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Effective dosing of isavuconazole in patients supported by extracorporeal membrane oxygenation (ECMO) is important due to the role of isavuconazole as a first-line treatment in patients with influenza- and COVID-19-associated pulmonary aspergillosis. To date, robust pharmacokinetic data in patients supported by ECMO are limited. Therefore, it is unknown whether ECMO independently impacts isavuconazole exposure. We measured isavuconazole plasma concentrations in two patients supported by ECMO and estimated individual pharmacokinetic parameters using non-compartmental analysis and two previously published population pharmacokinetic models. Furthermore, a narrative literature review on isavuconazole exposure in adult patients receiving ECMO was performed. The 24 h areas under the concentration–time curve and trough concentrations of isavuconazole were lower in both patients compared with exposure values published before. In the literature, highly variable isavuconazole concentrations have been documented in patients with ECMO support. The independent effect of ECMO versus critical illness itself on isavuconazole exposure cannot be deduced from our and previously published (case) reports. Pending additional data, therapeutic drug monitoring is recommended in critically ill patients, regardless of ECMO support.

AIMS: It is currently unclear how paracetamol should be dosed in order to increase its efficacy while warranting safety in very old adults. The objective was to evaluate the pharmacokinetics of 2 oral paracetamol formulations and its metabolites in hospitalized octogenarians. METHODS: Geriatric inpatients aged 80 years and older received a 1000-mg paracetamol tablet or granulate at 08.00, 14.00 and 20.00. After at least 4 consecutive gifts, plasma samples were collected around the 08.00 dose (trough, +0.5, +1, +2, +4, +5 and +6 h). Plasma concentrations of paracetamol and its metabolites were determined and individual pharmacokinetic parameters were derived. The Edmonton Frail Scale was used to assess frailty. An analgesic plasma target was defined as an average plasma concentration (Cavg ) of 10 mg/L. RESULTS: The mean (±standard deviation) age was 86.78 (±4.20) years. The majority (n = 26/36, 72%) received the tablet, 10 (28%) the granulate. Thirty patients (85%) were classified with moderate to severe frailty. Seven (21%) patients had a Cavg above 10 mg/L. The median [interquartile range] time to reach the peak concentration was 50.5 [31.50-92.50] and 42.50 [33.75-106.75] min for the tablet and granulate, respectively. The coefficient of variation was 95% for time to reach the peak concentration and 30% for Cavg of paracetamol. A correlation of Cavg of paracetamol was observed with female sex and total serum bilirubin. CONCLUSION: Large interindividual differences were found for pharmacokinetic parameters of oral paracetamol in frail inpatients after multiple dosing. Female sex and higher total serum bilirubin concentrations were associated with paracetamol exposure. No significant differences were observed between the tablet and granulate. ispartof: BRITISH JOURNAL OF CLINICAL PHARMACOLOGY vol:88 issue:3 pages:1020-1030 ispartof: location:England status: published

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Colistin (polymyxin E) is a polycation antibiotic which is increasingly used (administered as colistin methanesulfonate, CMS) as a salvage therapy in critically ill patients with multidrug resistant Gram-negative infections. Even though colistin has been used for more than 50 years, its metabolic fate is poorly understood. One of the current challenges for studying the pharmacokinetics (PK) is the precise and accurate determination of colistin in in vitro and in vivo studies. In the present study, we developed and validated a series of sensitive and robust liquid chromatography tandem mass spectrometry (LC-MS/MS) methods for analysing biological samples obtained from in vitro and in vivo disposition assays. After a zinc acetate-mediated precipitation, hydrophilic-lipophilic-balanced solid phase extraction (HLB-SPE) was used for the extraction of colistin. The compounds were retained on a hydrophilic interaction liquid chromatography (HILIC) column and were detected by MS/MS. CMS was quantified by determining the produced amount of colistin during acidic hydrolysis. The developed methods are sensitive with lower limits of quantification varying between 0.009 μg/mL and 0.071 μg/mL for colistin A, and 0.002 μg/mL to 0.013 μg/mL for colistin B. The intra- and inter-day precision and accuracy were within ±15%. Calibration curves of colistin were linear (0.063 μg/mL to 8.00 μg/mL) within clinically relevant concentration ranges. Zinc acetate-mediated precipitation and the use of a HILIC column were found to be essential. The developed methods are sensitive, accurate, precise, highly efficient and allow monitoring colistin and CMS in biological samples without the need for an internal standard.

