IntroductionModel-Informed Precision Dosing (MIPD) is increasingly used to optimize vancomycin therapy in critically ill patients. However, process evaluations randomized controlled trials (RCTs) of MIPD remain rare, particularly in neonatal and pediatric intensive care. They provide however valuable insights about how and why interventions work.AimThis study explored healthcare professionals' (HCPs) experiences with using the MIPD software for vancomycin during the BENEFICIAL-RCT in critically ill children and examined contextual factors influencing its use.MethodA qualitative descriptive exploratory study was conducted after the BENEFICIAL-RCT in 8 Belgian hospitals. Semi-structured interviews and focus groups were held between January and May 2025 with physicians, clinical pharmacists, clinical biologists, and trial nurses. Data were analyzed thematically.ResultsTwenty-one HCPs participated. Four overarching themes emerged: enhanced clinical confidence and professional empowerment, experienced workflow barriers, clinical and healthcare-system implications and conditions for sustained MIPD-adoption. Participants described that beyond faster attainment of target AUC, the software fostered professional empowerment through its visualizations and the ability to retain final decision authority. Experiences also underscored how infrequent clinical exposure to adopting MIPD hindered continuity of MIPD expertise. This was pertinent in settings with low vancomycin case volumes or frequent rotating medical staff. As experienced workflow barriers especially the pivotal role of nurses in ensuring accurate documentation of sampling and infusion times was mentioned. These documentation uncertainties were perceived as affecting trust in the dosing workflow. Participants also highlighted night-time operational challenges for which workarounds set up during the RCT would not be feasible for routine practice. Concerning conditions for sustained MIPD-implementation, HCPs emphasized the importance of MIPD integration in electronic health records and automated dose calculation. The need for local MIPD champions was recurrently emphasized, particularly to support onboarding of new HCPs in MIPD.ConclusionThe results highlight that to support broader implementation of MIPD in pediatric critical care, hospitals should prioritize electronic record integration, streamline workflows, and appoint internal MIPD champions. These measures may reduce workload and errors, and support sustainable use in daily practice.

Background and ObjectiveAccurate assessment of the glomerular filtration rate (GFR) is crucial in critically ill children, yet standard estimation formulas (eGFR) perform poorly, especially in the youngest. Iohexol plasma clearance is the reference standard for measured GFR; however, its routine use is limited by logistical constraints. This study aims to develop and internally validate a population pharmacokinetic model of iohexol in critically ill children, to derive a practical model-based GFR estimation formula (eGFRiohexol), and to compare its predictive performance against established eGFR formulas (eGFRSchwartz, eGFRSmeets/Pierce).MethodsAfter administration of iohexol, up to six blood samples were drawn from 107 patients over a 6-hour interval. Data from 93 patients were used for model building, and from 31 patients for internal validation. Reference clearances were obtained using the post hoc Bayesian clearance estimates. Predictive performances of eGFRiohexol, eGFRSchwartz, and eGFRSmeets/Pierce were compared with reference clearances using bias, imprecision, Total Deviation Index, concordance correlation coefficient, and the percentage of predictions within 10 and 30% error (P10, P30) around reference clearances.ResultsThe final model identified body surface area, serum creatinine, cystatin C, postoperative status, and clonidine treatment as significant predictors of iohexol clearance. eGFRiohexol demonstrated minimal bias (-0.8%) and imprecision (21%) and high accuracy (P30 = 87%), particularly in patients under 2 years of age (P30 = 90 vs 40% for eGFRSchwartz). Furthermore, eGFRiohexol also demonstrated superiority over eGFRSmeets/Pierce, which exhibited moderate bias (-5.4%) and reduced accuracy (P30 = 68%).ConclusionsA model-derived GFR estimation formula based on iohexol population pharmacokinetic modeling might allow for an accurate bedside assessment of kidney function in critically ill children, outperforming the Schwartz and Smeets/Pierce formulas, particularly in infants. External validation in larger pediatric intensive care unit populations, across the full age and GFR range, is warranted to confirm the generalizability of this equation and its potential for broader clinical application.Clinical Trial RegistrationClinicalTrials.gov NCT05179564, registered retrospectively on 5 January, 2022.

