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    Home > Active Ingredient News > Infection > Case sharing: In children with invasive fungal infection, can the dosage of the drug be scaled in proportion to the adult dosage?

    Case sharing: In children with invasive fungal infection, can the dosage of the drug be scaled in proportion to the adult dosage?

    • Last Update: 2021-10-11
    • Source: Internet
    • Author: User
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    Introduction Children are prone to invasive fungal infection (IFD) after transplantation due to poor skin and mucosal barrier function and immature immune system
    .

    Among them, Aspergillus is the most common and has a higher fatality rate
    .

    In addition, there are many differences between children and adults, and individualized treatment plans should be considered for medication
    .

    This article shares a case of Aspergillus infection after hematopoietic stem cell transplantation in a child, in order to improve the awareness of the disease and provide a reference for medication dosage
    .

    Expert profile The main research direction is children's hematopoietic stem cell transplantation, especially focusing on related transplantation such as hemophagocytosis and chronic active Epstein-Barr virus, transplantation-related nutrition, and post-transplant reproductive endocrine research
    .

    He has successively published many SCI and Chinese papers, participated in the editing and translation of many books
    .

    Yang Jun is currently the deputy chief physician of the Stem Cell Transplantation Department of the Blood Center of Beijing Children’s Hospital, Capital Medical University.
    A 2-year-old child patient was diagnosed with acute myeloid leukemia.
    Male, was admitted to the hospital on July 18, 2020 because of "intermittent nose bleeding, skin bleeding points for 8 months, fever for 8 days"
    .

    Bone marrow morphology showed that a large number of blasts accounted for 94.
    5%, immunophenotyping showed acute myeloid leukemia with T-line marker non-lymphocyte phenotype, AML-related gene mutations showed JAK3 positive, GATA1, BCOR positive, FISH and fusion Gene negative
    .

    Because the chromosomes show 48, XY, i(7)(q10), add(11)(p15), del(13)(q12q22), +21+21[10], they are karyotypes and are rated as high-risk
    .

    DAH, IAH, and IA chemotherapy were applied successively.
    The first course of 21-day bone puncture showed complete remission, and the MRD was 0.
    37%, which was followed by high risk; on the 28th day of the first course of treatment, bone puncture showed complete remission with negative MRD, and the second and third courses of treatment Reexamination of bone puncture on the 28th day showed complete remission and MRD was negative
    .

    Due to transplantation indications, the father was selected as the HLA 6/10 locus-matched haplotype hematopoietic stem cell donor, and no deep infection was assessed before transplantation
    .

    Frequent urination and fever occurred during transplant pretreatment, anti-infective treatment was given, fever recurred after surgery, and the initial diagnosis was graft-versus-host disease ➤Pretreatment plan: Cytarabine + Marilan + Cyclophosphamide + Semustine + ATG , AGVHD prevention: CSA+MTX+MMF
    .

    2020-11-05/06 the father's bone marrow + peripheral blood count (MNC count 23.
    75×108/kg, CD34 positive cells 5.
    98×106/kg)
    .

    Pretreatment for 6 days, the child developed frequent urination, red and white blood cells were seen in the urine examination, and the urine culture of Streptomonas maltophilia was sensitive to minocycline.
    The child was given minocycline orally to fight the infection.
    The symptoms of frequent urination improved
    .

    Two reexaminations of urine culture turned negative on +2 days after transplantation, and minocycline was stopped
    .

    Fever occurred during ATG, antibiotics were upgraded to Mepin + Teicoplanin, and voriconazole was added orally for -1 day
    .

    +5 days after oral mucosa appeared albuginea, +8 days appeared dry cough, lung auscultation was normal
    .

    +15 days for granulocyte implantation, +17 days for platelet implantation, +20 days after transplantation, the implantation rate of donors and recipients is 99.
    5%
    .

    Fever reappeared on day +15 after transplantation, and red rashes on the head, face and trunk began to appear on day +17.
    The diagnosis of graft-versus-host disease I° (skin level 2) was performed, and dexamethasone was given to suppress the immune response 8 times (3.
    5mg).
    QOD, +16 days to +31 days after transplantation), the child's fever gradually improved
    .

