Therapeutic Drug Monitoring Of Amoxicillin And Blood Brain Barrier Penetration Of Cefotaxime In Neonates

Because the organs of the neonate are not mature,the immune system of the body has not yet been established and the immunity is relatively low,which makes the neonate vulnerable to the invasion of pathogenic microorganisms and is prone to serious infections,causing sepsis and meningitis.The incidence of neonatal sepsis in China accounts for about 1 to 10 per cent of births,and the number of deaths accounts for 10%to 20%.Amoxicillin is commonly used for the treatment of neonatal sepsis.The incidence of neonatal meningitis in China is 10-50 cases per 100,000,of which preterm infants account for 80%.The incidence of very low birth weight infants is 5-20 times that of full-term infants,and the mortality rate also reaches 10-15%.Cefotaxime is often used clinically for the treatment of neonatal meningitis.However,it is found that the difference in efficacy between individuals is very large when the same treatment plan is givenin the clinical use of the above drugs.The reason mainly is that tissues and organs of the newborn are in the process of rapid development,the pharmacokinetics of the drug in the neonatal populationis difference.When the same treatment program is given,the drug concentrationis not same in the site of infection for each individual.So we need to optimize the dosing regimen for each individual to reach an effective concentrationin the site of infection.For the treatment of sepsis,a systemic infectious disease,the concentration of the anti-infective drug in the patient's blood is of great significance.Therefore,it is necessary to develop a blood drug concentration monitoring method that can be applied to the clinic.For the treatment of meningitis infectivity,the concentration of infectious drugs penetrating the blood-brain barrier into the cerebrospinal fluidis very important.Therefore,it is necessary to study the blood-brain barrier permeability of anti-infective drugs.After a protein precipitation method,amoxicillin for standards,quality control samples,and patient samples were separated with HPLC and quantified by UV detection method,tinidazole was used as the internal standardin the studyof the determination of amoxicillin blood concentration.The calibration range was 0.50-20.0?g/mL.Intra-and Inter-day precisions were less than 4%.The criteria for acceptance of accuracy(between 85 and 115%)were met in all cases.In order to achieve the limit of quantification of 0.50 ?g/mL,50 ?L of plasma volume was required.Only 51.5%(n=50)of 97neonates had trough concentrations higher than 2 ?g/mL.In conclusion,a simple,rapid and accurate HPLC-UV method has been established to determine the amoxicillin concentration in plasma.This method was successfully implicated in neonatal TDM practice.Thirty neonates and young infants(PMA range:25.4-47.4 weeks)were includedin the study of blood-brain barrier penetration of cefotaxime in neonates.A total of 67 plasma and 30 CSF samples were available for analysis.Cefotaxime plasma and CSF concentrations ranged from 2.30 to 175.42 mg/liter,and from 0.39 to 25.38 mg/liter,respectively.The median ratio of CSF to plasma concentrations was 0.28(range 0.06-0.76).Monte Carlo simulation demonstrated that 88.4%and 63.9%of hypothetical neonates treated with 50 mg/kg TID would reach the pharmacodynamic target(70%fT>MIC)using the standard EUCAST MIC susceptibility breakpoint of 2 mg/liter and 4 mg/liter,respectively.In this study,the blood brain barrier penetration of cefotaxime was systematically studied in neonatal population for the first time.Population pharmacokinetic approach coupled with opportunistic sampling paradigm is promising in CSF pharmacokinetic study in neonates.Model-based dosing regimen was developed to optimize cefotaxime treatment in neonatal meningitis.