Dose:    6 mg/kg/dose IV (optional loading dose of 10 mg/kg)
              3 mg/kg/dose PO (following a loading dose of 6 mg/kg)    

Frequency:     Q day (see comments).  

Comments:  Fluconazole is an antifungal agent with activity against a wide variety of fungal pathogens, including Candida albicans and Cryptococcal species. Fluconazole may not be an effective for treatment of CSF mycotic infections  The optimum daily dose, the total dose, and the length of treatment for fungal infections in the neonate are based on case reports and a few studies reporting pharmacokinetic data.  When used to treat oral candidiasis,   fluconazole (loading dose 6 mg/kg followed by 3 mg/kg/day for 7 days) was superior to nystatin in immuno-compromised infants and children.

Recent studies have shown evidence that fluconazole prophylaxis can be used to prevent fungal infections in very low birth weight infants.  Kicklighter (Pediatr 2001; 107:293-298) used prophylactic fluconazole to decrease rectal colonization of Candida in VLBW infants during the first month of life. Though well tolerated, there was no difference in the incidence of invasive candidal disease in VLBW infants who received fluconazole or placebo. Clerihew, Austin, and McGuire updated a cochrane review of Prophylactic systemic antifungal agents to prevent mortality and morbidity in very low birth weight infants in May, 2007 (www.nichd.nih.gov/cochrane/McGuire5/McGuire.htm). In their review, they found some evidence that prophylactic fluconazole reduced invasive fungal disease in very low birth weight infants though it does not appear to have an impact on overall  mortality. Lower dose regimens (3 mg/kg/dose) appeared as effective as higher dose regimens (6 mg/kg/dose). However the conclusions were tempered since the 95% confidence intervals were wide and there was ongoing concern about emergence of resistant organisms. The authors noted that currently some neonatologists target only high risk populations (< 26 weeks gestation and < 750 grams) to attempt to decrease the likelihood of emerging fungal resistance.
Since the Cochrane review, two additional studies have been reported. Healy (Pediatr 2008; 121:703-710). Fluconazole was give 3 mg/kg/dose IV every third day for 2 weeks, every other day for 2 weeks, followed by daily doses for 2 weeks as long as IV access existed. During 4 years of using fluconazole prophylaxis, the incidence of invasive fungal disease was decreased from 0.6% to 0.3% in low birth weight infants without the emergence of fluconazole-resistant Candida species. Uko (Pediatr 2007; 117:1243-1252 reported on a shorter course of fluconazole prophylaxis using the same dosing strategy but for a shorter period of time to reduce the possibility of hepatic injury. Infants < 29 weeks were given prophylaxis if they were treated with antibiotics > 3 days. Invasive fungal infections decreased from 6.3% in the control epoch to 1.1% in the fluconazole-prophylaxis epoch. However this was a retrospective observational study from a single center. Though both of these studies offer further support of the efficacy of fluconazole prophylaxis, large multi-center trials have not duplicated these results and the long-term safety of this treatment and potential of emerging fungal resistance remains uncertain.

At St. Johns, we decided to use prophylactic doses of fluconazole (3 mg/kg) given every other day for 3 doses in infants < 1000 grams at birth.

Toxicity:  In the report by Kicklighter, no adverse effects were noted though the study was small. Healy also noted the lack of association of fluconazole prophylaxis with the development of cholestasis. Other reports in infants have noted only minor changes in liver enzymes, eosinophilia, or anemia. Vomiting, diarrhea, and abdominal pain have been reported in 7% of adults. Neutropenia, anemia, thrombocytopenia and elevation in LFT's were reported in 8% of adults. The concurrent use of fluconazole and cisapride was contraindicated as life-threatening arrhythmias could develop.

Preparation: IV: Fluconazole (Diflucan) is vailable in a 2 mg/ml concentration in normal saline. Dextrose is not available as a diluent for the drug, but can be Y'd in during the infusion. Check compatibilities carefully. Doses less than 6 mg/kg can be infused over 60 minutes, doses equal to or greater than 6 mg/kg should be infused over 2 hours. 

PO: An oral suspension of fluconazole can be reconstituted to make a 10 mg/ml concentration.  Add 24 ml of distilled or purified water to the fluconazole powder. Shake well before using. Stable 2 weeks if refrigerated.