Children Are Being Left Behind as Antifungal Resistance Gathers Pace, Global Pediatric Group Warns

Invasive fungal diseases are among the most feared infections in modern medicine, and nowhere is the therapeutic arsenal thinner than at the bedside of a sick child. A new analysis from the International Pediatric Association’s Antimicrobial Resistance Working Group, published in Frontiers in Tropical Diseases, lays bare just how precarious the situation has become: of five novel antifungal agents now in late-stage development or newly approved, not one is supported by pediatric clinical efficacy data, and only a single registered pediatric pharmacokinetic study exists across the entire pipeline — a trial that was terminated early after enrolling just two adolescents.

The review, led by Dhanya Dharmapalan of Apollo Hospitals in Navi Mumbai and Zoi Dorothea Pana of the University of Nicosia Medical School, synthesizes trial registry records and published case reports on rezafungin, ibrexafungerp, fosmanogepix, olorofim and opelconazole. The records identified were too few and too heterogeneous to pool statistically, so the team conducted a qualitative synthesis, extracting data on trial phase, design, age eligibility, geographic recruitment and formulation characteristics from ClinicalTrials.gov and PubMed searches conducted in July and August 2025. What emerged is a portrait of a research enterprise that has largely treated children as an afterthought.

The clinical stakes are considerable. Invasive fungal diseases — infections in which fungi invade the blood, sterile body sites or deep organs — carry case-fatality rates that may exceed 40 percent in invasive candidiasis, which alone accounts for an estimated 700,000 cases globally each year. Among very low-birth-weight infants, systemic fungal infection affects up to 9 percent of this fragile population and kills close to a third of those affected. The number of immunocompromised children undergoing chemotherapy or hematopoietic stem cell transplantation continues to rise, and with it the expected incidence of these infections.

Compounding the burden is the steady march of antifungal resistance. In 2022, the World Health Organization released its first Fungal Priority Pathogens List, placing Candida auris, Aspergillus fumigatus, Cryptococcus neoformans and Candida albicans in the critical tier. Three emblematic resistance threats now dominate the landscape: multidrug-resistant C. auris spreading through healthcare settings, azole-resistant A. fumigatus linked in part to environmental azole use in agriculture, and the dermatophyte Trichophyton indotineae with its widespread terbinafine resistance. Climate change is shifting ecological niches and expanding the distribution of rare fungal pathogens, raising the prospect that atypical regional infections will begin appearing in pediatric populations in both high- and low-resource settings.

Pediatric data mirror these global trends with troubling specificity. In the neoOBS study conducted in low- and middle-income countries, 127 neonates with candidaemia were analyzed: 35 percent of isolates were C. albicans, 30 percent were C. parapsilosis and 14 percent were C. auris — and critically, 59 percent of the C. parapsilosis isolates were fluconazole-resistant. In Colombia, a cluster of neonatal C. auris infections at a large referral center underscored diagnostic challenges, and a broader epidemiological study reported 34 pediatric bloodstream infections due to C. auris with an in-hospital mortality of approximately 41 percent, highlighting the organism’s capacity for healthcare-associated cross-transmission.

The neonatal case deserves particular emphasis, the authors argue, because evidence generated in older children simply does not transfer. The epidemiology differs: systemic fungal infection in very low-birth-weight infants has no counterpart in older pediatric cohorts. The species distribution differs: the dominance of fluconazole-resistant C. parapsilosis in neonates would be unusual in older children. And the pharmacology differs most sharply of all — micafungin requires higher weight-based doses in neonates than in older children or adults because clearance is greater, and dissemination to the central nervous system is frequent enough that CNS penetration becomes a primary criterion for agent selection. Neither finding could have been arrived at by extrapolation from older patients.

Against this backdrop, the five novel agents in the pipeline represent genuine scientific progress — but progress that has largely bypassed children. Rezafungin, a next-generation echinocandin with an extended half-life enabling once-weekly intravenous dosing, was approved by both the FDA and EMA in 2023 for adult candidaemia and invasive candidiasis, demonstrating non-inferiority to caspofungin in the phase III ReSTORE trial. Yet its only registered pediatric study, a pharmacokinetic and safety trial spanning birth to under 18 years, was terminated early after enrolling just two adolescents, leaving rezafungin approved for adults alone with no pediatric dosing recommendation in any jurisdiction.

