Population Pharmacokinetics and Dosing Optimization of Ceftazidime in Infants.

Ceftazidime, a third-generation cephalosporin, can be used for the treatment of adults and children with infections due to susceptible bacteria. To date, the pediatric pharmacokinetic data are limited in infants, and therefore we aimed to evaluate the population pharmacokinetics of ceftazidime in infants and to define the appropriate dose to optimize ceftazidime treatment. Blood samples were collected from children treated with ceftazidime, and concentrations of the drug were quantified by high-performance liquid chromatography with UV detection (HPLC-UV). A population pharmacokinetic analysis was performed using NONMEM software (version 7.2.0). Fifty-one infants (age range, 0.1 to 2.0 years) were included. Sparse pharmacokinetic samples (n = 90) were available for analysis. A one-compartment model with first-order elimination showed the best fit with the data. A covariate analysis identified that body weight and creatinine clearance (CLCR) were significant covariates influencing ceftazidime clearance. Monte Carlo simulation demonstrated that the currently used dosing regimen of 50 mg/kg twice daily was associated with a high risk of underdosing in infants. In order to reach the target of 70% of the time that the free antimicrobial drug concentration exceeds the MIC (fT>MIC), 25 mg/kg every 8 h (q8h) and 50 mg/kg q8h were required for MICs of 4 and 8 mg/liter, respectively. The population pharmacokinetic characteristics of ceftazidime were evaluated in infants. An evidence-based dosing regimen was established based on simulation.

Penetration of Cefotaxime into Cerebrospinal Fluid in Neonates and Young Infants.

Cefotaxime is the first-line treatment for meningitis in neonates and young infants. However, limited data on cefotaxime cerebrospinal fluid (CSF) concentrations in neonates and young infants were available. The aim of the present study was to evaluate the penetration of cefotaxime into CSF in neonates and young infants. Blood and CSF samples were collected from neonates and young infants treated with cefotaxime using an opportunistic pharmacokinetic sampling strategy, and concentrations were quantified by high-performance liquid chromatography-tandem mass spectrometry. The analysis was performed using NONMEM and R software. Thirty neonates and young infants (postmenstrual age range, 25.4 to 47.4 weeks) were included. A total of 67 plasma samples 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 the CSF concentration to the plasma concentration was 0.28 (range, 0.06 to 0.76). Monte Carlo simulation demonstrated that 88.4% and 63.9% of hypothetical neonates treated with 50 mg/kg of body weight three times a day (TID) would reach the pharmacodynamic target (the percentage of the dosing interval that the free antimicrobial drug concentration remains above the MIC, 70%) using the standard EUCAST MIC susceptibility breakpoints of 2 mg/liter and 4 mg/liter, respectively. The penetration of cefotaxime into the CSF of neonates and young infants was evaluated using an opportunistic sampling approach. A dosage regimen of 50 mg/kg TID could cover the most causative pathogens with MICs of <2 mg/liter. Individual dosage adaptation was required for more resistant bacterial strains, such as Staphylococcus aureus.

Population Pharmacokinetics and Dosing Optimization of Azithromycin in Children with Community-Acquired Pneumonia.

Azithromycin is extensively used in children with community-acquired pneumonia (CAP). Currently, the intravenous azithromycin is used off-label in children partly due to lacking of pharmacokinetic data. Our objective was to evaluate the population pharmacokinetics (PPK) and optimize dose strategy in order to improve treatment in this distinctive population. This was a prospective, multicenter, open-labeled pharmacokinetic study. Blood samples were collected from hospitalized pediatric patients and concentrations were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). PPK analysis was conducted using NONMEM software. The pharmacokinetic data from 95 pediatric patients (age range, 2.1 to 11.7 years) were available for analysis. The PPK was best fitted by a two-compartment model with linear elimination. Covariate analysis verified that body weight and alanine aminotransferase (ALT) had significant effects on azithromycin pharmacokinetics, yielding a 24% decrease of clearance in patients with ALT of >40. Monte Carlo simulation showed that for children with normal liver function, a loading-dose strategy (a loading dose of 15 mg/kg of body weight followed by maintenance doses of 10 mg/kg) would achieve the ratio of the area under free drug plasma concentration-time curve over 24 h (fAUC) to MIC90 (fAUC/MIC) target of 3 h in 53.2% of hypothetical patients, using a normative MIC susceptibility breakpoint of 2 mg/liter. For children with ALT of >40, the proposed dose needed to decrease by 15% to achieve comparable exposure. The corresponding risk of overdose for the recommended dosing regimen was less than 5.8%. In conclusion, the PPK of azithromycin was evaluated in children with CAP and an optimal dosing regimen was constructed based on developmental pharmacokinetic-pharmacodynamic modeling and simulation.