OBJECTIVES:Optimal ciprofloxacin dosing in critically ill children is influenced by complex factors affecting drug disposition, including pathophysiological changes and supportive therapies. This study aimed to develop a population pharmacokinetic (PK) model for ciprofloxacin in critically ill children to identify predictors of interindividual variability, evaluate target attainment for both total and unbound exposure, and provide tailored dosing recommendations. METHODS:A prospective, open-label, multicentric PK study was conducted in 44 critically ill children (<16 years) receiving intravenous ciprofloxacin. Blood and urine samples were collected at two dosing occasions (10 mg/kg every 12 hours) and drug concentrations were assessed in plasma (total and unbound concentrations) and urine. PK parameters were analysed with population PK modelling. Probability of target attainment (PTA) was calculated based on the free or total area under the curve (AUC) and was simulated for different doses of ciprofloxacin. RESULTS:Ciprofloxacin PK was best described with an allometrically scaled two-compartment model. Typical fraction unbound ciprofloxacin in plasma, and the fraction excreted unchanged in urine were estimated to be 0.52 (IQR: 0.49-0.56) and 0.89 (IQR: 0.54-0.95), respectively. Clearance was found to be positively influenced by the glomerular filtration rate and negatively influenced when children were on mechanical ventilation. For a MIC of 0.25 mg/L, the study dose achieved a PTA of 75.3% for unbound exposure (fAUC/MIC >72 hours) and 79.7% for total exposure (AUC/MIC >125 hours). Adequate PTA (≥90%) requires 10 mg/kg every 12 hours in ventilated patients and 15 mg/kg every 8 hours (off-label) in nonventilated patients with normal renal function (80-130 mL/min/1.73m2). DISCUSSION:Standard dosing regimens of ciprofloxacin (20-30 mg/kg per day) fail to achieve adequate target attainment in nonventilated critically ill children with a normal or elevated renal function. Further research should prospectively evaluate the efficacy and safety of intensified ciprofloxacin dosing regimens.

Background AUC-based dosing with validated Bayesian software is recommended as a good approach to guide bedside vancomycin dosing.Objectives To compare treatment and vancomycin-associated acute kidney injury (AKI) costs between Bayesian AUC-based dosing and conventional therapeutic drug monitoring (TDM) using steady-state plasma concentrations of vancomycin administered as continuous infusion in hospitalized non-critically ill patients with severe Gram-positive infection.Methods A cost-benefit analysis presented as a return on investment (ROI) analysis from a hospital perspective was conducted using a decision tree model (TDM versus AUC-based dosing) to simulate treatment cost (personnel, serum sampling and drug cost), vancomycin-associated AKI risk and cost up to 14 days. ROI was calculated against AUC-based software cost. One-way and probabilistic sensitivity analyses (respectively OWSA and PSA) were performed to check for robustness.Results In base case, an overall cost per patient of 621.0 with TDM and 543.6 with AUC-based dosing resulted in a treatment saving of 77.4 per patient when applying AUC-based dosing. This saving against the software cost (26.9/patient) generated an ROI per patient of 1.9 per invested in software [1.9 (95% CI 1.6-2.2) in PSA]. Enrolling 900 AUC-based dosed patients annually translated to a net saving of 45 469. Software break-even was reached after 313 patients. In OWSA, a higher AKI risk with TDM strongly contributed to a positive ROI.Conclusions AUC-based dosing appeared a cost-saving strategy compared with conventional TDM when applying base-case settings of vancomycin-associated AKI risk, treatment and AKI costs.

