Antifungal Stewardship Program Research Articles

Invasive fungal infections (IFIs) are associated with significant morbidity and mortality, especially in immunocompromised and critically ill neonatal and pediatric patients. The challenges in establishing a definite diagnosis of IFIs, the lack of consensus in defining high-risk populations and the variability of pharmacokinetics in children have led to the overuse or misuse of antifungals in pediatrics. Inappropriate use of antifungals entails a substantial risk of toxicity and interactions, along with the emergence of resistance. Therefore, antifungal stewardship (AFS) programs need to be developed and implemented to optimize antifungal use, considering the unique needs of pediatric and neonatal populations. ANTIFUNGAL STEWARDSHIP PROGRAMS FOR PEDIATRIC AND NEONATAL PATIENTS A multidisciplinary team of experts comprising an infectious disease specialist, a clinical pharmacist, a microbiologist and a physician involved in antifungal prescription is essential to address the particularities of IFI epidemiology and antifungal use in this vulnerable population. The main principles of AFS can parallel antimicrobial stewardship programs, focusing on improving clinical outcomes by optimizing antifungal use, reducing healthcare costs and preventing the emergence of resistance. A consensus protocol (in the form of guidance and policy), including recent international evidence-based guidelines and local epidemiology, can be created by this expert team to ensure optimization of antifungal use. Practice of antifungal guidelines and their implementation should be the first step in the AFS roadmap (Table 1). TABLE 1. - Targeted Antifungal Stewardship Activities for Neonatal and Pediatric Patients Structure of AFS (System Prerequisites) Team:• Desired expertise in pediatric fungal infections. Leadership commitmentSurveillance systems including IT for tracking and reporting of• Antifungal prescribing: target indications for antifungal prophylaxis and combination antifungal therapy• Adherence to polices and guidelines (what) and audit and feedback (how)• Specific AFS outcome metrics: incidence of Invasive fungal infections (IFI), IFI associated morbidity and mortality AFS activities General• Written policies and guidelines for antifungal use and education ○ Local, national or international• Strategy: Audits and feedback on specific areas of antifungal use ○ Target antifungal indications where more clinical data are available (dose, length of therapy, toxicity)Tailored audits and opportunities for AFS implementation at department level• Neonatal ICUs: ○ Neonatal antifungal prophylaxis ○ Neonatal candidiasis ▪ When and why to start empiric Treatment• Pediatric oncology departments: ○ Antifungal prophylaxis: define risk factors ○ Promote diagnostic-driven treatment ○ Compliance with local/international guidelines for empiric Treatment of Febrile Neutropenia AFS implementation activities Identification of determinants of antifungal prescribing practices• Capacity for organizational change (ie, facilitate AFS activities)• Incentives and resources (ie, dedicated team and surveillance activities)• Guidelines factor (ie, Written policies and standard of procedures for fungal infections)• Individual health professional factors or professional interactions (i.e., multidisciplinary AFS team)• Patient factors (ie, compliance with written guidelines for risk factors)• Social, political and legal factors (ie, AFS program fully supported by institutional administration)Implementation of behavioral change activities in parallel to AFS education Strategies incorporating prior authorization and/or postprescription review and feedback in accordance with the updated 2016 Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America guidelines may be useful.1 Although stringent antifungal policies with formulary restrictions and clinical audits may be time-consuming, they constitute the core components of an effective AFS.2 Clinical audits are a useful means to highlight fields that require attention. Provision of educational programs, prescription evaluation and raising awareness of the proper use of antifungal agents are effective interventions to rationalize and optimize antifungal therapy. Efforts to achieve optimal antifungal use can be evaluated by observing the selection and duration of therapy, using quality indicators. Among volume-based metrics, days of therapy are recommended for monitoring drug consumption, whereas defined daily doses (DDDs) can be an alternative tool, although the latter is not as appropriate for young patients in whom the doses are based on the size of the patient. Moreover, in certain antifungal medications, such as fluconazole, itraconazole and amphotericin B formulations, DDDs can lead to overestimation of their use and can also be less accurate in patients with renal or hepatic insufficiency requiring dose adjustment.3 Although quantitative data are relatively simple to obtain, they do not reflect the appropriateness of prescriptions. Although healthcare-associated IFIs are truly opportunistic infections, they are rare