Ibrexafungerp, the first approved member of the triterpenoid class, offers oral activity against azole- and echinocandin-resistant Candida species, but its authorization extends only to postmenarchal female patients with vulvovaginal candidiasis — not to invasive disease, and not to younger girls. Its three phase III trials enrolled females aged 12 and older using adult oral tablets without pediatric dose adaptation. Olorofim, the first orotomide, targets fungal dihydroorotate dehydrogenase through a mechanism distinct from all existing classes and shows potent activity against azole-resistant Aspergillus; it holds Orphan Drug and Breakthrough Therapy designations but remains investigational, obtainable only through trials or expanded-access pathways. Opelconazole, an inhaled triazole designed for high pulmonary deposition with minimal systemic exposure, and fosmanogepix, a first-in-class Gwt1 inhibitor with broad-spectrum activity including against C. auris, likewise remain investigational, with fosmanogepix accessible only through an expanded-access program open to all ages.

Encouragingly, isolated compassionate-use reports demonstrate what is possible. Michel and colleagues described the first pediatric use of olorofim in a 14-year-old with X-linked chronic granulomatous disease and pan-azole-resistant pulmonary aspergillosis, achieving prolonged remission after lobectomy and therapeutic drug monitoring-guided oral therapy. Goggin and colleagues reported fosmanogepix in a 14-year-old with STAT3 hyper-IgE syndrome and invasive fusariosis, with complete lesion resolution and no nephrotoxicity. But across the seven analyzed trial and expanded-access records, only one was designed to include a broad pediatric cohort; the remainder were restricted to adolescents or adults, no phase III program enrolled children younger than 12, formulations were predominantly adult oral tablets, and recruitment was concentrated in North America and Europe with limited participation from sub-Saharan Africa, Southeast Asia and Latin America — regions carrying a disproportionate share of the disease burden.

To close these gaps, the IPA Working Group proposes urgent adoption of an AMR–AFR pediatric ACCELERATE framework, adapted from existing pediatric drug-development instruments and given defined implementation steps and measurable indicators. The framework calls for expanding awareness of pediatric invasive fungal disease burden, prioritizing early inclusion of pediatric cohorts in antifungal development through adaptive platform trials with pediatric arms from inception, investing in child-appropriate formulations such as dispersible tablets and nasogastric-compatible suspensions, strengthening diagnostics and resistance detection through referral laboratories in low- and middle-income countries, integrating real-world data from compassionate-use registries, creating formal mechanisms for early dialogue between pediatric networks, regulators and industry, ensuring geographic and demographic equity in trial enrolment, and harnessing artificial intelligence for population PK/PD modeling and safety signal detection. The authors caution, however, that AI models trained on sparse and heterogeneous pediatric datasets risk overfitting and inherited bias, and that until rigorous validation conditions are met, AI is best understood as a means of prioritizing and designing pediatric studies rather than substituting for them. Without decisive action, the widening lag in pediatric antifungal evidence risks leaving the most vulnerable patients — immunocompromised children and neonates — without effective options as fungal threats intensify worldwide.

Subject of Research: Gaps in pediatric antifungal drug development and resistance amid rising invasive fungal diseases in children and neonates

Article Title: Highlighting gaps in paediatric antifungal drugs: a qualitative synthesis of current data from the International Pediatric Association AMR Working Group

Article References: Highlighting gaps in paediatric antifungal drugs: a qualitative synthesis of current data from the International Pediatric Association AMR Working Group. (n.d.). https://doi.org/10.3389/fitd.2026.1970689

Image Credits: AI Generated

DOI: 10.3389/fitd.2026.1970689

Keywords: antifungal resistance, pediatric infectious diseases, invasive fungal disease, Candida auris, neonatology, drug development, clinical trials, WHO fungal priority pathogens, pharmacokinetics, child-appropriate formulations, low- and middle-income countries, artificial intelligence