เภสัชจลนศาสตร์ประชากรของยาวอริโคนาโซลในผู้ป่วยเด็กชาวไทย ที่เป็นโรคราแอสเปอร์จิลลัสชนิดรุกราน Population Pharmacokinetics of Voriconazole in Thai Children Patients with Invasive Aspergillosis

บทคัดย่อ วัตถุประสงค์: เพื่อประเมินเภสัชจลนศาสตร์ประชากรและปัจจัยที่เกี่ยวข้องของยาวอริโคนาโซลในผู้ป่วยเด็กที่ติดเชื้อราแอสเปอร์จิลลัสชนิดรุกราน วิธีการศึกษา: การศึกษานี้เก็บข้อมูลย้อนหลังจากโรงพยาบาล 2 แห่ง ในผู้ป่วยเด็กที่อายุน้อยกว่า 12 ปีที่ได้รับการวินิจฉัยเป็นโรคราแอสเปอร์จิลลัสชนิดรุกราน และได้รับการรักษาด้วยยาวอริโคนาโซล ตั้งแต่เดือนมกราคม 2557 ถึงเดือนธันวาคม 2561 วิเคราะห์เภสัชจลนศาสตร์ประชากรจากข้อมูลการตรวจติดตามระดับยาในเลือด โดยวิธี non-linear mixed-effect model ประเมินความถูกต้องเหมาะสมของแบบจำลองสุดท้ายด้วยวิธี bootstrap และ prediction corrected visual predictive check (pcVPC) ผลการศึกษา: จากข้อมูลระดับยาวอริโคนาโซลทั้งหมด 337 ตัวอย่าง จากผู้ป่วย 79 คน พบว่าแบบจำลอง one-compartment model with first-order absorption, linear elimination, and allometric scaling มีความเหมาะสมกับข้อมูลของการศึกษา ค่าเฉลี่ยของค่าการขจัดยาเท่ากับ 11.3 ลิตรต่อชั่วโมงต่อ 70 กิโลกรัม ค่าการกระจายตัวเท่ากับ 273 ลิตรต่อ 70 กิโลกรัม ค่าคงที่การดูดซึมยา1.19 ต่อชั่วโมง และค่าชีวประสิทธิผลของยารับประทาน เท่ากับ 0.796 ปัจจัยที่มีผลต่อค่าพารามิเตอร์คือ น้ำหนักโดยใช้สมการแอลโลเมตรี  (allometric equation) และ aspartate aminotransferase (AST) ต่อค่าการขจัดยา (P-value < 0.001) สรุป: แบบจำลองทางเภสัชจลนศาสตร์ประชากรสามารถนำมาช่วยประเมินพารามิเตอร์ทางเภสัชจลนศาสตร์ของยาวอริโคนาโซลและเป็นแนวทางในการกำหนดขนาดยาโดยคำนึงถึงปัจจัยที่เกี่ยวข้อง ได้แก่ น้ำหนักและ AST คำสำคัญ: เภสัชจลนศาสตร์ประชากร, ยาวอริโคนาโซล, เด็ก, ไทย, การติดเชื้อแอสเปอร์จิลลัสชนิดรุกรานAbstract Objective: To estimate the population pharmacokinetics of voriconazole, to identify factors influencing voriconazole pharmacokinetics in Thai children patients with invasive aspergillosis. Methods: This study was a two-center, retrospective study in children (<12 years) with invasive aspergillosis treated with voriconazole between January 2014 and December 2018. A population pharmacokinetics was conducted from routine voriconazole therapeutic drug monitoring data and was analyzed by a non-linear mixed-effect modeling approach. Bootstrap and prediction corrected visual predictive check (pcVPC) were used to validate the final models. Results: A total of 337 voriconazole plasma concentrations from 79 patients were collected in this study. The data were appropriately fitted by a one-compartment model with first-order absorption, linear elimination, and allometric scaling. The mean of clearance was 11.3 L/h/70 kg, volume of distribution was 273 L/70 kg, absorption rate constant was 1.19 h-1, and oral bioavailability was 0.796. Covariate analysis identified that body weight with allometric scaling improved the model, and aspartate aminotransferase (AST) presented a significant impact on clearance (P-value < 0.001). Conclusion: Final population pharmacokinetic model can be useful to assess the pharmacokinetic parameters of voriconazole and guide dosing strategies base on factors including body weight and AST. Keywords: population pharmacokinetics, voriconazole, pediatric, Thai, invasive aspergillosi

Dolutegravir twice-daily dosing in children with HIV-associated tuberculosis: a pharmacokinetic and safety study within the open-label, multicentre, randomised, non-inferiority ODYSSEY trial

