Clinical Pharmacokinetics of Triazoles in Pediatric Patients

Bury, Didi; Tissing, Wim J. E.; Muilwijk, Eline W.; Wolfs, Tom F. W.; Brüggemann, Roger J. M.

doi:10.1007/s40262-021-00994-3

Cited by 19 publications

(24 citation statements)

References 70 publications

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“…In adult patients, Isavuconazole has been recommended as therapeutic antifungal drug with contraindication to Amphotericin –B. The treatment guidelines have not approved the usage of Isavuconazole in paediatric patients [ 15 ]. In Lichtheimia species infection, the drug of choice is Amphotericin B (geometric mean of 0.07 mg litre −1 at 24 h), and among azoles-posaconazole (geometric mean of 0.34 mg litre −1 at 24 h) [ 14 ].…”

Section: Discussionmentioning

confidence: 99%

Necrotizing fasciitis in neonate by Lichtheimia ramosa : A case study

William

Kaur

Rawat

et al. 2022

Access Microbiology

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Zygomycetes have been known to cause life-threatening infections in humans which are often difficult to treat. We present a rare case of cutaneous mucormycosis in a premature neonate admitted with neonatal sepsis and necrotizing fasciitis. He was diagnosed with Lichtheimia ramosa infection and managed surgically along with Amphotericin B. Low birth weight, prematurity, respiratory distress, administration of corticosteroid and broad spectrum antibiotics were identified as the potential risk factors in this case which had led to the fungal infection. Early diagnosis and prompt management is critical in prevention of morbidity and mortality associated with the disease.

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Section: Discussionmentioning

confidence: 99%

Necrotizing fasciitis in neonate by Lichtheimia ramosa : A case study

William

Kaur

Rawat

et al. 2022

Access Microbiology

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“…Triazoles represent the most important class of antifungal agents for prophylaxis and treatment of invasive fungal infections ( Groll and Tragiannidis, 2010 ). Unfortunately, the use of azoles is challenged by several pharmacokinetic and pharmacogenetic issues in the paediatric scenario ( Bury et al, 2021 ). Large interindividual and intraindividual variability in azole exposure is frequently present among oncohaematologic paediatric patients, especially for voriconazole.…”

Section: Discussionmentioning

confidence: 99%

“…Our data support this, as in almost 30% of the CPAs delivered in onco-haematological paediatric dosing adjustments of voriconazole were needed. This approach could minimize the risk of antifungal underexposure that may cause breakthrough invasive fungal infections, and/or that of overexposure, possibly causing toxicity (e.g., hepatotoxicity), in relation to drug-drug interactions, pharmacogenetic issues, or disease-related organ failure ( Kyriakidis et al, 2017 ; Bury et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

A Proof of Concept of the Role of TDM-Based Clinical Pharmacological Advices in Optimizing Antimicrobial Therapy on Real-Time in Different Paediatric Settings