OBJECTIVE:Children who undergo cardiac surgery are prone to postoperative infections for which amoxicillin-clavulanate is a cornerstone antibiotic. Nevertheless, amoxicillin-clavulanate pharmacokinetics have not been studied in infants and children after cardiac surgery so far. Antibiotic exposure might be highly variable in this population due to the impact of growth, maturation, and specific pathophysiological and surgery-induced alterations. The objective of this study was to develop evidence-based amoxicillin-clavulanate dosing recommendations based on population pharmacokinetic analysis and probability of target attainment simulations in children after cardiac surgery. METHODS:Critically ill children (aged 1 day to 15 y) who underwent cardiac surgery and who were treated postoperatively with amoxicillin-clavulanate (30-60 mg/kg/6 h based on the amoxicillin component, infused in 30 min) were included. Up to five amoxicillin and clavulanate blood samples were collected per dose at predefined sampling times. Population pharmacokinetics analysis was performed using nonlinear mixed effects modelling software NONMEM. RESULTS:We collected 316 amoxicillin and 287 clavulanate blood samples from 37 patients. A three-compartment model for amoxicillin and a two-compartment model for clavulanate best described pharmacokinetics, with allometric weight scaling and maturation functions added a priori to scale for size and age. Clearance estimates were remarkably high, except in patients receiving vasopressors, which decreased clearance of amoxicillin-clavulanate by a third. Using a pharmacokinetic/pharmacodynamic target of 50%fT>MIC of 8 mg/L, patients not on vasopressors warranted 4-hourly dosing to achieve adequate drug exposure due to augmented amoxicillin clearance. Only in patients treated with vasopressors was the standard 6-hourly dosing regimen sufficient to attain amoxicillin concentrations above the MIC for half of the dosing interval. CONCLUSIONS:Current amoxicillin-clavulanate dosing regimens for critically ill children after cardiac surgery need to be updated to avoid subtherapeutic concentrations and clinical failure due to augmented clearance (ClinicalTrials.gov NCT02456974).

INTRODUCTION:β-Lactams are the most widely used antibiotics in children. Their optimal dosing is essential to maximize their efficacy, while minimizing the risk for toxicity and the further emergence of antimicrobial resistance. However, most β-lactams were developed and licensed long before regulatory changes mandated pharmacokinetic studies in children. As a result, pediatric dosing practices are poorly harmonized and off-label use remains common today. AREAS COVERED:β-Lactam pharmacokinetics and dose optimization strategies in pediatrics, including fixed dose regimens, therapeutic drug monitoring, and model-informed precision dosing are reviewed. EXPERT OPINION/COMMENTARY:Standard pediatric doses can result in subtherapeutic exposure and non-target attainment for specific patient subpopulations (neonates, critically ill children, e.g.). Such patients could benefit greatly from more individualized approaches to dose optimization, beyond a relatively simple dose adaptation based on weight, age, or renal function. In this context, Therapeutic Drug Monitoring (TDM) and Model-Informed Precision Dosing (MIPD) emerge as particularly promising avenues. Obstacles to their implementation include the lack of strong evidence of clinical benefit due to the paucity of randomized clinical trials, of standardized assays for monitoring concentrations, or of adequate markers for renal function. The development of precision medicine tools is urgently needed to individualize therapy in vulnerable pediatric subpopulations.

Data published on the oral clavulanic acid pharmacokinetics in the pediatric population is lacking. This research aimed to describe clavulanic acid disposition following oral and intravenous administration and to provide insights into clavulanic acid exposure based on threshold concentrations for (pre-)term neonates and infants. This pooled population pharmacokinetic study combined four datasets for analysis in NONMEM v7.4.3. Clavulanic acid exposure was simulated using the percentage of time above the threshold concentrations (%fT > CT). Multiple dosage regimens and amoxicillin/clavulanic acid dosage ratios were evaluated. The cohort consisted of 89 (42 oral, 47 intravenous) subjects (403 samples) with a median (range) postnatal age 54.5 days (0-365), gestational age 37.4 weeks (23.0-41.7), and current bodyweight 3.9 kg (0.6-9.0). A one-compartment model with first-order absorption best described clavulanic acid pharmacokinetics with postnatal age as a covariate on the inter-individual variability of clearance. Oral bioavailability was 24.4% in neonates up to 10 days of age. An oral dosing regimen 90 mg/kg/day amoxicillin/clavulanic acid (4:1 ratio) resulted in 40.2% of simulated patients achieving 100% fT > CT,2mg/L. An amoxicillin/clavulanic acid ratio of 4:1 is preferred for neonatal oral regimens due to the higher exposure along the entire %fT > CT range (0-100%) as ratios higher than 4:1 might result in inadequate exposure. Our results highlight substantial exposure differences (%fT > CT) when using threshold concentrations of 1 mg/L vs. 2 mg/L. This first population pharmacokinetic model for clavulanic acid in neonates may serve as a foundational step for future research, once more precise clavulanic acid targets become available.

