Plasma and Cerebrospinal Fluid Concentrations of Micafungin Administered at High Doses in Critically Ill Infants with Systemic Candidiasis: A Pooled Analysis of Two Studies

**Background:** Neonates with systemic candidiasis may require higher micafungin doses than adults due to increased plasma clearance, but data on optimal dosing and central nervous system penetration have been limited. Micafungin is the only echinocandin approved by the EMA for neonates and recently by the FDA for infants <4 months, yet dosing uncertainty persists. This pooled analysis aimed to characterize the pharmacokinetics of high-dose micafungin (8–15 mg/kg/day) in neonates and young infants.

**Methods:** Fifty-three neonates (62.3% male; median birth weight 1.30 kg, IQR 2.00–3.84; median gestational age 31 weeks, IQR 28–37) with proven or probable systemic candidiasis were treated with intravenous micafungin at 8–15 mg/kg/day for ≥14 days. Three infants had fungal meningitis with hydrocephalus drained via external shunt. Blood and CSF samples were collected 1 hour before and 1, 2, and 8 hours after infusion end between days 3–10 of therapy. Micafungin concentrations were measured by HPLC. Systemic exposure was assessed by AUC₀–₂₄, plasma clearance (CL), and half-life, stratified by chronological age (<28 days, 28–120 days, >120 days). The probability of target attainment (PTA) was estimated via Monte Carlo analysis using a target AUC ≥170 µg·h/mL from an experimental hematogenous Candida meningoencephalitis model.

**Key Results:** Fungal infection was microbiologically confirmed in 38 cases (71.7%), predominantly Candida albicans (37.7%) and Candida parapsilosis (24.5%). Mean micafungin clearance was higher in neonates <28 days (0.036 L/h/kg) than in infants >120 days (0.028 L/h/kg). Half-life was shorter in neonates <28 days (13.5 h) versus >120 days (14.4 h). CSF micafungin concentrations were measured in 5 assessments from 3 patients; higher doses produced higher CSF concentrations. The mean treatment duration was 16.7 days. Microbiological success was achieved in 83.3% of subjects with invasive candidiasis (95% CI 51.2–97.9), and all infants clinically recovered. One infant with C. parapsilosis required additional amphotericin B liposome. PTA analysis suggested 4–8 mg/kg may be sufficient for Candida spp. with MIC <0.064 mg/L, while 10 mg/kg may be warranted for MICs of 0.064–0.125 mg/L. Five infants (9.4%) died, all born before 27 weeks GA with birth weight <1500 g; deaths were attributed to underlying severe infection, not drug-related. Thirty-four patients (64.2%) had TEAEs; only three TEAEs (5.7%) were considered drug-related but non-serious: one transient hypertransaminasaemia (1.9%) and two transiently increased gamma-glutamyltransferase (3.8%), all resolving after drug discontinuation.

**Clinical Implications:** High-dose micafungin (8–15 mg/kg/day) appears safe and effective in neonates and young infants with systemic candidiasis, achieving therapeutic plasma and CSF concentrations. The higher clearance and shorter half-life in younger infants support the need for weight- and age-adjusted dosing above standard adult-equivalent doses. The drug crosses the blood–brain barrier at these doses, which is critical given that central nervous system involvement occurs in 45–63% of extremely low-birth-weight infants with invasive candidiasis. The transient, non-serious nature of liver enzyme elevations is reassuring, though monitoring remains prudent. These findings support recent FDA and EMA label updates expanding micafungin use to infants <4 months and provide practical dosing guidance, particularly important given the emergence of multidrug-resistant Candida auris in neonatal settings.