BACKGROUND AND OBJECTIVE:Cefepime-induced neurotoxicity (CIN) is a recognized side effect of excessive cefepime exposure and high plasma concentrations in adults. However, the relationship between cefepime concentrations and neurotoxic symptoms in paediatric patients is unknown. The objective of this paper is to explore the relationship between cefepime pharmacokinetics and CIN in a paediatric intensive care unit (PICU) cohort. PATIENTS AND METHODS:PICU patients with cefepime concentrations measured for a previous PK study were chosen for this cohort. CIN symptoms and related testing were evaluated by retrospective chart review and likelihood of causal association was determined using blinded adjudicators via the Naranjo adverse drug reaction probability scale. RESULTS:Among 73 patients with complete data, 43 patients (59%) had either no neurotoxicity or neurotoxicity doubtful to be CIN, while 25 (34%) patients had possible CIN and five (7%) had probable CIN. Symptoms of neurotoxicity included irritability, altered mental status, depressed level of consciousness, myoclonus, seizures and delirium. There were no differences in age, sex, severity of illness or renal dysfunction among groups. Patients with probable CIN had higher cefepime area under the curve (2250 versus 1107 mg*h/L, P = 0.03) and peak concentrations (232 versus 172 mg/L, P < 0.001). CONCLUSIONS:This investigation presents a paediatric cohort analysis of CIN and provides preliminary evidence supporting the hypothesis that neurotoxicity risk is probably concentration dependent in this age group and presents with similar spectrum of symptoms as those described in adults.

Objectives: Cefepime is a fourth-generation cephalosporin antibiotic with broad-spectrum activity widely prescribed for severe and nosocomial infections. Achieving optimal antibiotic exposure with cefepime in critically ill children and young adults is challenging due to significant pharmacokinetic (PK) variability. Suboptimal dosing may lead to treatment failure or toxicity. We aim to develop a parametric population PK model of cefepime for critically ill pediatric and young adult patients, identify factors influencing drug disposition, and conduct Monte Carlo simulations to determine the optimal initial dosing regimens._x000D_ _x000D_ Methods: Pediatric intensive care unit patients receiving cefepime 30-50 mg/kg Q8h as a 30-minute infusion were prospectively followed for clinical data collection and scavenged opportunistic plasma sampling.[1] Cefepime concentrations were measured using high-performance liquid chromatography. Nonlinear mixed effects modeling was conducted using NONMEM v7.5 interfaced with Pirana. Allometric body weight scaling was included a priori with fixed exponents to account for body size differences. Monte Carlo simulations were performed using the final model to determine the initial dosing regimen that maximizes the probability of maintaining free concentration above the minimum inhibitory concentration (MIC) of Pseudomonas aeruginosa (8 mg/L breakpoint) for the entire dosing interval (100% fT>MIC)._x000D_ _x000D_ Results: Data from 100 patients, aged 1 month to 30 years, with 510 samples, were described using a two-compartment model with first-order elimination. Inter-individual variability was estimated for clearance (CL) and central volume of distribution (V1), but could not be estimated for intercompartmental clearance (Q) or peripheral volume (V2). Estimated glomerular filtration rate (eGFR) and cumulative percentage of fluid balance were identified as covariates on CL and V1, respectively. The final parameters were estimated with good precision: CL 6.4 L/h/70 kg0.75, Q 3.7 L/h/70 kg0.75, V1 15 L/70 kg, and V2 8.9 L/70 kg. The goodness-of-fit plots showed no model misspecification. The Monte Carlo simulations suggested that the usual dose of 50 mg/kg requires a longer duration of infusion (3 hours) or a shorter dosing interval (every 6 hours) to ensure target attainment. The dose regimen of 50 mg/kg Q8h as a 30-minute infusion only had high probability of target attainment (>90%) in patients with renal impairment._x000D_ _x000D_ Conclusions: A cefepime PK model for critically ill pediatric patients was successfully developed accounting for patients' renal function, fluid status, and body size, using real world data and an opportunistic sampling approach. The model was internally validated with good precision and stability and may be used for model-informed precision dosing. The initial cefepime dosing regimen may require modifications such as a longer duration of infusion or a shorter dosing interval to ensure target attainment against Pseudomonas aeruginosa.Citations: [1] Tang Girdwood SC. et al., J Clin Pharmacol, 61(4), 565, 2020.

