Mendoza-Palomar et al. BMC Infectious Diseases (2021) 21:100 https://doi.org/10.1186/s12879-021-05774-9 RESEARCH ARTICLE Open Access Antifungal stewardship in a tertiary care paediatric hospital: the PROAFUNGI study Natalia Mendoza-Palomar1†, Beatriz Garcia-Palop2†, Susana Melendo1, Maria Teresa Martín3, Berta Renedo-Miró2, Pere Soler-Palacin1* and Aurora Fernández-Polo2 Abstract Background: The increasing use of antifungal drugs (AF) in children and the concern for related adverse events and costs has led to the development of specific AF stewardship programmes (AFS). Studies in adult patients have shown improvements in AF prescription and usage after implementation, but paediatric data are scant. The aim of this PROAFUNGI study was to describe the use and appropriateness of AF in a high complexity paediatric centre. Methods: Observational, prospective, single-centre, modified point-prevalence study (11 surveys, July–October 2018), including paediatric (< 18 years) patients receiving at least one systemic AF. Prescriptions were evaluated by the AFS team. Results: The study included 119 prescriptions in 55 patients (53% males, median age 8.7 years [IQR 2.4–13.8]). The main underlying condition was cancer (45.5% of patients; HSCT in 60% of them); and the first indication for AF was prophylaxis (75 prescriptions, 63.2%). Liposomal amphotericin B was used most commonly (46% prescriptions), mainly as prophylaxis (75%). Among the 219 evaluations, 195 (89%) were considered optimal. The reason for non- optimal prescriptions was mostly lack of indication (14/24), especially in critical patients with ventricular assist devices. The use of AF without paediatric approval accounted for 8/24 inappropriate prescriptions. Conclusions: A high rate of AF appropriateness was found for the children’s hospital as a whole, in relation with a well-established AFS. Nonetheless, the identification of specific areas of improvement should guide future actions of the AFS team, which will focus mainly on prophylaxis in critically ill patients receiving circulatory assistance and the use of non-approved drugs in children. Keywords: Antifungal therapy, Paediatrics, Antimicrobial management * Correspondence: psoler@vhebron.net † Natalia Mendoza-Palomar and Beatriz Garcia-Palop contributed equally to this work. 1 Pediatric Infectious Diseases and Inmunodeficiencies Unit, Hospital Universitari Vall d’Hebron, Institut de Recerca Vall d’Hebron, Universitat Autònoma de Barcelona, Passeig de la Vall d’Hebron, 119-129, 08035 Barcelona, Spain Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. 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BMC Infectious Diseases (2021) 21:100 Page 2 of 7 Background The PROAFUNGI study is an observational, pro- In recent years, the increase in the number of immuno- spective, single-centre, modified point-prevalence sur- suppressed children at risk of invasive fungal infection vey (mPPS) study performed from July to October (IFI) has led to a higher use of both prophylactic and 2018. Admitted patients receiving AF were identified therapeutic antifungal drugs (AF) in this population [1]. through the electronic prescription system (Silicon® In these patients, AF prescription may be challenging v11, Grifols International, S.A., Sant Cugat del Vallès, due to unspecific clinical presentation, lower perform- Spain and Centricity™ Critical Care 8.1 SP7, General ance of diagnostic tests, variable pharmacokinetics re- Electric Company, Barrington, United States) and data lated to maturation changes and lack of clinical trials in were collected weekly. All consecutive paediatric (< children [1–3]. 