Population pharmacokinetics of intravenous cefotaxime indicates that higher doses are required for critically ill children.

BACKGROUND: Cefotaxime is frequently used in critically ill children, however pharmacokinetic (PK) studies to support adequate dosing in this patient population are limited. OBJECTIVES: To characterize cefotaxime PK in critically ill children and evaluate exposures achieved by current and alternative dosing regimens. METHODS: Children (0-18 years) admitted to the paediatric ICU, receiving intravenous cefotaxime (100-150 mg/kg/day, interval 6-8 h) were included (Clinicaltrials.gov NCT03248349). Total plasma cefotaxime concentrations were measured on multiple study days. Population-PK analysis was performed using nonlinear mixed effects modelling (NONMEM™). Dose evaluations were performed using typical patients across the paediatric age range and target attainment was determined for MICs of 0.5, 2 and 4 mg/L. RESULTS: 479 cefotaxime plasma concentrations from 52 children (median age 1.6, range 0.03-17.7 years) were used to describe cefotaxime PK. We describe a two-compartment structural model with interindividual variability, including bodyweight as covariate for volume of distribution and clearance. Model predicted exposure for 150 mg/kg/day (current dose) showed trough concentrations <0.5 mg/L in patients >4 years of age. The maximum cefotaxime doses (200 mg/kg/day, interval 6 h) proved adequate for MICs ≤0.5 mg/L across the whole age range. Similar daily doses with increased frequency (interval 4 h) covered MICs up to 2 mg/L, while a loading dose followed by continuous infusion regimens are needed to adequately treat MICs of 4 mg/L. CONCLUSIONS: Higher cefotaxime doses are required for adequate exposure for most pathogens in critically ill children. A higher dose frequency or continuous infusion is advisable to improve target attainment for intermediately susceptible pathogens.

Current Ceftriaxone Dose Recommendations are Adequate for Most Critically Ill Children: Results of a Population Pharmacokinetic Modeling and Simulation Study.

BACKGROUND AND OBJECTIVE: Ceftriaxone is a cornerstone antibiotic for critically ill children with severe infections. Despite its widespread use, information on the pharmacokinetics of ceftriaxone is lacking in this population. We aimed to determine ceftriaxone pharmacokinetics in critically ill children and to propose ceftriaxone dosing guidelines resulting in adequate target attainment using population pharmacokinetic modeling and simulation. METHODS: Critically ill children (aged 0-18 years) treated with intravenous ceftriaxone (100 mg/kg once daily, infused in 30 minutes) and a central or arterial line in place were eligible. Opportunistic blood sampling for total and unbound ceftriaxone concentrations was used. Population pharmacokinetic analysis was performed using non-linear mixed-effects modeling on NONMEM™ Version 7.4.3. Simulations were performed to select optimal doses using probability of target attainment for two pharmacokinetic targets of the minimum inhibitory concentration (MIC) reflecting the susceptibility of pathogens (f T > MIC 100% and fT > 4 × MIC 100%). RESULTS: Two hundred and five samples for total and 43 time-matched samples for unbound plasma ceftriaxone concentrations were collected from 45 patients, median age 2.5 (range 0.1-16.7) years. A two-compartment model with bodyweight as the co-variate for volume of distribution and clearance, and creatinine-based estimated glomerular filtration rate as an additional covariate for clearance, best described ceftriaxone pharmacokinetics. For a typical patient (2.5 years, 14 kg) with an estimated glomerular filtration rate of 80 mL/min/1.73 m2, the current 100-mg/kg once-daily dose results in a probability of target attainment of 96.8% and 60.8% for a MIC of 0.5 mg/L and 4 × MIC (2 mg/L), respectively, when using fT > MIC 100% as a target. For a 50-mg/kg twice-daily regimen, the probability of target attainment was 99.9% and 93.4%, respectively. CONCLUSIONS: The current dosing regimen of ceftriaxone provides adequate exposure for susceptible pathogens in most critically ill children. In patients with an estimated glomerular filtration rate of > 80 mL/min/1.73 m2 or in areas with a high prevalence of less-susceptible pathogens (MIC ≥ 0.5 mg/L), a twice-daily dosing regimen of 50 mg/kg can be considered to improve target attainment. CLINICAL TRIAL REGISTRATION: POPSICLE study (ClinicalTrials.gov, NCT03248349, registered 14 August, 2017), PERFORM study (ClinicalTrials.gov, NCT03502993, registered 19 April, 2018).

The Oral Bioavailability and Metabolism of Midazolam in Stable Critically Ill Children: A Pharmacokinetic Microtracing Study.