Continuous kidney replacement therapy (CKRT) can influence pharmacokinetics (PK), including clearance (CL) of antibiotics like piperacillin (PIP). Both CKRT intensity, or "dialysis dose," and residual kidney function can alter PIP PK and pharmacodynamic (PD) target attainment (TA), defined by the percentage of time free PIP concentrations exceed the minimum inhibitory concentration (% fT > MIC). In existing reports, children receiving PIP and CKRT are usually oligoanuric, so PIP PK/PD in non-oligoanuric patients receiving high-intensity CKRT is unknown. This report analyzes free PIP PK/PD in a child with robust kidney function who received 30-minute infusions of 100 mg/kg PIP-tazobactam every 6 hours while on high-intensity CKRT after liver-kidney transplant for primary hyperoxaluria. Model-informed PK software was used to estimate PK/PD parameters for periods on and off CKRT. PIP CL on CKRT was 66% higher than off CKRT (5.59 L/hr vs 3.36 L/hr). Nearly 100% fT > 1xMIC (using 8 mg/L for Enterobacterales) was achieved whether on or off CKRT, but only 60% fT > 4xMIC was achieved on CKRT. CKRT CL was 40% of total CL on CKRT and 51% of the CKRT dialysis dose, suggesting PIP elimination was mostly renal despite high-intensity dialysis. Monitoring of free PIP concentrations may help ensure proper TA in non-oligoanuric patients receiving high-dose CKRT.

OBJECTIVE:Children with medical complexity (CMC), in whom drug efficacy and adverse drug events are difficult to assess, could benefit from pharmacogenetic (PGx) testing. We sought to determine the prevalence of prescribed medications with a high level of evidence for PGx-guided dosing and to identify their associated genes for testing among CMC. PATIENTS AND METHODS:This cross-sectional study included patients discharged from a complex care inpatient team from June 2019 to June 2020. We identified medications with level A evidence for PGx-guided dosing per the Clinical Pharmacogenetics Implementation Consortium (CPIC) in January 2023 (N = 73) from medication lists. We determined frequency of CPIC level A scheduled and as-needed (PRN) prescriptions. We compared these findings with a secondary dataset of patients who attend a complex care clinic. RESULTS:For CPIC level A medications prescribed to the inpatients, 60.2% were on at least 1 scheduled medication and 60.2% were on at least 1 PRN medication. The most commonly scheduled medications were lansoprazole (25.0%) and omeprazole (16.4%); the most common PRN medications were ibuprofen (50%), ondansetron (18.8%), and tramadol (3.9%). The outpatient cohort similarly had a large proportion on at least 1 scheduled or 1 PRN medication (44.4% and 47.6%, respectively), with proton pump inhibitors (PPIs) being commonly prescribed. The genes most highly associated with the medications prescribed to both populations were CYP2C19, CYP2C9, and CYP2D6. CONCLUSIONS:PPIs were the most common CPIC level A medications and are metabolized by CYP2C19, making it the most highly implicated gene. PPI-CYP2C19 should be a PGx testing priority.

This study aimed to develop a population pharmacokinetic model for cefepime in critically ill pediatric and young adult patients to inform dosing recommendations and to evaluate the model’s predictive performance for model-informed precision dosing. Patients in the pediatric intensive care unit receiving cefepime were prospectively enrolled for clinical data collection and opportunistic plasma sampling for cefepime concentrations. Nonlinear mixed effects modeling was conducted using NONMEM. Allometric body weight scaling was included as a covariate with fixed exponents. Monte Carlo simulations determined optimal initial dosing regimens against susceptible pathogens. The model’s predictions were evaluated with an external dataset. Data from 510 samples across 100 patients were best fit with a two-compartment model with first-order elimination. Estimated glomerular filtration rate and cumulative percentage of fluid balance were identified as significant covariates on clearance and central volume of distribution, respectively. Internal validation showed no model misspecification. External validation confirmed that bias and precision for both population and individual predictions were within commonly accepted ranges. Monte Carlo simulations suggested that the usual dose of 50 mg/kg may require a 3-h infusion or a 6-h dosing interval to keep concentrations above the Pseudomonas aeruginosa minimum inhibitory concentration (≤ 8 mg/L) throughout the dosing interval for patients with normal or augmented renal clearance. A cefepime population pharmacokinetic model for critically ill pediatric patients was successfully developed, accounting for patient renal function, fluid status, and body size, using real-world data. The model was internally and externally validated for use in optimal dosing simulations and model-informed precision dosing.