in patients without significantly impaired immunity. AFS programs should predominantly focus on patients in Pediatric Hematology-Oncology (PHO) departments and hematopoietic stem cell transplantation (HSCT) units as well as those in pediatric and neonatal intensive care units.4 Therefore, when implementing an antifungal stewardship program, training and consultative efforts should be aimed at departments with the largest numbers of prescriptions to monitor common prescribing errors and to recognize prevailing practices. Enhancement of judicious antifungal prescriptions improves clinical outcomes and secondarily minimizes unnecessary healthcare costs. To achieve this goal and adequately treat patients with IFIs for which there are few agents with clinical efficacy, antifungal susceptibility testing should be more widely available than it currently is. AFS IN UNITS WITH IMMUNOCOMPROMISED PEDIATRIC PATIENTS The populations most vulnerable to IFIs include pediatric patients with hematologic malignancies, HSCT and recipients of solid organ transplants (SOT). The extensive use of recently approved immunomodulatory therapies, such as CAR T-cell therapy, as well as newer chemotherapeutic drugs, such as tyrosine kinase inhibitors, indicated for pediatric patients, broadens the spectrum of patients at potential risk of developing IFIs.5 Although the term “high risk” is not always clearly defined, it is recommended that patients undergoing HSCT, those with acute myeloid leukemia (AML), or certain patients with acute lymphoblastic leukemia (ALL) (relapsed or refractory ALL) be considered at high risk for IFIs. Moreover, other clinical and laboratory factors that should also be considered include prolonged and profound neutropenia despite underlying malignancy, type of HSCT, steroid exposure, indwelling central venous catheter, parenteral nutrition and prolonged use of broad-spectrum antibiotics. Environmental factors, such as proximity to construction work, are predisposing factors, especially for the development of invasive aspergillosis. The most common indication for administering systemic antifungal medication across European pediatric hematology-oncology or bone marrow/SOT units, as revealed by the CALYPSO study, is prophylaxis.6 Primary antifungal prophylaxis is generally recommended for patients at high risk of IFIs, although specific guidelines issued by the IDSA and the European Conference on Infections in Leukemia (ECIL) for FN in children with cancer are not uniform.7,8 The expert panel of the IDSA does not clearly differentiate between adult and pediatric patients. However, pediatric-specific ECIL recommendations are based on randomized trials in adults, pediatric pharmacokinetics and safety data and regulatory approval of the appropriate doses. The leading causes of IFIs in children with pediatric malignancies include yeasts, such as Candida species, Aspergillus species and Mucorales. Prophylactic strategies generally use azole-based regimens, mainly fluconazole for low-risk patients and posaconazole, itraconazole or voriconazole with therapeutic drug monitoring (TDM) for high-risk patients. In leukemia patients, neurotoxicity impacts and narrows the therapeutic index of azoles, especially voriconazole. Therefore, alternative prophylactic schemes using echinocandins (caspofungin) or liposomal amphotericin B (L-AmB) have been described.9 In the future, oral or weekly intravenous administration of active antifungals may be a better solution. All 3 echinocandins and L-AmB are recommended and approved as empirical therapy for persistent febrile neutropenia and treatment of candidemia and invasive aspergillosis, respectively.10 Although challenging, the pre-emptive approach may be considered an alternative to empirical therapy in pediatric patients, leading to decreased antifungal exposure. Real-time surveillance of the evolving epidemiology of IFIs in pediatric oncology patients is an important tool for developing an effective prophylactic strategy. Confronted with the dilemma of the most suitable approach, the choice of the appropriate regimen should incorporate information of modifiers, such as the local epidemiology, comorbidities, toxicity profile and specific treatment modalities. Although antifungal drug combinations (AFCs) may be appealing for pediatric oncologists striving to improve the dismal outcomes among patients with IFIs, these approaches have not been broadly studied in clinical settings where host factors may greatly impact the final efficacy and pharmacokinetic disposition of drugs. Discordant results were yielded when AFC were studied in vivo, and antagonism among antifungal agents might occur. Infectious disease specialists play an important role in guiding and reminding prescribing doctors that CAF may increase potential for drug interactions and drug toxicities without proven clinical benefit. The use of CAF should be considered in unique settings such as refractory mucormycosis or salvage therapy for invasive aspergillosis, still with marginal strength recommendation. Only in cryptococcosis, CAF is well established and based on significant