Objectives PTA of protein-unbound ceftriaxone may be compromised in critically ill patients with community-acquired pneumonia (CAP) with augmented renal clearance (ARC). We aimed to determine an optimized ceftriaxone dosage regimen based on the probability of developing ARC on the next day (PARC,d+1; www.arcpredictor.com). Patients and methods Thirty-three patients enrolled in a prospective cohort study were admitted to the ICU with severe CAP and treated with ceftriaxone 2 g once daily. Patients contributed 259 total ceftriaxone concentrations, collected during 1 or 2 days (±7 samples/day). Unbound fractions of ceftriaxone were determined in all peak and trough samples (n = 76). Population pharmacokinetic modelling and simulation were performed using NONMEM7.4. Target attainment was defined as an unbound ceftriaxone concentration >4 mg/L throughout the dosing interval. Results A two-compartment population pharmacokinetic model described the data well. The maximal protein-bound ceftriaxone concentration decreased with lower serum albumin. Ceftriaxone clearance increased with body weight and PARC,d+1 determined on the previous day. A high PARC,d+1 was identified as a clinically relevant predictor for underexposure on the next day (area under the receiver operating characteristics curve 0.77). Body weight had a weak predictive value and was therefore considered clinically irrelevant. Serum albumin had no predictive value. An optimal PARC,d+1 threshold of 5.7% was identified (sensitivity 73%, specificity 69%). Stratified once- or twice-daily 2 g dosing when below or above the 5.7% PARC,d+1 cut-off, respectively, was predicted to result in 81% PTA compared with 47% PTA under population-level once-daily 2 g dosing. Conclusions Critically ill patients with CAP with a high PARC,d+1 may benefit from twice-daily 2 g ceftriaxone dosing for achieving adequate exposure on the next day.

Matthias Gijsen,1,2 Omar Elkayal,1 Pieter Annaert,1,3 Ruth Van Daele,1,2 Philippe Meersseman,4 Yves Debaveye,4 Joost Wauters,4 Erwin Dreesen,1 Isabel Spriet1,2 1Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium; 2Pharmacy Department, University Hospitals Leuven, Leuven, Belgium; 3BioNotus, Niel, Belgium; 4Department of Cellular and Molecular Medicine, KU Leuven, Leuven, BelgiumCorrespondence: Matthias GijsenPharmacy Department, University Hospitals Leuven, Herestraat 49, Leuven, 3000, BelgiumTel +32 16 340087Fax +32 16 343080Email mathias.gijsen@uzleuven.bePurpose: Critically ill patients with preserved or increased renal function have been shown to be at risk of underexposure to meropenem. Although many meropenem population pharmacokinetic (PK) models have been published, there is no large prospective population PK study with rich sampling focusing on patients most at risk of suboptimal pharmacokinetic/pharmacodynamic (PK/PD) target attainment. Therefore, the aim of the present study was to evaluate PK/PD target attainment and to perform a thorough covariate screening using population PK modelling of meropenem in septic patients with preserved or increased renal function.Patients and Methods: A single-centre prospective observational PK study was performed in the intensive care unit (ICU) of the University Hospitals Leuven. Patients with severe sepsis or septic shock and treated with meropenem in the ICU were screened for inclusion. Patients were excluded if they received renal replacement therapy or had an estimated glomerular filtration rate according to the Chronic Kidney Disease Epidemiology collaboration equation < 70 mL/min/1.73m2 on the day of PK sampling. Successful PK/PD target attainment was defined as an unbound meropenem trough concentration above 2 mg/L or 8 mg/L. Population PK modelling was performed with NONMEM7.4.Results: In total, 58 patients were included, contributing 345 plasma samples over 70 dosing intervals. The 2 mg/L and 8 mg/L targets were successfully attained in 46% and 11% of all dosing intervals, respectively. A two-compartment population PK model with linear elimination and interindividual variability on clearance best described meropenem PK. The estimated creatinine clearance according to the Cockcroft-Gault equation was the only covariate retained during population PK analysis.Conclusion: This study provided detailed insight into meropenem PK in critically ill patients with preserved or increased renal function. We observed poor PK/PD target attainment, for which renal function was the only significant covariate.Trial Registration: This study is registered at ClinicalTrials.gov (NCT03560557).Keywords: intensive care, PK/PD, exposure, dose optimization, augmented renal clearance