Dr Tang Girdwood is the site PI of two clinical trials sponsored by Kaizen Bioscience, Inc. and Pfizer, Inc, but these studies had no influence on this work. All other authors declared no competing interests for this work.

OBJECTIVES:To determine the frequency of early meropenem concentration target attainment (TA) in critically ill children with severe sepsis; to explore clinical, therapeutic, and pharmacokinetic factors associated with TA; and to assess how fluid resuscitation and volume status relate to early TA. DESIGN:Retrospective analysis of prospective observational cohort study. SETTING:PICU in a single academic quaternary care children's hospital. PATIENTS:Twenty-nine patients starting meropenem for severe sepsis (characterized as need for positive pressure ventilation, vasopressors, or >= 40 mL/kg bolused fluid), of which 17 were newly escalated to PICU level care. INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:Concentration-time profiles were analyzed using modeling software employing opportunistic sampling, Bayesian estimation, and a population pharmacokinetic model. Time above four times minimum inhibitory concentration (T > 4xMIC), using the susceptibility breakpoint of 1 mu g/mL, was determined for each patient over the first 24 hours of meropenem therapy, as well as individual clearance and volume of distribution (Vd) estimates. Twenty-one of 29 patients met a target of 40%T > MIC 4 mu g/mL. Reaching TA, vs. not, was associated with lower meropenem clearance. We failed to identify a difference in Vd or an association between the TA group and age, weight, creatinine-based estimated glomerular filtration rate (eGFR), or the amount of fluid administered. eGFR was, however, negatively correlated with overall T > MIC. CONCLUSIONS:Eight of 29 pediatric patients with early severe sepsis did not meet the selected TA threshold within the first 24 hours of meropenem therapy. Higher clearance was associated with failure to meet targets. Identifying patients likely to have higher meropenem clearance could help with dosing regimens.

Abstract Background Sepsis is a leading cause of acute kidney injury requiring continuous kidney replacement therapy (CKRT) and CKRT can alter drug pharmacokinetics (PK). Cefepime is used commonly in critically ill children and is cleared by CKRT, yet data regarding cefepime PK and pharmacodynamic (PD) target attainment in children receiving CKRT are scarce, so we performed Monte Carlo simulations (MCS) of cefepime dosing strategies in children receiving CKRT. Methods We developed a CKRT “module” in the precision dosing software Edsim++. The module was added into a pediatric cefepime PK model. 1000-fold MCS were performed using six dosing strategies in patients aged 2–25 years and ≥ 10 kg with differing residual kidney function (estimated glomerular filtration rate of 5 vs 30 mL/min/1.73 m2), CKRT prescriptions, (standard-dose total effluent flow of 2500 mL/h/1.73 m2 vs high-dose of 8000 mL/h/1.73 m2), and fluid accumulation (0–30%). Probability of target attainment (PTA) was defined by percentage of patients with free concentrations exceeding bacterial minimum inhibitory concentration (MIC) for 100% of the dosing interval (100% fT > 1xMIC) and 4xMIC using an MIC of 8 mg/L for Pseudomonas aeruginosa. Results Assuming standard-dose dialysis and minimal kidney function, > 90% PTA was achieved for 100% fT > 1x MIC with continuous infusions (CI) of 100–150 mg/kg/day (max 4/6 g) and 4-h infusions of 50 mg/kg (max 2 g), but > 90% PTA for 100% fT > 4x MIC was only achieved by 150 mg/kg CI. Decreased PTA was seen with less frequent dosing, shorter infusions, higher-dose CKRT, and higher residual kidney function. Conclusions Our new CKRT-module was successfully added to an existing cefepime PK model for MCS in young patients on CKRT. When targeting 100% fT > 4xMIC or using higher-dose CKRT, CI would allow for higher PTA than intermittent dosing.

