Systemic Antifungal Prescribing in Neonates and Children

34 Pages·2014·0.59 MB·English

AAC Accepts, published online ahead of print on 17 November 2014
Antimicrob. Agents Chemother. doi:10.1128/AAC.04109-14
Copyright © 2014, American Society for Microbiology. All Rights Reserved.
1 Systemic Antifungal Prescribing in Neonates and Children: Outcomes from the Antibiotic
2 Resistance and Prescribing in European Children (ARPEC) Study
3 Running Title: Antifungal Prescribing Practice in Pediatrics
4 Lestner JM1#, Versporten A2, Doerholt K1, Warris A3, Roilides E4, Sharland M1, Bielicki J1, D
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5 Goossens H2; ARPEC Project Group Members. wn
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6 1. Pediatric Infectious Diseases Unit, St George’s Hospital, London, UK e
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7 2. Laboratory of Medical Microbiology, Vaccine & Infectious Disease Institute, Faculty of m

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8 Medicine and Health Science, University of Antwerp, Belgium. tt
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9 3. Institute of Medical Sciences, Aberdeen Fungal Group, University of Aberdeen, UK c
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10 4. Infectious Diseases Unit, 3rd Department of Pediatrics, Faculty of Medicine, Aristotle .
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11 University School of Health Sciences, Hippokration Hospital, Thessaloniki, Greece /

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12 Corresponding Author a
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13 Dr Jodi Lestner r
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14 Paediatric Infectious Diseases Research Group ,
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15 St George's, University of London 9

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16 Jenner Wing, Level 2, Room 2.215E, Mail Point J2C
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17 London SW17 0RE s
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18 Tel: [phone]
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19 Email: [email protected]
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21 Conflict of Interest Declaration
22 JML has received grant support from Gilead.
23 ER has received research grant support from Pfizer, Gilead, Enzon, Schering, Wyeth, has served
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24 as consultant to Schering, Gilead, Astellas Gilead, Cephalon, Pfizer and has been in the speakers’ w
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25 bureau of Wyeth, Schering, Merck, Astellas. a
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26 AW has received unrestricted research grants from Pfizer and Gilead. r
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27 HG has received research grants from bioMérieux. tp
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28 Keywords c
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29 Antifungal, neonates, children, pediatrics, point prevalence survey, antimicrobial use, antifungal m
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30 use, antimicrobial surveillance g
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31 ABSTRACT a
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32 Appropriate use of systemic antifungals is vital in the prevention and treatment of invasive y