evidence. Until more core concrete evidence on CAF is available, caution is warranted when employing these strategies. NEONATAL CRITICALLY ILL PATIENTS Antifungal agents are frequently used in neonates for both the prophylaxis and treatment of IFIs. Invasive candidiasis is the leading IFI in this population and has been associated with high morbidity and mortality in this vulnerable population. Neonatal antifungal prophylaxis is a common strategy used in NICUs, mainly for high-risk neonates such as those with extremely low birth weight (ELBW). A recent study conducted in 12 centers in England found that systemic antifungal agents were prescribed in up to one-fifth of neonates admitted to neonatal wards.11 Almost 8 of 10 prescriptions were indicated as antifungal prophylaxis. A similarly high prevalence of antifungal prophylaxis was documented in a multicenter European study with 26 participating NICUs.12 In both studies, ELBW premature neonates constituted less than half of all the cases of antifungal prophylaxis. This could be a target for AFS and assess opportunities for the improvement of antifungal prophylaxis in NICUs. Current data on the appropriateness and benefits of neonatal antifungal prophylaxis suggest a more optional, customized and risk-based approach in NICUs.13 Fluconazole is the most used antifungal agent for both prophylaxis and treatment of neonates.12 However, significant variability in fluconazole dosing has been documented in several neonatal studies, and this could be another reasonable AFS opportunity for NICUs. In addition, neonatal AFS programs should encourage surveillance of local susceptibility patterns for fungal pathogens, especially when antifungal prophylaxis is recommended.11 Current evidence on the association between the use of antifungal prophylaxis in neonates and subsequent development of antifungal resistance is hampered by differences in local fungal epidemiology and study methodologies (ie, sample size).13 IMPROVING DIAGNOSTICS AND ANTIFUNGAL THERAPEUTIC DRUG MONITORING: TWO MAJOR CAPACITIES TO INCORPORATE AFS ACTIVITIES The absence of microbiological data limits opportunities to discontinue or de-escalate antifungals, contributing to prolonged courses of antifungal agents. Although intensive stewardship practices may be more effective in decreasing antibiotic utilization, it is unknown whether they are effective in restricting unnecessary antifungal exposure. Since the pathogen is not often identified in cultures, empiric treatment is the main treatment strategy. Although blood culture is the gold standard for de-escalation of therapy, it is time-consuming. The need for rapid results is of utmost importance in the effort to shift from empiric to pre-emptive antifungal treatment, which is a diagnostic-driven approach. Restraining empirical antifungal use relies mainly on the improvement of diagnostics. Close cooperation with clinical microbiology can ensure the utilization of rapid molecular identification methods, including matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) spectrometry, multiplex polymerase chain reaction and peptide nucleic acid fluorescent in situ hybridization for Candida and Aspergillus. Rapid molecular identification, when available, and nonculture-based diagnostics as a surrogate for culture data are valuable tools. Noninvasive fungal markers, such as serum galactomannan (GM) enzyme immunoassay (EIA), 1,3 β-D glucan (BDG) assays and fungal PCR, together with computed tomography and/or magnetic resonance tomography, exhibit excellent negative predictive values when invasive aspergillosis is excluded. Recent studies provide evidence that surveillance testing with GM EIA and BDG alone or in combination during periods of neutropenia, especially if patients are receiving antifungal prophylaxis, may not be necessary.14 The pediatric population shows pharmacokinetic and pharmacodynamic variability, which affects the target therapeutic levels. Therapeutic drug monitoring (TDM) of azole medications is important for mitigating adverse events and optimizing antifungal usage. A pharmacokinetic program with expert guidance from pharmacists or AFS members is an important strategy for AFS programs. Documentation of the dose optimization strategy for each antifungal agent using TDM may facilitate the timely attainment of therapeutic concentrations and overcome interpatient variability. Moreover, knowledge of azole resistance could counteract azole antifungals as a first-line choice for invasive candidemia given the emerging antifungal resistance of Candida spp. Among pediatric patients with malignancy, Candida albicans is the most prevalent colonizer, and azoles remain the most effective choice when used wisely. Especially in immunocompromised patients, susceptibility patterns may change over time, necessitating continuous surveillance of colonization patterns. CONCLUSION The development and validation of an effective AFS is challenging and entails the complexity of diagnosis, nonspecificity of clinical presentation and emergence of resistance in the context of the lack of new antifungal drugs in development.