Knowledge of clinical pharmacology concepts is essential to improve patients’ outcomes. Scarce data is available on the utilisation of these concepts in the paediatric intensive care unit (PICU). We aimed to investigate the self-perceived knowledge of clinical pharmacology concepts, educational needs and identify priorities for pharmacological research across European PICUs. From July to November 2022 an online survey was distributed to evaluate i) the self-reported knowledge, and ii) application of key pharmacology concepts in clinical practice (using a likert scale from 1 = never apply to 10 = always apply); iii) need for additional education on them; and iv) key areas for future pharmacological research. The survey was distributed to European Society of Paediatric and Neonatal Intensive Care (ESPNIC) members and other European national PICUs societies members. Two-hundred-thirty-seven responses from 149 PICUs were collected. 54

Prospective audit with feedback during infectious diseases ward rounds (IDWR) is a common antimicrobial stewardship (AMS) practice on the Paediatric Intensive Care Unit (PICU). These interdisciplinary meetings rely on the quality of handover, with high risk of omission of information. We developed an electronic platform integrating infection-related patient data (COSARAPed). In the mixed PICU of a Belgian tertiary hospital we conducted an observational prospective cohort study comparing patient handovers during IDWRs using the COSARAPed-platform to those with access only to conventional resources. The quality of handover was investigated directly by assessment if the narrative was in accordance with Situation-Background-Assessment-Recommendation principles and if adequate demonstration of diagnostic information occurred, and also indirectly by registration if this was only achieved after intervention by the non-presenting AMS team members. We also recorded all AMS-recommendations. During a 6-month study period, 24 IDWRs and 82 patient presentations were assessed. We could only find a statistically significant advantage in favor of COSARAPed by indirect evaluation. We registered 92 AMS-recommendations, mainly resulting in reduced antibiotic pressure. We concluded that the IDWR is an appropriate platform for AMS on the PICU and that the utilisation of COSARAPed may enhance the quality of patient handover.

Background and ObjectiveDrug dosing should ideally be based on the drug concentrations at the target site, which, for most drugs, corresponds to the tissue. The exact influence of growth and development on drug tissue distribution is unclear. This systematic review compiles the current knowledge on the tissue distribution of systemically applied drugs in children, with the aim to identify priorities in tissue pharmacokinetic (PK) research in this population.MethodsA systematic literature search was performed in the MEDLINE and Embase databases.ResultsForty-two relevant articles were identified, of which 71% investigated antibiotics, while drug classes from the other studies were anticancer drugs, antifungals, anthelmintics, sedatives, thyreostatics, immunomodulators, antiarrhythmics, and exon skipping therapy. The majority of studies (83%) applied tissue biopsy as the sampling technique. Tonsil and/or adenoid tissue was most frequently examined (70% of all included patients). The majority of studies had a small sample size (median 9, range 1-93), did not include the youngest age categories (neonates and infants), and were of low reporting quality. Due to the heterogeneous data from different study compounds, dosing schedules, populations, and target tissues, the possibility for comparison of PK data between studies was limited.ConclusionThe influence of growth and development on drug tissue distribution continues to be a knowledge gap, due to the paucity of tissue PK data in children, especially in the younger age categories. Future research in this field should be encouraged as techniques to safely investigate drug tissue disposition in children are available.

Vancomycin is a commonly prescribed antibiotic to treat serious Gram-positive infections in children. The efficacy of vancomycin is known to be directly related to the pharmacokinetic/pharmacodynamic (PK/PD) index of the area under the concentration–time curve (AUC) divided by the minimal inhibitory concentration (MIC) of the pathogen. In most countries, steady-state plasma concentrations are used as a surrogate parameter for this target AUC/MIC, but this practice has some drawbacks. Hence, AUC-based dosing using model-informed precision dosing (MIPD) tools has been proposed for increasing the target attainment rate and reducing vancomycin-related nephrotoxicity. Solid scientific evidence for these claimed benefits is lacking in children. This randomized controlled trial aims to investigate the large-scale utility of MIPD dosing of vancomycin in critically ill children. Participants from 14 neonatal intensive care, pediatric intensive care, and pediatric hemo-oncology ward units from 7 hospitals are randomly allocated to the intervention or standard-of-care comparator group. In the intervention group, a MIPD dosing calculator is used for AUC-based dosing, in combination with extra sampling for therapeutic drug monitoring in the first hours of treatment, as compared to standard-of-care. An AUC24h between 400 and 600 is targeted, assuming an MIC of 1 mg/L. Patients in the comparator group receive standard-of-care dosing and monitoring according to institutional guidelines. The primary endpoint is the proportion of patients reaching the target AUC24h/MIC of 400–600 between 24 and 48 h after the start of vancomycin treatment. Secondary endpoints are the proportion of patients with (worsening) acute kidney injury during vancomycin treatment, the proportion of patients reaching target AUC24h/MIC of 400–600 between 48 and 72 h after the start of vancomycin treatment, time to clinical cure, ward unit length-of-stay, hospital length-of-stay, and 30-day all-cause mortality. This trial will clarify the propagated benefits and provide new insights into how to optimally monitor vancomycin treatment in critically ill children. Eudract number: 2019–004538-40. Registered on 2020–09-08 ClinicalTrials.gov NCT046666948. Registered on 2020–11-28

