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Chikungunya virus is a re-emerging arbovirus that has caused epidemic outbreaks in recent decades. Patients in older age groups with high viral load and severe immunologic response during acute infection are likely to develop chronic arthritis and severe joint pain. Currently, no antiviral drug is available. Previous studies suggested that a flavone derivative, 8-bromobaicalein, was a potential dengue and Zika replication inhibitor in a cell-based system targeting flaviviral polymerase. Here we characterized that 8-bromobaicalein inhibited chikungunya virus replication with EC 50 of 0.49 ± 0.11 µM in Vero cells. The molecular target predicted at viral nsP1 methyltransferase using molecular binding and fragment molecular orbital calculation. Additionally, oral administration of 250 mg/kg twice daily treatment alleviated chikungunya-induced musculoskeletal inflammation and reduced viral load in healthy adult mice. Pharmacokinetic analysis indicated that the 250 mg/kg administration maintained the compound level above EC 99.9 for 12 h. Therefore, 8-bromobaicalein should be a potential candidate for further development as a pan-arboviral drug.

To treat critically ill patients, early achievement of the target area under the plasma concentration-time curve/minimum inhibitory concentration (AUC/MIC) in the first 24 h is recommended. However, accurately calculating the AUC before steady state is an obstacle to this goal. A first-order pharmacokinetic equation to calculate vancomycin AUC after a first dose of vancomycin has never been studied. We sought to estimate AUC using two first-order pharmacokinetic equations, with different paired concentration time points, and to compare these to the actual first dose vancomycin AUC calculated by the linear-log trapezoid rule as a reference. The equations were validated using two independent intensive first dose vancomycin concentration time data sets, one from 10 adults and another from 14 children with severe infection. The equation with compensation for the alpha distribution phase using a first vancomycin serum concentration from 60 to 90 min and the second concentration from 240 to 300 min after the completed infusion showed good agreement and low bias of calculated AUC, with mean differences <5% and Lin's correlation coefficient >0.96. Moreover, it gave an excellent correlation with Pearson's r > 0.96. Estimating the first dose vancomycin AUC calculated using this first-order pharmacokinetic equation is both reliable and reproducible in clinical practice settings.

Objectives: This study investigated the steady-state pharmacokinetic profiles of 3-month weekly rifapentine plus isoniazid (3HP) in children with latent tuberculosisinfection (LTBI). We also assessed other factors, including tablet integrity, food, and pharmacogenetics., Methods: During the 3HP treatment, blood and urine samples were collected in week 4. Isoniazid and rifapentine levels were measured using a high-performance liquid chromatography technique. The genetic variation of arylamine N-acetyltransferase 2 (NAT2) and arylacetamide deacetylase (AADAC) were assessed by the MassARRAY®. Safety and clinical outcomes at week 48 were monitored., Results: A total of 12 children with LTBI (age 3.8 [range 2.1-4.9 years old]) completed the treatment (isoniazid and rifapentine dose 25.0 [range 21.7-26.8] and 25.7 [range 20.7-32.1] mg/kg, respectively). No serious adverse events or active TB occurred. Tablet integrity was associated with decreased area under the concentration-time curve (91 vs 73 mg.h/l, P= 0.026) and increased apparent oral clearance of isoniazid (0.27 vs 0.32 l/h/kg, P= 0.019) and decreased rifapentine's renal clearance (CL R , 0.005 vs 0.003 l/h, P= 0.014). Food was associated with increased CL R of isoniazid (3.45 vs 8.95 l/h, P= 0.006) but not rifapentine. Variability in NAT2 and AADAC did not affect the pharmacokinetics of both drugs., Conclusion: There is high variability in the pharmacokinetic profiles of isoniazid and rifapentine in young children with LTBI. The variability was partly influenced by tablet integrity and food, but not pharmacogenetics. Further study in a larger cohort is warranted to display the relationship of these factors to treatment outcomes., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: To evaluate the pharmacokinetic parameters of the 2020 World Health Organization (WHO)-recommended