The past 2 decades have seen a considerable increase in both the number and relevance of invasive fungal diseases in immunocompromised and critically ill pediatric patients of all age groups. At the same time, major advances have been made in our knowledge of the biology of fungal diseases, the recognition of patients at risk, the microbiological detection, and imaging modalities, the algorithms of antifungal interventions, and the design and implementation of clinical trials. Most importantly, however, several new antifungal agents of different classes have become available for children and have made antifungal therapy safer and more effective but also more complicated.1,2 Consequently, a thorough updated understanding of the available antifungal armamentarium is essential for its judicious use and the successful management of individual patients. This article reviews the clinical trials that led to the recent pediatric approval of anidulafungin and posaconazole and their respective indications, provides an update on the pediatric development of isavuconazole and very briefly presents 4 new antifungal agents that are in clinical development. ANTIFUNGAL TRIAZOLES The antifungal triazoles have become an essential component of the antifungal armamentarium. They are acceptably well tolerated, possess a broad spectrum of activity and have demonstrated clinical efficacy under many circumstances. The triazoles function by inhibiting the cytochrome P450 dependent conversion of lanosterol to ergosterol, which leads to altered membrane properties and inhibition of cell growth and replication. Whereas fluconazole, itraconazole and voriconazole have been available to pediatric patients for most of the past 2 decades, posaconazole has been approved for children only in the past year, and the pediatric development of isavuconazole is still ongoing.2 Posaconazole Posaconazole is a lipophilic antifungal triazole with potent and broad-spectrum activity against opportunistic, endemic and dermatophytic fungi in vitro. The compound has a large volume of distribution in the order of 5 L/kg and a prolonged elimination half-life of approximately 20 hours. Posaconazole is not metabolized through the cytochrome P450 enzyme system but primarily excreted in unchanged form in the feces. It is inhibitory against cytochrome P3A4 but has no effects on 1A2, 2C8, 2C9, 2C19, 2D6 and 2E1 isoenzymes, and therefore, a limited spectrum of drug-drug interactions. The compound is overall well tolerated, with gastrointestinal disturbances, headaches and elevated hepatic transaminases being the most frequently reported adverse events (AEs).2 Important indications approved for adults include antifungal prophylaxis in high-risk patients with hematologic malignancies and patients with graft versus host disease post allogeneic hematopoietic cell transplantation and, since 2021, the use for first-line treatment of invasive aspergillosis. Posaconazole is available as an intravenous (i.v.) solution in sulfobutylether-β-cyclodextrin and 3 different oral formulations (oral suspension, gastro-resistant/delayed release tablets and a novel gastro-resistant/delayed-release powder for oral suspension [PFS]). Posaconazole was first approved in adults in 2006 in the form of the oral suspension. In 2007, a pediatric multicenter sequential dose-escalation trial of the pharmacokinetics (PKs) and safety of the oral suspension was initiated. Enrolled subjects were divided into 3 age groups and 3 dosage cohorts and received 7–28 days of posaconazole with systematic PK sampling. The dosing target was predefined as ~90% of subjects with mean steady state plasma concentrations (Cavg; area under the concentration [AUC]/dosing interval) between 500 and 2500 ng/mL, with an anticipated Cavg of ~1200 ng/mL. Unfortunately, despite dosages as much as 18 mg/kg/d 3 times daily, the percentage of subjects meeting the PK target was <90% across all age groups and dosage cohorts (range: 31–80%). The study was discontinued after 8 years in 2015. The lack of a dose-exposure relationship and high variability in exposures were likely because of absorption properties of the oral suspension.3 After the introduction of the i.v. solution and the gastro-resistant/delayed-release tablets