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33 fungal infection (IFI) in immunosuppressed children and neonates. This multi-centre 2
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34 observational study describes the inpatient prescribing practice of antifungal drugs in children
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35 and neonates, and identifies factors associated with prescribing variability. A single day point g
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36 prevalence study of antimicrobial use in hospitalised neonates and children was performed t
37 between October and December 2012. Data were entered through a study-specific web-based
38 portal using a standardised data-entry protocol. Data were recorded from 17,693 patients within
39 226 centres. A total of 136 centres recorded data from 1092 children and 380 neonates receiving
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40 at least one antifungal agent. The most frequently prescribed systemic antifungals were
41 fluconazole (n=355) and amphotericin B deoxycholate (n=195). The most common indications
42 for antifungal administration in children were medical prophylaxis (n=325), empiric treatment of
43 febrile neutropenia (n=122) and treatment of confirmed or suspected IFI (n=100, 14%).
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44 Treatment of suspected IFI in low birth weight neonates accounted for the majority of
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45 prescriptions in neonatal units (n=103). ANOVA analysis demonstrated no significant effect of n
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46 clinical indication (prophylaxis or treatment of systemic or localised infection) on total daily de
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47 dose (TDD). Fewer than half of patients (n=371) received a TDD within the dosing range fr
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48 recommended in current guidelines. Sub-therapeutic doses were prescribed in 416 cases (47%). h
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49 The predominance of fluconazole and high incidence of sub-therapeutic doses in participating :/
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50 hospitals may contribute to suboptimal clinical outcomes and an increased predominance in c
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51 resistant pathogenic fungi. A global consensus on antifungal dosing and coordinated stewardship m
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52 programmes are needed to promote consistent and appropriate use of antifungal drugs in g
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53 neonates and children.
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54 INTRODUCTION a
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55 Antimicrobial agents are amongst the most commonly prescribed drugs in neonates and children. 2
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56 Widespread use of broad-spectrum antimicrobials is known to contribute to antimicrobial
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57 resistance, while failure to initiate appropriate treatment is associated with significantly increased g
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58 attributable mortality. (1) Appropriate use of antifungals is of particular importance in the t
59 prevention and treatment of infection in the presence of severe inter-current illness, prematurity
60 and immunosuppression. Invasive fungal infections (IFI) continue to be associated with an
61 unacceptably high mortality in these vulnerable populations. In low and extremely low
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62 birthweight neonates IFI is associated with an attributable mortality of 30-40%. (2) In the setting
63 of haematopoietic stem cell transplantation (HSCT) attributable mortality rates from IFI are 30-
64 40% for yeast infections and up to 70% for mould infections. (3, 4)
65
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66 Surveillance of antimicrobial use in hospitals is an important means of observing prescribing
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67 trends, linking results with antimicrobial resistance patterns, and identifying areas for n
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68 improvement in safe and effective prescribing. Cross-sectional point prevalence surveys (PPS) de
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69 have provided informative data on patterns of antimicrobial prescribing in adults and more fr
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70 recently in children. (5, 6) To our knowledge PPS methodologies have until now not been used h
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71 to describe antifungal use in children and neonates. Here we present the data on antifungal :/
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72 prescribing from the ARPEC study, a multi-centred global observational study investigating c
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73 current variation in antimicrobial prescribing in hospitals. m
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74 g
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75 MATERIALS AND METHODS
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76 A single-day point prevalence study (PPS) of antimicrobial use was carried out in 226 centres. u
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77 Details of the ARPEC study design have been outlined elsewhere. (5) Briefly, the ARPEC study
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78 group was a collaborative partnership between members of the European Surveillance of 0
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79 Antimicrobial Consumption, European Society of Paediatric Infectious Diseases and Global b
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80 Research in Paediatrics networks. Hospital-based physicians caring for neonates or children u
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81 within these networks were invited to participate. Departments within participating centres t
82 recorded data between October and December 2012. All inpatients below the age of 18 years
83 present at 8 AM on the day of survey were included in the denominator. Data were recorded for
84 patients prescribed antimicrobial agents on the day of survey. Neonates and children receiving
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85 antifungal agents known to have negligible bioavailability administered via the oral route
86 (amphotericin B, nystatin and miconazole) were excluded from analysis. Patient exclusion
87 criteria included emergency admissions on the day of study, patients on psychiatric wards, and
88 patients younger than 18 years admitted to an adult ward.
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90 Anonymised patient data were collected through a study-specific online portal using a n
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91 standardised data-entry protocol. The project focused on European centres. In addition, centres de
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92 outside Europe that collected and submitted data according to the same methodology during the fr
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93 study periods were included in analysis. Data collected for all patients receiving antimicrobials h
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94 included patients’ age, gender, current and birth weights, ventilation status, prescribed :/
