Pharmacokinetics of Generic Pediatric Dolutegravir Dispersible Tablet in Thai Young Children Living With HIV Weighing Below Twenty Kilograms.

INTRODUCTION: Dolutegravir (DTG) dispersible tablet (DTG-DT) is a pediatric-friendly formulation. We aimed to describe the pharmacokinetics and virologic responses of generic DTG-DT in children weighing <20 kg. METHODS: Children living with HIV-1 and <7 years of age weighing 6 to <20 kg were eligible. A generic 10-mg scored DTG-DT was administered to children using 3 weight bands (WB): WB1 (6 to <10 kg), WB2 (10 to <14 kg) and WB3 (14 to <20 kg), at doses of 20 mg (higher than World Health Organization recommendation of 15 mg), 20 mg and 25 mg, respectively. Steady-state intensive pharmacokinetics (PK) was performed in fasting condition with blood sampling at predose and 1, 2, 3, 4, 6 and 24 hours postdose. DTG PK parameters were estimated using a noncompartmental analysis, and DTG trough concentrations (C24) and 24-hour area under the concentration-time curve were calculated. Comparisons were made with ODYSSEY and IMPAACT 2019. And 90% effective concentration of 0.32 mg/L was used as a reference individual DTG C24 concentration. RESULTS: From August 2021 to March 2023, 29 Thai children with a median (interquartile range) age of 3.2 (1.5-4.8) years were enrolled; 8 in WB1, 9 in WB2 and 12 in WB3. All children were treatment experienced and 59% had HIV RNA <200 copies/mL. Overall geometric mean (coefficient of variation percentage) DTG C24 was 1.0 (46%) mg/L [WB1, 0.9 (53%); WB2, 0.9 (27%); WB3, 1.2 (51%)]. Geometric mean (coefficient of variation percentage) 24-hour area under the concentration-time curve was 83.2 (24%) mg h/L [WB1, 84.3 (31%); WB2, 76.9 (16%); WB3, 87.6 (25%)]. At weeks 24 and 48, 90% and 92% of participants had plasma HIV RNA <200 copies/mL. CONCLUSIONS: Generic DTG-DT provided adequate drug exposure in children weighing 6 to <20 kg. The exploratory dose of DTG 20 mg for children weighing 6 to <10 kg showed similar PK parameters to World Health Organization doses in the other WB.

Genetic and clinical predictors of rifapentine and isoniazid pharmacokinetics in paediatrics with tuberculosis infection.

OBJECTIVES: Twelve weekly doses of rifapentine and isoniazid (3HP regimen) are recommended for TB preventive therapy in children with TB infection. However, they present with variability in the pharmacokinetic profiles. The current study aimed to develop a pharmacokinetic model of rifapentine and isoniazid in 12 children with TB infection using NONMEM. METHODS: Ninety plasma and 41 urine samples were collected at Week 4 of treatment. Drug concentrations were measured using a validated HPLC-UV method. MassARRAY® SNP genotyping was used to investigate genetic factors, including P-glycoprotein (ABCB1), solute carrier organic anion transporter B1 (SLCO1B1), arylacetamide deacetylase (AADAC) and N-acetyl transferase (NAT2). Clinically relevant covariates were also analysed. RESULTS: A two-compartment model for isoniazid and a one-compartment model for rifapentine with transit compartment absorption and first-order elimination were the best models for describing plasma and urine data. The estimated (relative standard error, RSE) of isoniazid non-renal clearance was 3.52 L·h-1 (23.1%), 2.91 L·h-1 (19.6%), and 2.58 L·h-1 (20.0%) in NAT2 rapid, intermediate and slow acetylators. A significant proportion of the unchanged isoniazid was cleared renally (2.7 L·h-1; 8.0%), while the unchanged rifapentine was cleared primarily through non-renal routes (0.681 L·h-1; 3.6%). Participants with the ABCB1 mutant allele had lower bioavailability of rifapentine, while food prolonged the mean transit time of isoniazid. CONCLUSIONS: ABCB1 mutant allele carriers may require higher rifapentine doses; however, this must be confirmed in larger trials. Food did not affect overall exposure to isoniazid and only delayed absorption time.

The 8-bromobaicalein alleviated chikungunya-induced musculoskeletal inflammation and reduced the viral load in healthy adult mice.

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 EC50 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 EC99.9 for 12 h. Therefore, 8-bromobaicalein should be a potential candidate for further development as a pan-arboviral drug.

Predicting the Area under the Plasma Concentration-Time Curve (AUC) for First Dose Vancomycin Using First-Order Pharmacokinetic Equations.

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.