Children show important developmental and maturational changes, which may contribute greatly to pharmacokinetic (PK) variability observed in pediatric patients. These PK alterations are further enhanced by disease-related, non-maturational factors. Specific to the intensive care setting, such factors include critical illness, inflammatory status, augmented renal clearance (ARC), as well as therapeutic interventions (e.g., extracorporeal organ support systems or whole-body hypothermia [WBH]). This narrative review illustrates the relevance of both maturational and non-maturational changes in absorption, distribution, metabolism, and excretion (ADME) applied to antibiotics. It hereby provides a focused assessment of the available literature on the impact of critical illness-in general, and in specific subpopulations (ARC, extracorporeal organ support systems, WBH)-on PK and potential underexposure in children and neonates. Overall, literature discussing antibiotic PK alterations in pediatric intensive care is scarce. Most studies describe antibiotics commonly monitored in clinical practice such as vancomycin and aminoglycosides. Because of the large PK variability, therapeutic drug monitoring, further extended to other antibiotics, and integration of model-informed precision dosing in clinical practice are suggested to optimise antibiotic dose and exposure in each newborn, infant, or child during intensive care. ispartof: ANTIBIOTICS-BASEL vol:10 issue:10 ispartof: location:Switzerland status: published

Existing evidence is inconclusive whether meropenem dosing should be adjusted in patients receiving extracorporeal membrane oxygenation (ECMO). Therefore, the aim of this observational matched cohort study was to evaluate the effect of ECMO on pharmacokinetic (PK) variability and target attainment (TA) of meropenem. Patients admitted to the intensive care unit (ICU) simultaneously treated with meropenem and ECMO were eligible. Patients were matched 1:1, based on renal function and body weight, with non-ECMO ICU patients. Meropenem blood sampling was performed over one or two dosing intervals. Population PK modelling was performed using NONMEM7.5. TA was defined as free meropenem concentrations &gt, 2 or 8 mg/L (i.e., 1 or 4× minimal inhibitory concentration, respectively) throughout the whole dosing interval. In total, 25 patients were included, contributing 27 dosing intervals. The overall TA was 56% and 26% for the 2 mg/L and 8 mg/L target, respectively. Population PK modelling identified estimated glomerular filtration rate according to the Chronic Kidney Disease Epidemiology equation and body weight, but not ECMO, as significant predictors. In conclusion, TA of meropenem was confirmed to be poor under standard dosing in critically ill patients but was not found to be influenced by ECMO. Future studies should focus on applying dose optimisation strategies for meropenem based on renal function, regardless of ECMO.