BACKGROUND:Meropenem, a β-lactam antibiotic commonly prescribed for severe infections, poses dosing challenges in critically ill patients due to highly variable pharmacokinetics. OBJECTIVES:We sought to develop a population pharmacokinetic model of meropenem for critically ill paediatric and young adult patients. PATIENTS AND METHODS:Paediatric intensive care unit patients receiving meropenem 20-40 mg/kg every 8 h as a 30 min infusion were prospectively followed for clinical data collection and scavenged opportunistic plasma sampling. Nonlinear mixed effects modelling was conducted using Monolix®. Monte Carlo simulations were performed to provide dosing recommendations against susceptible pathogens (MIC ≤ 2 mg/L). RESULTS:Data from 48 patients, aged 1 month to 30 years, with 296 samples, were described using a two-compartment model with first-order elimination. Allometric body weight scaling accounted for body size differences. Creatinine clearance and percentage of fluid balance were identified as covariates on clearance and central volume of distribution, respectively. A maturation function for renal clearance was included. Monte Carlo simulations suggested that for a target of 40% fT > MIC, the most effective dosing regimen is 20 mg/kg every 8 h with a 3 h infusion. If higher PD targets are considered, only continuous infusion regimens ensure target attainment against susceptible pathogens, ranging from 60 mg/kg/day to 120 mg/kg/day. CONCLUSIONS:We successfully developed a population pharmacokinetic model of meropenem using real-world data from critically ill paediatric and young adult patients with an opportunistic sampling strategy and provided dosing recommendations based on the patients' renal function and fluid status.

Elevated cefepime blood concentrations can cause neurotoxicity in adults. The consequences of elevated cefepime concentrations among pediatric patients are unknown. Future exploration of such effects requires first identifying patients at risk for elevated cefepime exposure. We investigated the role of acute kidney injury as a risk factor for increased cefepime concentrations in critically ill children. This was a retrospective analysis at a single pediatric intensive care unit. Analyzed patients received at least 24 h of cefepime and had at least two opportunistic samples collected for total cefepime concentration measurement. Individual pharmacokinetic (PK) profiles during treatment courses were reconstructed using Bayesian estimation with an established population PK model. Elevated trough concentration (Cmin) was defined as ≥ 30 mg/L based on adult toxicity studies. The effect of kidney dysfunction on cefepime PK profiles was interrogated using a mixed-effect model. Eighty-seven patients were included, of which 13 (14.9

Paice, Kelli; Tang Girdwood, Sonya; Pavia, Kathryn; Mizuno, Tomoyuki; Kaplan, Jennifer Author Information