with improved oral bioavailability in adults, a novel pediatric gastro-resistant/delayed-release PFS was developed and subsequently investigated with the i.v. solution in an open-label, sequential dose-escalation, phase 1b trial in children 2–17 years of age with documented or expected neutropenia.4 Participants received posaconazole i.v. at 3.5, 4.5 or 6.0 mg/kg/d for ≥10 days, with an option to switch to posaconazole PFS at the identical dose for ≤ 18 days. In this study, i.v. dosages of 4.5 and 6.0 mg/kg/d achieved the target exposure of ~90% of participants with a Cavg ≥ 500 ng/mL and Cavg of ~1200 ng/mL. Both posaconazole i.v. and PFS were well tolerated and had safety profiles similar to those reported for adults: 4 of 115 evaluable patients (3.5%) discontinued the study drug because of drug-related AEs; no correlation between drug-related AEs and exposure were observed.4 Based on the results of this pivotal dose-finding trial, posaconazole was approved by both Food and Drug Administration and European Medicines Agency in 2021 for pediatric patients 2 years and older for prophylaxis of invasive fungal diseases in high-risk patient populations (Table 1). Of note, pending completion of a phase II clinical trial in pediatric patients >2 years, approval for first-line treatment of invasive aspergillosis has been deferred. In addition, a phase I/II trial of safety and PKs of i.v. and PFS in neonates, infants and young children <2 years with proven/probable IFDs is part of the agreed commitments of the pediatric investigation plan (PIP), and pending its completion, approval of the compound in this population may be expected at some point in the future. TABLE 1. - Compounds, Formulations, Dosages and Clinical Indications Approved or Targeted for Approval in Pediatric Patients Antifungal Agent (Brand Name) Formulation Adult Dose Pediatric Dosage Approved or Targeted Pediatric Indications Posaconazole (Noxafil®) Posaconazole intravenous solution delayed-release tablets oral suspension powder for delayed release oral suspension 300 mg once daily (day 1: twice daily)300 mg once daily (day 1: twice daily)200 mg three times daily (≥ 13 yr [FDA])Not approved ≥ 2 yr old:6 mg/kg once daily (maximum 300 mg; day 1: twice daily)>40 kg: 300 mg once daily (day 1: twice daily)Not approved (EMA)≤40 kg: weight-based once daily dosing (day 1: twice daily). For details, see SPC. Prophylaxis in high-risk patients receiving remission-induction chemotherapy for AML or MDS expected to result in prolonged neutropenia, and HSCT recipients who are undergoing high-dose immunosuppressive therapy for GVHD (EMA)/Prophylaxis of invasive Aspergillus and Candida infections in high risk patients including HSCT recipients with GVHD or those with hematologic malignancies with prolonged neutropenia from chemotherapy (FDA).Treatment of invasive aspergillosis (EMA/FDA; targeted). Anidulafungin (U.S.: Eraxis®; E.U.: Ecalta®) Anidulafungin intravenous solution 100 mg once daily (day 1: 200 mg) ≥ 1 mo old:1.5 mg/kg (not to exceed 100 mg) of anidulafungin once daily (day 1: 3.0 mg/kg; not to exceed 200 mg) Treatment of invasive candidiasis (EMA)/Treatment of candidemia and other forms of Candida infections (intra-abdominal abscess and peritonitis) (FDA). Investigational: Isavuconazole (Cresemba®) Isavuconazonium sulfate oral capsules intravenous solution 372 mg isavuconazonium sulfate (equivalent to 200 mg of isavuconazole) once daily (days 1 and 2: three times daily) ≥ 1 yr old:10 mg/kg of isavuconazonium sulfate once daily (days 1 and 2: three times daily); investigational Treatment of invasive aspergillosis (EMA/FDA); targeted.Treatment of invasive mucormycosis (FDA) in patients for whom amphotericin B is inappropriate (EMA); targeted. AML indicates acute myelogenous leukemia; EMA, European Medicines Agency; FDA, Food and Drug Administration; GVHD, graft versus host disease; HSCT, hematopoietic stem cell transplant; MDS, myelodysplastic syndromes; SPC, summary of product characteristics. Isavuconazole Isavuconazole, administered as the water-soluble prodrug isavuconazo-nium sulfate, is an i.v. and oral antifungal triazole approved since 2015 in adults for first-line treatment of invasive aspergillosis and treatment of mucormycosis. The compound