There are concerns about the stability of meropenem in plasma samples, even when frozen at -20 °C. Previous smaller studies suggested significant degradation of meropenem at -20 °C after 3-20 days. However, in several recent clinical studies, meropenem plasma samples were still stored at -20 °C, or the storage temperature and/or time were not mentioned in the paper. The aim of this study was to describe and model meropenem degradation in human plasma at -20 °C over 1 year. Stability of meropenem in human plasma at -20 °C was investigated at seven concentrations (0.44, 4.38, 17.5, 35.1, 52.6, 70.1, and 87.6 mg/L) representative for the range of relevant concentrations encountered in clinical practice. For each concentration, samples were stored for 0, 7, 14, 21, 28, 42, 56, 70, 84, 112, 140, 168, 196, 224, 252, 280, 308, 336, and 364 days at -20 °C before being transferred to -80 °C until analysis. Degradation was modeled using polynomial regression analysis and artificial neural network (ANN). Meropenem showed significant degradation over time in human plasma when stored at -20 °C. Degradation was present over the whole concentration range and increased with higher concentrations until a concentration of 35.1 mg/L. Both models showed accurate prediction of meropenem degradation. In conclusion, this study provides detailed insights into the concentration-dependent degradation of meropenem in human plasma stored at -20 °C over 1 year. Meropenem in human plasma is shown to be stable at least up to approximately 80 days when stored at -20 °C. The polynomial model allows calculating original meropenem concentrations in samples stored for a known period of time at -20 °C. ispartof: ANTIBIOTICS-BASEL vol:10 issue:4 ispartof: location:Switzerland status: published

Background: Voriconazole is an antifungal drug used as one of the first-line treatments for invasive aspergillosis. This drug is extensively metabolized, predominantly via cytochrome P450 enzymes. An interaction between flucloxacillin and voriconazole, leading to subtherapeutic voriconazole concentrations, has previously been reported. We aimed to demonstrate that flucloxacillin independently influences voriconazole exposure. Methods: Patients from three Belgian hospitals, treated with a combination of voriconazole and flucloxacillin, were included in this retrospective study. Voriconazole concentrations were collected both in a timeframe with and without flucloxacillin co-treatment. Multivariate analyses were performed to study the independent effect of flucloxacillin treatment on voriconazole exposure and the possible influence of the flucloxacillin dose. Results: Thirty-three patients were included in this study and 145 trough concentrations (51 with, and 94 without concomitant flucloxacillin treatment) were analyzed. The median (IQR) voriconazole trough concentration sampled during flucloxacillin co-treatment was 0.5 (0–1.8) mg/L, whereas samples without flucloxacillin co-treatment had a median (IQR) voriconazole trough concentration of 3.5 (1.7–5.1) mg/L (p = 0.002), while receiving similar voriconazole doses. Subtherapeutic concentrations (&lt, 1 mg/L) were observed in 69% and 7% of the samples with flucloxacillin co-treatment versus samples without flucloxacillin co-treatment, respectively. Conclusion: This study shows that flucloxacillin co-treatment independently decreases voriconazole exposure. Caution is needed when these two drugs are administered simultaneously.

INTRODUCTION: Little is known about the use of bioelectrical impedance analysis (BIA) in critically ill patients. The objective of this study was to evaluate the reproducibility of BIA measurements by comparing non-dominant versus dominant body-side measurements at 2 separate time points in healthy volunteers in order to extrapolate key elements that may be of relevance in critically ill patients. MATERIAL AND METHODS: A prospective observational validation experiment was carried out in healthy volunteers. Full-body and segmental multiple frequency BIA measurements were carried out at the non-dominant and the dominant body side, consecutively, and on 2 separate occasions within 1 week. Parameters of interest were both raw data (impedance and phase angle) at the individual frequencies (5-50-100-200 kHz) and body fluid compartment volume estimations (total body water, extracellular water volume, intracellular water volume, volume excess). RESULTS: A total of 42 measurements were performed in 22 volunteers. Median (interquartile range) age and time between measurements was 26 years (24; 35) and 2.07 days (1.00; 2.99), respectively. The intraclass-correlation coefficients (ICCs) for body fluid compartment volumes estimated by full-body BIA, were greatly above 90%, showing excellent agreement, except for volume excess which showed moderate agreement. Full-body raw impedance and phase angle measurements showed highly variable and much lower ICCs. For both estimated body fluid compartment volumes and raw measurements, segmental BIA showed also highly variable and low ICCs. CONCLUSIONS: Overall this study showed that in healthy volunteers, BIA-derived fluid parameters are reproducible, and differences can be attributed to the changes in clinical status. ispartof: ANAESTHESIOLOGY INTENSIVE THERAPY vol:53 issue:3 pages:193-199 ispartof: location:Poland status: published

