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.

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.

A comparison study between GeXP-based multiplex-PCR and serology assay for Mycoplasma pneumoniae detection in children with community acquired pneumonia.

BACKGROUND: Diagnosis of community-acquired pneumonia (CAP) caused by Mycoplasma pneumoniae (Mp) in children has been hampered by difficulty in obtaining convalescent serum and time constraints. In this study, the two diagnostic assays that targeted respectively on Mp-antibody and Mp-DNA were retrospectively investigated. METHODS: A total of 3146 children were clinically diagnosed to have CAP and were confirmed by chest X-ray during March 2015 to February 2016 in Children's hospital of Hebei Province (China). Both of the sera and sputum samples were collected in 24 h after their admission. The Mp-antibody was examined by the passive particle agglutination assay and a fourfold or greater increase of antibody titers of paired sera or≧1:160 titer of single serum was set as the serology positive. Mp-DNA in the sputum samples was tested by a multiplex-PCR method named GeXP assay (multiplex PCR combined with automated capillary electrophoresis). In order to eliminate the false positive results caused by the asymptomatic carriage after infected by M. pneumoniae, the inconsistent samples were tested by the real-time isothermal transcription-mediated RNA amplification assay (SAT). RESULTS: The inter-rated agreement test was performed in 3146 CAP patients, with a highest kappa value in the school-age children as 0.783. There were 6.29% (198/3146) cases showed inconsistent results determined by GeXP and serology assay. All of the 19 GeXP(+)/Serology (-) samples and a randomly chosen 27 from 179 GeXP(-)/Serology (+) samples were tested by SAT assay, and a 97.8% diagnosis agreement was observed between SAT and GeXP assay, but not with the serology assay. In addition, patients who were detected only by serology or only by multiplex-PCR were significantly younger than those with both methods positive (3.0 and 1.5 years vs. 5.0 years, p < 0.01). The Viral-Mp coinfection accounted for 37.0% (97/262), which was more common in winter and spring (p < 0.05) and in the infantile group (p < 0.01), compared to the pure Mp positive ones. CONCLUSION: In some children CAP cases, the Mp laboratory diagnosis was inconsistent between serology and multiplex-PCR assay. Verified by the SAT assay, the GeXP showed a more sensitive and reliable performance compared with the serology assay. Furthermore, employing the multiplex-PCR could provide more information on the associated pathogens for clinical assessment of CAP.

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.

A GeXP-Based Assay for Simultaneous Detection of Multiple Viruses in Hospitalized Children with Community Acquired Pneumonia.

The GeXP-based assay has recently been developed for simultaneous detection of multiple pathogens. So far, the application of the GeXP assay to test larger clinical samples has hardly been reported. Community-acquired pneumonia (CAP) is the leading cause of death in children worldwide and a substantial proportion of childhood CAP is caused by viruses. Rapid and accurate diagnosis of virus infection is important for the clinical management of CAP. In this study, we explored the GeXP assay for simultaneous detection of 20 types/subtypes of viruses in hospitalized children with CAP. A total of 1699 nasopharyngeal swabs were prospectively collected and viral nucleic acid was extracted and assayed. Using viral genomic DNA or RNA as template, we showed that at the concentration of 104 copies of DNA or RNA of each virus/µl, all 20 target viruses were simultaneously identified by the GeXP assay. Fifteen control microorganisms, in contrast, failed to be amplified by the assay. About 65% of cases tested in this study had viral infection, with patients aged <3 years having a 70% positive rate, significantly higher than that in patients aged > 3 years (40%). The most frequently detected virus was RSV followed by PIV3, HRV, ADV and HBoV. Seasonal distribution analysis revealed that RSV was the most predominant in autumn and winter, while in spring and summer PIV3 and RSV were the most frequently identified with similar positive percentages. One hundred twenty randomly-chosen samples tested by the GeXP assay were re-evaluated by mono-RT-PCR, the results showed 97.5% diagnosis agreement between these 2 methods. Our findings suggest that the GeXP assay could be a valuable diagnostic tool for virus infection in pediatric patients with CAP.