Background: Children with HIV-associated tuberculosis (TB) have few antiretroviral therapy (ART) options. We aimed to evaluate the safety and pharmacokinetics of dolutegravir twice-daily dosing in children receiving rifampicin for HIV-associated TB. Methods: We nested a two-period, fixed-order pharmacokinetic substudy within the open-label, multicentre, randomised, controlled, non-inferiority ODYSSEY trial at research centres in South Africa, Uganda, and Zimbabwe. Children (aged 4 weeks to <18 years) with HIV-associated TB who were receiving rifampicin and twice-daily dolutegravir were eligible for inclusion. We did a 12-h pharmacokinetic profile on rifampicin and twice-daily dolutegravir and a 24-h profile on once-daily dolutegravir. Geometric mean ratios for trough plasma concentration (Ctrough), area under the plasma concentration time curve from 0 h to 24 h after dosing (AUC0–24 h), and maximum plasma concentration (Cmax) were used to compare dolutegravir concentrations between substudy days. We assessed rifampicin Cmax on the first substudy day. All children within ODYSSEY with HIV-associated TB who received rifampicin and twice-daily dolutegravir were included in the safety analysis. We described adverse events reported from starting twice-daily dolutegravir to 30 days after returning to once-daily dolutegravir. This trial is registered with ClinicalTrials.gov (NCT02259127), EudraCT (2014–002632-14), and the ISRCTN registry (ISRCTN91737921). Findings: Between Sept 20, 2016, and June 28, 2021, 37 children with HIV-associated TB (median age 11·9 years [range 0·4–17·6], 19 [51%] were female and 18 [49%] were male, 36 [97%] in Africa and one [3%] in Thailand) received rifampicin with twice-daily dolutegravir and were included in the safety analysis. 20 (54%) of 37 children enrolled in the pharmacokinetic substudy, 14 of whom contributed at least one evaluable pharmacokinetic curve for dolutegravir, including 12 who had within-participant comparisons. Geometric mean ratios for rifampicin and twice-daily dolutegravir versus once-daily dolutegravir were 1·51 (90% CI 1·08–2·11) for Ctrough, 1·23 (0·99–1·53) for AUC0–24 h, and 0·94 (0·76–1·16) for Cmax. Individual dolutegravir Ctrough concentrations were higher than the 90% effective concentration (ie, 0·32 mg/L) in all children receiving rifampicin and twice-daily dolutegravir. Of 18 children with evaluable rifampicin concentrations, 15 (83%) had a Cmax of less than the optimal target concentration of 8 mg/L. Rifampicin geometric mean Cmax was 5·1 mg/L (coefficient of variation 71%). During a median follow-up of 31 weeks (IQR 30–40), 15 grade 3 or higher adverse events occurred among 11 (30%) of 37 children, ten serious adverse events occurred among eight (22%) children, including two deaths (one tuberculosis-related death, one death due to traumatic injury); no adverse events, including deaths, were considered related to dolutegravir. Interpretation: Twice-daily dolutegravir was shown to be safe and sufficient to overcome the rifampicin enzyme-inducing effect in children, and could provide a practical ART option for children with HIV-associated TB

Neuropsychiatric manifestations and sleep disturbances with dolutegravir-based antiretroviral therapy versus standard of care in children and adolescents: a secondary analysis of the ODYSSEY trial

BACKGROUND: Cohort studies in adults with HIV showed that dolutegravir was associated with neuropsychiatric adverse events and sleep problems, yet data are scarce in children and adolescents. We aimed to evaluate neuropsychiatric manifestations in children and adolescents treated with dolutegravir-based treatment versus alternative antiretroviral therapy. METHODS: This is a secondary analysis of ODYSSEY, an open-label, multicentre, randomised, non-inferiority trial, in which adolescents and children initiating first-line or second-line antiretroviral therapy were randomly assigned 1:1 to dolutegravir-based treatment or standard-of-care treatment. We assessed neuropsychiatric adverse events (reported by clinicians) and responses to the mood and sleep questionnaires (reported by the participant or their carer) in both groups. We compared the proportions of patients with neuropsychiatric adverse events (neurological, psychiatric, and total), time to first neuropsychiatric adverse event, and participant-reported responses to questionnaires capturing issues with mood, suicidal thoughts, and sleep problems. FINDINGS: Between Sept 20, 2016, and June 22, 2018, 707 participants were enrolled, of whom 345 (49%) were female and 362 (51%) were male, and 623 (88%) were Black-African. Of 707 participants, 350 (50%) were randomly assigned to dolutegravir-based antiretroviral therapy and 357 (50%) to non-dolutegravir-based standard-of-care. 311 (44%) of 707 participants started first-line antiretroviral therapy (ODYSSEY-A; 145 [92%] of 157 participants had efavirenz-based therapy in the standard-of-care group), and 396 (56%) of 707 started second-line therapy (ODYSSEY-B; 195 [98%] of 200 had protease inhibitor-based therapy in the standard-of-care group). During follow-up (median 142 weeks, IQR 124–159), 23 participants had 31 neuropsychiatric adverse events (15 in the dolutegravir group and eight in the standard-of-care group; difference in proportion of participants with ≥1 event p=0·13). 11 participants had one or more neurological events (six and five; p=0·74) and 14 participants had one or more psychiatric events (ten and four; p=0·097). Among 14 participants with psychiatric events, eight participants in the dolutegravir group and four in standard-of-care group had suicidal ideation or behaviour. More participants in the dolutegravir group than the standard-of-care group reported symptoms of self-harm (eight vs one; p=0·025), life not worth living (17 vs five; p=0·0091), or suicidal thoughts (13 vs none; p=0·0006) at one or more follow-up visits. Most reports were transient. There were no differences by treatment group in low mood or feeling sad, problems concentrating, feeling worried or feeling angry or aggressive, sleep problems, or sleep quality. INTERPRETATION: The numbers of neuropsychiatric adverse events and reported neuropsychiatric symptoms were low. However, numerically more participants had psychiatric events and reported suicidality ideation in the dolutegravir group than the standard-of-care group. These differences should be interpreted with caution in an open-label trial. Clinicians and policy makers should consider including suicidality screening of children or adolescents receiving dolutegravir