Background Posaconazole is an antifungal drug used for prophylaxis and treatment of invasive fungal infections. Severe influenza has been identified as a risk factor for invasive pulmonary aspergillosis in critically ill patients. In this population, extracorporeal membrane oxygenation (ECMO) is used as rescue therapy, although little is known about the pharmacokinetics (PK) of posaconazole during ECMO. Objectives To determine the PK and target attainment of six patients treated with IV posaconazole under ECMO and to develop a population PK model that can be used to simulate the PTA. Methods Critically ill patients treated with posaconazole and ECMO were included in this study. Plasma samples were collected at several timepoints within one dosing interval on two occasions: an early (Day 2–3) and a late (Day 4–7) sampling day. Daily trough concentrations were measured. Results The median (IQR) AUC0–24, CL and Vd were 34.3 (28.3–37.7) mg·h/L, 8.7 (8.0–10.6) L/h and 389 (314–740) L, if calculated with non-compartmental analysis based on the observed concentrations. All measured trough concentrations were ≥0.7 mg/L and 11/16 were ≥1 mg/L, which are the haematological thresholds for prophylaxis and treatment of invasive aspergillosis, respectively. The targeted PTA (>90%) was attained for prophylaxis but not for treatment. Conclusions ECMO does not appear to influence posaconazole exposure compared with haematology patients. However, some trough levels were below the lower limit for treatment. An a priori dose adjustment does not appear to be necessary but drug monitoring is recommended.

Objectives Augmented renal clearance might lead to subtherapeutic plasma levels of drugs with predominant renal clearance. Early identification of augmented renal clearance remains challenging for the ICU physician. We developed and validated our augmented renal clearance predictor, a clinical prediction model for augmented renal clearance on the next day during ICU stay, and made it available via an online calculator. We compared its predictive performance with that of two existing models for augmented renal clearance. Design Multicenter retrospective registry-based cohort study. Setting Three Belgian tertiary care academic hospitals. Patients Adult medical, surgical, and cardiac surgery ICU patients. Interventions None. Measurements and main results Development of the prediction model was based on clinical information available during ICU stay. Out of 33,258 ICU days, we found augmented renal clearance on 19.6% of all ICU days in the development cohort. We retained six clinical variables in our augmented renal clearance predictor: day from ICU admission, age, sex, serum creatinine, trauma, and cardiac surgery. We assessed performance by measuring discrimination, calibration, and net benefit. We externally validated the final model in a single-center population (n = 10,259 ICU days). External validation confirmed good performance with an area under the curve of 0.88 (95% CI 0.87-0.88) and a sensitivity and specificity of 84.1 (95% CI 82.5-85.7) and 76.3 (95% CI 75.4-77.2) at the default threshold probability of 0.2, respectively. Conclusions Augmented renal clearance on the next day can be predicted with good performance during ICU stay, using routinely collected clinical information that is readily available at bedside. Our augmented renal clearance predictor is available at www.arcpredictor.com.