pediatric dosage of levofloxacin and the higher-than-WHO dosage., Methods: Children aged 1-15 years with tuberculosis who received levofloxacin-based treatment for at least 7 days were enrolled. First, five children were enrolled to receive the WHO-recommended dosage (15-20 mg/kg/day), then an additional five children received a dosage higher than the WHO-recommended dosage (20-30 mg/kg/day). Blood samples were collected at predose and postdose 1, 2, 4, 6, 8, and 12 hours. A target of the ratio of the free area under the concentration-time curve to minimum inhibitory concentration (fAUC/MIC) was 100., Results: The median (interquartile range) age was 9.6 (4.9-10.5) and 12.0 (10.1-12.3) years in the WHO dosage and higher-than-WHO dosage groups, respectively. The median (interquartile range) duration of antituberculosis treatment was 24 (8-24) weeks. The geometric mean (95% confidence interval) of fAUC/MIC was 60.4 (43.5-84.0) and 103.2 (70.1-151.8) in the WHO and higher-than-WHO dosage groups, respectively. There was no adverse event of QT prolongation or any other grade 3 or 4 adverse events., Conclusion: Levofloxacin at a higher dose of 20-30 mg/kg/day could achieve the fAUC/MIC target in children., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: To compare the unbound plasma meropenem concentrations at mid-dosing intervals (C mid , 50%fT), end-dosing intervals (C trough , 100%fT), and proportions of patients achieving 50%fT and 100%fT above minimum inhibitory concentration (MIC) (50%fT >MIC and 100%fT >MIC ) between extended infusion (EI) and intermittent bolus (IB) administration in a therapeutic drug monitoring (TDM) program in children., Methods: A prospective observational study was conducted in children aged 1 month to 18 years receiving meropenem every 8 hours by either EI or IB. Meropenem C mid , C trough , and proportions of patients achieving 50%fT >MIC and 100%fT >MIC were compared., Results: TDM data from 72 patients with a median age (interquartile range [IQR]) of 12 months (3-37) were used. Meropenem dose was 120 and 60 mg/kg/day in EI and IB groups, respectively. Geometric mean (95% confidence interval [CI]) C mid of EI versus IB was 17.3 mg/L (13.7-21.8) versus 3.4 mg/L (1.7-6.7) (P <0.001). Geometric mean (95% CI) C trough of EI versus IB was 2.3 mg/L (1.6-3.4) versus 0.8 mg/L (0.4-1.5) (P=0.005). Greater proportions of patients achieving 50%fT >MIC and 100%fT >MIC were observed in the EI group., Conclusions: A meropenem dose of 20 mg/kg/dose given by IB should not be used in critically ill children, even if they are not suspected of having a central nervous system infection. A dose of 40 mg/kg/dose given by EI resulted in higher C mid , C trough , and proportions of patients achieving 50%fT >MIC and 100%fT >MIC ., Competing Interests: Declaration of competing interests The authors have no competing interests to declare., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Population pharmacokinetic analysis in critically ill infants remains a challenge for lack of information., Objectives: To determine the population pharmacokinetic parameters of meropenem and evaluate the covariates affecting population pharmacokinetic parameters., Methods: A prospective study was conducted on 35 patients. A total of 160 blood samples were collected and determined free of drug concentrations of meropenem. Population pharmacokinetic data were analyzed using NONMEM software. Internal validation methods, including bootstrapping and prediction-corrected visual predictive checks, were applied to evaluate the robustness and predictive power of the final model., Results: A one-compartment model with first-order elimination showed the best fit to the data. The typical clearance (CL) values and volume of distribution (V d ) were 1.33 L/h and 2.27 L, respectively. Weight and creatinine clearance were influential covariates for CL, while weight was a significant covariate for V d of meropenem. The model evaluation results suggested robustness and good predictability of the final model. The standard dosage regimens of meropenem achieved 40% f T >MIC but not enough if a more aggressive target of 80% f T >MIC at MIC value of ≥ 16 µg/mL is desired., Conclusions: This population pharmacokinetic model could be used for suggesting individualized meropenem dosage regimens in critically ill infants., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: The aim of this study was to describe the population