| Background:In children,community acquired pneumonia(CAP)is one of a major reason for morbidity and mortality which leads to immense rate of pediatric hospital admissions.According to study performed in '2013' in China,there were 16,585 CAP inpatient cases registered,among which high percentage 37.3%was in individuals?5 years and in individuals above 65 years was 28.7%.Comparatively,in only 9.2%of adults(26-45 years)infection developed.Pneumonia was a main cause of deaths in children with age below 5 years in China Among the 6.3 million pediatric patient's deaths,14.8%were pneumonia cases in children with age under 5.Ceftriaxone,a third-generation cephalosporin,possess broad-spectrum of antibacterial activity.It is widely used in the clinical treatment of various bacterial infections in children.The pharmacological activity of ceftriaxone depends on unbound concentration However,direct measurement of unbound concentration is obstructive,and high individual variability of the unbound fraction of ceftriaxone was shown in children.At present,the dosage schemes of ceftriaxone used in the clinical practice of children in various centres and hospitals are quite different.Also infants' physiology is under constant changes and development which may affect the pharmacokinetics of drugs.Presently,there are few studies on the ceftriaxone pharmacokinetics in the pediatric populations.Most of these studies are performed in adult population and also it has small number of patients,narrow age-range or less powerful PK analysis method.Therefore,our goal was to assess the population pharmacokinetics of ceftriaxone using a large sample size covering entire age range of children and infants to establish an evidence-based dosage regimen based on the developmental pharmacokinetics-pharmacodynamicsMethods:Blood samples were obtained using an opportunistic sampling design from pediatric patients using ceftriaxone.The concentration was measured through high performance liquid chromatography ultraviolet detection(HPLC-UV)and metronidazole was used as internal standard.In cephalosporin group,to achieve the maximum antibacterial effects,a probability of target-attainment of about 70%was required for a 60%to 70%dosing interval and MIC 2 mg/L was selected as the pharmacokinetic pharmacodynamic breakpoint.The non-linear mixed effects modelling(NONMEM)program was used for population pharmacokinetic analysis.Results:A total of 99 children(175 PK samples)and 66 infants(169 PK samples)were included in the present study.The best-fit with the data was displayed by the one compartment model with first-order elimination.According to covariates analysis weight and age had significant impacts on the clearance of ceftriaxone.The average total and unbound ceftriaxone concentrations were 126.18±81.46 ?g/mL and 18.82±21.75 pg/mL,and the unbound fraction varied greatly from 4.75%to 39.97%.The disease adapted equation showed the best predictive performance of unbound ceftriaxone concentrations.By using Monte-Carlo simulations,a dosing regimen of 100 mg/kg QD for children(2-12 years old),30 mg/kg BID for infants aged 1-2 years old and 20 mg/kg for children aged<1 years old achieved satisfactory target attainment rates in CAP treatmentConclusion:This study proposes a recommended dosing regimen based on developmental pharmacokinetics-pharmacodynamics,microbiology,and safety for specific indications and specific age groups of children.This study results provide meaningful guidance for the rational use of ceftriaxone in children,and provide data support for individualized therapy. |
PDF Full Text Request