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In the intensive care unit (ICU), infection-related mortality is high. Although adequate antibiotic treatment is essential in infections, beta-lactam target non-attainment occurs in up to 45% of ICU patients, which is associated with a lower likelihood of clinical success. To optimize antibiotic treatment, we aimed to develop beta-lactam target non-attainment prediction models in ICU patients. Patients from two multicenter studies were included, with intravenous intermittent beta-lactam antibiotics administered and blood samples drawn within 12–36 h after antibiotic initiation. Beta-lactam target non-attainment models were developed and validated using random forest (RF), logistic regression (LR), and naïve Bayes (NB) models from 376 patients. External validation was performed on 150 ICU patients. We assessed performance by measuring discrimination, calibration, and net benefit at the default threshold probability of 0.20. Age, sex, serum creatinine, and type of beta-lactam antibiotic were found to be predictive of beta-lactam target non-attainment. In the external validation, the RF, LR, and NB models confirmed good discrimination with an area under the curve of 0.79 [95% CI 0.72–0.86], 0.80 [95% CI 0.73–0.87], and 0.75 [95% CI 0.67–0.82], respectively, and net benefit in the RF and LR models. We developed prediction models for beta-lactam target non-attainment within 12–36 h after antibiotic initiation in ICU patients. These online-accessible models use readily available patient variables and help optimize antibiotic treatment. The RF and LR models showed the best performance among the three models tested., Statistics

In the intensive care unit (ICU), infection-related mortality is high. Although adequate antibiotic treatment is essential in infections, beta-lactam target non-attainment occurs in up to 45% of ICU patients, which is associated with a lower likelihood of clinical success. To optimize antibiotic treatment, we aimed to develop beta-lactam target non-attainment prediction models in ICU patients. Patients from two multicenter studies were included, with intravenous intermittent beta-lactam antibiotics administered and blood samples drawn within 12–36 h after antibiotic initiation. Beta-lactam target non-attainment models were developed and validated using random forest (RF), logistic regression (LR), and naïve Bayes (NB) models from 376 patients. External validation was performed on 150 ICU patients. We assessed performance by measuring discrimination, calibration, and net benefit at the default threshold probability of 0.20. Age, sex, serum creatinine, and type of beta-lactam antibiotic were found to be predictive of beta-lactam target non-attainment. In the external validation, the RF, LR, and NB models confirmed good discrimination with an area under the curve of 0.79 [95% CI 0.72–0.86], 0.80 [95% CI 0.73–0.87], and 0.75 [95% CI 0.67–0.82], respectively, and net benefit in the RF and LR models. We developed prediction models for beta-lactam target non-attainment within 12–36 h after antibiotic initiation in ICU patients. These online-accessible models use readily available patient variables and help optimize antibiotic treatment. The RF and LR models showed the best performance among the three models tested.

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 (P-ARC,P-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 P-ARC,P-d+1 determined on the previous day. A high P-ARC,P-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 P-ARC,P-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% P-ARC,P-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 P-ARC,P-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 interv

We aimed to evaluate the predictive performance and predicted doses of a single-model approach or several multi-model approaches compared with the standard therapeutic drug monitoring (TDM)-based vancomycin dosing. We performed a hospital-wide monocentric retrospective study in adult patients treated with either intermittent or continuous vancomycin infusions. Each patient provided two randomly selected pairs of two consecutive vancomycin concentrations. A web-based precision dosing software, TDMx, was used to evaluate the model-based approaches. In total, 154 patients contributed 308 pairs. With standard TDM-based dosing, only 48.1% (148/308) of all of the second concentrations were within the therapeutic range. Across the model-based approaches we investigated, the mean relative bias and relative root mean square error varied from −5.36% to 3.18% and from 24.8% to 28.1%, respectively. The model averaging approach according to the squared prediction errors showed an acceptable bias and was the most precise. According to this approach, the median (interquartile range) differences between the model-predicted and prescribed doses, expressed as mg every 12 h, were 113 [−69; 427] mg, −70 [−208; 120], mg and 40 [−84; 197] mg in the case of subtherapeutic, supratherapeutic, and therapeutic exposure at the second concentration, respectively. These dose differences, along with poor target attainment, suggest a large window of opportunity for the model-based TDM compared with the standard TDM-based vancomycin dosing. Implementation studies of model-based TDM in routine care are warranted.

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., <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 ne

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., SCOPUS: ar.j, info:eu-repo/semantics/published

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.