Voriconazole plasma concentrations (PC) are highly variable, particularly in children. Dose recommendations in 2–12-year-old patients changed in 2012. Little data on therapeutic drug monitoring (TDM) after these new recommendations are available. We aimed to evaluate voriconazole monitoring in children with invasive fungal infection (IFI) after implementation of new dosages and its relationship with safety and effectiveness. A prospective, observational study, including children aged 2–12 years, was conducted. TDM was performed weekly and doses were changed according to an in-house protocol. Effectiveness, adverse events, and factors influencing PC were analysed. A total of 229 PC from 28 IFI episodes were obtained. New dosing led to a higher rate of adequate PC compared to previous studies; still, 35.8% were outside the therapeutic range. In patients aged < 8 years, doses to achieve therapeutic levels were higher than recommended. Severe hypoalbuminemia and markedly elevated C-reactive protein were related to inadequate PC. Therapeutic PC were associated with drug effectiveness and safety. Higher doses in younger patients and a dose adjustment protocol based on TDM should be considered. Voriconazole PC variability has decreased with current updated recommendations, but it remains high and is influenced by inflammatory status. Additional efforts to control inflammation in children with IFI should be encouraged.

Isavuconazole (ISA) is approved for treating invasive aspergillosis and mucormycosis in adults, but its use in children remains off-label. We report on the use of ISA in real-world pediatric practice with 15 patients receiving ISA for treatment of invasive fungal infections. Therapeutic drug monitoring (TDM) was performed in all patients, with 52/111 (46.8%) C _trough determinations out of range, thus supporting the need for TDM in children, especially those receiving extracorporeal membrane oxygenation (ECMO).

A previously healthy 9-year-old girl developed fulminant myocarditis due to severe influenza A infection complicated with methicillin-resistant Staphylococcus aureus pneumonia, requiring extracorporeal membrane oxygenation (ECMO) support. Twelve days after admission, Aspergillus fumigatus was isolated in tracheal aspirate, and 12 h later she suddenly developed anisocoria. Computed tomography (CT) of the head showed fungal brain lesions. Urgent decompressive craniectomy with lesion drainage was performed; histopathology found hyphae in surgical samples, culture-positive for Aspergillus fumigatus (susceptible to azoles, echinocandins, and amphotericin B). Extension workup showed disseminated aspergillosis. After multiple surgeries and combined antifungal therapy (isavuconazole plus liposomal amphotericin B), her clinical course was favorable. Isavuconazole therapeutic drug monitoring was performed weekly. Extensive immunological study ruled out primary immunodeficiencies. Fluorine-18 fluorodeoxyglucose positron emission tomography/CT (¹⁸F-FDG PET/CT) follow-up showed a gradual decrease in fungal lesions. Influenza-associated pulmonary aspergillosis is well-recognized in critically ill adult patients, but pediatric data are scant. Clinical features described in adults concur with those of our case. Isavuconazole, an off-label drug in children, was chosen because our patient had severe renal failure. To conclude, influenza-associated pulmonary aspergillosis is uncommon in children admitted to intensive care for severe influenza, but pediatricians should be highly aware of this condition to enable prompt diagnosis and treatment.