The Pattern of Microorganisms and Drug Susceptibility in Pediatric Oncologic Patients with Febrile Neutropenia

Objective. The study aimed to describe the pattern of causative microorganisms, drug susceptibility, risk factors of antibiotic-resistant bacterial infection, and clinical impact of these organisms on pediatric oncology patients with febrile neutropenia. Methods. A retrospective descriptive study of oncologic patients aged less than 15 years who were diagnosed with febrile neutropenia in King Chulalongkorn Memorial Hospital was conducted between January 2013 to December 2017. Characteristics and clinical outcomes of febrile neutropenia episodes, causative pathogens, and their antibiotic susceptibilities were recorded. Result. This study included 267 patients with 563 febrile neutropenia episodes. The median (range) age was 5.1 years (1 month–15 years). The most common underlying disease was acute lymphoblastic leukemia (42.7%). Of 563 febrile episodes, there were 192 (34.1%) with microbiologically documented infection. Among these 192 episodes of microbiologically documented infection, there were 214 causative pathogens: 154 bacteria (72%), 32 viruses (15%), 27 fungus (12.6%), and 1 Mycobacterium tuberculosis (0.4%). Gram-negative bacteria (48.6%) accounted for most of the causative pathogens. Twenty-three percent of them were multidrug resistant, and 18% were carbapenem resistant. Among Gram-positive bacterial infection which accounted for 23.4% of all specimens, the proportion of MRSA was 20%. The 2-week mortality rate was 3.7%. Drug-resistant Gram-negative bacterial infection caused significant adverse events and mortality compared to nonresistant bacterial infection (p<0.05). Conclusion. There is high rate of drug-resistant organism infection in pediatric oncology patients in a tertiary-care center in Thailand. Infection with drug-resistant Gram-negative bacterial infection was associated with significant morbidity and mortality. Continuous surveillance for the pattern of drug-resistant infections is crucial

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 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

Low Measles Seropositivity Rate among Thai Adolescents in the Thai National Immunization Program

To achieve the goal of measles elimination, herd immunity with 95% seroprotection in the community is required. This study aimed to describe the measles seropositivity rate among Thai children and adolescents. A cross-sectional study was conducted among children aged 3&ndash;18 years in Bangkok and its suburbs. Measles IgG antibodies were measured using a EUROIMMUN enzyme-linked immunosorbent assay kit. Seropositivity is defined as a measles IgG titer of &ge;200 IU/L, due to a correlation with a &gt;85% positive rate with a plaque reduction neutralizing titer of &gt;120. Factors associated with seropositivity were analyzed using logistic regression analysis. From May to July 2020, 570 children with a median (IQR) age of 11.7 (9.4&ndash;14.8) years were enrolled. The geometric mean titer (GMT) of anti-measles IgG was 281 IU/L (95% CI; 257&ndash;306). The proportion of children with seropositivity was inversely correlated with age; 3&ndash;5 years 85.3%, 6&ndash;9 years 72.5%, 10&ndash;14 years 50.7%, and 15&ndash;18 years 56.3%. Adolescents aged 10&ndash;18 years had a lower measles seropositivity rate compared with young children; aOR 0.29 (95% CI 0.17&ndash;0.48). Only half of the adolescents who received two doses of measles-containing vaccine maintained measles IgG above the seropositive level. A measles booster dose for young adults may be needed to achieve the measles elimination goal

