774 - Comparative Safety of Fluconazole Loading Dose Regimens in Infants

In the extremely premature infant, invasive candidiasis (IC; positive culture from normally sterile body fluid) is common and often fatal. Fluconazole is first line therapy for IC and a loading dose is commonly used in adults with IC. The safety of fluconazole loading dose in infants has not been described.

Objective:

To evaluate the safety of a 25 mg/kg compared to a ≤12 mg/kg loading dose of fluconazole in infants.

Design/Methods:

We performed an observational cohort study of infants < 1 year from 9 sites who received >2 consecutive days of fluconazole. We obtained safety outcomes for 7 days following administration of a 25 mg/kg or ≤12 mg/kg loading dose including hepatic dysfunction, QTc interval prolongation, adrenal insufficiency (AI), renal dysfunction, and new or increased seizure activity. We describe infant characteristics, safety outcomes, clinical outcomes, and microbiologic clearance.

Results:

We included 1424 infants of which 84 (6%) received a 25 mg/kg and 1340 (94%) received a ≤12 mg/kg loading dose of fluconazole (Table 1). We found no difference in safety outcomes, except for a higher rate of AI in the 25 mg/kg group when defined as new or increased hydrocortisone [26 (31%) vs. 288 (22%), p=0.04] compared to the ≤12 mg/kg group (Table 2). Infants in the 25 mg/kg group has a higher rate of in-hospital death [30 (35%) vs. 230 (17%), p< 0.001] except in those who died on fluconazole [12 (40%) vs. 64 (28%), p=0.17]; shorter median length of hospitalization [48 (20, 102) vs. 75 (32, 128) days, p=0.002] except among survivors [76 (28, 116) vs. 81 (34, 129) days, p=0.63]; and less likely to have evidence of dissemination [20 (37%) vs. 184 (53%), p=0.03) compared to the ≤12 mg/kg group (Table 3).

Conclusion(s):

A loading dose of 25 mg/kg for fluconazole shows a favorable safety profile in infants < 1 year and decreased evidence of fungal dissemination following a positive blood culture. There was an increased rate of death in the 25 mg/kg group, however, this likely reflects greater illness severity that was not able to be fully captured. Additional analysis should be done to address residual bias and confounding by indication.