Pharmacokinetics of isoniazid and rifapentine in young pediatric patients with latent tuberculosis infection.

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 (CLR, 0.005 vs 0.003 l/h, P= 0.014). Food was associated with increased CLR 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.

Pharmacokinetics and Safety of WHO-Recommended Dosage and Higher Dosage of Levofloxacin for Tuberculosis Treatment in Children: a Pilot Study.

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.

Therapeutic drug monitoring of meropenem and pharmacokinetic-pharmacodynamic target assessment in critically ill pediatric patients from a prospective observational study.

OBJECTIVES: To compare the unbound plasma meropenem concentrations at mid-dosing intervals (Cmid, 50%fT), end-dosing intervals (Ctrough, 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 Cmid, Ctrough, 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]) Cmid 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) Ctrough 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 Cmid, Ctrough, and proportions of patients achieving 50%fT>MIC and 100%fT>MIC.

Sexually transmitted infections incidence in young Thai men who have sex with men and transgender women using HIV pre-exposure prophylaxis.

BACKGROUND: Sexually transmitted infections are a major public health issue worldwide. HIV pre-exposure prophylaxis (PrEP) use among youth may be associated with increased incidence of sexually transmitted infections (STIs). OBJECTIVES: To measure the prevalence and incidence of STIs among young men who have sex with men (YMSM) and young transgender women (YTGW) using PrEP. METHODS: A prospective cohort of 15- to 19-year-old YMSM and YTGW with HIV risk defined as inconsistent condom use and/or multiple sex partners were enrolled. Participants were provided daily oral tenofovir disoproxil fumarate/emtricitabine. STI screening was done at baseline and month 6 for syphilis, urine, and anal swab nucleic acid amplification testing for C. trachomatis (CT) and N. gonorrheaoe (NG). RESULTS: From March 2018 to June 2019, 200 adolescents (147 MSM and 53 TGW) with a median (IQR) age of 18 years (17-19) were enrolled. STI prevalence was 22.5% (95% CI 16.7-28.3). STI incidence was 25.2 per 100 person-years (95% CI 14.7, 40.3). Factors associated with STI incidence were self-reported >2 sex partners in the past month (unadjusted rate ratio [uRR] 4.6, 95% CI 1.0, 20.6), and moderate PrEP adherence (uRR 7.3, 95% CI 1.6, 32.6). CONCLUSIONS: STI incidence in YMSM and YTGW PrEP users was high at approximately one in five. Regular screening and treatment of STIs should be implemented in youth HIV prevention packages.

Population pharmacokinetics of meropenem in critically ill infant patients.

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 (Vd) 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 Vd 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.

Dose recommendations for intravenous colistin in pediatric patients from a prospective, multicenter, population pharmacokinetic study.

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 (Css,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 Css,avg of 2 mg/l. With a lower targeted Css,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 Css,avg.

Comparison of piperacillin plasma concentrations in a prospective randomised trial of extended infusion versus intermittent bolus of piperacillin/tazobactam in paediatric patients.

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 (Cmid, 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 Cmid. 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 Cmid 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 Cmid compared with IB. In settings with increased piperacillin MICs, this approach should be implemented, particularly during the empirical treatment period.

Acceptance and outcome of interventions in a meropenem de-escalation antimicrobial stewardship program in pediatrics.

BACKGROUND: Prospective audit and feedback is a method that allows the antimicrobial stewardship program (ASP) team to interact with attending physicians to tailor antibiotic therapy, including de-escalation, as appropriate. This study aimed to evaluate the acceptance and outcomes of ASP de-escalation recommendations in children who received meropenem. METHODS: A prospective cohort study was conducted in children aged 1 month to 18 years who received meropenem in a tertiary-care teaching hospital. The ASP team gave recommendation between 72 and 120 h after initiating meropenem therapy. Acceptance of de-escalation recommendations among primary physicians was evaluated within 24 h of recommendation. Outcomes included clinical success rate on the 7th day and incidence rate of acquisition of carbapenem-resistant gram-negative bacteria (CR-GNB) within 30 days. RESULTS: From March to December 2019, 217 children with a median (interquartile range) age of 2.1 (0.6, 9.5) years received meropenem. The ASP team gave recommendations in 127 (58.5%) of cases for continuation of meropenem therapy and 90 (41.5%) of cases for de-escalation. The overall acceptance of ASP de-escalation recommendations was 57.8% (95%CI: 46.9-68.1%). Clinical success rates were 85.2% in the accepted group compared to 77.5% in the rejected group (P = 0.06). The incidence rate of acquisition of CR-GNB within 30 days after treatment was 5.8% in the accepted group and 15.8% in the rejected group (P = 0.03). CONCLUSIONS: About half of the recommendations to de-escalate meropenem prescriptions were accepted through the ASP intervention. Carbapenem-resistant gram-negative bacteria acquisitions was less likely in the de-escalation group. A robust de-escalation strategy 72 h following carbapenem initiation should be encouraged to combat multidrug-resistant organisms.