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95 antimicrobial agents, single unit dose and number of doses per 24 hours, route of administration, c
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96 and indication (therapeutic or prophylaxis). To facilitate data collection on underlying diagnosis m
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97 and reason for treatment, a pre-defined list of grouped “underlying conditions”, “acute g
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98 diagnoses” and “anatomical site of infection” were used and are described elsewhere. (5)
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99 Individual centre and department type were recorded categorically. Neonates were defined based u
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100 on postmenstrual age at the time of participation. Classification of level of neonatal care was
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101 defined locally following predetermined categories as described previously. (7) Where dose 0
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102 frequencies were less than daily, and an antifungal agent consequently prescribed but not b
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103 administered on the day of study, patients were included and doses decimalised to account for u
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104 frequency of administration. t
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106 Descriptive statistical analysis was carried out using STATA 10 and R (version 2.15.3). (8, 9)
107 Analysis of antifungal dosing was performed using total daily dose in 24 hours (TDD). TDD
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108 were analysed per unit of current weight or estimated surface area (kg or m2) according to
109 current guidance for each drug (see table 1). The following Anatomical Therapeutic Chemical
110 classes (version 2011) were analysed: antimycotics (ATC J02), antifungals for systemic use
111 (ATC D01B), and intestinal anti-infectives (ATC A07). (10) Dosing regimens were analysed by
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112 nation and macro-geographical regions UN geo-scheme. (11)
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113 n
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114 The mean and variance of TDDs for each antifungal agent were compared to currently de
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115 recommended regimens. Recommended daily doses (RDD) were defined using collated guidance fr
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116 from the Summary of Product Characteristics (SPC), the European Society of Paediatric h
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117 Infectious Disease (ESPID) Blue Book: Manual of Childhood Infections European Formulary :/
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118 and the Report of the committee Red Book®: 2012 Report of the Committee on Infectious Diseases c
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119 American Academy of Pediatrics. Where specific dosing recommendations for paediatric or m
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120 neonatal populations could be derived from the respective SPC these formed the basis of total g
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121 daily dose recommendations. Where specific dosing recommendations for paediatric or neonatal
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122 populations could be derived from the respective SPC these formed the basis of total daily dose u
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123 recommendations. Dosing recommendations are summarized in table 1.
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124 0
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125 b
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126 Upper and lower limits for recommended TDD were identified from the range produced from the u
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127 collated dosing recommendations and used to define maximum recommended daily doses t
128 (MaxRDD) and minimum recommended daily doses (MinRDD). Dosing errors were defined as
129 prescription of medications at a dose meeting one of the following criteria: (1) TDD prescribed
130 at 110% or more than MaxRDD; (2) TDD prescribed at 90% or less than MinRDD. For example,
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131 the MinRDD and MaxRDD for voriconazole in children aged 2-12 years were determined as
132 follows: the highest current recommended dosing regimen (excluding loading doses) was 8
133 mg/kg 12 h, and the lowest dosing regimen 4 mg/kg 12 h (see table 1) during the study period.
134 (12-20) The MaxRDD and MinRDD were therefore calculated as 16 mg/kg and 8 mg/kg daily,
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135 respectively, and supra- and sub-therapeutic doses calculated as ≥ 17.6 mg/kg and ≤ 7.2 mg/kg,
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136 respectively. Doses were defined according to age categories and route of administration (where n
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137 specified in guidelines). A full description of this methodology is described in detail elsewhere. de
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138 (21) Doses exceeding values 10-fold above MaxRDD or below MinRDD were considered fr
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139 isolated prescribing or data entry errors and were censored from analysis. h
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140 :/
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141 This study was funded by the European Commission Health and Consumer Protection s
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142 Directorate General (DG SANCO) through the Executive Agency for Health and Consumers o
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143 (EAHC). In accordance with European regulation, anonymised data obtained during this o
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144 observational study was gathered without additional therapy, monitoring procedures, or change a
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145 from existing clinical practice. Submission to the institutional review board of participating r
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146 centres was at the discretion of individual lead investigators. ,
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147 b
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148 RESULTS u
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149 Patient demographics t
150 Data were recorded from 17,693 neonatal and paediatric inpatients from 226 centres.
151 Participating centres were from 19 European countries and 17 countries outside of Europe (see
152 table 2). A total of 1345 inpatients from 136 centres were prescribed at least one oral or
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153 parenteral antifungal. This included 203 neonates and 379 children receiving antifungal agents
154 known to have negligible bioavailability administered via the oral route (amphotericin B,
155 nystatin and miconazole) and were therefore excluded. Data from five patients were excluded
156 due to errors in data entry. In total 885 patients were evaluable (see figure 1); 174 neonates and
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157 711 children (one month to 18 years). The median age of neonates and children in the study were
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158 13 days (IQR=7-19 days) and 6.5 years (IQR=1-13 years), respectively. n
