Epithelial lining fluid concentrations of ceftriaxone in children with community-acquired pneumonia.

Ceftriaxone is widely used in children with community-acquired pneumonia. Currently, there are no available data regarding epithelial lining fluid (ELF) concentrations of ceftriaxone in children. Thus, blood and bronchoalveolar lavage fluids samples were collected by using an opportunistic sampling design, then we determined plasma and ELF concentrations in 22 children (0.5-11.7 years), with a total of 36 plasma and 22 ELF samples available for analysis. Ceftriaxone plasma and ELF concentrations ranged from 1.07 to 138.71 mg/L and from 0.61 to 26.69 mg/L, respectively. Ceftriaxone concentration in ELF was 12.18 ± 5.15 (mean ± standard deviation) times higher than that in plasma, ranging from 1.29 to 20.44.

Meropenem for children with severe pneumonia: Protocol for a randomized controlled trial.

Background: Pneumonia, caused by infection or other factors, seriously endangers the health of children. Meropenem is an effective broad-spectrum antibiotic using in the treatment of infectious diseases. In the therapy of pneumonia, meropenem is mostly employed for the treatment of moderate to severe pneumonia. Previously, we established a population pharmacokinetics (PPK) model for meropenem in pediatric severe infection and simulated the control rate of the time during which the free plasma concentration of meropenem exceeds the minimum inhibitory concentration (MIC) is 70% of the dosing interval (70% fT > MIC). Therefore, we plan to conduct a multicenter randomized controlled trial (RCT) to compare the efficacy and safety between conventional regimen and model regimen for meropenem in pediatric severe pneumonia. Methods: One hundred patients (aged 3 months to 15 years) will be recruited in this RCT. They will be assigned randomly (at a 1:1 ratio) to a conventional treatment group (20 mg/kg, q8h, with 0.5-1 h infusion) and a model treatment group (20 mg/kg, q8 h, with 4 h infusion). The primary outcome will be 70% fT > MIC. Secondary outcomes will be the prevalence of meropenem therapy failure, duration of antibiotic therapy, changes in levels of inflammatory indicators, changes in imaging examination results, and prevalence of adverse events. Ethical approval of our clinical trial has been granted by the ethics committee of Beijing Children's Hospital ([2022]-E-133-Y). This trial has been registered in the Chinese Clinical Trial Registry (ChiCTR2200061207). Discussion: Based on our previous PPK data, we have designed this RCT. It is hoped that it will promote rational use of antibacterial drugs in children suffering from severe pneumonia. Clinical Trial Registration: http://www.chictr.org.cn identifier, ChiCTR2200061207.

Developmental Population Pharmacokinetics-Pharmacodynamics of Meropenem in Chinese Neonates and Young Infants: Dosing Recommendations for Late-Onset Sepsis.

The pharmacokinetic (PK) studies of meropenem in Chinese newborns with late-onset sepsis (LOS) are still lacking. Causative pathogens of LOS and their susceptibility patterns in China differ from the data abroad. We, therefore, conducted a developmental population pharmacokinetic−pharmacodynamic analysis in Chinese newborns with the goal to optimize meropenem dosing regimens for LOS therapy. An opportunistic sampling strategy was used to collect meropenem samples, followed by model building and validation. A Monte Carlo simulation was performed to show the probability of target attainment (PTA) for various dosages. The information from 78 newborns (postmenstrual age: 27.4−46.1 weeks) was compiled and had a good fit to a 1-compartment model that had first order elimination. The median (range) values of estimated weight−normalized volume of distribution (V)and clearance (CL) were 0.60 (0.51−0.69) L/kg and 0.16 (0.04−0.51) L/h/kg, respectively. Covariate analysis revealed that postnatal age (PNA), gestational age (GA) and current weight (CW) were the most important factors in describing meropenem PK. Simulation results showed for LOS with a minimal inhibitory concentration (MIC) of 8 mg/L, the doses of 30 mg/kg 3 times daily (TID) as a 1-h infusion for newborns with GA ≤ 37 weeks and 40 mg/kg TID as a 3-h infusion for those with GA > 37 weeks were optimal, with PTA of 71.71% and 75.08%, respectively. In conclusion, we proposed an evidence-based dosing regimen of meropenem for LOS in Chinese newborns by using the population pharmacokinetic−pharmacodynamic analysis, based on domestic common pathogens and their susceptibility patterns.

Clinical utility of a model-based amoxicillin dosage regimen in neonates with early-onset sepsis.

