Pharmacokinetic parameters over time during sepsis and the association of target attainment and outcomes in critically ill children and young adults receiving ceftriaxone.

INTRODUCTION: Early sepsis results in pharmacokinetic (PK) changes due to physiologic alterations. PK changes can lead to suboptimal drug target attainment, risking inadequate coverage from antibiotics like ceftriaxone. Little is known about how ceftriaxone PK and target attainment quantitatively change over time in patients with sepsis or the association between target attainment and outcomes in critically ill children and young adults. METHODS: A retrospective analysis of a prospective study was conducted in a single-center pediatric intensive care unit. Septic patients given at least one ceftriaxone dose (commonly as 50 mg/kg every 12 h) and who had blood obtained in both the first 48 h of therapy (early) and afterwards (late) were included. Normalized clearance and central volume were estimated and compared in both sepsis phases. We evaluated target attainment, defined as concentrations above 1× or 4× the minimum inhibitory concentration (MIC) for 100% of dosing intervals, and investigated the association between target attainment and clinical outcomes. RESULTS: Fifty-five septic patients (median age: 7.5 years) were included. Normalized clearance and central volume were similar in both phases (6.18 ± 1.48 L/h/70 kg early vs. 6.10 ± 1.61 L/h/70 kg late, p = 0.60; 26.6 [IQR 22.3, 31.3] L/70 kg early vs. 24.5 [IQR 22.0, 29.4] L/70 kg late, p = 0.18). Individual percent differences in normalized clearance and central volume between sepsis phases ranged from -39% to 276% and -51% to 212% (reference, late sepsis), respectively. Fewer patients attained the 1× MIC target in late sepsis (82% late vs. 96% early, p = 0.013), which was associated with transition to once daily dosing, typically done due to transfer from the pediatric intensive care unit (PICU) to a lower acuity unit. Failure to attain either target in late sepsis was associated with antibiotic broadening. CONCLUSION: Ceftriaxone PK parameters were similar between early and late sepsis, but there were large individual differences. Fewer patients attained MIC targets in late sepsis and all who did not attain the less stringent target received once daily dosing during this period. The failure to attain targets in late sepsis was associated with antibiotic broadening and could be an area for antibiotic stewardship intervention.

Dexamethasone Versus Prednisone in Children Hospitalized With Asthma Exacerbation.

OBJECTIVES: Dexamethasone is increasingly used for the management of children hospitalized with asthma in place of prednisone, yet data regarding the effectiveness of dexamethasone in children with asthma exacerbation severe enough to require hospitalization are limited. Our objective is to compare the effectiveness of dexamethasone versus prednisone in children hospitalized with an asthma exacerbation on 30-day reutilization. METHODS: We conducted a retrospective cohort study at an urban, quaternary children's hospital of children aged 4 to 17 years, hospitalized from January 1, 2014 to December 31, 2017, with a primary discharge diagnosis of asthma. A covariate-balanced propensity score was derived to account for physician discretion in steroid selection. A generalized linear model, including inverse probability treatment weighting, was used to detect differences in 30-day return utilization (unplanned readmission or emergency department visit) between children whose first dose of corticosteroid was dexamethasone versus prednisone. RESULTS: Inclusion criteria were met by 1161 patients, of which 510 (44%) first received dexamethasone versus 651 (56%) who first received prednisone. The total cohort had a mean age of 8.5 years (SD 3.4). The covariate-balanced cohort had no significant differences in demographic characteristics or illness severity between groups. The dexamethasone group had a return utilization of 3.9% (20 of 510) versus 2.2% (14 of 651) for children treated with prednisone. The propensity score-adjusted analysis revealed the steroid treatment was not found to significantly affect the 30-day reutilization (adjusted odds ratio [aOR] 1.61; 95%CI 0.80-3.31). CONCLUSIONS: The initial steroid choice (dexamethasone versus prednisone) was not associated with 30-day reutilization after hospitalization for an asthma exacerbation.

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.

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).