et al. 2021

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Introduction: Antimicrobial treatment is quite common among hospitalized children. The dynamic age-associated physiological variations coupled with the pathophysiological alterations caused by underlying illness and potential drug-drug interactions makes the implementation of appropriate antimicrobial dosing extremely challenging among paediatrics. Therapeutic drug monitoring (TDM) may represent a valuable tool for assisting clinicians in optimizing antimicrobial exposure. Clinical pharmacological advice (CPA) is an approach based on the correct interpretation of the TDM result by the MD Clinical Pharmacologist in relation to specific underlying conditions, namely the antimicrobial susceptibility of the clinical isolate, the site of infection, the pathophysiological characteristics of the patient and/or the drug-drug interactions of cotreatments. The aim of this study was to assess the role of TDM-based CPAs in providing useful recommendations for the real-time personalization of antimicrobial dosing regimens in various paediatric settings.Materials and methods: Paediatric patients who were admitted to different settings of the IRCCS Azienda Ospedaliero-Universitaria of Bologna, Italy (paediatric intensive care unit [ICU], paediatric onco-haematology, neonatology, and emergency paediatric ward), between January 2021 and June 2021 and who received TDM-based CPAs on real-time for personalization of antimicrobial therapy were retrospectively assessed. Demographic and clinical features, CPAs delivered in relation to different settings and antimicrobials, and type of dosing adjustments were extracted. Two indicators of performance were identified. The number of dosing adjustments provided over the total number of delivered CPAs. The turnaround time (TAT) of CPAs according to a predefined scale (optimal, <12 h; quasi-optimal, between 12–24 h; acceptable, between 24–48 h; suboptimal, >48 h).Results: Overall, 247 CPAs were delivered to 53 paediatric patients (mean 4.7 ± 3.7 CPAs/patient). Most were delivered to onco-haematological patients (39.6%) and to ICU patients (35.8%), and concerned mainly isavuconazole (19.0%) and voriconazole (17.8%). Overall, CPAs suggested dosing adjustments in 37.7% of cases (24.3% increases and 13.4% decreases). Median TAT was 7.5 h (IQR 6.1–8.8 h). Overall, CPAs TAT was optimal in 91.5% of cases, and suboptimal in only 0.8% of cases.Discussion: Our study provides a proof of concept of the helpful role that TDM-based real-time CPAs may have in optimizing antimicrobial exposure in different challenging paediatric scenarios.

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“…For instance, an OTC azole fungicide such as clotrimazole has shown strong endocrine disrupting effects in vitro and in vivo at very low concentrations, even below human therapeutically used concentrations ( Munkboel et al, 2019 ; Draskau et al, 2021 ). A second example, fluconazole, also displays endocrine disrupting potential ( Mogensen et al, 2017 ; Munkboel et al, 2019 ), almost completely avoids metabolization ( Bury et al, 2021 ), and can rapidly penetrate from plasma into female genital organs including uterus, ovary, and oviduct ( Mikamo et al, 1999 ). These examples are cause for some concern regarding azole use during pregnancy and concomitant exposure of the unborn child.…”

Section: Adverse Reproductive Effects Of Azole Fungicidesmentioning

confidence: 99%

Azole Fungicides and Their Endocrine Disrupting Properties: Perspectives on Sex Hormone-Dependent Reproductive Development

Draskau

Svingen

2022

Front. Toxicol.

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Azoles are antifungal agents used in both agriculture and medicine. They typically target the CYP51 enzyme in fungi and, by so doing, disrupt cell membrane integrity. However, azoles can also target various CYP enzymes in mammals, including humans, which can disrupt hormone synthesis and signaling. For instance, several azoles can inhibit enzymes of the steroidogenic pathway and disrupt steroid hormone biosynthesis. This is of particular concern during pregnancy, since sex hormones are integral to reproductive development. In other words, exposure to azole fungicides during fetal life can potentially lead to reproductive disease in the offspring. In addition, some azoles can act as androgen receptor antagonists, which can further add to the disrupting potential following exposure. When used as pharmaceuticals, systemic concentrations of the azole compounds can become significant as combatting fungal infections can be very challenging and require prolonged exposure to high doses. Although most medicinal azoles are tightly regulated and used as prescription drugs after consultations with medical professionals, some are sold as over-the-counter drugs. In this review, we discuss various azole fungicides known to disrupt steroid sex hormone biosynthesis or action with a focus on what potential consequences exposure during pregnancy can have on the life-long reproductive health of the offspring.

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Clinical Pharmacokinetics of Triazoles in Pediatric Patients

Cited by 19 publications

References 70 publications

Necrotizing fasciitis in neonate by Lichtheimia ramosa : A case study

Necrotizing fasciitis in neonate by Lichtheimia ramosa : A case study

A Proof of Concept of the Role of TDM-Based Clinical Pharmacological Advices in Optimizing Antimicrobial Therapy on Real-Time in Different Paediatric Settings

Azole Fungicides and Their Endocrine Disrupting Properties: Perspectives on Sex Hormone-Dependent Reproductive Development

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