Fluconazole was introduced in 1990 and is still a first-line antifungal agent for the treatment and prophylaxis of invasive candidiasis in children and infants (1, 2). The bioavailability of orally administered fluconazole is over 90%, and fluconazole has excellent penetration in tissue and body fluids (3, 4). The pharmacokinetic/pharmacodynamic parameter that best predicts the outcome of the fluconazole treatment is the area under the concentration-time curve over 24 h in steady state divided by the MIC (AUC/MIC) (5, 6). To ensure an AUC/MIC of Ն50, which corresponds to a favorable outcome, an AUC of Ն400 mg · h/liter is required for Candida species with a MIC breakpoint of Յ8 mg/ liter (7-10). Routine therapeutic drug monitoring (TDM) of fluconazole is currently not advised due to its high bioavailability, linear dose-concentration relationship, and good safety profile (1, 11, 12). However, children and infants are at risk of suboptimal drug exposure, due to developmental changes in the gastrointestinal and renal function, metabolic capacity, and volume of distribution (13). A previous study showed that the serum fluconazole concentration was correlated with the age, weight, and renal function of critically ill pediatric patients and that the fluconazole exposure was not sufficient in pediatric cancer patients (14). TDM of fluconazole can therefore be useful to prevent possible underexposure in critically ill pediatric patients (14, 15). Since obtaining a blood sample from children is often more complicated than for adults and children often fear needles, oral fluid sampling can be a noninvasive, painless alternative to plasma or serum (16). Previous studies showed a mean ratio of the saliva drug concentration to the plasma drug concentration of approximately 1 for fluconazole in healthy volunteers (3,17,18). However, in another study, a saliva-to-plasma concentration ratio of 0.4 was found (19). A median saliva-to-plasma ratio of 1.1 to 1.3 was seen in adult patients with HIV or AIDS (20, 21) and a mean ratio of 1.4 in adult cancer patients who underwent radiotherapy (22). The correlation between fluconazole in oral fluid and in plasma or serum has not yet been studied in children. The purpose of this study was to develop and clinically validate a method of analysis of fluconazole in oral fluid in hospitalized children with an (invasive) Candida infection and to evaluate the fluconazole exposure in these children. MATERIALS AND METHODSStudy design. This prospective observational study was conducted in the 150-bed pediatric department of the University Medical Center Groningen, Groningen, The Netherlands, from July 2007 to March 2014. Patients were eligible for inclusion if the following criteria were met: (i) age, 0 to 18 years; (ii) admission to a pediatric ward or pediatric/neonatal intensive care unit (ICU); (iii) oral or intravenous treatment with fluconazole; and (iv) scheduled routine TDM of fluconazole in serum. Children from whom it was impossible to get oral fluid or who had serious mucositis of thei...
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