Pediatric hematopoietic stem cell transplant (HSCT) patients are at risk of developing both sepsis and altered kidney function. Cefepime is used for empiric coverage postHSCT and requires dose adjustment based on kidney function. Since cefepime 's antimicrobial efficacy is determined by the time free concentrations exceed bacterial minimum inhibitory concentration (MIC), it is important to assess kidney function accurately to ensure adequate concentrations. Serum creatinine (SCr) is routinely used to estimate glomerular filtration rate (eGFR) but varies with muscle mass, which can be significantly lower in HSCT patients, making SCr an inaccurate kidney function biomarker. Cystatin C (CysC) eGFR is independent of muscle mass, though steroid use increases CysC. Objectives of this study were to describe how eGFR impacts cefepime pharmacokinetic/ pharmacodynamic (PK/PD) target attainment in pediatric HSCT patients, to investigate which method of estimating GFR (SCr, CysC, combined) best predicts cefepime clearance, and to explore additional predictors of cefepime clearance. Patients admitted to the pediatric HSCT unit who received >= 2 cefepime doses were prospectively enrolled. We measured total cefepime peak/trough concentrations between the second and fourth cefepime doses and measured SCr and CysC if not already obtained clinically within 24h of cefepime samples. eGFRs were calculated with Chronic Kidney Disease in Children U25 equations. Bayesian estimates of cefepime clearance were determined with a pediatric cefepime PK model and PK software MwPharm++. Simple linear regression was used to compare cefepime clearance normalized to body surface area (BSA) to BSA -normalized SCr-, CysC-, and SCr-/CysC-eGFRs, while multiple linear regression was used to account for additional predictors of cefepime clearance. For target attainment, we assessed the percentage of time free cefepime concentrations exceeded 1x MIC (% f T >1x MIC) and 4x MIC (% f T >4x MIC) using a susceptibility breakpoint of 8 mg/L for Pseudomonas aeruginosa . We enrolled 53 patients (ages 1 to 30 years, median 8.9 years). SCr- and CysC-eGFRs were lower in patients who attained 100% f T >1xMIC compared to those who did not attain this target: 115 versus 156 mL/min/1.73m (2) ( p = .01) for SCr-eGFR and 73.5 versus 107 mL/ min/1.73m (2) ( p < .001) for CysC-eGFR. SCr-eGFR was weakly positively correlated with cefepime clearance (adjusted [a]r (2) = 0.14), while CysC-eGFR and SCr-/CysC-eGFR had stronger positive correlations (ar( 2) = 0.30 CysC, ar (2) = 0.28 combo. There was a weak, significant linear association between increasing CysC-eGFR and decreased % f T >1xMIC (ar (2) = 0.32) and %f T >4xMIC (ar (2) = 0.14). No patients with a CysC-eGFR >120 mL/min/ 1.73 m( 2) achieved 100% f T >1xMIC or 50% f T >4x MIC. In multiple regression models, underlying diagnosis of hemoglobinopathy (in all models) and being pretransplant (in SCr and combined models) were associated with increased cefepime clearance, while concomitant use of calcineurin inhibitors was associated with decreased cefepime clearance in all models. Overall, the combo-eGFR model with timing pretransplant, hemoglobinopathy, and use of calcineurin inhibitors had the best performance (ar (2) = 0.63). CysC-based eGFRs (CysC alone and combined) predicted cefepime clearance better than SCr-eGFR, even after considering steroid use. Increasing CysC eGFR correlated with decreased probability of PD target attainment, raising concerns for underdosing at high eGFRs. CysC should be included when estimating kidney function to provide adequate dosing of cefepime in pediatric HSCT patients. (c) 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Background: Studies in adult patients suggest cefepime can cause neurotoxicity, including disorientation, seizures, and coma, particularly when present at high concentrations. Patients with underlying kidney dysfunction or central nervous system anomalies are at particularly high risk. There is a relative paucity of pediatric literature on the neurotoxic effects of cefepime. Case Report: Herein is reported the case of a 2-year-old patient with chronic kidney disease receiving cefepime for Serratia marcescens bacteremia who experienced agitation, tremor, and inconsolability in the setting of an elevated cefepime trough that improved with cefepime discontinuation alone. Conclusions: Pediatric patients with acute and chronic kidney disease are at risk of cefepime-related neurologic changes. Therapeutic drug monitoring for cefepime in patients with kidney dysfunction or baseline neurologic abnormalities may help inform appropriate antimicrobial dosing and avoidance of toxicity.

There has been rising interest in using model-informed precision dosing to provide personalized medicine to patients at the bedside. This methodology utilizes population pharmacokinetic models, measured drug concentrations from individual patients, pharmacodynamic biomarkers, and Bayesian estimation to estimate pharmacokinetic parameters and predict concentration-time profiles in individual patients. Using these individualized parameter estimates and simulated drug exposure, dosing recommendations can be generated to maximize target attainment to improve beneficial effect and minimize toxicity. However, the accuracy of the output from this evaluation is highly dependent on the population pharmacokinetic model selected. This tutorial provides a comprehensive approach to evaluating, selecting, and validating a model for input and implementation into a model-informed precision dosing program. A step-by-step outline to validate successful implementation into a precision dosing tool is described using the clinical software platforms Edsim++ and MwPharm++ as examples.