No increased acute kidney injury rate through giving an intravenous colistin loading dose in pediatric patients.

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 m2. 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 m2. 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.

Risk factors of severe hospitalized respiratory syncytial virus infection in tertiary care center in Thailand.

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.

High prescribing rates of third-generation cephalosporins in children hospitalized with acute lower respiratory infections at a university hospital.

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.

Greater optimisation of pharmacokinetic/pharmacodynamic parameters through a loading dose of intravenous colistin in paediatric patients.

Use of colistin in children is rising in line with the increase of multidrug-resistant Gram-negative bacteria (MDR-GNB). In adults, a colistin loading dose is recommended to achieve therapeutic concentrations within 12-24 h. Here we aimed to describe the pharmacokinetic (PK) parameters of a loading dose versus a recommended initial dose of intravenous colistimethate sodium (CMS) in paediatric patients. A prospective, open-label, PK study was conducted in paediatric patients (age 2-18 years) with normal renal function. Patients (n = 20) were randomly assigned to receive either a CMS loading dose (LD group) of 4 mg of colistin base activity (CBA)/kg/dose or a standard initial dose (NLD group) of 2.5 mg (12-h interval) or 1.7 mg (8-h interval) of CBA/kg/dose. Serial blood samples were collected. Plasma concentrations of formed colistin were measured by LC-MS/MS. PK parameters were reported. Acute kidney injury (AKI) was monitored by serum creatinine and urine NGAL. The median (interquartile range) age and body weight were 8.5 (3.5-11.3) years and 21.5 (13.5-20.0) kg. The mean (standard deviation) of first-dose PK parameters of the LD group versus the NLD group were: Cmax, 6.1 (2.4) vs. 4.1 (1.3) mg/L; AUC0-t, 26.5 (12.5) vs. 13.5 (3.6) mg/L·h; Vd, 0.7 (0.4) vs. 0.6 (0.3) L/kg; and t1/2, 2.9 (0.6) vs. 2.6 (0.4) h. No patient developed AKI by serum creatinine criteria. A CMS loading dose is beneficial for improvement of colistin exposure without increased AKI. A higher daily dose of CMS should be considered, especially for MDR-GNB treatment.

Efficacy of chlorhexidine patches on central line-associated bloodstream infections in children.

BACKGROUND: Central line-associated bloodstream infections (CLABSIs) are important hospital-acquired infections. Chlorhexidine-impregnated dressings (also known as chlorhexidine patches, CHG patches) are reported to decrease CLABSIs in adults. This study aims to determine the efficacy of CHG patches in reducing CLABSIs in children. METHODS: An open-label randomized controlled trial was conducted in children aged 2 months to 18 years, requiring a short-term catheter. Patients were randomized into two groups, allocated to receive CHG patches or standard transparent dressings. Care of the catheter was in accordance with Asia Pacific Society of Infection Control (APSIC) recommendations. Central-line-associated bloodstream infections were defined using National Healthcare Safety Network surveillance criteria. RESULTS: From April 2017 to April 2018, 192 children were enrolled. There were 108 CHG patch catheters and 101 standard dressing catheters, contributing to 3,113 catheter days. The median duration of catheter dwelling was 13 days, with an interquartile range (IQR) of 8-20 days. Half were placed at the jugular vein and 22% at the femoral vein. There were 23 CLABSI events. Incidence rates for CHG patches and standard dressings were 7.98 (95% confidence interval (CI), 4.25-13.65) and 6.74 (95% CI, 3.23-12.39) per 1,000 catheter days, respectively (incidence rate ratio 1.18; 95% CI, 0.52-2.70). The CLABSI pathogens were 15 Gram-negative bacteria, six Gram-positive bacteria, and two Candida organisms. Catheter colonization of CHG patches and standard dressings were 2.02 (95% CI, 0.42-5.91) and 3.07 (95% CI, 1.00-7.16) per 1,000 catheter days, respectively. Only local adverse effects occurred in 6.8% of the participants. CONCLUSIONS: In our setting, there was no difference in CLABSI rates when the chlorhexidine patch dressings were compared with the standard transparent dressings. Strengthening of CLABSI prevention bundles is mandatory.

