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... Show moreBackground 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 (TM)). 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 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. Show less
Hartman, S.J.F.; Upadhyay, P.J.; Hagedoorn, N.N.; Mathot, R.A.A.; Moll, H.A.; Flier, M. van der; ... ; Wildt, S.N. 2021
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... Show moreBackground 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 (TM) 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 x 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 m(2), 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 x 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 m(2) 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. Show less
Hartman, S.; Upadhyay, P.; Hagedoorn, N.; Krekels, E.H.J.; Mathot, R.; Moll, H.; ... ; Wildt, S. de 2021
Background Patients with an IgG subclass deficiency (IgSD) +/- specific polysaccharide antibody deficiency (SPAD) often present with recurrent infections. Previous retrospective studies have shown... Show moreBackground Patients with an IgG subclass deficiency (IgSD) +/- specific polysaccharide antibody deficiency (SPAD) often present with recurrent infections. Previous retrospective studies have shown that prophylactic antibiotics (PA) and immunoglobulin replacement therapy (IRT) can both be effective in preventing these infections; however, this has not been confirmed in a prospective study. Objective To compare the efficacy of PA and IRT in a randomized crossover trial. Methods A total of 64 patients (55 adults and 9 children) were randomized (2:2) between two treatment arms. Treatment arm A began with 12 months of PA, and treatment arm B began with 12 months of IRT. After a 3-month bridging period with cotrimoxazole, the treatment was switched to 12 months of IRT and PA, respectively. The efficacy (measured by the incidence of infections) and proportion of related adverse events in the two arms were compared. Results The overall efficacy of the two regimens did not differ (p = 0.58, two-sided Wilcoxon signed-rank test). A smaller proportion of patients suffered a related adverse event while using PA (26.8% vs. 60.3%, p < 0.0003, chi-squared test). Patients with persistent infections while using PA suffered fewer infections per year after switching to IRT (2.63 vs. 0.64, p < 0.01). Conclusion We found comparable efficacy of IRT and PA in patients with IgSD +/- SPAD. Patients with persistent infections during treatment with PA had less infections after switching to IRT. Clinical Implication Given the costs and associated side-effects of IRT, it should be reserved for patients with persistent infections despite treatment with PA. Show less
Bastiaans, D.E.T.; Immohr, L.I.; Zeinstra, G.G.; Strik-Albers, R.; Pein-Hackelbusch, M.; Flier, M. van der; ... ; Warris, A. 2017