Early-onset sepsis (EOS) is one of the most significant causes of morbidity and mortality in neonates. Currently, amoxicillin is empirically used to treat neonates with EOS. However, data on its effectiveness in neonates with EOS are still limited. Therefore, we aimed to evaluate the pharmacodynamics (PD) target attainment and effectiveness of a model-based amoxicillin dosage regimen in these neonates. We used a previously developed model and collected additional clinical data from the EOS neonates who used the model-based dosage regimen (25 mg/kg every 12 h). The primary outcomes were PD target attainment (free drug concentration above minimum inhibitory concentration during 70% of the dosing interval) and treatment failure rate. The secondary endpoints were length of amoxicillin treatment, duration of hospitalization etc. Seventy-five neonates (postmenstrual age 28.4-41.6 wk) were enrolled. A total of 70 (93.3%) neonates reached their PD target using 1 mg/L as the minimum inhibitory concentration breakpoint. The treatment failure rate was 10.7%.

Population Pharmacokinetic Study of Cefathiamidine in Infants With Augmented Renal Clearance.

Objectives: Augmented renal clearance (ARC) of primarily renally eliminated antibacterial agents may result in subtherapeutic antibiotic concentrations and, as a consequence, worse clinical outcomes. Cefathiamidine is frequently used as empirical antimicrobial therapy in children with ARC, but pharmacokinetic studies in infants are lacking. This population pharmacokinetic study in infants with ARC was conducted to determine optimal dosing regimens of cefathiamidine. Methods: The population pharmacokinetics was conducted in 20 infants treated with cefathiamidine. Plasma samples of cefathiamidine were collected using opportunistic sampling, and the concentrations were detected by UPLC-MS/MS. Data analysis was performed to determine pharmacokinetic parameters and to characterize pharmacokinetic variability of cefathiamidine using nonlinear mixed effects modelling (NONMEM) software program. Results: The data (n = 36) from 20 infants (age range, 0.35-1.86 years) with ARC were fitted best with a 1-compartment model. Allometrically scaled weight and age as significant covariates influenced cefathiamidine pharmacokinetics. The median (range) values of estimated clearance and the volume of distribution were 0.22 (0.09-0.29) L/h/kg and 0.34 (0.24-0.41) L/kg, respectively. Monte Carlo simulations showed that the cefathiamidine doses of 100 mg/kg/day q12 h, 50 mg/kg/day q8 h and 75 mg/kg/day q6 h were chosen for bacteria with MIC 0.25, 0.5 and 2 mg/L, respectively. Conclusion: The population pharmacokinetic model of cefathiamidine for infants with ARC was developed. The PTA - based dosing regimens were recommended based on the final model.

Individualized Study of Posterior Hemivertebra Excision and Short-Segment Pedicle Screw Fixation for the Treatment of Congenital Scoliosis.

OBJECTIVES: To compare the surgical effect of children with symmetrical screw fixation and asymmetric screw fixation during posterior hemivertebra excision and short-segment pedicle screw fixation for the treatment of congenital scoliosis (CS). METHODS: A total of 30 children with CS who underwent posterior hemivertebra excision and short-segment bilateral pedicle screw fixation in our hospital from 2012 to 2018 were retrospectively included and were divided into two groups: symmetric fixation group (n = 18) and asymmetric fixation group (n = 12). The total main curve, segmental main curve, cranial compensatory curve, caudal compensatory curve, coronal balance, and apical vertebra translation were measured in the coronal plane. The segmental kyphosis, thoracic kyphosis, lumbar lordosis, and sagittal balance were measured in the sagittal plane. RESULTS: Of the 30 children, 28 hemivertebrae were resected. Twenty-two children had one hemivertebra, three had two hemivertebrae, and five were rib deformities. The average operation time was 268 min (180-420 min). The average blood loss was 291 mL (150-550 mL). The average follow-up was 21.1 months (12-47 months). For symmetric fixation group and there were significant differences among postoperative and follow-up parameters including the total main curve, segmental main curve, cranial compensatory curve, caudal compensatory curve, apical vertebra translation and segmental kyphosis compared with those of preoperative parameters (P < 0.05). The postoperative coronal balance was significantly lower than preoperative coronal balance (P < 0.05). The follow-up thoracic kyphosis was significantly higher than preoperative and postoperative thoracic kyphosis (P < 0.05). For asymmetric fixation group, the postoperative and follow-up parameters including the total main curve, segmental main curve, cranial compensatory curve, caudal compensatory curve, apical vertebra translation, and segmental kyphosis had statistical differences compared with those of preoperative parameters (P < 0.05). The postoperative sagittal balance was significantly higher than preoperative postoperative (P < 0.05). There were no significant differences in the postoperative and follow-up correction rate and correction loss between the two groups (P > 0.05). There were three complications in 30 children in our study, including two cases who had poor wound healing, and the wound healed smoothly after half a month of sterile dressing change. Postoperative curve progression occurred in one case after T12 and L3 hemivertebra resection and thoracic hemivertebra resection was planned again. CONCLUSION: For pedicles which were difficult for screw fixation, adjacent segments can be chosen for screw fixation and it is safe and effective for vertebral pedicles ≤3 without internal fixation.

Population Pharmacokinetics and Dosing Optimization of Amoxicillin in Chinese Infants.