18 years) patients receiving at least one systemic AF Unnecessary AF use entails substantial risk of toxicity were included. Patients were included again if a new and interactions, along with higher drug resistances and AF course was started. Additionally, one AF prescrip- significant costs [3]. In the last 5 years, AF drugs tion was recorded for each week in which the drug accounted for around one-third of antimicrobial usage was prescribed. Patients receiving AF for less than 48 (13.79% of all days of therapy [DOT] per 100 patient- h were excluded. days [PD]) but 75% (€638,403) of total annual anti- Demographic, clinical and treatment data were infective expenditure in our hospital (unpublished data). obtained from the patient’s electronic medical record In response to this concern, specific AF stewardship (SAP© NetWeaver 7.0 SPS37, California, United programmes (AFS) are being developed to improve the States), including age, sex, underlying disease, AF in- clinical outcome of patients receiving AF drugs and to dication and IFI category. The patient’s IFI was classi- ensure optimal prescription in terms of spectrum, dose, fied as possible, probable or proven according to the therapeutic drug monitoring, duration and route of ad- European Organization for Research and Treatment ministration while avoiding adverse effects and unneces- of Cancer/Mycoses Study Group (EORTC/MSG) defi- sary costs [3]. Interventions are extrapolated from the nitions [9]. Additionally, patients at risk of IFI and or antibiotic stewardship programmes and include audits with clinical suspicion of IFI were added as other cat- with feedback, guideline and protocol development, edu- egories to include situations not listed in the EORTC/ cational programmes and prescription evaluation [4, 5]. MSG criteria. The AF indication was classified as Although AFS are relatively new, a systematic review in prophylaxis (primary or secondary) or treatment (em- 2017 identified 14 papers describing AFS in adult pa- pirical, pre-emptive or targeted). Pharmacological data tients and the improvements in AF prescription and use (AF, route of administration, dose and frequency) after implementation [6]. In contrast, data about paediat- were collected from the abovementioned electronic ric AFS are scant and mainly limited to adult pro- prescription systems. grammes including children or to specific situations After the collection, data were evaluated by two in- such as invasive Candida spp. infection or cancer [7, 8]. dependent members of the AFS team. In case of The aim of this PROAFUNGI study was to describe disagreement, a third member was consulted to the use and appropriateness of AF in a high complexity achieve consensus. Following the guidelines for the paediatric centre. implementation of antimicrobial stewardship programs in Spanish hospitals, optimal prescription was defined Methods as “necessary” (if the clinical situation required the The children’s hospital at Vall d’Hebron Barcelona Hos- use of an AF, either prophylactic and therapeutic), pital Campus is a reference tertiary care centre with a “appropriate” (if the drug was active against the national reference programme of solid organ transplant- causative microorganism and adjusted to the patient’s ation (SOT) and hematopoietic stem cell transplantation characteristics), and “adequate” (if the dose, duration (HSCT) with 35 and 40 yearly transplantations, respect- and route of administration were correct, while in ively, as well as a 20-bed paediatric ICU (PICU), a 44- concordance with local protocols, or international bed neonatal ICU (NICU) and a large surgery guidelines if local protocols were not available) [10]. programme with around 2700 inpatient procedures per Qualitative variables were described as the number year. The institutional paediatric antimicrobial steward- and percentage, and quantitative variables as the mean ± ship program (PROA-NEN) was formally founded in standard deviation (SD) or median (IQR). The statistical 2015 and aims to improve clinical outcomes, reduce analysis was carried out with Microsoft® Office Excel® antimicrobial-related adverse events and ensure the 2007 (12.0.4518.1014). cost-effective use of treatments. During 2018, a specific The local Ethics Committee for Clinical Research AFS team was created, involving 3 pharmacists, 3 paedi- approved the study in March 2018 (code VAL-ANT- atric infectious diseases specialists and 1 microbiologist. 