Population Pharmacokinetic Modeling of Total and Free Ceftriaxone in Critically Ill Children and Young Adults and Monte Carlo Simulations Support Twice Daily Dosing for Target Attainment

Abstract

Critical illness, including sepsis, causes significant pathophysiologic changes that alter the pharmacokinetics (PK) of antibiotics. Ceftriaxone is one of the most prescribed antibiotics in patients admitted to the pediatric intensive care unit (PICU). We sought to develop population PK models of both total ceftriaxone and free ceftriaxone in children admitted to a single-center PICU using a scavenged opportunistic sampling approach. We tested if the presence of sepsis and phase of illness (before or after 48 hours of antibiotic treatment) altered ceftriaxone PK parameters. We performed Monte Carlo simulations to evaluate whether dosing regimens commonly used in PICUs in the United States (50 mg/kg every 12 hours vs. 24 hours) resulted in adequate antimicrobial coverage. We found that a two-compartment model best described both total and free ceftriaxone concentrations. For free concentrations, the population clearance value is 6.54 L/h/70 kg, central volume is 25.4 L/70 kg and the peripheral volume is 19.6 L/70kg. For both models, we found that allometric weight scaling, post-menstrual age, creatinine clearance and daily highest temperature had significant effects on clearance. Presence of sepsis or phase of illness did not have a significant effect on clearance or volume of distribution. Monte Carlo simulations demonstrated that to achieve free concentrations above 1 μg/mL for 100% of the dosing intervals, a dosing regimen of 50 mg/kg every 12 hours is recommended for most patients. A continuous infusion could be considered if the target is to maintain free concentrations four times above the minimum inhibitory concentrations (4 μg/mL).

Initial sirolimus dosage recommendations for pediatric patients with PIK3CD mutation-related immunodeficiency disease

“…Population pharmacokinetic (PPK), combined with a Monte Carlo simulation, provide feasible technical support for solving initial dosage recommendations in clinical practice. In recent years, more and more related research has been reported, which further verifies the reliability and practicability of this method (Jaruratanasirikul et al, 2019;Ren et al, 2019;Ghoneim et al, 2021;Rinaldi et al, 2021;Tang Girdwood et al, 2022). Hence, the present study recommends initial dosages of sirolimus in pediatric patients with PIK3CD mutationrelated immunodeficiency disease based on PPK and a Monte Carlo simulation.…”

Retrospective Comparison of the Effectiveness and Safety of Ceftriaxone 1 g Twice Daily versus 2 g Once Daily for Treatment of Aspiration Pneumonia

“…From the viewpoint of pharmacokinetics/pharmacodynamics (PK/PD), beta-lactams increase clinical efficacy by increasing the frequency of administrations [ 16 ]. In fact, clinical studies reported the effectiveness of ceftriaxone twice daily [ 17 , 18 ]. Ceftriaxone exerts its bactericidal effect in a time-dependent manner, and the time spent above the MIC (%TAM) is an important PK/PD parameter for estimating clinical efficacy.…”

β-lactam precision dosing in critically ill children: Current state and knowledge gaps

“…SIRS criteria are often met through presence of fever and tachycardia, especially in the setting of infection, in critically ill children. Our model of ceftriaxone in critically ill children also showed that fever increased ceftriaxone clearance ( Tang Girdwood et al, 2021 ). Fever is not a covariate that is frequently considered in the development of population PK models.…”

“…Patients with higher antibiotic clearance are at risk of low exposures and suboptimal antibacterial efficacy. In Table 1 , we summarize several population PK models in critically ill children for ceftriaxone, piperacillin/tazobactam, cefepime and meropenem, the β-lactam antibiotics often used for sepsis in the pediatric ICU (PICU) ( Li et al, 2013 ; Cies et al, 2014a ; Nichols et al, 2016 ; Shoji et al, 2016 ; Cies et al, 2017 ; De Cock et al, 2017 ; Beranger et al, 2019 ; Al-Shaer et al, 2020b ; Hartman et al, 2021 ; Saito et al, 2021 ; Tang Girdwood et al, 2021 ; Yonwises et al, 2021 ; de Cacqueray et al, 2022 ). The one patient factor that consistently demonstrates an effect on clearance is estimated glomerular filtration, typically based on creatinine.…”

“…The lack of monitoring in children is concerning as PK variability may be higher due to maturation effect at younger ages and due to highly variable weights at older ages ( Lu and Rosenbaum, 2014 ). It is known that standard intermittent β-lactam dosing in critically ill adult and pediatric patients leads to highly variable concentrations (up to 100-fold) ( Roberts et al, 2010 ; Garot et al, 2011 ; Duszynska et al, 2012 ; Roberts et al, 2012 ; Sime et al, 2012 ; Kongthavonsakul et al, 2016 ; Shoji et al, 2016 ; De Cock et al, 2017 ; Beranger et al, 2019 ; Al-Shaer et al, 2020a ; Abdulla et al, 2020 ; Tang Girdwood et al, 2020a ; Lonsdale et al, 2020 ; Saito et al, 2020 ; Hartman et al, 2021 ; Tang Girdwood et al, 2021 ). This high PK variability leads to inconsistent PD target attainment, placing patients at risk of suboptimal bactericidal activity.…”