has a broad spectrum of antifungal activity, linear PKs, a long half-life and high oral bioavailability. Its interaction and safety profile are similar to those of other triazoles with advantages in reduced hepatotoxicity, visual effects and neurotoxicity in direct comparison with voriconazole.2 Based on a population PK model developed in adults, allometric scaling and Monte-Carlo simulations, a dosage of 10 mg/kg isavuconazonium sulfate (maximum 372 mg), administered i.v. every 8 hours for the first 2 days (loading doses) and once daily thereafter (maintenance dose), was predicted to likely result in adequate steady/state exposures in pediatric patients 2–17 years of age.5 The PKs and safety of this dosage regimen were subsequently studied in an age-stratified phase 1 clinical trial in 46 immunocompromised pediatric patients after either i.v. or oral dosing. Using population PK and stepwise covariate modeling, no covariates with significant effects on PK parameters could be identified. Prediction of the AUC time curve at steady state by Monte Carlo simulations and assessment of the probability of target attainment (AUC time curve at steady state range, 60–233 ug·h/mL) revealed predicted plasma drug exposures within the target range observed in adults for >80% and >76% of simulated pediatric patients after i.v. or oral administration, respectively. Administration of isavuconazonium sulfate at the studied dosage of 10 mg/kg was well tolerated with AEs leading to study drug discontinuation in 5 patients.5 A phase 2 multicenter study is currently under way to evaluate the safety, efficacy and PKs of isavuconazonium sulfate for treatment of invasive aspergillosis or mucormycosis in pediatric subjects ≥1 years of age (9766-CL-0107) as part of the agreed commitments of the PIP of the compound. Development in patients from birth to less than 1 year of age has been waived on the grounds that the compound may not represent a significant therapeutic benefit over existing treatments in this population. ECHINOCANDIN LIPOPEPTIDES The echinocandins are a distinct class of semisynthetic amphiphilic lipopeptides that act by inhibiting the synthesis of (1→3)-β-D-glucan of the cell wall of pathogenic fungi. This homopolysaccharide provides osmotic stability and is important for cell growth and cell division. Currently, 3 i.v. echinocandins with extended antifungal spectrum against Candida and Aspergillus spp., very favorable safety profile and PK characteristics are available: anidulafungin, caspofungin and micafungin. The accumulated data indicate that these agents are not fundamentally different from each other with respect to their antifungal or pharmacodynamic properties. However, they are distinct in their metabolism and excretion. Apart from invasive candidiasis, they also have slightly different indications.2 Whereas caspofungin and micafungin are approved in pediatric patients of all age groups for several years, the pediatric development of anidulafungin has been completed only recently. Anidulafungin Anidulafungin has been licensed in the United States and in the European Union since 2006 in patients ≥18 years of age for primary therapy of candidemia, other forms of invasive Candida infections and for esophageal candidiasis. The compound has linear and stable PKs, a long half-life allowing for once daily dosing, is eliminated by slow chemical degradation in plasma, does not interact to a relevant extent with CYP450 isoenzymes and is generally very well tolerated without specific safety concerns. Data from early studies in pediatric patients revealed that after body weight-based dosing, PK parameters are similar across age groups and dosage cohorts and similar relative to adult subjects. In a phase I/II multicenter sequential dose escalation study of the PKs and safety of anidulafungin in 19 granulocytopenic children of 2 age cohorts (2–11 and 12–17 years), no drug-related serious AEs were recorded. After single and multiple daily doses of 0.75 and 1.5 mg/kg, plasma concentration data corresponded to those in adults following a daily 50 and 100 mg dose, respectively.6 In a second phase I/II study, i.v. anidulafungin was administered to 15 infants and neonates over 3–5 days. Neonates and infants receiving 1.5 