2017-01). Mendoza-Palomar et al. BMC Infectious Diseases (2021) 21:100 Page 3 of 7 Results prescriptions, 24 (11%) were considered non-optimal. As Patient and fungal infection characteristics shown in Table 2, the main reason for a non-optimal During the study period, 55 patients were included; 53% evaluation was lack of indication (14/24), followed by were males and median age was 8.7 years (IQR 2.4–13.8 disagreement with the local protocols (12/24), mainly in years). The main underlying condition was cancer (25, heart-transplanted and HSCT patients. Institutional 45.5%; 15 [60%] of them having undergone HSCT); and protocols were available for 117/144 (81%) prophylactic the most common situation leading to AF prescription and 40/75 (53%) treatment prescriptions. Moreover, the was patients at risk of IFI (27; 49%). Detailed data are departments with the highest AF use (cancer department provided in Table 1. and PICU) issued most non-optimal prescriptions (16.7 and 58.3%, respectively). Antifungal prescription characteristics Liposomal amphotericin B (LAMB) was used commonly A total of 119 AF prescriptions were analysed. The indi- and was also the main drug considered non-optimal cation was prophylaxis in 75 (63.2%) cases (70 primary (Table 3), essentially due to non-optimal prescriptions re- and 5 secondary) and treatment in 44 (36.8%): 30 (25%) lated to prophylaxis in patients receiving circulatory assist- empirical; 1 (0.8%) pre-emptive; 13 (11%) targeted. Drug ance (7/12): 2 patients with ventricular assist device (VAD) distribution by type of patient and indication is detailed who had an unnecessary prescription and 1 receiving extra- in Table 2. Most drugs (93.3%) were prescribed as corporeal membrane oxygenation (ECMO) support who had monotherapy (52 patients), while dual and triple therapy an inappropriate prescription due to an excessive dosage. were only used in 1 patient (2 prescriptions, 1.7%) and 2 Two non-approved drugs in paediatrics at the time of patients (6 prescriptions, 5%), respectively. the study, isavuconazole (5 prescriptions in one patient) and anidulafungin (3 prescriptions in one patient), Prescription quality assessment accounted for a significant number of non-optimal pre- During the study period, the PROAFUNGI working scriptions due to the availability of alternative approved group performed a total of 11 surveys, including 219 drugs as empirical treatment in one patient with HSCT prescription evaluations. From the 219 evaluated and acute renal impairment who could have been treated with oral voriconazole and one patient with por- Table 1 Patient Characteristics tal cavernomatosis who could have been treated with Total micafungin, respectively. Clinical characteristics, n 55 • Age, y, median (IQR) 8.7 (2.4–13.8) Discussion • Male sex, n (%) 29 (53) The present study demonstrates a significantly high Underlying disease percentage of optimal prescription of AF in children at a • Cancer, n (%) 25 (45.5) referral hospital but has also detected some points of im- provement mainly related to prophylaxis in critically ill • HSCT, n (%) 15/25 (60) patients receiving circulatory assistance and the use of • Critical paediatric patients, n (%) 14 (25.5) non-approved drugs in children. • Critical newborns, n (%) 5 (9) According to previous published articles, cancer pa- • Primary immunodeficiencies, n (%) 5 (9) tients were those receiving AF more frequently [8, 11, • Solid organ transplant, n (%) 3 (5.5) 12]. In a retrospective cohort study conducted in 25 • Other, n (%) 3 (5.5) paediatric hospitals in the USA, patients with malignan- a cies represented 42% of overall AF use [11]. In our co- Clinical situation hort, a large proportion of AF prescriptions were • Risk of IFI, n (%) 27 (49) ordered for HSCT patients (15 patients, accounting for • Suspicion of IFI, n (%) 6 (11) 43 prescriptions, 36% of all AF prescriptions and 67% of • Possible IFI, n (%) 14 (25) cancer patient prescriptions), as our centre is a national • Probable IFI, n (%) 2 (4) referral transplant unit. Similarly, in a study including • Proven IFI, n (%) 6 (11) only children with cancer, HSCT patients accounted for 78% of overall AF prescriptions [8]. Regarding patients’ Microorganisms age, the Antibiotic Resistance and Prescribing in Euro- • Candida spp. 2/6 pean Children (ARPEC) study reported higher AF use in • Moulds 4/6 paediatric patients (83%) compared with newborns Abbreviations: IFI invasive fungal infection (17%), as did another survey including more than 50 a IFI category was defined according to the European Organization for Research and Treatment of Cancer/Mycoses Study Group hospitals in the USA (76 DOT/1000 patient-days in (EORTC/MSG) definitions paediatric patients compared with 14 DOT/1000 Mendoza-Palomar et al. BMC Infectious Diseases (2021) 21:100 Page 4 of 7 Table 2 Antifungal Prescription Characteristics and Adequacy Total Prophylaxis Treatment Antifungal prescriptions, n 119 75 44 Indication for AF therapy Primary prophylaxis, n (%) 70 (58.8) 70 (93.3) Secondary prophylaxis, n (%) 5 (4.4) 5 (6.7) Empirical therapy, n (%) 30 (25) 30 (68.2) Pre-emptive therapy, n (%) 1 (0.8) 1 (2.3) Targeted therapy, n (%) 13 (11) 13 (29.5) Underlying disease Cancer, n (%) 64 (54) 48 (64) 16 (36.4) HSCT, n (%) 43/64 (67) 35/48 (73) 8/16 (50) Critical paediatric patients, n (%) 29 (24) 16 (21.4) 13 (29.5) Critical newborns, n (%) 7 (6) 3 (4) 4 (9.1) Primary immunodeficiencies, n (%) 11 (9) 7 (9.3) 4 (9.1) Solid organ transplant, n (%) 3 (3) 0 (0) 3 (6.8) Other, n (%) 5 (4) 1 (1.3) 4 (9.1) AF agent Liposomal amphotericin B, n (%) 55 (46.2) 41 (54.6) 14 (32) Posaconazole, n (%) 21 (17.7) 21 (28) 0 (0) Anidulafungin, n (%) 13 (10.9) 3 (4) 10 (23) Fluconazole, n (%) 12 (10.1) 6 (8) 6 (14) Micafungin, n (%) 6 (5.0) 2 (2.7) 4 (9) Isavuconazole, n (%) 5 (4.2) 0 (0) 5 (11) Voriconazole, n (%) 4 (3.4) 0 (0) 4 (9) Itraconazole, n (%) 2 (1.7) 2 (2.7) 0 (0) Caspofungin, n (%) 1 (0.8) 0 (0) 1 (2) Antifungal prescription evaluations, n 219 144 75 Non-optimal prescriptions, n (%) 24 (11) 12 (8) 12 (16) Unnecessary, n (%) 14 (6) 10 (7) 4 (5) Inappropriate, n (%) 2 (1) 0 (0) 2 (3) Inadequate Incorrect dose, n (%) 7 (3) 4 (3) 3 (4) Incorrect route of administration, n (%) 0 (0) 0 (0) 0 (0) Incorrect duration, n (%) 7 (3) 7 (5) 0 (0) a a Disagreement with institutional protocol, when available, n (%) 12 (8) 4 (3) 8 (20)a Non-optimal prescription distribution among underlying disease, n (%) Cancer 4 (16.7) 2 (16.7) 2 (16.7) HSCT, n (%) 4/4 (100) 2/2 (100) 2/2 (100) Critical paediatric patients, n (%) 14 (58.3) 8 (66.7) 6 (50) Critical newborns, n (%) 1 (4.2) 1 (8.3) 0 (0) Primary immunodeficiencies, n (%) 1 (4.2) 1 (8.3) 0 (0) Solid organ transplant, n (%) 1 (4.2) 0 (0) 1 (8.3) Other, n (%) 3 (12.5) 0 (0) 3 (25) Abbreviations: AF antifungal a Calculated as a percentage of the prescriptions for which a local institutional protocol was available: 157 total, 117 prophylaxis, 40 treatment Mendoza-Palomar et al. BMC Infectious Diseases (2021) 21:100 Page 5 of 7 Table 3 Assessment of Prescription Quality According to Drug Drug Patients, Prescriptions Non-optimal Prescriptions Cause a n Evaluated, n (n, %) Liposomal 27 105 12 (11%) - Unnecessary (9) amphotericin B - Inappropriate (2) - Inadequate: incorrect dose (5), incorrect duration (7), disagreement with institutional protocol b (5) Posaconazole 12 32 1 (3%) - Inadequate, incorrect dose (1) Anidulafungin 11 29 3 (10%) - Unnecessary (3) Fluconazole 11 25 1 (4%) - Inadequate, incorrect dose (1) Isavuconazole 2 9 5 (56%) - Inadequate: disagreement with institutional protocol** (5) Micafungin 3 7 2 (29%) - Unnecessary (2) - Inadequate: disagreement with institutional protocol b (2) Voriconazole 2 5 0 N/A Caspofungin 1 4 0 N/A Itraconazole 2 3 0 N/A Abbreviations: N/A not applicable a The same prescription may not be optimal for more than one reason b Disagreement with institutional protocol, when available patient-days in newborns) [12, 13]. Remarkably, AF use commonly prescribed agent [7, 11–13]. Nonetheless, all in neonates was even lower in our centre (5 patients, ac- these studies include a high