BACKGROUND:Vancomycin is widely used to treat serious Gram-positive infections but is difficult to dose given its narrow therapeutic index and risk of acute kidney injury at high doses. We aimed to study whether model-informed precision dosing (MIPD) of vancomycin, compared with standard-of-care therapeutic drug monitoring (TDM), increases pharmacokinetic and pharmacodynamic target attainment, is safe, and reduces vancomycin-associated acute kidney injury in children with severe illness. METHODS:The BENEFICIAL trial is a pragmatic, individually randomised, controlled superiority trial done in 14 paediatric or neonatal intensive care and haemato-oncology units in seven hospitals in Belgium. Critically ill patients younger than 18 years initiating intravenous vancomycin for suspected or confirmed Gram-positive infection were eligible. Key exclusion criteria were extracorporeal support, severe acute kidney injury, chronic kidney disease, and imminent death. The intervention combined the use of an MIPD dosing calculator for starting and follow-up doses, with extra sampling for TDM in the first hours of treatment compared with standard-of-care TDM. Patients were randomly assigned (1:1) to MIPD or standard-of-care TDM of vancomycin using stratified permuted blocks by ward type. Allocation occurred via a secure web interface; patients, families, and the biostatistician were masked, but treating physicians and pharmacist staff were not. The intervention used Bayesian software with early sampling to estimate AUC. The primary outcome was the proportion of patients with a 24-h AUC-to-MIC ratio of 400-600 mg·h/L, assuming a minimum inhibitory concentration of 1 mg/L, 24-48 h after treatment initiation. A key secondary outcome was the proportion of patients with new or worsening acute kidney injury or death. These outcomes were assessed in the intention-to-treat (ITT) population (all randomly assigned patients who provided informed consent). Safety was evaluated in all patients who received at least one dose of vancomycin. This trial is registered with ClinicalTrials.gov (NCT04666948) and the EU Clinical Trials register (EudraCT 2019-004538-40), and is closed to recruitment. FINDINGS:Between Dec 28, 2020, and Dec 14, 2023, 332 patients aged between 1 day and 18 years were randomly assigned, 165 to the standard-of-care group and 167 to the intervention group. 18 participants were excluded from the analysis when their deferred consent was not followed by informed consent; therefore 314 patients (179 male and 135 female) were included in the analysis. Target AUC-to-MIC ratio attainment at 24-48 h was found in 82 (53·9%) of 152 patients with available data in the standard-of-care group and 112 (71·8%) of 156 in the MIPD group (absolute difference 18·9% [1·7 to 34·7]). The proportion of patients with acute kidney injury or all-cause mortality was numerically but not significantly lower in the intervention group (26 [16·9%] of 154 vs 19 [12·4%] of 153; absolute difference -4·5% [95% CI -11·6 to 3·5]). Serious adverse events occurred in eight (5%) of 158 patients in the standard-of-care group and eight (5%) of 156 patients in the intervention group. One patient in the intervention group died due to a serious adverse event at least possibly related to the vancomycin administration method. INTERPRETATION:AUC-based MIPD improves AUC-to-MIC ratio-based target attainment and has a low risk of harm. Given that elevated vancomycin AUC is a well established driver of acute kidney injury, the lower cumulative exposure observed in this trial support the use of MIPD in severely ill children, particularly in those who require long treatment durations or present with additional acute kidney injury risk factors. FUNDING:Belgian Federal Knowledge Centre Trials Programme.

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.

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 Critical illness may affect many pharmacokinetic (PK) processes. Research in adults suggests an impaired tissue penetration of beta-lactam antibiotics in critically ill patients compared to healthy individuals. Currently, data in critically ill children are lacking. This study aimed (1) to investigate the tissue penetration of piperacillin-tazobactam, a frequently used broad-spectrum beta-lactam/beta-lactamase inhibitor combination and (2) to assess the safety of microdialysis experiments in critically ill children. Methodology This pilot study included seven mechanically ventilated children (age range: 1 month - 13 years) receiving piperacillin-tazobactam (75 mg per kg bodyweight, based on the piperacillin component, every 6 h as a 30 min infusion). A microdialysis catheter (10 mm membrane) was inserted in the thigh muscle. Benzylpenicillin was used as internal standard for microdialysis calibration. During one or two dosing intervals, plasma and microdialysis samples were collected (max. stay of microdialysis catheter: 35 h). PK data were analyzed with non-compartmental PK analysis (Phoenix®, Certara). The tissue penetration was calculated by taking the ratio of the AUC(0-inf) in tissue and in plasma. Results In total, 12 dosing intervals were sampled. Median tissue penetration was 0.68 (IQR 0.55 – 0.84) for piperacillin and 1.10 (0.92 – 1.38) for tazobactam. The extrapolated part of the AUC(0-inf) accounted for less than 20% of the total AUC(0-inf). No adverse events occurred during microdialysis catheter insertion, microdialysis sampling, and catheter removal. Conclusion To the best of our knowledge, this study is the first to report on tissue penetration of piperacillin-tazobactam in critically ill children. Similarly to what was found in critically ill adult patients (septic shock cohort (Joukhadar 2001): mean 0.19 ± SE 0.03/post cardiac surgery cohort (Brunner 2000): mean 0.27 ± SE 0.04), the tissue penetration of piperacillin is impaired in critically ill children, albeit to a lesser extent than what has been reported in critically ill adults. These findings underscore the limitations of plasma as a surrogate for tissue exposure in critical illness. Contrary to general belief, this study shows that piperacillin and tazobactam have a different PK behavior, with a good tissue penetration of the beta-lactamase inhibitor. Microdialysis is a safe and feasible method for tissue pharmacokinetic research in critically ill children.