Midazolam is metabolized by the developmentally regulated intestinal and hepatic drug-metabolizing enzyme cytochrome P450 (CYP) 3A4/5. It is frequently administered orally to children, yet knowledge is lacking on the oral bioavailability in term neonates up until 1 year of age. Furthermore, the dispositions of the major metabolites 1-OH-midazolam (OHM) and 1-OH-midazolam-glucuronide (OHMG) after oral administration are largely unknown for the entire pediatric age span. We aimed to fill these knowledge gaps with a pediatric [14 C]midazolam microtracer population pharmacokinetic study. Forty-six stable, critically ill children (median age 9.8 (range 0.3-276.4) weeks) received a single oral [14 C]midazolam microtracer (58 (40-67) Bq/kg) when they received a therapeutic continuous intravenous midazolam infusion and had an arterial line in place enabling blood sampling. For midazolam, in a one-compartment model, bodyweight was a significant predictor for clearance (0.98 L/hour) and volume of distribution (8.7 L) (values for a typical individual of 5 kg). The typical oral bioavailability in the population was 66% (range 25-85%). The exposures of OHM and OHMG were highest for the youngest age groups and significantly decreased with postnatal age. The oral bioavailability of midazolam, largely reflective of intestinal and hepatic CYP3A activity, was on average lower than the reported 49-92% for preterm neonates, and higher than the reported 21% for children> 1 year of age and 30% for adults. As midazolam oral bioavailability varied widely, systemic exposure of other CYP3A-substrate drugs after oral dosing in this population may also be unpredictable, with risk of therapy failure or toxicity.

External Validation of Model-Based Dosing Guidelines for Vancomycin, Gentamicin, and Tobramycin in Critically Ill Neonates and Children: A Pragmatic Two-Center Study.

BACKGROUND: The Dutch Pediatric Formulary (DPF) increasingly bases its guidelines on model-based dosing simulations from pharmacokinetic studies. This resulted in nationwide dose changes for vancomycin, gentamicin, and tobramycin in 2015. OBJECTIVE: We aimed to evaluate target attainment of these altered, model-based doses in critically ill neonates and children. METHODS: This was a retrospective cohort study in neonatal intensive care unit (NICU) and pediatric ICU (PICU) patients receiving vancomycin, gentamicin, or tobramycin between January 2015 and March 2017 in two university hospitals. The first therapeutic drug monitoring concentration for each patient was collected, as was clinical and dosing information. Vancomycin and tobramycin target trough concentrations were 10-15 and ≤ 1 mg/L, respectively. Target gentamicin trough and peak concentrations were < 1 and 8-12 mg/L, respectively. RESULTS: In total, 482 patients were included (vancomycin [PICU] n = 62, [NICU] n = 102; gentamicin [NICU] n = 97; tobramycin [NICU] n = 221). Overall, median trough concentrations were within the target range for all cohorts but showed large interindividual variability, causing nontarget attainment. Trough concentrations were outside the target range in 66.1%, 60.8%, 14.7%, and 23.1% of patients in these four cohorts, respectively. Gentamicin peak concentrations were outside the range in 69% of NICU patients (term neonates 87.1%, preterm infants 57.1%). Higher creatinine concentrations were associated with higher vancomycin and tobramycin trough concentrations. CONCLUSION: This study illustrates the need to validate model-based dosing advice in the real-world setting as both sub- and supratherapeutic concentrations of vancomycin, gentamicin, and tobramycin were very prevalent. Our data underline the necessity for further individualization by addressing the high interindividual variability to improve target attainment.

Proenkephalin as a new biomarker for pediatric acute kidney injury - reference values and performance in children under one year of age.

Objectives Acute kidney injury (AKI) is common in critically ill children, but current biomarkers are suboptimal. Proenkephalin A 119-159 (PENK) is a promising new biomarker for AKI in adults, but pediatric data is lacking. We determined PENK reference intervals for healthy children, crucial for clinical implementation, and explored concentrations in critically ill infants aged under 1 year. Methods Observational cohort study in healthy infants and critically ill children aged 0-1 years. Reference values were determined using generalized additive models. Plasma PENK concentrations between healthy children and critically ill children with and without AKI, were compared using linear mixed modelling. The performance of PENK as AKI biomarker was compared to cystatin C (CysC) and ß-trace protein (BTP) using receiver-operating-characteristic (ROC) analysis. Results PENK concentrations in 100 healthy infants were stable during the first year of life (median 517.3 pmol/L). Median PENK concentrations in 91 critically ill children, were significantly higher in those with AKI (n=40) (KDIGO Stage 1 507.9 pmol/L, Stage 2 704.0 pmol/L, Stage 3 930.5 pmol/L) than non-AKI patients (n=51, 432.2 pmol/L) (p < 0.001). PENK appeared to relate better to AKI diagnosis than CysC and BTP (AUROC PENK 0.858, CysC 0.770 and BTP 0.711) in the first 24 h after recruitment. Conclusions PENK reference values are much higher in young infants than adults, but clearly discriminate between children with and without AKI, with comparable or better performance than CysC and BTP. Our results illustrate the importance of establishing age-normalized reference values and indicate PENK as a promising pediatric AKI biomarker.

A New Framework to Implement Model-Informed Dosing in Clinical Guidelines: Piperacillin and Amikacin as Proof of Concept.