The pharmacokinetics (PK) of piperacillin/tazobactam (PIP/TAZ) is highly variable across different patient populations and there are controversies regarding non-linear elimination as well as the fraction unbound of PIP (fUNB_PIP). This has led to a plethora of subgroup-specific models, increasing the risk of misusing published models when optimising dosing regimens. In this study, we aimed to develop a single model to simultaneously describe the PK of PIP/TAZ in diverse patient populations and evaluate the current dosing recommendations by predicting the PK/pharmacodynamics (PD) target attainment throughout life. Population PK models were separately built for PIP and TAZ based on data from 13 studies in various patient populations. In the development of those single-drug models, postnatal age (PNA), postmenstrual age (PMA), total body weight (TBW), height, and serum creatinine (SCR) were tested as covariates. Subsequently, a combined population PK model was established and the correlations between the PK of PIP and TAZ were tested. Monte Carlo simulations were performed based on the final combined model to evaluate the current dosing recommendations. The final combined model for PIP/TAZ consisted of four compartments (two for each drug), with covariates including TBW, PMA, and SCR. For a 70-kg, 35-year-old patient with SCR of 0.83 mg L−1, the PIP values for V1, CL, V2 and Q2 were 10.4 L, 10.6 L h−1, 11.6 L and 15.2 L h−1, respectively, and the TAZ values were 10.5 L, 9.58 L h−1, 13.7 L and 16.8 L h−1, respectively. The CL for both drugs show maturation in early life, reaching 50

OBJECTIVES:Flucloxacillin has the most narrow spectrum to treat staphylococcal infections, but has a large variability in bioavailability which hampers its intravenous (iv) to oral switch. To identify patients with adequate absorption, the use of an oral absorption test (OAT) measuring total plasma concentrations of flucloxacillin before and after an oral dose of 1 gram flucloxacillin, was previously published. The current pilot study aims to evaluate the fraction of patients with adequate absorption using a similar OAT; to assess the therapeutic consequences and to identify potential factors associated with adequate absorption. METHODS:Demographic data of adult patients treated with iv flucloxacillin and requiring prolonged therapy were collected retrospectively between May 2020 and November 2021 at Ghent University Hospital. A previously published OAT protocol was used, with addition of a protocol for intermittent dosing of iv flucloxacillin. Adequate absorption was defined as an increase in plasma concentration of at least 10 mg/L. RESULTS:The flucloxacillin OAT was performed in 99 patients, of which 62% were men, with a median age of 58 years and 95% received intermittent dosing of iv flucloxacillin. Of the 99 patients, 55% had a result indicating an adequate absorption and 49% of all patients were switched to oral flucloxacillin afterwards. Inadequate absorption was found to be associated with higher Body Mass Index and higher flucloxacillin baseline concentration, while co-administration of acetylsalicylic acid was associated with an adequate absorption. CONCLUSIONS:Based on the OAT, 49% of all patients were switched to oral flucloxacillin instead of broader-spectrum anti-staphylococcal antibiotics. This implicates that an OAT could be a valuable antimicrobial stewardship measure by restricting the use of broad-spectrum antibiotics. For each of the associations found, a hypothesis was formulated about the underlying reason or mechanism; these should be confirmed in future studies with prospective and multicentric design.