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.

Unfractionated heparin is the most used anticoagulative agent for extracorporeal settings in children, including acute hemodialysis modalities. In certain situations, such as heparin-induced thrombocytopenia, alternatives must be applied. The direct thrombin inhibitor bivalirudin has come forth as an attractive substitute. Bivalirudin is currently only approved for adult use in specific percutaneous coronary intervention settings. However, it has a growing off-label popularity in different contexts for both adult and pediatric patients. Experience with bivalirudin in children is mainly limited to extracorporeal membrane oxygenation, ventricular assist devices and during cardiopulmonary bypass surgery. Literature about its use as anticoagulation strategy for pediatric hemodialysis is very scarce. Here, we present two pediatric cases where bivalirudin was used during acute hemodialysis, followed by a short summary of recent literature.

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.

Introduction Augmented renal clearance(ARC) of hydrophilic drugs is frequent in PICU patients and warrants adjustment of standard dosing regimens to prevent therapeutic failure. Knowledge of patient-, disease- and therapy-related factors associated with ARC, would allow to predict before the start of treatment, which patients would benefit from higher drug doses. We aimed to identify predictors of ARC in critically ill children with normal serum creatinine(Scr) using iohexol plasma clearance (CLiohexol) to quantify renal function. Methods We performed a post hoc analysis of data collected from an interventional study conducted at our academic PICU, which measured glomerular filtration rate (GFR) by CLiohexol in patients with normal Scr. ARC was defined as GFR exceeding normal values for age plus 2 standard deviations. Multivariable logistic regression analysis was performed to identify predictors of ARC. Results GFR was measured in 85 patients, median age was 16 [IQR 5;89] months, 59% had a surgical profile. Median CLiohexol was 122[IQR 75;152] ml/min/1.73m2. Fourthy patients out of 85 (47%) expressed ARC. Postoperative status was identified as independent predictor of ARC (p=0.014, OR 4.253, 95%CI 1.338–13.517). However, in patients after cardiac surgery the odds of developing ARC were significantly lower (p=0.010, OR 0.163, 95%CI 0.041 –0.644). There was a trend suggesting more ARC in male patients and in those without need for vaso-active drugs, however, this was not statistically significant. Conclusion Our findings raise clinicians’ awareness about ARC potentially being present in children after major surgery. This knowledge allows to anticipate on enhanced elimination of drugs by using empirically adjusted dosing regimens immediately from the start of treatment.

Augmented renal clearance (ARC) holds a risk of subtherapeutic drug concentrations. Knowledge of patient-, disease-, and therapy-related factors associated with ARC would allow predicting which patients would benefit from intensified dosing regimens. This study aimed to identify ARC predictors and to describe ARC time-course in critically ill children, using iohexol plasma clearance (CLiohexol) to measure glomerular filtration rate (GFR). This is a retrospective analysis of data from the “IOHEXOL” study which validated GFR estimating formulas (eGFR) against CLiohexol. Critically ill children with normal serum creatinine were included, and CLiohexol was performed as soon as possible after pediatric intensive care unit (PICU) admission (CLiohexol1) and repeated (CLiohexol2) after 48–72 h whenever possible. ARC was defined as CLiohexol exceeding normal GFR for age plus two standard deviations. Eighty-five patients were included; 57