Introduction: Meropenem (MEM) is a β-lactam antibiotic with efficacy dependent on the time concentrations remain above minimum inhibitory concentrations (T>MIC). Early initiation of antibiotics is key to sepsis treatment. The goal of this study is to assess how often critically ill patients with severe sepsis attain early T>MIC MEM targets and the association of target attainment with patient factors. Our hypothesis was that non target-attaining patients are more likely to have negative clinical outcomes. Methods: This was a prospective study of patients admitted to Cincinnati Children’s PICU from 2018-21 and treated with one of 4 β-lactams. For this analysis, patients newly starting MEM were eligible if they had severe sepsis defined as >=7 days of antibiotics (or death), and requirement within 12-24hrs of MEM start of >=1 of the following: vasopressor, >=40 ml/kg bolus fluid, or positive pressure ventilation above baseline. Patients were included if plasma total MEM concentrations were measured via opportunistic sampling within 4 doses of MEM initiation, and excluded if on extracorporeal support or started on MEM in surgery. Concentration-time profiles of the first 3 dosing intervals of MEM (~24hrs) were created using a published pharmacokinetic model (Saito et al, AAC, 2021) and Bayesian estimation (MWPharm++). Intermediate-resistant Enterococcus MIC (2µg/mL) was used. Association of T>MIC target attainment with patient factors and outcome measures was assessed via Student’s T, Fisher’s Exact or Mann-Whitney Rank Sum tests. Results: 28 patients with severe sepsis were included (median age 4y, median weight 16.3kg, 64% male). Only 16/28 (57%) achieved 100% T>MIC 2µg/mL. Hospital and PICU length of stay were not associated with target attainment. All 4 patients who died were in the target-attaining group. Target-attaining patients had lower allometric clearance (8.4+/-3.5 vs 22+/-7.1 L/hr/70kg-BW^0.75, p< 0.001), and higher PRISMIII scores (11.2+/-8.2 vs 5.6+/-3.2, p=0.03) than patients who did not attain target levels. Conclusions: Early in therapy, children with severe sepsis do not consistently achieve MEM concentrations sufficient to treat resistant bacteria. Lower clearance and higher PRISM scores may reflect organ dysfunction resulting in higher likelihood of MEM target attainment for some patients.

Introduction: Studies have associated excessive beta-lactam exposure with toxicity, including cefepime (FEP) and neurotoxicity. It is critical to identify patient factors associated with high FEP exposures that may increase risk of toxicity. Work from our group showed that elevated FEP troughs occur in children with impaired renal function. Here we use modeling to expand our analysis to include patients with samples collected throughout the dosing interval, hypothesizing that patients with acute kidney injury (AKI) have higher risk of elevated FEP exposure. Methods: An IRB approved study was conducted at a tertiary children’s hospital. Patients who received at least 24h of FEP in the pediatric intensive care unit (PICU) and had at least two opportunistic samples collected were eligible for inclusion. Total FEP concentrations were measured using a validated high performance liquid chromatography assay. Concentrations throughout the dosing interval were modeled in MwPharm++ (Mediware, Czech Republic) using a previously established population PK model of cefepime in pediatrics (Shoji, 2016), observed concentrations, and Bayesian estimation. Elevated Cmin were defined as ≥30µg/mL based on adult toxicity studies. AKI was defined by Kidney Disease-Improving Global Outcomes (KDIGO) creatinine criteria. Demographics and clinical characteristics were analyzed using Mann-Whitney rank sum tests and Chi-square analysis. Results: Ninety-two patients were included, of which 18 patients (19.6%) had at least one Cmin ≥30µg/mL. Patients with and without elevated Cmin were similar in age, weight, sex, PICU and hospital length of stays, PRISM III scores, and duration of FEP therapy. Patients with elevated Cmin, compared to patients without elevated Cmin, were more likely to have pre-existing chronic kidney disease (28% vs 3%, p=0.003) and AKI during the study period (89% vs 57%, p=0.01). Mortality at 28 days was significantly higher in patients with elevated Cmin than those without (11% vs 4%, p=0.05). Conclusions: Among critically ill children, impaired renal function either from chronic kidney disease or acute kidney injury increases risk of elevated serum cefepime concentrations. Identifying these high-risk patients is a critical first step toward evaluating clinical consequences of elevated cefepime concentrations.