Background: Primary antifungal prophylaxis in paediatric allogeneic HSCT recipients is mainly based on azoles, which can have related toxicity and drug interactions. Low-dose liposomal amphotericin B (L-AmB) is an attractive intravenous alternative because of its low toxicity and lower risk of interactions.Objectives: To evaluate the effectiveness and safety of L-AmB (1 mg/kg/day) for primary antifungal prophylaxis in pre-engraftment paediatric HSCT patients.Patients and methods: Retrospective, observational study including all consecutive patients aged ≤18 years who underwent HSCT and received antifungal prophylaxis with intravenous L-AmB (1 mg/kg/day, from day −1 to 48 h before discharge) between January 2012 and December 2016.Results: In total, 125 HSCT procedures in 118 patients were included, median age 7.2 years (IQR 4.2–11.5). Haematological malignancies were the main underlying condition (63.6%), and 109 (87.2%) were considered at high risk for invasive fungal infection (IFI). Ten patients (7.7%), all high risk, developed breakthrough IFI (three Candida spp., seven invasive mould infections) and tended to have higher overall mortality. The only statistically significant risk factor for IFI was cytomegalovirus co-infection. Adverse events, all grade I, occurred in 25 (20%), requiring L-AmB withdrawal in one case. Overall survival at 30 days was 99.2%. At study completion, one patient had died of IFI.Conclusions: The incidence of breakthrough IFI was comparable to that of previous reports, with a very low rate of significant toxicity. Thus, prophylactic L-AmB may be a safe, effective option for antifungal prophylaxis in the pre-engraftment phase for children undergoing HSCT, even those at high risk.

Introduction: Actions to reduce and optimize antimicrobial use are crucial in the management of infectious diseases to counteract the emergence of short- and long-term resistance. This is particularly important for pediatric patients due to the increasing incidence of serious infections caused by resistant bacteria in this population. The aim of this study was to evaluate the impact of a pediatric antimicrobial stewardship program (PROA-NEN) implemented in a Spanish tertiary hospital by assessing the use of systemic antimicrobials, clinical indicators, antimicrobial resistance, and costs. Methods: In this quasi-experimental, single-center study, we included pediatric patients (0–18 years) admitted to specialized pediatric medical and surgical units, as well as pediatric and neonatal intensive care units, from January 2015 to December 2019. The impact of the PROA-NEN program was assessed using process (consumption trends and prescription quality) and outcome indicators (clinical and microbiological). Antibiotic prescription quality was determined using quarterly point prevalence cross-sectional analyses. Results: Total antimicrobial consumption decreased during the initial three years of the PROA-NEN program, followed by a slight rebound in 2019. This decrease was particularly evident in intensive care and surgical units. Antibiotic use, according to the WHO Access, Watch and Reserve (AWaRe) classification, remained stable during the study period. The overall rate of appropriate prescription was 83.2%, with a significant increase over the study period. Clinical indicators did not substantially change over the study period. Direct antimicrobial expenses decreased by 27.3% from 2015 to 2019. Conclusions: The PROA-NEN program was associated with reduced antimicrobial consumption, improved appropriate use, and decreased costs without compromising clinical and/or microbiological outcomes in patients.

Background and Objectives: Isavuconazole (ISA) has been recently approved for the treatment of invasive aspergillosis and mucormycosis in patients aged >1 year. Prior to this approval, it was used in paediatric patients under compassionate use. The objective of this study is to describe the experience with ISA use in children. Patients and methods: A descriptive, retrospective, multicentre study conducted in nine Spanish hospitals, including patients aged ≤18 years who received ≥7 days of ISA between 2018 and 2023. Therapeutic drug monitoring (TDM) was performed with pre-dose [trough concentration (Ctrough)] levels measured according to local protocols. A therapeutic range of 2.5–5 mg/L was used for analysis. Results: A total of 107 patients (median age: 11 years, 56% male) were included. ISA was used as a treatment (95 patients), mostly as second-line therapy (64 patients, 67%), due to toxicity from previous antifungals (27 patients, 42%). Of 53 patients with proven/probable invasive fungal disease (IFD), 32 (60%) showed a favourable response and 21 (40%) died, 13 due to IFD. Twelve patients received ISA as prophylaxis and none developed breakthrough IFD. Overall, 27/107 (25%) patients experienced adverse effects, the most common being hepatotoxicity, with 10 requiring discontinuation. TDM was performed in 76/95 patients (80%), revealing 59% of Ctrough values outside the therapeutic range. Conclusions: ISA appears to be a safe and effective option for treating IFD in children, especially when first-line agents have failed or caused excessive toxicity. Although no correlation between Ctrough and clinical outcomes was observed, the significant proportion of patients with out-of-range Ctrough emphasizes the need for TDM in paediatrics.