Prevalence and Risk Factors of Healthcare-Associated Infections among Hospitalized Pediatric Patients: Point Prevalence Survey in Thailand 2021

Background: Healthcare-associated infections (HAIs) pose a grave threat to patient safety, morbidity, and mortality, contributing to antimicrobial resistance. Thus, we estimated the point prevalence, risk factors, types, and pathogens of HAIs in hospitalized pediatric patients. Methods: A point prevalence survey (PPS) of HAIs in hospitalized pediatric patients p = 0.80). Significant independent risk factors were extended hospital length of stay (LOS) and central venous catheter (CVC) use. Compared to an LOS of 14 days had adjusted odds ratios (aORs) of 2.65 (95% CI 1.05, 6.68), 5.19 (95% CI 2.00, 13.4), and 9.03 (95% CI 3.97, 20.5), respectively. The use of a CVC had an aOR of 2.45 (95% CI 1.06–5.66). Lower respiratory tract infection (LRTI) was the most common HAI type (46.4%: 26/56). The highest prevalence of HAIs was predominantly observed in LRTI diagnoses, with the highest among these in the <1 month age category at 2.3% (17/738). Conclusion: The prevalence of HAIs in hospitalized pediatric patients was 3.9%. Extended LOS and use of CVC were HAI risk factors. A strategy for reducing LOS and reviewing insertion indications or the early planned removal of a CVC was implemented. The surveillance of HAIs stands as a cornerstone and fundamental component of IPC, offering invaluable insights that enhance hospital IPC interventions aimed at preventing HAIs

Behavioral problems in perinatally HIV-infected young children with early antiretroviral therapy and HIV-exposed uninfected young children: prevalence and associated factors

Although behavioral problems have been observed in children and adolescents with perinatally-acquired HIV infection (PHIV), behavioral information regarding younger PHIV children are scarce. This study aims to identify behavioral problems in PHIV and HIV-exposed uninfected (HEU) children and to evaluate factors associated with such problems. A prospective study of PHIV and HEU young children was conducted. Behavioral problems were assessed with the Child Behavior Checklist (CBCL) at baseline and 12 months later among children aged 18–60 months old. The Patient Health Questionnaire-9 and the Parenting Styles & Dimensions Questionnaire identified primary caregivers’ symptoms of depression and parenting styles, respectively, at both visits. Chi-squared analyses were used to compare the prevalence of behavioral problems between groups. Factors associated with behavioral problems were analyzed by logistic regression. From 2016 to 2017, 121 children (41 PHIV and 80 HEU) were assessed with no significant differences in prevalence of Total, Internalizing, Externalizing, and Syndrome scales problems between PHIV and HEU at both visits (p > 0.5). Primary caregivers’ depression and lower education in addition to authoritarian and permissive parenting styles were significantly related to child behavioral problems. Family-centered care for families affected by HIV, including positive parenting promotion, mental health care, and education are warranted

Immunogenicity of BNT162b2 Vaccination against SARS-CoV-2 Omicron Variant and Attitudes toward a COVID-19 Booster Dose among Healthy Thai Adolescents

Despite the BNT162b2 vaccination coverage, rapid transmission of Omicron SARS-CoV-2 has occurred, which is suspected to be due to the immune escape of the variant or waning vaccine efficacy of multiple BNT162b2 vaccination doses. Our study aims to compare immunogenicity against Omicron prior to and post a booster dose of BNT162b2 in healthy adolescents, and to evaluate their attitudes toward booster dose vaccination. A cross sectional study was conducted among healthy adolescents aged 12–17 who received two doses of BNT162b2 more than 5 months ago. Participants and their guardians performed self-reported questionnaires regarding reasons for receiving the booster. A 30 ug booster dose of BNT162b2 was offered. Immunogenicity was evaluated by a surrogate virus neutralization test (sVNT) against the Omicron variant, and anti-spike-receptor-binding-domain IgG (anti-S-RBD IgG) taken pre-booster and 14-days post-booster. From March to April 2022, 120 healthy Thai adolescents with a median age of 15 years (IQR 14–16) were enrolled. sVNT against Omicron pre- and post-booster had 11.9 (95%CI 0–23.9) and 94.3 (90.6–97.4) % inhibition. Geometric means (GMs) of anti-S-RBD IgG increased from 837 (728, 953) to 3041 (2893, 3229) BAU/mL. Major reasons to receive the booster vaccination were perceived as vaccine efficacy, reduced risk of spreading infection to family, and safe resumption of social activities. A booster dose of BNT162b2 elicits high immunogenicity against the Omicron variant. Motivation for receiving booster doses is to reduce risk of infection