pharmacokinetics of intravenous colistin use in children and to propose optimal dosage regimens., Methods: A prospective, multicenter, population pharmacokinetic (PPK) study was conducted. Phoenix 64 version 8.3 was used for the PPK analysis. Simulations were performed to estimate the probability of target attainment for patients achieving target plasma colistin average steady-state concentrations (C ss,avg )., Results: A total of 334 plasma colistin concentrations were obtained from 79 pediatric patients with a median age (interquartile range) of 2.6 years (0.8-6.8 years); 73 (92.4%) were admitted to intensive care units. Colistin pharmacokinetics were adequately described by a one-compartment model with first-order elimination along with serum creatinine (SCr) as a significant covariate in colistin clearance. The simulation demonstrated that the recommended dose of 5 mg of colistin base activity (CBA)/kg/day resulted in 18.2-63.0% probability of achieving a target C ss,avg of 2 mg/l. With a lower targeted C ss,avg of 1 mg/l, colistin dosing with 7.5 mg and 5 mg of CBA/kg/day were adequate for children with SCr levels of 0.1-0.3 mg/dl and >0.3 mg/dl, respectively., Conclusions: SCr is a significant covariate in colistin clearance in children. Colistin dosing should be selected according to the patient's SCr level and the desired target C ss,avg ., Competing Interests: Conflict of interest All authors declare no conflicts of interest for this manuscript., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: To be effective, piperacillin/tazobactam (PTZ) unbound plasma levels need to be above the minimum inhibitory concentration (MIC) at least 50% of the time between dosing intervals (50% fT >MIC ). This study aimed to compare the plasma piperacillin concentrations at the mid-dosing intervals (C mid , 50% fT) and the proportion of patients achieving 50% fT >MIC between extended infusion (EI) and intermittent bolus (IB) methods in children., Methods: A prospective, randomised trial of EI versus IB of PTZ was conducted in children aged 1 month to 18 years. The PTZ dose was 100 mg/kg intravenously every 8 h. Patients were randomly assigned to receive EI (4-h infusion) or IB (30-min infusion). The primary outcome that was measured was plasma piperacillin C mid ., Results: Ninety patients with a median age (IQR) of 48 months (16-127) were enrolled. The most common indication for PTZ use was pneumonia (32.2%). Geometric mean (95% CI) plasma piperacillin C mid of EI versus IB was 51.9 mg/L (40.6-66.6) versus 6.0 mg/L (4.2-8.6) (P < 0.01). The EI group had a trend of higher proportion of patients who achieved 50% fT >4xMIC (72.7% versus 30.0%; P = 0.06)., Conclusions: PTZ administration with EI resulted in a higher C mid compared with IB. In settings with increased piperacillin MICs, this approach should be implemented, particularly during the empirical treatment period., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: A colistin loading dose is required to achieve adequate drug exposure for the treatment of multidrug-resistant Gram-negative bacteria. However, data on acute kidney injury (AKI) rates associated with this approach in children have been unavailable. The aim of this study was to examine AKI rates in children who were prescribed a colistin loading dose., Methods: A retrospective study was conducted in patients aged 1 month to 18 years who had received intravenous colistin for ≥48 h. Loading dose (LD) was defined as colistin methanesulfonate at 4-5 mg of colistin base activity/kg/dose. AKI was defined according to KDIGO serum creatinine (SCr) criteria - SCr ≥ 1.5 times the baseline, measured 3-7 days after colistin initiation. Augmented renal clearance (ARC) was defined as an estimated glomerular filtration rate (eGFR) >150 mL/min/1.73 m 2 . The rates of AKI were compared between children receiving or not receiving an LD, and between different eGFR groups., Results: In total, 181 children were enrolled. The mean age was 4.3 years (95% confidence interval [CI], 3.6-4.9 years). Ninety-five of the subjects (52.5%) were male. There were 157 children with a baseline eGFR of ≥ 80 mL/min/1.73 m 2 . The overall AKI rate within the first week in this group was 20.4% (95% CI, 14.4-27.6%): LD, 16.1% vs no LD, 23.2% (p = 0.29). Subgroup analysis, excluding patients with ARC, showed a lower AKI rate of 12.8% (95% CI, 6.8-21.3%): LD, 9.7% vs no LD, 14.3% (p = 0.53)., Conclusions: AKI rate was