Accurate renal function assessment is crucial to guide intensive care decision-making and drug dosing. Estimates of glomerular filtration rate (eGFR) are routinely used in critically ill children; however, these formulas were never evaluated against measured GFR (mGFR) in this population. We aimed to assess the reliability of common eGFR formulas compared to iohexol plasma clearance (CLiohexol) in a pediatric intensive care (PICU) population. Secondary outcomes were the prevalence of acute kidney injury (AKI) (by pRIFLE criteria) and augmented renal clearance (ARC) (defined as standard GFR for age + 2 standard deviations (SD)) within 48 h after admission based on mGFR and eGFR by the revised Schwartz formula and the difference between these two methods to diagnose AKI and ARC. In children, between 0 and 15 years of age, without chronic renal disease, GFR was measured by CLiohexol and estimated using 26 formulas based on creatinine (Scr), cystatine C (CysC), and betatrace protein (BTP), early after PICU admission. eGFR and mGFR results were compared for the entire study population and in subgroups according to age, using Bland–Altman analysis with calculation of bias, precision, and accuracy expressed as percentage of eGFR results within 30% (P30) and 10% (P10) of mGFR. CLiohexol was measured in 98 patients. Mean CLiohexol (± SD) was 115 ± 54 ml/min/1.73m2. Most eGFR formulas showed overestimation of mGFR with large bias and poor precision reflected by wide limits of agreement (LoA). Bias was larger with CysC- and BTP-based formulas compared to Scr-based formulas. In the entire study population, none of the eGFR formulas showed the minimal desired P30 > 75%. The widely used revised Schwartz formula overestimated mGFR with a high percentage bias of − 18 ± 51% (95% confidence interval (CI) − 29; − 9), poor precision with 95% LoA from − 120 to 84% and insufficient accuracy reflected by P30 of only 51% (95% CI 41; 61), and P10 of 21% (95% CI 13; 66) in the overall population. Although performance of Scr-based formulas was worst in children below 1 month of age, exclusion of neonates and younger children did not result in improved agreement and accuracy. Based on mGFR, prevalence of AKI and ARC within 48 h was 17% and 45% of patients, respectively. There was poor agreement between revised Schwartz formula and mGFR to diagnose AKI (kappa value of 0.342, p < 0.001; sensitivity of 30%, 95% CI 5; 20%) and ARC (kappa value of 0.342, p < 0.001; sensitivity of 70%, 95% CI 33; 58). Conclusion: In this proof-of-concept study, eGFR formulas were found to be largely inaccurate in the PICU population. Clinicians should therefore use these formulas with caution to guide drug dosing and therapeutic interventions in critically ill children. More research in subgroup populations is warranted to conclude on generalizability of these study findings. ClinicalTrials.gov NCT05179564, registered retrospectively on January 5, 2022.

OBJECTIVES: In critically ill children, severely altered pharmacokinetics may result in subtherapeutic β-lactam antibiotic concentrations when standard pediatric dosing regimens are applied. However, it remains unclear how to recognize patients most at risk for suboptimal exposure and their outcome. This study aimed to: 1) describe target attainment for β-lactam antibiotics in critically ill children, 2) identify risk factors for suboptimal exposure, and 3) study the association between target nonattainment and clinical outcome. DESIGN: Post hoc analysis of the “Antibiotic Dosing in Pediatric Intensive Care” study (NCT02456974, 2012–2019). Steady-state trough plasma concentrations were classified as therapeutic if greater than or equal to the minimum inhibitory concentration of the (suspected) pathogen. Factors associated with subtherapeutic concentrations and clinical outcome were identified by logistic regression analysis. SETTING: The pediatric and cardiac surgery ICU of a Belgian tertiary-care hospital. PATIENTS: One hundred fifty-seven patients (aged 1 mo to 15 yr) treated intravenously with amoxicillin-clavulanic acid, piperacillin-tazobactam, or meropenem. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Three hundred eighty-two trough concentrations were obtained from 157 patients (median age, 1.25 yr; interquartile range, 0.4–4.2 yr). Subtherapeutic concentrations were measured in 39 of 60 (65%), 43 of 48 (90%), and 35 of 49 (71%) of patients treated with amoxicillin-clavulanic acid, piperacillin-tazobactam, and meropenem, respectively. Estimates of glomerular filtration rate (eGFR; 54% increase in odds for each sd increase in value, 95% CI, 0.287–0.736; p = 0.001) and the absence of vasopressor treatment (2.8-fold greater odds, 95% CI, 1.079–7.253; p = 0.034) were independently associated with target nonattainment. We failed to identify an association between antibiotic concentrations and clinical failure. CONCLUSIONS: Subtherapeutic β-lactam concentrations are common in critically ill children and correlate with renal function. eGFR equations may be helpful in identifying patients who may require higher dosing. Future studies should focus on the impact of subtherapeutic concentrations on clinical outcome.

