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In recent years, the global public health community has increasingly recognized the importance of antimicrobial stewardship (AMS) in the fight to improve outcomes, decrease costs, and curb increases in antimicrobial resistance around the world. However, the subject of antifungal stewardship (AFS) has received less attention. While the principles of AMS guidelines likely apply to stewarding of antifungal agents, there are additional considerations unique to AFS and the complex field of fungal infections that require specific recommendations. In this article, we review the literature on AMS best practices and discuss AFS through the lens of the global core elements of AMS. We offer recommendations for best practices in AFS based on a synthesis of this evidence by an interdisciplinary expert panel of members of the Mycoses Study Group Education and Research Consortium. We also discuss research directions in this rapidly evolving field. AFS is an emerging and important component of AMS, yet requires special considerations in certain areas such as expertise, education, interventions to optimize utilization, therapeutic drug monitoring, and data analysis and reporting., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Importance: Children, adolescents, and young adults with acute myeloid leukemia are at high risk of life-threatening invasive fungal disease with both yeasts and molds., Objective: To compare the efficacy of caspofungin vs fluconazole prophylaxis against proven or probable invasive fungal disease and invasive aspergillosis during neutropenia following acute myeloid leukemia chemotherapy., Design, Setting, and Participants: This multicenter, randomized, open-label, clinical trial enrolled patients aged 3 months to 30 years with newly diagnosed de novo, relapsed, or secondary acute myeloid leukemia being treated at 115 US and Canadian institutions (April 2011-November 2016; last follow-up June 30, 2018)., Interventions: Participants were randomly assigned during the first chemotherapy cycle to prophylaxis with caspofungin (n = 257) or fluconazole (n = 260). Prophylaxis was administered during the neutropenic period following each chemotherapy cycle., Main Outcomes and Measures: The primary outcome was proven or probable invasive fungal disease as adjudicated by blinded central review. Secondary outcomes were invasive aspergillosis, empirical antifungal therapy, and overall survival., Results: The second interim efficacy analysis and an unplanned futility analysis based on 394 patients appeared to have suggested futility, so the study was closed to accrual. Among the 517 participants who were randomized (median age, 9 years [range, 0-26 years]; 44% female), 508 (98%) completed the trial. The 23 proven or probable invasive fungal disease events (6 caspofungin vs 17 fluconazole) included 14 molds, 7 yeasts, and 2 fungi not further categorized. The 5-month cumulative incidence of proven or probable invasive fungal disease was 3.1% (95% CI, 1.3%-7.0%) in the caspofungin group vs 7.2% (95% CI, 4.4%-11.8%) in the fluconazole group (overall P = .03 by log-rank test) and for cumulative incidence of proven or probable invasive aspergillosis was 0.5% (95% CI, 0.1%-3.5%) with caspofungin vs 3.1% (95% CI, 1.4%-6.9%) with fluconazole (overall P = .046 by log-rank test). No statistically significant differences in empirical antifungal therapy (71.9% caspofungin vs 69.5% fluconazole, overall P = .78 by log-rank test) or 2-year overall survival (68.8% caspofungin vs 70.8% fluconazole, overall P = .66 by log-rank test) were observed. The most common toxicities were hypokalemia (22 caspofungin vs 13 fluconazole), respiratory failure (6 caspofungin vs 9 fluconazole), and elevated alanine transaminase (4 caspofungin vs 8 fluconazole)., Conclusions and Relevance: Among children, adolescents, and young adults with acute myeloid leukemia, prophylaxis with caspofungin compared with fluconazole resulted in significantly lower incidence of invasive fungal disease. The findings suggest that caspofungin may be considered for prophylaxis against invasive fungal disease, although study interpretation is limited by early termination due to an unplanned interim analysis that appeared to have suggested futility., Trial Registration: ClinicalTrials.gov Identifier: NCT01307579.

Purpose To update a clinical practice guideline (CPG) for the empirical management of fever and neutropenia (FN) in children with cancer and hematopoietic stem-cell transplantation recipients. Methods The International Pediatric Fever and Neutropenia Guideline Panel is a multidisciplinary and multinational group of experts in pediatric oncology and infectious diseases that includes a patient advocate. For questions of risk stratification and evaluation, we updated systematic reviews of observational studies. For questions of therapy, we conducted a systematic review of randomized trials of any intervention applied for the empirical management of pediatric FN. The Grading of Recommendation Assessment, Development and Evaluation approach was used to make strong or weak recommendations and to classify levels of evidence as high, moderate, low, or very low. Results Recommendations related to initial presentation, ongoing management, and empirical antifungal therapy of pediatric FN were reviewed; the most substantial changes were related to empirical antifungal therapy. Key differences from our 2012 FN CPG included the listing of a fourth-generation cephalosporin for empirical therapy in high-risk FN, refinement of risk stratification to define patients with high-risk invasive fungal disease (IFD), changes in recommended biomarkers and radiologic investigations for the evaluation of IFD in prolonged FN, and a weak recommendation to withhold empirical antifungal therapy in IFD low-risk patients with prolonged FN. Conclusion Changes to the updated FN CPG recommendations will likely influence the care of pediatric patients with cancer and those undergoing hematopoietic stem-cell transplantation. Future work should focus on closing research gaps and on identifying ways to facilitate implementation and adaptation.