Background and ObjectiveThe interstitial fluid of tissues is the effect site for antibiotics targeting extracellular pathogens. Microdialysis studies investigating these concentrations in muscle and subcutaneous tissue have reported notable variability in tissue penetration. This study aimed to comprehensively summarise the existing data on interstitial fluid penetration in these tissues and to identify potential factors influencing antibiotic distribution.MethodsA literature review was conducted, focusing on subcutaneous and intramuscular microdialysis studies of antibiotics in both adult healthy volunteers and patients. Random-effect meta-analyses were used to aggregate effect size estimates of tissue penetration. The primary parameter of interest was the unbound penetration ratio, which represents the ratio of the area under the concentration-time curve in interstitial fluid relative to the area under the concentration-time curve in plasma, using unbound concentrations.ResultsIn total, 52 reports were incorporated into this analysis. The unbound antibiotic exposure in the interstitial fluid of healthy volunteers was, on average, 22% lower than in plasma. The unbound penetration ratio values were higher after multiple dosing but did not significantly differ between muscle and subcutaneous tissue. Unbound penetration ratio values were lower for acids and bases compared with neutral antibiotics. Neither the molecular weight nor the logP of the antibiotics accounted for the variations in the unbound penetration ratio. Obesity was associated with lower interstitial fluid penetration. Conditions such as sepsis, tissue inflammation and tissue ischaemia were not significantly associated with altered interstitial fluid penetration.ConclusionsThis study highlights the variability and generally lower exposure of unbound antibiotics in the subcutaneous and intramuscular interstitial fluid compared with exposure in plasma. Future research should focus on understanding the therapeutic relevance of these differences and identify key covariates that may influence them.

Background Vancomycin is a commonly prescribed antibiotic to treat gram-positive infections. The efficacy of vancomycin is known to be directly related to the pharmacokinetic/pharmacodynamic (PK/PD) index of the area under the concentration-time curve (AUC) divided by the minimal inhibitory concentration (MIC) of the pathogen. However, in most countries, steady-state plasma concentrations are used as a surrogate parameter of target AUC/MIC, but this practice has some drawbacks. Hence, direct AUC-guided monitoring of vancomycin using model-informed precision dosing (MIPD) tools has been proposed for earlier attainment of target concentrations and reducing vancomycin-related nephrotoxicity. However, solid scientific evidence for these benefits in clinical practice is still lacking. This randomized controlled trial (RCT) aims to investigate the clinical utility of MIPD dosing of vancomycin administered via continuous infusion in hospitalized adults. Methods Participants from 11 wards at two Belgian hospitals are randomly allocated to the intervention group or the standard-of-care comparator group. In the intervention group, clinical pharmacists perform dose calculations using CE-labeled MIPD software and target an AUC24h of 400 to 600 mg × h/L, whereas patients in the comparator group receive standard-of-care dosing and monitoring according to the institutional guidelines. The primary endpoint is the proportion of patients reaching the target AUC24h/MIC of 400–600 between 48 and 72 h after start of vancomycin treatment. Secondary endpoints are the proportion of patients with (worsening) acute kidney injury (AKI) during and until 48 h after stop of vancomycin treatment, the proportion of patients reaching target AUC24h/MIC of 400–600 between 72 and 96 h after start of vancomycin treatment, and the proportion of time within the target AUC24h/MIC of 400–600. Discussion This trial will clarify the propagated benefits and provide new insights into how to optimally monitor vancomycin treatment. Trial registration EudraCT number: 2021-003670-31. Registered June 28, 2021. ClinicalTrials.gov identifier: NCT05535075. Registered September 10, 2022. Protocol version 3, protocol date: April 21, 2023.

Objectives: Knowledge on the tissue penetration of piperacillin-tazobactam in children with sepsis is lack -ing. In this study, the feasibility and performance of microdialysis experiments were explored in septic piglets and children as part of a translational research project.Methods: Multiple-day microdialysis investigations were performed in muscle tissue of 22 piglets (of which 11 were septic) and 6 children with sepsis. An in vitro experiment preceded the (pre)clinical trials to derive optimal experimental settings and calibration technique. Linear mixed-effects models quanti-fied the impact of sepsis on relative recovery (RR) and intercatheter, interindividual, interoccasion, and residual variability.Results: In vivo microdialysis was well tolerated in piglets and children, with no significant adverse events reported. Using identical experimental settings, lower RR values were recorded in healthy and septic piglets (range: piperacillin, 17.2-29.1% and tazobactam, 23.5-29.1%) compared with the in vitro experiment (piperacillin, 43.3% and tazobactam, 55.3%), and there were unacceptably low values in chil-dren with sepsis ( < 10%). As a result, methodological changes were made in the pediatric trial. Realistic tissue concentration-time curves were derived in piglets and children. In piglets, sepsis reduced the RR. The greatest contributors to RR variability were residual ( > 40%) and interoccasion ( > 30%) variability. The internal standard method was the preferred calibration technique in both piglets and children.Conclusions: Microdialysis is a safe and applicable method for the measurement of tissue drug concen-trations in piglets and children. This study demonstrated the impact of experimental settings, sepsis, and target population on individual RR.(c) 2023 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.