Determination of cefoperazone and sulbactam in serum by HPLC-MS/MS: An adapted method for therapeutic drug monitoring in children.

A rapid, accurate and specific high-performance liquid chromatography-tandem mass spectrometry method has been validated for the simultaneous determination of cefoperazone and sulbactam in a small volume sample for children. A Shim-pack XR-ODS C18 column with gradient elution of water (0.1% formic acid) and acetonitrile (0.1% formic acid) solution was used for separation at a flow rate of 0.3 mL/min. The calibration curves of two analytes in serum showed excellent linearity over the concentration ranges of 0.03-10 µg/mL for cefoperazone, and 0.01-3 µg/mL for sulbactam, respectively. This method involves simple sample preparation steps and was validated according to standard US Food and Drug Administration and European Medicines Agency guidelines in terms of selectivity, linearity, detection limits, matrix effects, accuracy, precision, recovery and stability. This assay can be easily implemented in clinical practice to determine concentrations of cefoperazone and sulbactam in children.

Population pharmacokinetics and dosing optimization of latamoxef in neonates and young infants.

OBJECTIVES: There has been recent renewed interest in historical antibiotics because of the increased antibiotic-resistant bacterial strains. Latamoxef, a semi-synthetic oxacephem antibiotic developed in 1980s, has recently been brought back into use for treatment of infections in newborns; however, it is still used off-label in neonatal clinical practice due to the lack of an evidence-based dosing regimen. This study was performed to evaluate the pharmacokinetics of latamoxef in neonates and young infants, and to provide an evidence-based dosing regimen for newborns based on developmental pharmacokinetics-pharmacodynamics (PK-PD). METHODS: Opportunistic blood samples from newborns treated with latamoxef were collected to determine the latamoxef concentration by high-performance liquid chromatography with UV detection. Population PK-PD analysis was conducted using NONMEM and R software. A total of 165 plasma samples from 128 newborns (postmenstrual age range 28.4-46.1 weeks) were available for analysis. RESULTS: A two-compartment model with first-order elimination showed the best fit with the data. Current body weight, birth weight, and postnatal age were identified as significant covariates influencing latamoxef clearance. Simulation indicated that the current dosing regimen (30 mg/kg q12h) is adequate with an MIC of 1 mg/L. For an MIC of 4 mg/L, 30 mg/kg q8h was required to achieve a target rate of 70% of patients having a free antimicrobial drug concentration exceeding the MIC during 70% of the dosing interval. CONCLUSIONS: Based on the developmental PK-PD analysis of latamoxef, a rational dosing regimen of 30 mg/kg q12h or q8h was required in newborns, depending on the pathogen.

Population pharmacokinetics and dosing optimization of cefathiamidine in children with hematologic infection.

PURPOSE: Cefathiamidine, a first-generation cephalosporin, has approval from the China Food and Drug Administration for the treatment of infections caused by susceptible bacteria in both adults and children. As pharmacokinetic data are limited in the pediatric population, we aimed to evaluate the population pharmacokinetics of cefathiamidine in children and to define the appropriate dose in order to optimize cefathiamidine treatment. METHODS: Blood samples were collected from children treated with cefathiamidine, and concentrations were quantified by high-performance liquid chromatography and tandem mass spectrometry. Population pharmacokinetic analysis was conducted using NONMEM software. RESULTS: Fifty-four children (age range: 2.0-11.8 years) were included. Sparse pharmacokinetic samples (n=120) were available for analysis. A two-compartment model with first-order elimination showed the best fit with the data. A covariate analysis identified that bodyweight had a significant impact on cefathiamidine pharmacokinetics. Monte Carlo simulation demonstrated that the currently used dosing regimen of 100 mg/kg/day q12h was associated with a high risk of underdosing in pediatric patients. To reach the target 70% fT>MIC, a dose of 100 mg/kg/day cefathiamidine q6h is required for effective treatment against Haemophilus influenzae. CONCLUSION: A population pharmacokinetics model of cefathiamidine in children with hematologic disease was established. A dosing regimen of 100 mg/kg/day cefathiamidine q6h should be used in clinical practice against H. influenza infections.