Cefepime is a first-line antibiotic for the treatment of febrile neutropenia (FN) in haematological cancer patients. Therapeutic drug monitoring (TDM) of cefepime is frequently advocated. However, it remains unclear what range of concentrations should be targeted for maximal efficacy and minimal toxicity. Therefore, we examined the relationship between cefepime exposure and clinical efficacy or neurotoxicity in FN patients. This prospective, observational, single-centre study included all adult hospitalised patients presenting with FN at the haematology ward and treated with cefepime from August 2019 until October 2020. Primary outcomes were incidence of breakthrough infection and neurotoxicity and their relationship with free cefepime serum trough concentrations. A total of 76 patients were included, contributing 96 cefepime treatment courses. The median (interquartile range) estimated glomerular filtration rate according to the Chronic Kidney Disease Epidemiology Collaboration equation (eGFRCKD-EPI) and free cefepime trough concentration were 101 (85-112) mL/min/1.73m2 and 8.6 (4.9-16.2) mg/L, respectively. Interpatient and intrapatient variability in cefepime trough concentrations was largely explained by renal function. No cefepime-related breakthrough infections occurred during cefepime treatment. Neurotoxicity, probably induced by cefepime administration, occurred during 6/96 (6.3%) treatment courses. Patients with neurotoxicity showed a significant trend for higher trough concentrations (median 15.4 mg/L vs. 8.6 mg/L; P 1 mg/L.

ispartof: CRITICAL CARE vol:24 issue:1 ispartof: location:England status: published

Background Therapeutic drug monitoring for cefepime is increasingly being performed because of the potential relation between exposure and neurotoxicity. An in vitro pilot study suggested significant carryover of cefepime from central venous catheters when blood sampling is carried out via the same catheter used for administration of cefepime. Therefore, the aim of this study was to evaluate carryover of cefepime in a real-life clinical setting. Methods A prospective single-center study was conducted at the hematology department of the University Hospitals Leuven. Patients treated with cefepime, and having a central venous catheter, were included. Cefepime trough samples were taken simultaneously via the central venous catheter and peripheral venepuncture. Results Twenty-four patients were included in this study, resulting in 28, 11 and 5 paired samples for tunnelled catheters, implantable port catheters and peripherally inserted central catheters, respectively. No statistically nor clinically significant difference was found between cefepime concentrations measured in centrally versus peripherally obtained blood samples, overall and for all three types of central venous catheters separately. Of note, four paired samples showed a difference larger than 10%, with lower central concentrations probably reflecting a dilution error. Conclusion There was no significant carryover of cefepime from long-term central venous catheters. Cefepime samples can be drawn reliably via the central venous catheter, after flushing and discarding the first blood sample. Although, flushing and discard volumes should be standardized to avoid potential dilution errors.

BackgroundAugmented renal clearance (ARC) might lead to subtherapeutic plasma levels of drugs with predominant renal clearance. Early identification of ARC remains challenging for the intensive care unit (ICU) physician. We developed and validated the ARC predictor, a clinical prediction model for ARC on the next day during ICU stay, and made it available via an online calculator. Its predictive performance was compared with that of two existing models for ARC.MethodsA large multicenter database including medical, surgical and cardiac ICU patients (n = 33258 ICU days) from three Belgian tertiary care academic hospitals was used for the development of the prediction model. Development was based on clinical information available during ICU stay. We assessed performance by measuring discrimination, calibration and net benefit. The final model was externally validated (n = 10259 ICU days) in a single-center population.ResultsARC was found on 19.6% of all ICU days in the development cohort. Six clinical variables were retained in the ARC predictor: day from ICU admission, age, sex, serum creatinine, trauma and cardiac surgery. External validation confirmed good performance with an area under the curve of 0.88 (95% CI 0.87 – 0.88), and a sensitivity and specificity of 84.1 (95% CI 82.5 – 85.7) and 76.3 (95% CI 75.4 – 77.2) at the default threshold probability of 0.2, respectively.ConclusionARC on the next day can be predicted with good performance during ICU stay, using routinely collected clinical information that is readily available at bedside. The ARC predictor is available at www.arcpredictor.com.