proportion, or exclusively counting for 7 prescriptions, 6%), in relation to a mini- include, neonates in whom Candida spp. is the main mum incidence of neonatal candidiasis (0.6%) that and almost only fungal pathogen [7, 11, 12]. Conversely, precludes the use of universal AF prophylaxis in low for paediatric, particularly children with cancer, PID or birth weight neonates [14, 15]. HSCT (a majority in our cohort), filamentous fungi Regarding AF indication, prophylaxis was the main should be considered, and other AFs with a broader reason for prescriptions (63.2%), followed by empirical spectrum play a major role [2, 10, 18, 19]. treatment (25%) and targeted treatment (11%). These Regarding AF prescription evaluations, a high pro- findings are consistent with data from the study per- portion (89%) of prescriptions were considered cor- formed by Santiago-García et al. that included 56 chil- rect, similar to the study by Santiago-García et al., dren with cancer and also the arm of paediatric patients that described 93% of appropriate AF prescriptions in from the ARPEC study [8, 12]. In the neonate arm, a paediatric cancer department [8]. In contrast, a prophylaxis was the reason for 46% of prescriptions, multicentric study by Ferreras-Antolín et al. consid- while treatment of suspected candidaemia accounted for ered that only 34% of prescriptions were optimal, the other 44% [12]. similar to another study focused on adult patients In terms of the distribution of AF, LAMB was the with hospital-acquired candidemia that found 47% of most prescribed drug in our study, followed by posaco- correct prescriptions [7, 20]. Remarkably, the level of nazole. At our hospital, low-dose LAMB is the drug of non-optimal prescriptions was higher in patients re- choice for AF prophylaxis in high-risk cancer patients ceiving treatment (12/75; 16%) compared with (relapsed or refractory leukaemia, HSCT pre- prophylaxis (12/144, 8%), probably due to the higher engraftment phase) due to its effectiveness and safety availability of institutional protocols aimed at prophy- profile as shown in a previous paper by our group [16]. laxis. Protocols were available for 117/144 (81%) LAMB is also used in critically ill paediatric patients due prophylactic prescriptions and for 40/75 (53%) treat- to its stability with the concomitant use of continuous ment prescriptions. renal replacement therapy, as opposed to azole elimin- Regarding the cause of incorrect prescription, the lead- ation [17]. On the other hand, posaconazole is mainly ing reason was the lack of indication (unnecessary) (14/ indicated in the HSCT post-engraftment period and in 24), followed by disagreement with current recommen- some primary immunodeficiencies (PID) such as chronic dations (12/24), incorrect dose (7/24), incorrect duration granulomatous disease. These data was quite different (7/24) and inappropriate choice of AF (2/24). Interest- from other studies in which fluconazole is the most ingly, the proportions were generally similar to Santiago- Mendoza-Palomar et al. BMC Infectious Diseases (2021) 21:100 Page 6 of 7 Garcia et al., that described the lack of indication as the Abbreviations main cause of non-optimal prescription (7/13), followed AF: Antifungal drugs; AFS: Antifungal stewardship programmes; ARPE C: Antibiotic Resistance and Prescribing in European Children; by incorrect dosage (5/13) or incorrect route of adminis- ECMO: Extracorporeal membrane oxygenation; EORTC/MSG: European tration (1/13) [8]. Organization for Research and Treatment of Cancer/Mycoses Study Group; Some incorrect prescriptions were related to drugs not HSCT: Hematopoietic stem cell transplantation; IFI: Invasive fungal infection; LAMB: Liposomal amphotericin B; mPPS: modified point-prevalence survey; approved for paediatric use at the time of study (such as NICU: Neonatal ICU; PICU: Paediatric ICU; PID: Primary immunodeficiencies; anidulafungin or isavuconazole). Although these drugs SOT: Solid organ transplantation; VAD: Ventricular assist device have shown clinical benefits in