Optimizing Vancomycin Use Through 2-Point AUC-Based Therapeutic Drug Monitoring in Pediatric Patients.

The 24-hour vancomycin area under the serum concentration-time curve (AUC24 ) divided by the minimum inhibitory concentration (MIC) (AUC24 /MIC) is more closely related to patient outcomes than serum trough concentrations (Ctrough ). Two-point simplified equations for calculating AUC based on serum peak concentrations (Cpeak ) and Ctrough , named equation A (EqA) and equation B (EqB), have recently been adopted into clinical use for adult pediatric patients. We aimed to find the agreement between predicted AUC24 using the reference method (ref) relative to EqA and EqB and the correlation between Ctrough and AUC24 . From June to December 2018, 43 pediatric patients with normal renal function, receiving 15 mg/kg of vancomycin intravenously every 6 hours, were enrolled. The pediatric patients' median age was 2.2 years (range 0.1-15.3). At steady state, vancomycin Cpeak and Ctrough were measured at 2 hours after infusion completion and within 30 minutes before the next dosing, respectively. AUC24 was estimated using ref, EqA, and EqB. From Bland-Altman analysis, the 2 AUC24 s estimated by ref and EqA showed less bias than those estimated by ref and EqB (bias 1.3 and -72.1 mg⋅h/L, respectively). Ctrough and AUC24 using either ref or EqA were correlated more closely (r2 = 0.94) than with EqB (r2 = 0.86). Assuming a vancomycin MIC of 1 mg/L, an AUC24 ≥400 mg⋅h/L was targeted. Regardless of the method used, AUC24 ≥400 mg⋅h/L was never seen with Ctrough <8 mg/L but was always seen with Ctrough >10 mg/L. In conclusion, EqA based on the 2 measured serum concentrations was sufficiently accurate for AUC24 estimation. Ctrough >10 mg/L correlated highly to AUC24 ≥400 mg⋅h/L.

A randomized open-label trial of 2-dose or 3-dose pre-exposure rabies prophylaxis among Thai children.

BACKGROUND: World Health Organization changed the recommendation for pre-exposure rabies prophylaxis from 3-dose to 2-dose regimen in 2018. Given limited data of 2-dose regimens in pediatric population, this study aimed to compare the immunogenicity between 2-dose and 3-dose pre-exposure rabies immunization. METHODS: This study was conducted among healthy children aged 2-12 years. They were randomized to 2-dose vaccination (2D) on days 0 and 28 or 3-dose vaccination (3D) on days 0, 7, and 28. Purified Vero cell rabies vaccine (PVRV-Verorab™) was administered intramuscularly. Rabies virus neutralizing antibody (RVNA) titers were measured at 3 time points: 14-day after complete vaccination, 1-year pre-booster vaccination, and 7-day post-booster dose to mimic scenario of rabies exposure. RVNA titers ≥0.5 IU/ml were considered adequate antibody. T cell specific response to rabies vaccine antigen was measured using the interferon-gamma enzyme linked immunospot assay. RESULTS: From September to October 2017, 107 participants (51% males), 78 in 2D group and 29 in 3D group were enrolled. Median age was 5.8 years (IQR 4.4-7.3). All participants had RVNA titers ≥0.5 IU/ml after primary vaccination [GMT 2D: 18.6 (95%CI 15.9-21.8) and 3D: 16.3 (95%CI 13.2-20.1 IU/ml), p = 0.35]. At 1-year prior to receiving the booster, only 80% of the children in 2D group maintained RVNA titers ≥0.5 IU/ml compared to 100% of the children in 3D group (p = 0.01). However, all participants in both groups had RVNA ≥0.5 IU/ml at 7-day post booster vaccination [GMT 2D: 20.9 (95%CI 17.4-25.3) and 3D: 22.2 (95%CI 15.8-31.4) IU/ml (P = 0.75)]. The median number of IFN-γ secreting cells at 7-day post-booster dose was 98 and 128 SFCs per 106 PBMCs in the 2D and 3D groups, respectively (P = 0.30). CONCLUSIONS: Two-dose primary rabies immunization provided adequate antibody at post primary vaccination and post booster. The results support 2-dose regimen of pre-exposure rabies immunization in the pediatric population.

Abdominal Actinomycosis in Children: A Case Report and Literature Review.

Abdominal actinomycosis is an uncommon pediatric infection that often manifests with a tumor-like lesion. We describe a previously healthy 11-year-old girl who presented with right lower quadrant abdominal pain and drainage. Computed tomography scan showed an abdominal wall mass. Surgical debridement cultures grew Actinomyces meyeri. Literature review identified 18 additional pediatric cases since 1964 that we have summarized.