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 h 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 of body weight every 12 h versus 24 h) 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 peripheral volume is 19.6 L/70 kg. For both models, we found that allometric weight scaling, postmenstrual age, creatinine clearance, and daily highest temperature had significant effects on clearance. The 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 h is recommended for most patients. A continuous infusion could be considered if the target is to maintain free concentrations four times above the MICs (4 μg/ml).

Keywords: beta-lactams; ceftriaxone; critically ill; pharmacodynamics; pharmacokinetics.

FIG 1

(A) Total volume of fluid administered as boluses on study days 1 and 2 versus study days 3 to 7. (B) Cumulative percent fluid balance in patients still on ceftriaxone therapy on each study day. Negative percent fluid balance indicates there was higher cumulative fluid output than intake until that study day. n, number of patients from which percent fluid balance was calculated. For each box plot, the dark horizontal line is the median, the upper border of the box is the 75th percentile, and the lower border of the box is the 25th percentile. Circles represent individual outlier observations.

FIG 2

Goodness-of-fit plots for total ceftriaxone model (A) and free ceftriaxone model (B). Top left, individual predictions versus observed concentrations (μg/ml). Black line is the line of identity. Top right, population predictions versus observed concentrations (μg/ml). Black line is the line of identity. Bottom left, conditional weighted residuals (CWRES) versus population prediction concentrations. Bottom right, CWRES versus time, in hours, after first dose. Figure was generated by R with Pirana interface.

FIG 3

Prediction-corrected visual predictive check (pcVPC) plots of total ceftriaxone model (A) and free ceftriaxone model (B). Open circles, prediction-corrected observed plasma concentrations. Red solid line, median of prediction-corrected observed concentrations. Red dashed lines, 5th and 95th percentiles of the prediction-corrected observed concentrations. Shaded areas are the simulation-based 95% confidence interval around the 5th, 50th, and 95th, percentiles.

FIG 4

Probability of target attainment obtained from Monte Carlo simulations for a target defined as 100% fT>_MIC for patients with a fever (temperature ≥ 38.5°C) and augmented renal clearance (ARC) (2 to 6 standard deviations above the median clearance for age). Blue circles, 50 mg/kg every 12 h regimen. Gray squares, 50 mg/kg every 24 h regimen. Orange triangles, 50 mg/kg given continuously every 24 h. Green filled circles, 100 mg/kg every 24 h.