adults, paediatric use Acknowledgements should be carefully evaluated and restricted to cases with We thank Helen Casas for English language support. no approved alternative for children. Moreover, for im- proving prescription’s quality, decisions regarding anti- Authors’ contributions fungals should be made by a multi-disciplinary team. In PSP and AFP concepted and designed the study. NMP and BGP collected and analysed the patient data. NMP, BGP, PSP and AFP interpreted the data centres with persuasive ASP, following experts’ advice is and wrote the manuscript. SM, MTM and BR also contributed to the data of utmost importance. evaluation and interpretation. All authors read and approved the submitted With regards to dose, the incorrect rate (3%) was sig- version and have agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or nificantly lower than in a previous study by Lestner et al. integrity of any part of the work are appropriately investigated, resolved, and that found an inadequate dose as the main cause of in- the resolution documented in the literature. correct AF use in paediatrics, identifying 47% of cases with doses lower than recommended by international Funding This study was supported by an Investigator-Sponsored Research grant from guidelines [12]. The existence of specific tools for Gilead Sciences. Gilead provided grant support for this study, but did not electronic prescription and the daily revision by the take part in the study design, data collection, or analysis of the results. Pharmacy Department have probably contributed to this Availability of data and materials high rate of adequate dosing. The datasets used and/or analysed during the current study are available The limitations of this study were its single-centre na- from the corresponding author on reasonable request. ture and its PPS format, which may have meant that some prescriptions were missed. Moreover, a 4-month Ethics approval and consent to participate The Research Ethics Committee with Medicines from Vall d’Hebron Research period including 11 surveys may not be sufficiently rep- Institute (Barcelona, Spain) approved the study in March 2018 (code VAL- resentative of overall practice, as several periods of viral ANT-2017-01). The referred committee granted permission to access and epidemics can produce fever without bacterial cause and analyse the study data. Patients’ data was anonymised before its use. Study participants consent to participate is not applicable. thus lead to increased empirical AF use. However, the results of this study regarding AF use are similar to an- Consent for publication nual AF consumption (DOT/100 PD) in our hospital Not Applicable. (unpublished data). In 2018, most AF usage occurred in Competing interests standard hospitalization patients, followed by PICU pa- The authors declare that they have no competing interests. tients (63 and 34%, respectively). In our cohort, these pa- tients accounted for 70 and 24% of prescriptions, Author details 1 Pediatric Infectious Diseases and Inmunodeficiencies Unit, Hospital respectively. By therapeutic group, the AFs used most Universitari Vall d’Hebron, Institut de Recerca Vall d’Hebron, Universitat often in 2018 were azoles (45% DOT/100 PD), LAMB Autònoma de Barcelona, Passeig de la Vall d’Hebron, 119-129, 08035 (32% DOT/100 PD), and echinocandins (23% DOT/100 Barcelona, Spain. 2Pharmacy Department, Hospital Universitari Vall d’Hebron, Institut de Recerca Vall d’Hebron, Barcelona, Spain. 3Microbiology PD). In terms of AF distribution in this PROAFUNGI Department, Hospital Universitari Vall d’Hebron, Institut de Recerca Vall study; LAMB was the most prescribed drug (46.2%), d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain. followed by azoles (37%) and echinocandins (16.7%). Received: 6 October 2020 Accepted: 6 January 2021 Conclusions References A high rate of optimal AF evaluation was globally dem- 1. Hamdy RF, Zaoutis TE, Seo SK. Antifungal stewardship considerations for adults and pediatrics. 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