not different among children who received an intravenous colistin loading dose. This approach should be implemented to ensure the necessary drug exposure required for good treatment outcomes., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aim: To determine factors associated with severe hospitalized Respiratory syncytial virus (RSV)-associated LRTI and to describe management in tertiary care center., Methods: Retrospective medical record review was conducted among children under 5 years old hospitalized with RSV-associated LRTI at King Chulalongkorn Memorial Hospital. Severe RSV-associated LRTI was defined as death, mechanical ventilator, or positive pressure ventilation use, prolonged hospitalization >7 days. Factors associated with severe RSV were analyzed using univariate and multivariate logistic regression., Results: From January 2011 to December 2016, 427 children were hospitalized. Median age was 10 months (IQR 4.2-23.0). One hundred seventy-four (41%) patients had severe RSV (11 deaths, 56 mechanical ventilators, 19 positive pressure ventilation, and 88 prolonged hospitalization). Factors associated with severe RSV were chronic lung disease (aOR 15.16 [4.26-53.91]), cirrhosis/biliary atresia (aOR 15.01 [3.21-70.32]), congenital heart disease (aOR 5.11 [1.97-13.23]), chemotherapy (aOR 4.7 [1.34-16.56]), and pre-term (aOR 2.03 [1.13-3.67]). Oxygen therapy was mainly low flow oxygen delivery. 88% of cases received bronchodilator. Parenteral antibiotics were prescribed in 37.9% of cases., Conclusions: Children with co-morbidities have higher risk of severe RSV-associated LRTI. More than two-third of patients received bronchodilator, of which was not recommended by American Academy of Pediatrics. The specific treatment and prevention for RSV are urgently needed., (© 2020 The Authors. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

Objective: Antibiotics are frequently prescribed for the treatment of acute lower respiratory infections (ALRI) in children ≤5 years of age, even though viral aetiologies are the most common. The aim of this study was to describe antibiotic prescribing rates and patterns in children ≤5 years of age hospitalized with ALRI., Methods: A retrospective study was conducted involving patients aged 1 month to 5 years hospitalized with ALRI at a university hospital. Patient demographics, ALRI diagnosis, microbiological data, antibiotics prescribed, and treatment outcomes were recorded and analysed., Results: A total of 1283 patients were enrolled. Their median age was 1.6 years (interquartile range 0.8-2.8 years). Thirty-six percent had a co-morbidity. The diagnosis at discharge was viral ALRI in 81% and bacterial pneumonia in 19%. The mortality rate was 0.4%. The overall antibiotic prescribing rate was 46% (95% confidence interval 43-49%). Antibiotic prescribing rates were higher among children with co-morbidities (65% vs 35%, p < 0.001) and older children (57% for >2-5 years vs 39% for ≤2 years, p < 0.001). Parenteral third-generation cephalosporins were prescribed in up to 68% of all prescriptions., Conclusions: Nearly-half of hospitalized children with ALRI were prescribed antibiotics. The majority of prescribed antibiotics were third-generation cephalosporins. An antimicrobial stewardship programme and antibiotic guidelines should be implemented to promote the judicious use of antibiotics., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To compare the use of bisacodyl suppository with placebo in resolving postoperative ileus after elective colectomy in a randomized controlled trial., Methods: Twenty elective colectomy patients were randomized to receive either bisacodyl or placebo suppository on the third postoperative day. Outcomes included time to first defaecation, length of hospital stay, and postoperative complications. Participants and the primary investigator were unaware of the treatment assignment., Results: All 10 participants in the bisacodyl group defaecated on the third postoperative day, while participants in the placebo group defaecated on days 3 (2/10), 4 (5/10) and 5 (3/10) (p < 0.001). The average lengths of hospital stay for the bisacodyl and placebo groups were 8.5 +/- 2.7 days and 10.4 +/- 5.3 days, respectively (p = 0.325). No significant complications occurred in either group., Conclusion: Bisacodyl suppository seems to be effective and safe in resolving postoperative ileus after elective colectomy in colon cancer patients.