Therapeutic drug monitoring (TDM) requires a multidisciplinary approach with different stakeholders (nurse, bio-analyst, pharmacist, pharmacologist, pharmacometrician, physician). In recent years, a pharmacist-guided TDM dosing advice service, mainly for anti-infective therapy, has been installed at the Ghent University Hospital, a tertiary hospital in Flanders, Belgium. From this experience, advantages, pitfalls and opportunities for centralized TDM services are being summarized. Together with the previous talk, this talk will serve as a basis for discussion with the audience.

(Patho)physiological changes in older people may influence the pharmacokinetics (PK), and consequently the target attainment, of ß-lactam antibiotics using standard dosing regimens. This systematic review compiles the current knowledge on the PK and target attainment of ß-lactam antibiotics in older people, with the aim to identify priorities for dose optimization in this patient population. A systematic literature search of the PubMed and EMBASE databases was conducted. Relevant articles published prior to 1 December 2021 were identified as eligible when they included data on the PK of ß-lactam antibiotics in adults ≥ 65 years of age. Extracted information included reported PK parameters (volume of distribution, clearance [CL], elimination rate constant, intercompartmental CL, elimination half-life, area under the concentration-time curve, maximum and trough concentration), covariates on PK parameters, target attainment rate, and dosing recommendations. Ninety-one relevant articles were included in this review. Four main ß-lactam subclasses were represented: 59.3

Abstract Background Model-informed precision dosing can streamline the dosing individualization of vancomycin in patients with severe bacterial infections. Yet, currently utilized models are limited to predicting the pharmacokinetics (PK). In this study, a pharmacometric model was developed that described the longitudinal relationship between PK and CRP after continuous infusion of vancomycin. Subsequently, its forecasting performance was evaluated. Methods In a clinical dataset in 67 patients with sepsis, the PK was linked to the CRP time courses using a turnover model with an effect compartment. For the forecasting analysis, scenarios with different numbers of TDM samples were tested to investigate how many are needed for valid predictions of future (unobserved) PK and CRP samples. Results Overall, the developed pharmacometric model described the PK and CRP data well, except sudden CRP increases potentially occurring due to other effects than the treated infection. The half maximal effective concentration of vancomycin was estimated to be 20.3 mg/L (95 % CI= 18.9 - 21.5 mg/L). The usage of just one CRP concentration from routine clinical data led to imprecise predictions. The inclusion of a single vancomycin concentration improved the predictive performance, but a second plasma sample of vancomycin and CRP was required to increase accuracy and precision significantly.Figure 3.Comparison of the predictive performance of the model for the pharmacokinetics (PK) and pharmacodynamics (PD) of future (unobserved) data using the relative bias and the relative root mean squared error when different amounts of information (observed data from 0-3 or all occasions) were provided to the model. Conclusion The present study corroborates the currently used therapeutic range for continuously infused vancomycin of 20-25 mg/L. The future tendency of the time course of up to 14 (range: 1-14) CRP measurements and vancomycin concentrations with a given vancomycin therapy regime was adequately predicted when at least two measurements of CRP and vancomycin were provided to the model, in particular if the tendency of CRP was increasing or decreasing was predicted well. These predictions are only trustworthy if there are no other events with an influence on the CRP concentration. Further biomarkers with a higher specificity for bacterial infections should be investigated or the model needs to be refined to handle such events. Disclosures All Authors: No reported disclosures

Journal of Veterinary Pharmacology and TherapeuticsVolume 46, Issue S1 p. 32-32 ORAL PRESENTATIONS O9 | Antibiotic tissue penetration in the septic piglet versus the child – Lessons learnt from microdialysis First published: 11 June 2023 https://doi.org/10.1111/jvp.13175Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. Volume46, IssueS1Special Issue: 15th International Congress of the European Association for Veterinary Pharmacology and Toxicology held Bruges, Belgium, July 2–5, 2023June 2023Pages 32-32 RelatedInformation