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 commitment
Surveillance 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.

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