Systemic antifungal prescribing in neonates and children: outcomes from the Antibiotic Resistance and Prescribing in European Children (ARPEC) Study

Abstract

The appropriate use of systemic antifungals is vital in the prevention and treatment of invasive fungal infection (IFI) in immunosuppressed children and neonates. This multicenter observational study describes the inpatient prescribing practice of antifungal drugs for children and neonates and identifies factors associated with prescribing variability. A single-day point prevalence study of antimicrobial use in hospitalized neonates and children was performed between October and December 2012. The data were entered through a study-specific Web-based portal using a standardized data entry protocol. Data were recorded from 17,693 patients from 226 centers. A total of 136 centers recorded data from 1,092 children and 380 neonates receiving at least one antifungal agent. The most frequently prescribed systemic antifungals were fluconazole (n=355) and amphotericin B deoxycholate (n=195). The most common indications for antifungal administration in children were medical prophylaxis (n=325), empirical treatment of febrile neutropenia (n=122), and treatment of confirmed or suspected IFI (n=100 [14%]). The treatment of suspected IFI in low-birthweight neonates accounted for the majority of prescriptions in the neonatal units (n=103). An analysis of variance (ANOVA) demonstrated no significant effect of clinical indication (prophylaxis or treatment of systemic or localized infection) on the total daily dose (TDD). Fewer than one-half of the patients (n=371) received a TDD within the dosing range recommended in the current guidelines. Subtherapeutic doses were prescribed in 416 cases (47%). The predominance of fluconazole and high incidence of subtherapeutic doses in participating hospitals may contribute to suboptimal clinical outcomes and an increased predominance of resistant pathogenic fungi. A global consensus on antifungal dosing and coordinated stewardship programs are needed to promote the consistent and appropriate use of antifungal drugs in neonates and children.

FIG 1

Study flowchart and reasons for patient data eligibility/exclusion.

FIG 2

Numbers of patients receiving individual antifungal agents. For each drug, the left bar is pediatric patients and the right bar is neonates. Supratherapeutic (TDD, ≥110% of published MaxRDD), therapeutic, and subtherapeutic (TDD, ≤90% of published MinRDD) doses are represented in dark gray, light gray, and black, respectively. DAmB, amphotericin B deoxycholate; LAmB, liposomal amphotericin B; ABLC, amphotericin B lipid complex.

FIG 3

Total daily dosing of fluconazole prescribed as treatment for invasive fungal infection in pediatric patients by macrogeographical regions (A) and center type (B). Interquartile range (IQR), median, 1.5× the IQR, and outlying data points are represented by boxes, central lines, whiskers, and open circles, respectively. The minimum and maximum recommended daily doses are indicated by the dashed lines.