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

Analysis of Pulmonary Inflammation and Function in the Mouse and Baboon after Exposure to Mycoplasma pneumoniae CARDS Toxin

Mycoplasma pneumoniae produces an ADP-ribosylating and vacuolating toxin known as the CARDS (Community Acquired Respiratory Distress Syndrome) toxin that has been shown to be cytotoxic to mammalian cells in tissue and organ culture. In this study we tested the ability of recombinant CARDS (rCARDS) toxin to elicit changes within the pulmonary compartment in both mice and baboons. Animals responded to a respiratory exposure to rCARDS toxin in a dose and activity-dependent manner by increasing the expression of the pro-inflammatory cytokines IL-1α, 1β, 6, 12, 17, TNF-α and IFN-γ. There was also a dose-dependent increase in several growth factors and chemokines following toxin exposure including KC, IL-8, RANTES, and G-CSF. Increased expression of IFN-γ was observed only in the baboon; otherwise, mice and baboons responded to CARDS toxin in a very similar manner. Introduction of rCARDS toxin to the airways of mice or baboons resulted in a cellular inflammatory response characterized by a dose-dependent early vacuolization and cytotoxicity of the bronchiolar epithelium followed by a robust peribronchial and perivascular lymphocytic infiltration. In mice, rCARDS toxin caused airway hyper-reactivity two days after toxin exposure as well as prolonged airway obstruction. The changes in airway function, cytokine expression, and cellular inflammation correlate temporally and are consistent with what has been reported for M. pneumoniae infection. Altogether, these data suggest that the CARDS toxin interacts extensively with the pulmonary compartment and that the CARDS toxin is sufficient to cause prolonged inflammatory responses and airway dysfunction

Mycoplasma pneumoniae pneumonia in children

Mycoplasma pneumoniae (MP), the smallest self-replicating biological system, is a common cause of upper and lower respiratory tract infections, leading to a wide range of pulmonary and extra-pulmonary manifestations. MP pneumonia has been reported in 10 to 40% of cases of community-acquired pneumonia and shows an even higher proportion during epidemics. MP infection is endemic in larger communities of the world with cyclic epidemics every 3 to 7 years. In Korea, 3 to 4-year cycles have been observed from the mid-1980s to present. Although a variety of serologic assays and polymerase chain reaction (PCR) techniques are available for the diagnosis of MP infections, early diagnosis of MP pneumonia is limited by the lack of immunoglobulin (Ig) M antibodies and variable PCR results in the early stages of the infection. Thus, short-term paired IgM serologic tests may be mandatory for an early and definitive diagnosis. MP infection is usually a mild and self-limiting disease without specific treatment, and if needed, macrolides are generally used as a first-choice drug for children. Recently, macrolide-resistant MP strains have been reported worldwide. However, there are few reports of apparent treatment failure, such as progression of pneumonia to acute respiratory distress syndrome despite macrolide treatment. The immunopathogenesis of MP pneumonia is believed to be a hyperimmune reaction of the host to the insults from MP infection, including cytokine overproduction and immune cell activation (T cells). In this context, immunomodulatory treatment (corticosteroids or/and intravenous Ig), in addition to antibiotic treatment, might be considered for patients with severe infection

A Strategy To Estimate Unknown Viral Diversity in Mammals

The majority of emerging zoonoses originate in wildlife, and many are caused by viruses. However, there are no rigorous estimates of total viral diversity (here termed “virodiversity”) for any wildlife species, despite the utility of this to future surveillance and control of emerging zoonoses. In this case study, we repeatedly sampled a mammalian wildlife host known to harbor emerging zoonotic pathogens (the Indian Flying Fox, Pteropus giganteus) and used PCR with degenerate viral family-level primers to discover and analyze the occurrence patterns of 55 viruses from nine viral families. We then adapted statistical techniques used to estimate biodiversity in vertebrates and plants and estimated the total viral richness of these nine families in P. giganteus to be 58 viruses. Our analyses demonstrate proof-of-concept of a strategy for estimating viral richness and provide the first statistically supported estimate of the number of undiscovered viruses in a mammalian host. We used a simple extrapolation to estimate that there are a minimum of 320,000 mammalian viruses awaiting discovery within these nine families, assuming all species harbor a similar number of viruses, with minimal turnover between host species. We estimate the cost of discovering these viruses to be ~$6.3 billion (or ~$1.4 billion for 85% of the total diversity), which if annualized over a 10-year study time frame would represent a small fraction of the cost of many pandemic zoonoses. IMPORTANCE Recent years have seen a dramatic increase in viral discovery efforts. However, most lack rigorous systematic design, which limits our ability to understand viral diversity and its ecological drivers and reduces their value to public health intervention. Here, we present a new framework for the discovery of novel viruses in wildlife and use it to make the first-ever estimate of the number of viruses that exist in a mammalian host. As pathogens continue to emerge from wildlife, this estimate allows us to put preliminary bounds around the potential size of the total zoonotic pool and facilitates a better understanding of where best to allocate resources for the subsequent discovery of global viral diversity

Business intelligence for detecting possible surgical site infections from post-cesarean section operation with a focus on antibiotic prescriptions in Ramathibodi Hospital, Thailand

Abstract Objective: To evaluate the effectiveness of postcaesarean infection surveillance using the Power Business Intelligence (BI) program, focusing on antibiotic prescriptions. Second, to compare the workload between the traditional and new approaches. Design: A diagnostic accuracy and workload evaluation. Setting: A tertiary care university hospital in metropolitan Bangkok, Thailand. Participants: All patients who underwent cesarean section between January 1, 2019, and September 30, 2020. Method: ICD-10 diagnoses, microbiological cultures, and postcesarean section antibiotic prescriptions in 3,243 medical records were captured by the Power BI program to detect surgical site infections (SSIs). All cases underwent conventional surveillance, which independently performed by infection control nurses. All patients were under surveillance until 45 days after surgery to capture delayed SSI diagnosis. SSIs were compared with sensitivity and specificity used to evaluate the new method. The Wilcoxon signed-rank test was employed to compare workload differences between the two methods in a paired-sample design. Results: The findings demonstrated the high sensitivity (100%) (95% CI: 66.4–100%) and specificity (93%) (95% CI: 90.5–95.4%) of the Power BI method when focusing on antibiotic prescriptions between 8- and 45-days postoperation. Additionally, the Power BI infection monitoring system significantly reduced the number of cases requiring review from 452 to 39 patients (a 91% reduction), indicating a substantial decrease in workload after implementation (P < .001). Conclusion: This antibiotic prescription-based, semi-automated surveillance program significantly reduced workload, demonstrating its potential to enhance infection monitoring in postcesarean section cases