    The lung CT showed parenchymal infiltration in the lungs, and the clinical diagnosis of fungal pneumonia infection was improved after adjusting the treatment plan.
    After discharge from the hospital +18 days after transplantation, lung CT: flocculation of the left lung tongue and subpleural mass of the left lower lung , The brightness of the surrounding lungs increases
    .

    Conclusion: Parenchymal infiltration in the lung, infection? Further check G (+), GM (-), clinical diagnosis of fungal pneumonia infection
    .

    Treatment adjustment: Meping was downgraded to ceftazidime, and oral voriconazole was switched to intravenous voriconazole for antifungal
    .

    Re-examination of lung CT on +26 days after transplantation showed that the parenchymal lesions between the left lung and lingual lobes were slightly better than before, and the subpleural mass in the posterior costophrenic angle area of ​​the left lower lung was shadowed and the cavity was formed in the subpleural mass, with pale shadows around and sputum the next day.
    NGS suggests Aspergillus flavus
    .

    Imaging and etiology support fungal pneumonia, and monitor the concentration of voriconazole: 1.
    5ug/ml (1.
    5-5.
    0 ug/ml)
    .

    The antifungal treatment was strengthened again, caspofungin combined with voriconazole was used for antifungal for 2 weeks, and antibiotics were gradually reduced
    .

    Lung CT on day +34 after transplantation: The parenchymal lesions between the left lung and tongue lobes improved compared to before, and the subpleural mass of the left lower lung improved slightly
    .

    Discharged on +40 days after transplantation, continue to take voriconazole orally after discharge, and the concentration is maintained at (1.
    62-2.
    82 ug/ml)
    .

    Lung CT on day +62 after transplantation: A limited cluster of shadows can be seen under the pleura of the left lower lung, the surrounding lungs have increased brightness, and no obvious lesions are seen in the hilar area.
    Compared with the previous left lower lung subpleural lesions, there is no change
    .

    Re-examination of lung CT at 3.
    5m after transplantation showed that there was a little cord shadow under the pleura in the lower lobe of the left lung, and there was no obvious parenchymal infiltration in the remaining lung
    .

      (Figure 1 Lung CT after transplantation) Discussion: How should children with IFD use anti-infective drugs correctly? In recent years, with the use of broad-spectrum antibiotics, adrenal cortex hormones, and immunosuppressive agents, the incidence of fungal infections in China has increased year by year.
    Among them, children have the highest incidence of fungal infections, accounting for 31.
    2% of the annual global incidence of fungal infections1
    .

    Compared with adults, children’s skin and mucosal barrier function is poor, fungi are easy to colonize, especially in premature infants and newborns, phagocytes and T lymphocytes are not yet mature, and their ability to clear fungi is insufficient.
    These factors all contribute to the development of IFD in children.
    The chance is greater than that of an adult 2
    .

    Candida and Aspergillus are the main pathogenic fungi in children with IFD in China
    .

    A retrospective study of 164 children with hematological diseases and IFD found that Candida albicans has the highest detection rate, reaching 51.
    5%, followed by Aspergillus, Candida glabrata, Candida tropicalis, Candida krusei and Parasmoothum Candida 3
    .

    The mortality rate of Aspergillus infection is higher than that of Candida infection, and the overall mortality rate of children with IFD is 32%
    .

    The mortality rate of invasive Candida (IC) is between 20%-30%, and the mortality rate of invasive aspergillosis (IA) is 70%.
    IA is 2.
    5 to 3.
    5 times the mortality rate of IC4
    .

    If Aspergillus infection involves the central nervous system, or in bone marrow transplantation and advanced HIV infection, the mortality rate is as high as 88%, 87%, and 86%, respectively5
    .

    In terms of drug treatment, newborns, infants, and children are different from adults in many ways.
    The ability of drug metabolizing enzymes and kidney function are also changed due to organ maturation and development, leading to changes in drug exposure and response6
    .

    Therefore, in addition to considering the usual physiological, pathological, genetic and environmental factors (drug interactions, drug-food interactions, etc.
    ), it is also necessary to consider the particularity of children and adopt individualized treatment plans
    .

    The pharmacokinetic and pharmacodynamic data of children cannot be simply scaled directly from adults 7
    .