Background and aims In critically ill children, severely altered pharmacokinetics often result in subtherapeutic antibiotic concentrations. However, it remains unclear how to recognize those patients most at risk for suboptimal exposure and outcome data are lacking. This study aimed to identify risk factors for target non-attainment and clinical failure in critically ill children treated with beta-lactam antibiotics. Methods This observational cohort study included critically ill children aged 1 month to 15 years, treated intravenously with amoxicillin-clavulanic acid, piperacillin-tazobactam or meropenem. Steady-state trough plasma concentrations were considered therapeutic if ≥ MIC of the (suspected) pathogen. Risk factors were identified by logistic regression analysis. Results 382 trough concentrations were obtained from 157 patients (median age 1.25 years, Q1 0.4; Q3 4.2). Subtherapeutic concentrations were measured in 75.0%, 97.9% and 61.2% of patients treated with amoxicillin-clavulanic acid, piperacillin-tazobactam and meropenem, respectively. eGFR (p <0.001) and the absence of vasopressor treatment (p=0.026) were found as independent predictors of target non-attainment, whilst log transformed CRP was significantly related to clinical outcome (p=0.049). An association between antibiotic concentrations and clinical failure (22.9%) was not observed. Conclusions Subtherapeutic β-lactam antibiotic concentrations are common in critically ill children and correlate with renal function. Commonly used eGFR equations are helpful to identify patients who require higher doses. Future studies should focus on dose optimization and evaluation of its effect on clinical outcome.

The glomerular filtration rate (GFR) is considered the best overall index for the renal function. Currently, one of the most promising exogenous markers for GFR assessment is iohexol. In this study, the suitability of volumetric absorptive microsampling (VAMS) as alternative for the conventional blood sampling and quantification of iohexol in paediatric plasma was assessed. Therefore, a new, fully validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed. Subsequently, the clinical suitability was evaluated in 20 paediatric patients by comparing plasma iohexol concentrations and associated GFR values obtained by the VAMS method with those obtained by conventional blood sampling and quantification of iohexol in plasma. The developed, simple and cost-effective LC-MS/MS-method fulfilled all pre-set validation acceptance criteria. Iohexol could be accurately quantified within a haematocrit range of 20?60% and long-term stability of iohexol in VAMS was demonstrated up to 245 days under different storage temperatures. Both iohexol plasma concentrations (r = 0.98, mean bias: -4.20%) and derived GFR values (r = 0.99; mean bias: 1.31%), obtained by a conventional plasma and the VAMS method, demonstrated good correlation and acceptable bias. The agreement between the two methods was especially good for GFR values higher than 60 mL/min/1.73 m2. Nevertheless, for GFR values <60 mL/min/1.73 m2 the accuracy compared to the plasma method was lower. However, small adjustments to the sampling protocol could probably solve this problem.

Background and aims In critically ill children, severely altered pharmacokinetics often result in subtherapeutic antibiotic concentrations. However, it remains unclear how to recognize those patients most at risk for suboptimal exposure and outcome data are lacking. This study aimed to identify risk factors for target non-attainment and clinical failure in critically ill children treated with beta-lactam antibiotics. Methods This observational cohort study included critically ill children aged 1 month to 15 years, treated intravenously with amoxicillin-clavulanic acid, piperacillin-tazobactam or meropenem. Steady-state trough plasma concentrations were considered therapeutic if ≤ MIC of the (suspected) pathogen. Risk factors for subtherapeutic concentrations and clinical failure were identified by logistic regression analysis. Clinical failure was defined as insufficient lessening of signs and symptoms and the need for alternate antimicrobial therapy. Results 382 trough concentrations were obtained from 157 patients (median age 1.25 years, Q1 0.4; Q3 4.2). Subtherapeutic concentrations were measured in 75.0%, 97.9% and 61.2% of patients treated with amoxicillin-clavulanic acid, piperacillin-tazobactam and meropenem, respectively. eGFR (p <0.001) and the absence of vasopressor treatment (p=0.026) were found as independent predictors of target non-attainment, whilst log transformed CRP was significantly related to clinical outcome (p=0.049). An association between antibiotic concentrations and clinical failure (22.9%) was not observed. Conclusions Subtherapeutic β-lactam antibiotic concentrations are common in critically ill children and correlate with renal function. Commonly used eGFR equations are helpful in daily practice to identify patients who require higher doses. Future studies should focus on dose optimization and evaluation of its effect on clinical outcome.