WHAT IS KNOWN AND OBJECTIVES: Formulae estimating glomerular filtration rate (GFR) are frequently used to guide drug dosing. The objectives of this prospective single-center study were to evaluate agreement between these equations and measured creatinine clearance (CrCl) in non-critically ill surgery patients with normal kidney function and augmented renal clearance (ARC, CrCl ≥ 130 mL/min/1.73 m²), to determine predictors for disagreement, define a GFR estimator cut-off value identifying ARC and determine the ARC prevalence and duration in non-critically ill surgical patients. METHODS: Hospitalized adult non-critically ill abdominal and trauma surgery patients were eligible for inclusion. Measured CrCl based on an 8-hour urinary collection (CrCl8h ) was used as the primary method for determining kidney function. Agreement between equations and measured CrCl8h was assessed in terms of precision, defined as a bias within ±10 mL/min/1.73 m². Predictors for disagreement were identified for the most precise estimator using an ordinal logistic regression model with negative bias, agreement and positive bias as outcome variables. A receiver operating characteristic (ROC) analysis was performed to identify an estimator cut-off predicting ARC, which was subsequently applied for the daily proportion of patients displaying ARC and ARC duration. RESULTS AND DISCUSSION: During the study period (14/11/2013 - 13/05/2014), in 232 adult non-critically ill abdominal and trauma surgery patients, all estimators tend to underestimate CrCl8h (mean bias ranging from 17 to 22 mL/min/1.73 m²), especially in patients displaying ARC (mean bias ranging from 44 to 56 mL/min/1.73 m²). eGFRCKD-EPI performed the best. Younger age and low ASA score independently predicted underestimation of CrCl8h . Three different eGFRCKD-EPI cut-offs with decreasing sensitivity and increasing specificity (84, 95 and 112 mL/min/1.73 m²) identified, respectively, 65%, 44% and 14% patients displaying ARC. The median ARC duration was 4, 4 and 3 days, respectively. WHAT IS NEW AND CONCLUSION: In surgical patients, eGFR frequently underestimates measured CrCl, especially in young patients with low ASA score. eGFR cut-offs predicting ARC were identified. ispartof: JOURNAL OF CLINICAL PHARMACY AND THERAPEUTICS vol:43 issue:5 pages:695-706 ispartof: location:England status: published

The impact of ceftriaxone pharmacokinetic alterations on protein binding and PK/PD target attainment still remains unclear. We evaluated pharmacokinetic/pharmacodynamic (PK/PD) target attainment of unbound ceftriaxone in critically ill patients with severe community-acquired pneumonia (CAP). Besides, we evaluated the accuracy of predicted vs. measured unbound ceftriaxone concentrations, and its impact on PK/PD target attainment. A prospective observational cohort study was carried out in adult patients admitted to the intensive care unit with severe CAP. Ceftriaxone 2 g q24h intermittent infusion was administered to all patients. Successful PK/PD target attainment was defined as unbound trough concentrations above 1 or 4 mg/L throughout the whole dosing interval. Acceptable overall PK/PD target attainment was defined as successful target attainment in ≥90% of all dosing intervals. Measured unbound ceftriaxone concentrations (CEFu) were compared to unbound concentrations predicted from various protein binding models. Thirty-one patients were included. The 1 mg/L and 4 mg/L targets were reached in 26/32 (81%) and 15/32 (47%) trough samples, respectively. Increased renal function was associated with the failure to attain both PK/PD targets. Unbound ceftriaxone concentrations predicted by the protein binding model developed in the present study showed acceptable bias and precision and had no major impact on PK/PD target attainment. We showed suboptimal (i.e., &lt, 90%) unbound ceftriaxone PK/PD target attainment when using a standard 2 g q24h dosing regimen in critically ill patients with severe CAP. Renal function was the major driver for the failure to attain the predefined targets, in accordance with results found in general and septic ICU patients. Interestingly, CEFu was reliably predicted from CEFt without major impact on clinical decisions regarding PK/PD target attainment. This suggests that, when carefully selecting a protein binding model, CEFu does not need to be measured. As a result, the turn-around time and cost for ceftriaxone quantification can be substantially reduced.

ispartof: INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS vol:57 issue:5 ispartof: location:Netherlands status: published