraconazole for systemic prophylaxis. METHODS Critically ill lung transplant recipients with postoperative posaconazole or itraconazole prophylaxis and therapeutic drug monitoring from February 2016 to November 2019 were retrospectively included in the study. Positive fungal cultures or Aspergillus antigen tests resulting in a transition from antifungal prophylaxis to therapy were analyzed from the first day of prophylaxis until 7 days after the last sample for each patient. Adequate plasma concentrations were defined as ≥500 µg/L for itraconazole and ≥700 µg/L for posaconazole. RESULTS Two hundred seventy-five samples from 73 patients were included in the analysis. Overall, 60% of the posaconazole and 55% of the itraconazole concentrations were subtherapeutic. Administration of posaconazole suspension resulted significantly (P

Purpose Optimization of antibiotic therapy is still urgently needed in critically ill patients. The aim of the ONTAI survey (online survey on the use of Therapeutic Drug Monitoring of antibiotics in intensive care units) was to evaluate which strategies intensive care physicians in Germany use to improve the quality of antibiotic therapy and what role a Therapeutic Drug Monitoring (TDM) plays. Methods Among the members of the German Society for Anaesthesiology and the German Society for Medical Intensive Care Medicine and Emergency Medicine, a national cross-sectional survey was conducted using an online questionnaire. Results The questionnaire was completely answered by 398 respondents. Without TDM, prolonged infusion was judged to be the most appropriate dosing regimen for beta lactams. A TDM for piperacillin, meropenem and vancomycin was performed in 17, 22 and 75% of respondents, respectively. For all beta lactams, a TDM was requested more often than it was available. There was great uncertainty as to the optimal pharmacokinetic/pharmacodynamic index for beta-lactams. 86% of the respondents who received minimal inhibitory concentrations adapted the therapy accordingly. Conclusion German intensive care physicians are convinced of TDM for dose optimization. However, practical implementation, the determination of MICs and defined target values are still lacking.

Background Therapeutic drug monitoring (TDM) of beta-lactam antibiotics has become a valuable tool to guide dosing in critically ill patients. The main goal of the study was to compare two routinely used techniques for beta-lactam TDM in intensive care unit (ICU) patient samples, namely isotope dilution liquid chromatography tandem mass spectrometry (ID-LC-MS/MS) and high-performance liquid chromatography combined with ultra-violet detection (HPLC-UV). Methods A set of 80 sera/plasma samples from ICU patients receiving therapeutic meropenem or piperacillin dosage was investigated. Sample duplicates and quality assessment samples were assayed in parallel with an in-house LC-MS/MS and a commercially available IVD HPLC-UV kit. A pharmacokinetic and pharmacodynamic (PK/PD) target with ≥ 22.5 mg/L for piperacillin and ≥ 8.0 mg/L for meropenem was used for medical assessment of trough sample (n = 40) antibiotic concentrations. Results There was no difference between serum and Li-heparin plasmas. Concentration deviations were found for 4% of meropenem and 17% of piperacillin samples. Eliminating the influence of the systemic bias of approximately 10% for piperacillin, measurement discrepancies ≥ 25% between LC-MS/MS and HPLC-UV analyses were only observed for ≈ 4 - 6% of all samples. In the same way, identical PK/PD target attainment rates of 50 - 60% could be obtained. Conclusions After correction of the analytical bias for piperacillin measurements, both methods showed comparable results, also with respect to clinical decision limits. HPLC-UV analysis is an adequate TDM methodology for testing of beta-lactam antibiotics in centers where no special knowledge in LC-MS/MS based TDM is present. However, potential matrix effects, interferences, and calibration issues for both methods must be taken into account.

Highlights • Multi-analyte LC–MS/MS method for the quantification of repurposed COVID-19 drugs in human serum. • Two-dimensional chromatography combined with isotope dilution standardization. • Rapid and robust analysis applicable to therapeutic drug monitoring (TDM)., Background The present COVID-19 pandemic has prompted worldwide repurposing of drugs. The aim of the present work was to develop and validate a two-dimensional isotope-dilution liquid chromatrography tandem mass spectrometry (ID-LC–MS/MS) method for accurate quantification of remdesivir and its active metabolite GS-441524, chloroquine, hydroxychloroquine, lopinavir, ritonavir, favipiravir and azithromycin in serum; drugs that have gained attention for repurposing in the treatment of COVID-19. Methods Following protein precipitation, samples were separated with a two-dimensional ultra-high performance liquid chromatography (2D-UHPLC) setup, consisting of an online solid phase extraction (SPE) coupled to an analytical column. For quantification, stable isotope-labelled analogues were used as internal standards for all analytes. The method was validated on the basis of the European Medicines Agency bioanalytical method validation protocol. Results Detuning of lopinavir and ritonavir allowed simultaneous quantification of all analytes with different concentration ranges and sensitivity with a uniform injection volume of 5 μL. The method provided robust validation results with inaccuracy and imprecision values of ≤ 9.59 % and ≤ 11.1 % for all quality controls. Conclusion The presented method is suitable for accurate and simultaneous quantification of remdesivir, its metabolite GS-441525, chloroquine, hydroxychloroquine, lopinavir, ritonavir, favipiravir and azithromycin in human serum. The quantitative assay may be an efficient tool for the therapeutic drug monitoring of these potential drug candidates in COVID-19 patients in order to increase treatment efficacy and safety.

Introduction The aim of this project was to develop and validate an isotope-dilution liquid chromatography high resolution mass spectrometry (LC-HRMS) method for the quantification of the 11 most widely used systemic antimycotics and to study whether HRMS is a feasible alternative for therapeutic drug monitoring (TDM) when compared to tandem MS (MS/MS) technology. Methods After protein precipitation, followed by automated online sample clean-up the analytes were separated within 4 min on a C18 column using an acetonitrile-water gradient. Eleven antimycotics, namely 5-flucytosine, amphotericin B, anidulafungin, fluconazole, isavuconazole, itraconazole, ketoconazole, micafungin, OH-itraconazole, posaconazole and voriconazole were finally quantified in full MS scan mode using positive electrospray ionization (ESI +) with a mass range fromm/z 110–1300 using HRMS. The method was comprehensively validated on the basis of the European Medicines Agengy (EMA) method validation protocol using commercially available IVD kit components. Results Good linear relationship between peak area responses and drug concentrations (R2 > 0.995) and excellent selectivity were observed for all antimycotics in this study. Inaccuracy and imprecision of all quality controls were consistently below ± 12.6% and ± 8.1%, respectively. Quantification results were in agreement with an IVD LC–MS/MS method. Conclusion HRMS was shown to be suitable for TDM of small molecules when compared to tandem mass spectrometry. The novel HRMS method is quickly installed and may be a robust and reliable tool for routine TDM of antimycotics in clinical laboratories.

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.

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.

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

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.