Background: Modeling and simulation is increasingly used to study pediatric pharmacokinetics, but clinical implementation of age-appropriate doses lags behind. Therefore, we aimed to develop model-informed doses using published pharmacokinetic data and a decision framework to adjust dosing guidelines based on these doses, using piperacillin and amikacin in critically ill children as proof of concept. Methods: Piperacillin and amikacin pharmacokinetic models in critically ill children were extracted from literature. Concentration-time profiles were simulated for various dosing regimens for a virtual PICU patient dataset, including the current DPF dose and doses proposed in the studied publications. Probability of target attainment (PTA) was compared between the different dosing regimens. Next, updated dosing recommendations for the DPF were proposed, and evaluated using a new framework based on PK study quality and benefit-risk analysis of clinical implementation. Results: Three studies for piperacillin (critically ill children) and one for amikacin (critically ill pediatric burn patients) were included. Simulated concentration-time profiles were performed for a virtual dataset of 307 critically ill pediatric patients, age range 0.1-17.9 y. PTA for unbound piperacillin trough concentrations >16 mg/L was >90% only for continuous infusion regimens of 400 mg/kg/day vs. 9.7% for the current DPF dose (80 mg/kg/6 h, 30 min infusion). Amikacin PTA was >90% with 20 mg/kg/d, higher than the PTA of the DPF dose of 15 mg/kg/d (63.5%). Using our new decision framework, altered DPF doses were proposed for piperacillin (better PTA with loading dose plus continuous infusion), but not for amikacin (studied and target population were not comparable and risk for toxicity with higher dose). Conclusions: We show the feasibility to develop model-informed dosing guidelines for clinical implementation using existing pharmacokinetic data. This approach could complement literature and consensus-based dosing guidelines for off-label drugs in the absence of stronger evidence to support pediatricians in daily practice.

Pharmacokinetics and Target Attainment of Antibiotics in Critically Ill Children: A Systematic Review of Current Literature.

BACKGROUND: Pharmacokinetics (PK) are severely altered in critically ill patients due to changes in volume of distribution (Vd) and/or drug clearance (Cl). This affects the target attainment of antibiotics in critically ill children. We aimed to identify gaps in current knowledge and to compare published PK parameters and target attainment of antibiotics in critically ill children to healthy children and critically ill adults. METHODS: Systematic literature search in PubMed, EMBASE and Web of Science. Articles were labelled as relevant when they included information on PK of antibiotics in critically ill, non-neonatal, pediatric patients. Extracted PK-parameters included Vd, Cl, (trough) concentrations, AUC, probability of target attainment, and elimination half-life. RESULTS: 50 relevant articles were identified. Studies focusing on vancomycin were most prevalent (17/50). Other studies included data on penicillins, cephalosporins, carbapenems and aminoglycosides, but data on ceftriaxone, ceftazidime, penicillin and metronidazole could not be found. Critically ill children generally show a higher Cl and larger Vd than healthy children and critically ill adults. Reduced target-attainment was described in critically ill children for multiple antibiotics, including amoxicillin, piperacillin, cefotaxime, vancomycin, gentamicin, teicoplanin, amikacin and daptomycin. 38/50 articles included information on both Vd and Cl, but a dosing advice was given in only 22 articles. CONCLUSION: The majority of studies focus on agents where TDM is applied, while other antibiotics lack data altogether. The larger Vd and higher Cl in critically ill children might warrant a higher dose or extended infusions of antibiotics in this patient population to increase target-attainment. Studies frequently fail to provide a dosing advice for this patient population, even if the necessary information is available. Our study shows gaps in current knowledge and encourages future researchers to provide dosing advice for special populations whenever possible.

Target attainment of cefotaxime in critically ill children with meningococcal septic shock as a model for cefotaxime dosing in severe pediatric sepsis.

Reduced target attainment of ß-lactam antibiotics is reported in critically ill patients. However, as target attainment of cefotaxime in severely ill pediatric sepsis patients may differ from adults due to age-related variation in pharmacokinetics, we aimed to assess target attainment of cefotaxime in this pilot study using meningococcal septic shock patients as a model for severe sepsis. Secondary analysis of prospectively collected data from a randomized controlled trial. Children with meningococcal septic shock (1 month to 18 years) included in this study received cefotaxime 100-150 mg/kg/day as antibiotic treatment. Left-over plasma samples were analyzed using LC-MS/MS to determine cefotaxime concentrations. MIC values from EUCAST were used to determine target attainment of cefotaxime for Neisseria meningitidis (0.125 mg/l), but also for Streptococcus pneumoniae (0.5 mg/l), Enterobacteriaceae (1 mg/l), and Staphylococcus aureus (4 mg/l). Target attainment was adequate when all samples exceeded MIC or fourfold MIC values. One thirty-six plasma samples of 37 severe septic shock patients were analyzed for cefotaxime concentrations. Median age was 2 years with a median PRISM-score of 24 and mortality of 24.8%. The median unbound cefotaxime concentration was 4.8 mg/l (range 0-48.7). Target attainment ranged from 94.6% for the MIC of N. meningitidis to 16.2% for fourfold the MIC S. aureus. Creatinine levels were significantly correlated with cefotaxime levels. Target attainment of cefotaxime with current dosing guidelines seems to be adequate for N. meningitidis but seems to fail for more frequently encountered pathogens in severely ill children.