Background: Invasive fungal infections cause significant morbidity and mortality for children with acute myeloid leukemia (AML). Data on the comparative effectiveness of antifungal prophylaxis in this population are limited., Methods: A pediatric AML cohort was assembled from the Pediatric Health Information System database using ICD-9 codes and pharmacy data. Antifungal prophylaxis status was determined by pharmaceutical data review within 21 days of starting induction chemotherapy. Patients were followed until end of induction, death, or loss to follow-up. Cox regression analyses compared induction mortality and resources utilized between patients receiving and not receiving antifungal prophylaxis. A propensity score accounted for variation in demographic factors, location of care, and severity of illness at presentation., Results: Eight hundred seventy-one AML patients were identified; the induction case fatality rate was 3.7%. In the adjusted Cox regression model, patients receiving antifungal prophylaxis (57%) had a decreased hazard for induction mortality (hazard ratio [HR], 0.42; 95% confidence interval [CI], .19-.90). Children receiving prophylaxis were less frequently exposed to broad-spectrum gram-positive (incidence rate ratio [IRR], 0.87; 95% CI, .79-.97) and antipseudomonal β-lactam agents (HR, 0.91; 95% CI, .85-.96), had fewer blood cultures (IRR, 0.78; 95% CI, .71-.86), and had fewer chest CT scans (IRR, 0.73; 95% CI, .60-.88)., Conclusions: Antifungal prophylaxis in pediatric AML patients was associated with reduced induction mortality rates and supportive care resources. Further investigation is necessary to determine whether antifungal prophylaxis should include antimold activity.

Seriously ill or immunocompromised children are at increased risk of invasive fungal infections, particularly candidemia. Candida albicans and Candida parapsilosis are the two most frequent causes of candidemia in pediatric patients. Candidemia in children is associated with high morbidity and mortality, increased length of hospital stays, and higher healthcare costs. Early effective antifungal therapy is the key to improved outcomes. Risk factors for candidemia may be used to identify patients suitable for empiric therapy. Such risk factors include prolonged stay in an intensive care unit, immunosuppression, prior bacterial infection, and recent surgery, as well as the use of a central venous catheter, mechanical ventilation, and/or total parenteral nutrition. Recent guidelines from the Infectious Diseases Society of America recommend consideration of fluconazole or an echinocandin for empiric therapy in suitable candidates, with a preference for an echinocandin in patients with moderate-to-severe disease, recent azole exposure, or high risk of Candida glabrata or Candida krusei infection. Fluconazole or an echinocandin is also preferred initial therapy for non-neutropenic candidemia, depending on disease severity and other characteristics. The guidelines recommend treatment with an echinocandin or lipid formulation of amphotericin B for most patients with neutropenic candidemia, although fluconazole is identified as an alternative for less critically ill patients without recent azole exposure. Risk factors for candidemia - and, hence, criteria for prophylaxis - are less well established in older children than in neonates. Further research is needed to better establish criteria for antifungal prophylaxis in children at high risk for candidemia.

We analyzed the caspofungin safety experience in 5 clinical registration studies in 171 pediatric patients, 1 week to 17 years of age. Caspofungin was administered for 1 to 87 (mean 12.1) days. The most common drug-related adverse events were fever, increased AST, increased ALT, and rash; few events were serious or required treatment discontinuation. Caspofungin was well tolerated in this pediatric population.

Background: Acute increases in serum inorganic phosphorus (Pi) up to 4.75 mmol/l in the absence of hypocalcemia and tissue deposition of calcium phosphate were noted in 3 patients receiving liposomal amphotericin B (L-AMB). We investigated L-AMB as a possible cause of pseudohyperphosphatemia., Methods: Serum samples from the index patient were analyzed for Pi content by our laboratory's primary analyzer (Synchron LX20) and by an alternate analyzer (Vitros). Clear and lipemic serum pools, and normal saline, were spiked with L-AMB and analyzed by the LX20 Pi method. Ultrafiltration studies were performed on patient and spiked sera., Results: Increased Pi values were obtained only from the LX20 analyzer. There was a direct linear relationship between the concentration of L-AMB in the spiked samples and the LX20 Pi results, indicating a 0.9 mmol/l Pi increase for every 100 mg/l increase in L-AMB. Ultrafiltration normalized the Pi results., Conclusion: Serum Pi results may be falsely increased in patients receiving L-AMB when measured by the LX20 analyzer. This novel cause of pseudohyperphosphatemia is due to interference of L-AMB with the method and is corrected by ultrafiltration of the specimen. Since the LX20 analyzer is widely used by the clinical laboratories clinicians and laboratory personnel should recognize this interference in order to avoid unnecessary diagnostic procedures and interventions.

Purpose of Review: This review focuses on recent data regarding antifungal prophylaxis and antifungal treatment of neonatal candidiasis., Recent Findings: Candida species are the leading cause of invasive fungal infection in the neonatal intensive care unit, and are the third most common blood culture isolates recovered from cases of late-onset sepsis in the neonatal intensive care unit. Neonatal candidemia is associated with significant morbidity and mortality. Risk factors for neonatal candidiasis have been elucidated, and prophylaxis of high-risk infants has been found to be effective, particularly in neonatal intensive care units with a high incidence of candidemia. Amphotericin B has been the mainstay of antifungal therapy for candidemia in the neonatal intensive care unit but newer agents such as echinocandins and azoles are currently being evaluated., Summary: Neonatal candidiasis is a serious infection especially in extremely low-birthweight infants and prophylaxis has been shown to be effective in preventing candidiasis in high-risk infants. Newer pharmacokinetic, safety and efficacy data for both older and newer antifungal agents are emerging in neonates, and these data may help us achieve more effective management of neonatal candidiasis.