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159 de
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160 Antifungal use fr
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161 The most commonly prescribed agent for neonates and children during the study was h
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162 fluconazole, accounting for 355 (40%) of prescriptions (see figure 2). Second generation :/
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163 triazoles were less commonly prescribed (voriconazole, n=87, 10%; posaconazole, n=14, 2%). c
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164 Fifty children (6%) received oral itraconazole. Amphotericin B deoxycholate was the second m
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165 most frequently prescribed drug. Of 262 patients prescribed amphotericin B, 197 (75%) were g
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166 prescribed amphotericin B deoxycholate (DAmB). The majority of DAmB prescriptions (n=150,
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167 76%) were from European centres. Lipid amphotericin B preparations (liposomal, lipid complex u
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168 and colloid dispersion) were prescribed less frequently than conventional amphotericin B (n=65,
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169 8%), of which 51 prescriptions (78%) were within European centres. Use of echinocandins was 0
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170 less common than amphotericin B formulations and azoles (caspofungin, n=55, 6%; micafungin, b
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171 n=32, 4%). One child received parenteral flucytosine for treatment of catheter-related u
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172 bloodstream infection. Forty-two patients received combination antifungal therapy. The most t
173 commonly prescribed drug combinations used were amphotericin B/fluconazole (n=7),
174 amphotericin B/caspofungin (n=6) and caspofungin/voriconazole (n=6).
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176 Indication
177 Systemic antifungal treatment was reported in 174 neonates. Extremely low birth weight
178 neonates accounted for the majority of antifungal prescriptions (n=103, 60%). The most common
179 indications for systemic antifungal treatment in neonates were medical prophylaxis in 80 cases
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180 (46%) and treatment of suspected IFI in 77 cases (44%). Treatment of localised infection was
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181 uncommonly reported (cardiac infection, n=2; CNS infection, n=4; genito-urinary tract infection, n
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182 n=3; lower respiratory tract infection, n=2; other/infective source unknown, n=4). ANOVA de
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183 analysis demonstrated no significant effect of clinical indication (prophylaxis or treatment of fr
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184 systemic or localised infection) on TDD (F = 1.1, p = 0.342). h
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185 :/
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186 The most common indication for antifungal administration in children was medical prophylaxis c
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187 (n=325, 46%), followed by empiric treatment of febrile neutropenia (n=122, 17%) and treatment m
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188 of confirmed or suspected IFI (n=100, 14%). Antifungal treatment of localised infection was less g
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189 commonly reported (respiratory tract n=41, skin and soft tissue n=15, urinary tract n=14,
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190 gastrointestinal n=12, CNS n=4, joint and bone n=4, cardiac n=4). In 70 cases the indication for u
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191 treatment was not known or recorded.
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192 0
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193 Route of administration b
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194 Systemic antifungals were administered via the oral and parenteral route in children was 58% u
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195 and 42%, respectively. The majority of prescriptions in neonates were via the parenteral route t
196 (n=154, 89%). Twenty neonates received oral fluconazole. In children, oral administration
197 accounted for 108/254 (43%) of fluconazole prescriptions and 50/87 (57%) of voriconazole
198 prescriptions. Mean TDD for children receiving fluconazole via the oral route was significantly
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199 lower ((cid:1850)(cid:3364)=1.8 mg-1kg-1d, SD=8.3) than via the intravenous route ((cid:1850)(cid:3364)=3.5 mg-1kg-1d, SD=6.2;
200 p=<0.001). Similarly, mean TDD for children receiving oral voriconazole was lower ((cid:1850)(cid:3364)=6.1 mg-
201 1kg-1d, SD=4.9) than intravenous voriconazole ((cid:1850)(cid:3364)=7.3 mg-1kg-1d, SD=5.8; p=0.257).
202
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203 Dosing o
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204 The proportions of patients receiving doses outside MinRDD and MaxRDD for each antifungal lo
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205 agent in neonates and children are shown in figure 2. Overall, fewer than half of patients (n=371, e
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206 42%) received a TDD within the dosing range recommended in current guidelines. Sub- ro
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207 therapeutic doses (<90% of the MinRDD) were prescribed in 416 cases (47%). The most h
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208 commonly prescribed drug, fluconazole, was prescribed at sub-therapeutic doses in 242/384 //
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209 (63%) of cases (figure 3). Amphotericin B deoxycholate was prescribed at sub-therapeutic TDD .
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210 in 83/200 (42%) cases. Two neonates received amphotericin B lipid complex at a dose of 5 mg- m
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211 1kg-1d. Recently the efficacy and population pharmacokinetics of ABLC have been described in g/

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212 neonates, and a dose of 2.5–5 mg-1kg-1d incorporated into European guidelines for the treatment J
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213 of invasive candidiasis. (22) u
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214 1
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215 Centre and department category 0
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216 The majority of neonatal antifungal prescriptions occurred in tertiary (level III) neonatal units (n b
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217 = 146, 84%). For the pediatric population, antifungals were prescribed most frequently in u
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218 haematology-oncology wards (n=352, 50%) and pediatric intensive care units (n=121, 17%).
219 Less frequently, antifungal prescriptions were recorded in surgical transplant units (n=75),
220 general pediatric wards (n=73), surgical wards (n=32), cardiac wards (n=16) and other specialist
221 pediatric wards (n=42).
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