Evidence of excessive concentrations of 5-flucytosine in children aged below 12 years: a 12-year review of serum concentrations from a UK clinical assay reference laboratory

Soltani, Mehnam; Tobin, C. M.; Bowker, Karen E.; Sunderland, J.; MacGowan, Alasdair; Lovering, Andrew

doi:10.1016/j.ijantimicag.2006.07.013

Cited by 45 publications

(15 citation statements)

References 20 publications

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“…The elimination half-life is 3–5 hours, and administration in 3–4 daily doses is required [179]. Data on 5-FC PK in children are limited, but drug clearance appears slower in children compared with adults [23, 180]; as a result, the adult dose of 100 mg/kg/day might lead to overexposure. In addition, the elimination half-life in neonates is nearly twice as long as in adults (4 hours vs. 7 hours) [23, 180], suggesting that the dosing interval should be longer (8 hours to 24 hours).…”

Section: Nucleoside Analogsmentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of Antifungals in Children: Clinical Implications

Autmizguine

Guptill

Cohen‐Wolkowiez

et al. 2014

Drugs

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Invasive fungal disease (IFD) remains life-threatening in premature infants and immunocompromised children despite the recent development of new antifungal agents. Optimal dosing of antifungals is one of the few factors clinicians can control to improve outcomes of IFD. However, dosing in children cannot be extrapolated from adult data because IFD pathophysiology, immune response, and drug disposition differ from adults. We critically examined the literature on pharmacokinetics (PK) and pharmacodynamics (PD) of antifungal agents and highlight recent developments in treating pediatric IFD. To match adult exposure in pediatric patients, dosing adjustment is necessary for almost all antifungals. In young infants, the maturation of renal and metabolic functions occurs rapidly and can significantly influence drug exposure. Fluconazole clearance doubles from birth to 28 days of life and, beyond the neonatal period, agents like fluconazole, voriconazole, and micafungin require higher dosing than in adults due to faster clearance in children. As a result, dosing recommendations are specific to bracketed ranges of age. Pharmacodynamics principles of antifungals mostly rely on in vitro and in vivo models but very few pharmacodynamics studies specifically address IFD in children. Exposure-response relationship may differ in younger children compared with adults, especially in infants with invasive candidiasis who are at higher risk of disseminated disease and meningoencephalitis, and by extension severe neurodevelopmental impairment. Micafungin is the only antifungal agent for which a specific target of exposure was proposed based on a neonatal hematogenous Candida meningoencephalitis animal model. In this review, we found that pediatric data on drug disposition of newer triazoles and echinocandins are lacking, dosing of older antifungals such as fluconazole and amphotericin B products still need optimization in young infants, and that target PK/PD indices need to be clinically validated for almost all antifungals in children. A better understanding of age-specific PK and PD of new antifungals in infants and children will help improve clinical outcomes of IFD by informing dosing and identifying future research areas.

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Section: Nucleoside Analogsmentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of Antifungals in Children: Clinical Implications

Autmizguine

Guptill

Cohen‐Wolkowiez

et al. 2014

Drugs

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“…Although recent analyses of therapeutic drug monitoring (TDM) data in children and pharmacokinetic bridging models suggest that lower dosages may be more appropriate [33,34], the approved starting dosage of 100 mg/ kg daily divided into three or four doses is currently recommended for both adults and children. TDM is advised; peak plasma levels between 40 and 60 lg/mL correlate with antifungal activity, but are seldom associated with marrow toxicity [35].…”

Section: -Fluorocytosinementioning

confidence: 99%

Update on antifungal agents for paediatric patients

Groll¹,

Tragiannidis

2010

Clinical Microbiology and Infection

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Paediatric age groups display important differences in host biology, predisposing conditions, epidemiology and presentation of fungal infections relative to the adult population. During the past decade, several new antifungal agents have been developed. Although not all of these agents are yet approved for children, the paediatric development of antifungal agents has moved forwards in an exemplary manner. Invasive fungal infections will remain important causes of morbidity and mortality in immunocompromised paediatric patients. Whereas the availability of new therapeutic options is an important advance, antifungal therapy has become increasingly complex, and a thorough understanding of the available antifungal armamentarium is essential for the successful management of the individual patient. This article provides an update on the pharmacokinetics, safety and dosing of antifungal agents in paediatric patients, and their clinical indications.

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“…High levels of variability in serum concentrations of flucytosine have been documented, with retrospective reviews of concentrations measured in both adult and pediatric populations demonstrating that only about 20 % of serum concentrations analyzed were within therapeutic range [88,89]. However, there are significant limitations to these data given that flucytosine doses were not recorded.…”

Section: Flucytosine Inter-patient Variabilitymentioning

confidence: 99%

Antifungal Drug Therapeutic Monitoring: What are the Issues?

Myers

Ashley

2015

Curr Clin Micro Rpt

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Therapeutic drug monitoring (TDM), an established practice for many antimicrobials, has recently seen increasing utilization in the management of patients receiving antifungal agents. There is a growing body of literature supporting the use of TDM for itraconazole, voriconazole, posaconazole, and flucytosine. In addition, clinical practice guidelines have been recently published that give recommendations on the appropriate use of TDM for antifungal agents. However, there are still uncertainties regarding the optimal use of antifungal TDM in clinical practice. We conducted a review of recent literature in order to describe the clinical situations and specific antifungal agents for which TDM is ideal and summarize key information about the pharmacokinetics, pharmacodynamics, drug toxicities, TDM concentration targets, and dose adjustment algorithms for antifungals in which routine TDM is performed.

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Evidence of excessive concentrations of 5-flucytosine in children aged below 12 years: a 12-year review of serum concentrations from a UK clinical assay reference laboratory

Cited by 45 publications

References 20 publications

Pharmacokinetics and Pharmacodynamics of Antifungals in Children: Clinical Implications

Pharmacokinetics and Pharmacodynamics of Antifungals in Children: Clinical Implications

Update on antifungal agents for paediatric patients

Antifungal Drug Therapeutic Monitoring: What are the Issues?

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