mg/kg/d had similar exposure levels with children receiving similar weight-based dosing and adult patients receiving 100 mg/d. No drug-related serious AEs were observed.7 In a subsequent pooled population, PK analysis including data from these and 2 further studies across a full range of adult and pediatric ages estimated systemic anidulafungin exposures were similar across age groups (neonates to adults) at the weight-based doses studied in pediatric patients. No clear associations were identified between anidulafungin exposure and efficacy or safety end points.8 The efficacy and safety of i.v. anidulafungin were later studied in a prospective, noncomparative multicenter study of first-line therapy of invasive candidiasis including candidemia in 49 pediatric patients 2 to <18 years old. Patients received anidulafungin for 10–35 days at a dosage of 1.5 mg/kg (day 1: 3 mg/kg). Efficacy, measured by global (clinical and microbiologic) response, was assessed at end of i.v. treatment (EOIVT), end of treatment, weeks 2 and 6 follow-up, while safety was measured through week 6 follow-up. All patients reported ≥1 treatment-emergent AE, with gastrointestinal disturbances and pyrexia being most frequent. Four patients discontinued treatment because of AEs considered related to anidulafungin. All-cause mortality was 8.2% by EOIVT and 14.3% by week 6 follow-up. None of the 7 deaths during the study period was considered treatment related. Global response success rate was 70.8% at EOIVT.9 In 19 additional patients (1 month to <2 years of age with [ = 16] or at high risk of [n = 3]) with invasive candidiasis who were enrolled in the same trial but published separately, most treatment-emergent AEs were mild or moderate, and no treatment-related deaths occurred. EOIVT global response rate was 68.8%.10 Based on these data, anidulafungin was approved in 2020 by both Food and Drug Administration and European Medicines Agency for treatment of invasive candidiasis in pediatric patients aged 1 month to <18 years. A waiver has been issued to study neonates because of need for 2–3 times increased dosages to cover hematogenous Candida meningoencephalitis and the potential toxicity of the polysorbate-80 solvent in this population. NEW ANTIFUNGAL AGENTS IN DEVELOPMENT New populations at risk, the emergence of resistance and limitations of existing antifungal agents warrant a continuous search for more antifungal drug options. Whereas no new class has been licensed during the last 2 decades, and only 1 single new agent from a known antifungal class has been approved in the last decade, several new antifungal compounds are currently in late-stage clinical development. These include rezafungin (a stabilized form of anidulafungin with an extended half-life dosed once weekly), ibrexafungerp (a first-in-class oral and i.v. triterpenoid targeting (1→3)-β-D-glucan synthesis with limited cross-resistance to echinocandins), fosmanogepix (a novel oral and i.v. Gwt1 enzyme/glycosylphosphatidylinositol anchor protein inhibitor with broad antifungal spectrum) and olorofim (a novel oral and i.v. inhibitor of dihydroorotate dehydrogenase involved in pyrimidine synthesis with broad activity against filamentous and dimorphic fungi).11,12 PIPs exist for all of these compounds, and pediatric phase I/II clinical trials are in advanced stages of planning. One may therefore expect that these compounds may complement our antifungal armamentarium within the next 5–10 years. CONCLUSIONS Over the past 3 decades, major advances have been made in the field of medical mycology. Most importantly, an array of new antifungal agents has entered the clinical arena. While the pediatric development of some of these agents was tedious, all except isavuconazole now have a pediatric label. As invasive fungal diseases remain important causes for morbidity and mortality in immunocompromised and critically ill pediatric patients, the availability of alternative therapeutic options is essential for improving outcome. At the same time, however, antifungal management has become increasingly complex and calls for comprehensive antifungal stewardship programs in pediatric centers that provide care for patients at risk.

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