Amoxicillin is used to treat various bacterial infections (eg, pneumonia, sepsis, meningitis) in infants. Despite its frequent use, there is a lack of population pharmacokinetic studies in infants, resulting in a substantial variability in dosing regimens used in clinical practice. Therefore, the objective of this study was to evaluate the population pharmacokinetics of intravenous amoxicillin in infants and suggest an optimal dosage regimen. Blood samples were collected for the determination of amoxicillin concentrations using an opportunistic sampling strategy. The amoxicillin plasma concentrations were determined using high-performance liquid chromatography. Population pharmacokinetic analysis was performed using NONMEM. A total of 62 pharmacokinetic samples from 47 infants (age range, 0.09 to 2.0 years) were available for analysis. A 2-compartment model with first-order elimination was most suitable to describe the population pharmacokinetics of amoxicillin, and covariate analysis showed that only current body weight was a significant covariate. Monte Carlo simulation demonstrated that the currently used dosage regimen (25 mg/kg twice daily) resulted in only 22.4% of infants reaching their pharmacodynamic target, using a minimum inhibitory concentration (MIC) break point of 2 mg/L, whereas a dosage regimen (60 mg/kg thrice daily), as supported by the British National Formulary for Children, resulted in 80.9% of infants achieving their pharmacodynamic target. It is recommended to change antibiotics for infections caused by Escherichia coli (MIC = 8.0 mg/L) because only 27.9% of infants reached target using 60 mg/kg thrice daily.

Optimal Dosing of Ceftriaxone in Infants Based on a Developmental Population Pharmacokinetic-Pharmacodynamic Analysis.

Ceftriaxone is a third-generation cephalosporin used to treat infants with community-acquired pneumonia. Currently, there is a large variability in the amount of ceftriaxone used for this purpose in this particular age group, and an evidence-based optimal dose is still unavailable. Therefore, we investigated the population pharmacokinetics of ceftriaxone in infants and performed a developmental pharmacokinetic-pharmacodynamic analysis to determine the optimal dose of ceftriaxone for the treatment of infants with community-acquired pneumonia. A prospective, open-label pharmacokinetic study of ceftriaxone was conducted in infants (between 1 month and 2 years of age), adopting an opportunistic sampling strategy to collect blood samples and applying high-performance liquid chromatography to quantify ceftriaxone concentrations. Developmental population pharmacokinetic-pharmacodynamic analysis was conducted using nonlinear mixed effects modeling (NONMEM) software. Sixty-six infants were included, and 169 samples were available for pharmacokinetic analysis. A one-compartment model with first-order elimination matched the data best. Covariate analysis elucidated that age and weight significantly affected ceftriaxone pharmacokinetics. According to the results of a Monte Carlo simulation, with a pharmacokinetic-pharmacodynamic target of a free drug concentration above the MIC during 70% of the dosing interval (70% fT>MIC), regimens of 20 mg/kg of body weight twice daily for infants under 1 year of age and 30 mg/kg twice daily for those older than 1 year of age were suggested. The population pharmacokinetics of ceftriaxone were established in infants, and evidence-based dosing regimens for community-acquired pneumonia were suggested based on developmental pharmacokinetics-pharmacodynamics.

Apolipoprotein E gene polymorphism and the risk of subarachnoid hemorrhage: a meta-analysis of case-control studies.

BACKGROUND: Studies investigating the association between the apolipoprotein E gene (APOE) polymorphism and the risk of subarachnoid hemorrhage (SAH) have reported inconsistent results. So we performed a meta-analysis to estimate the association between APOE polymorphism and SAH susceptibility. METHODS: Relevant studies published before 5 November 2015 were identified by searching PubMed, Embase, EBSCO, and ISI web of knowledge. The strength of relationship between the APOE gene and SAH susceptibility was assessed using odds ratio (OR) and corresponding 95 % confidence interval (95 % CI). RESULTS: A total number of six case-control studies including 638 SAH cases and 2,341 controls were identified. No association was found in dominant model or allele contrast genetic model (ε4 dominant model: OR = 1.06, 95 % CI = 0.91-1.25; ε3 dominant model: OR = 0.99, 95 % CI = 0.97-1.01; ε2 dominant model: OR = 0.99, 95 % CI = 0.78-1.25; ε4 versus ε3: OR = 1.14, 95 % CI = 0.96-1.35; ε4 versus ε2: OR = 1.07, 95 % CI = 0.90-1.28; ε3 versus ε2: OR = 1.00, 95 % CI = 0.96-1.04) for APOE polymorphism and SAH susceptibility. In the subgroup analyzed that was stratified by ethnicity, increased risk of SAH was found in Asian subjects when ε4 allele compared with ε3 allele (ε4 vs ε3, OR = 1.55, 95 % CI = 1.07-2.52). CONCLUSIONS: Our meta-analysis suggested that there is no association between APOE polymorphism and SAH risk for overall population. Due to several limitations in the present study, well-designed epidemiological studies with large sample size among different ethnicities should be performed in the future.