    Instead, choosing the correct dosage under the premise of symptomatically and guaranteeing the curative effect is essential to ensure the safety of children's medication
    .

    If the dose is too small, it is difficult to ensure the primary purpose of the medication-effective treatment of the disease; while the dose is too large, there may be toxic side effects (although the harm to liver and kidney function may not be manifested in the short term), and it will also cause unnecessary waste
    .

    The guidelines recommend voriconazole as the first-line treatment for Aspergillus.
    Exposure to voriconazole can reduce the risk of Aspergillus colonization, with a high response rate to treatment, which can reduce patient mortality and improve survival
    .

    At the same time, voriconazole TDM monitoring can reduce the rate of discontinuation of adverse reactions and increase the success rate of treatment
    .

    Pediatric patients have a higher clearance rate of voriconazole, so higher doses are required.
    In the absence of other drug interactions, the loading dose of 9 mg/kg iv q12h is equivalent to the adult loading dose of 6 mg/kg iv, and the maintenance dose is 8 mg/ kg iv q12h is equivalent to adult 4mg/kg iv exposure, 9mg/kg po q12h (maximum 350mg) is equivalent to adult 200mg po q12h exposure
    .

    For transplant patients, due to drug interactions, the starting dose of 4-6 mg/kg can be considered, and the dosage should be adjusted according to the monitoring of the voriconazole concentration
    .

    Big coffee commented that Wang Bin, chief physician of Beijing Children's Hospital of Capital Medical University, has worked in the department of pediatrics and hematological tumors in children for more than 20 years.
    His research direction is hematopoietic stem cell transplantation in children.
    This is a relatively common case of Aspergillus infection after blood transplantation
    .

    With the development of children's blood transplantation technology and the improvement of the detection level of pathogenic microorganisms, the incidence of IFD in children in China is increasing year by year
    .

    Among them, Aspergillus is the most concerned fungal infection after blood transplantation.
    If the treatment is not timely or standardized, the mortality rate is relatively high
    .

    Like adults, invasive fungal infections in children are the main cause of death in immunosuppressed children after blood transplantation
    .

    Therefore, early diagnosis and early initiation of antifungal treatment are the best treatment measures
    .

    Clinically, galactomannan antigen detection and lung CT examination are commonly used for diagnosis.
    If necessary, sputum or blood NGS can be tested to improve the detection rate of pathogenic microorganisms
    .

    For children with immunodeficiency after blood transplantation, antifungal therapy can be initiated empirically before the diagnosis, and antifungal drugs based on voriconazole are usually used, which can achieve better results
    .

    Compared with adults, children's antifungal treatment also needs to pay attention to its individualized dosing regimen
    .

    Due to the particularity of children, its pharmacokinetics and pharmacodynamic data cannot be scaled from adults
    .

    Therefore, choosing the correct dosage is the key to ensuring the successful treatment of fungal infections in children
    .

    Considering that voriconazole in children has a higher clearance rate and a non-linear metabolism drug, a higher dose is required when using voriconazole.
    Clinically, the dosage regimen needs to be adjusted according to the results of TDM monitoring, and the blood concentration range of treatment should be controlled.
    In 1.
    5-5.
    0 ug/ml
    .

    References: 1.
    Gu Fen, et al.
    Pediatrics of Integrated Traditional Chinese and Western Medicine, 2017, 9(3): 265-268.
    2.
    Wan Chaomin, et al.
    Journal of Practical Pediatrics, 2012, 27(22): 1697-1700.
    3.
    Liao Xiongyu, et al.
    Chinese Journal of Experimental Hematology.
    2019;27(5):1672-1677.
    4.
    Ankrah AO, et al.
    Clin Transl Imaging.
    2016;4:57-72.
    5.
    Hlophe ST, et al.
    Afr J Thorac Crit Care Med.
    2018 Apr 3;24(1):10.
    7196/AJTCCM.
    2018.
    v24i1.
    172.
    6.
    Rodieux F, et al.
    Clin Pharmacokinet.
    2015;54(12):1183-204.
    7.
    Wang Xiaoling, et al.
    International Journal of Pharmaceutical Research, 2016,43(4):621-631.

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