Fluconazole Dosing for the Prevention or Treatment of Invasive Candidiasis in Young Infants

Background: Young infants are susceptible to developmental factors influencing the pharmacokinetics of drugs. Fluconazole is increasingly used to prevent and treat invasive candidiasis in infants. Dosing guidance remains empiric and variable because limited pharmacokinetic data exist. Methods: Our population pharmacokinetic model derived from 357 fluconazole plasma concentrations from 55 infants (23-40 week gestation) illustrates expected changes in fluconazole clearance based upon gestational age, postnatal age, weight, and creatinine. We used a Monte Carlo simulation approach based on parametric description of a patient population's pharmacokinetic response to fluconazole to predict fluconazole exposure (median: 10th and 90th percentile population variability range) after 3, 6, and 12 mg/kg dosing. Results: For the treatment of invasive candidiasis, a dose of in least 12 mg/kg/d in the first 90 days after birth is needed to achieve an area under the concentration curve (AUC) of >400 mg*h/L and all AUC/minimum inhibitory concentration (MIC) >50 for Candida species with MIC <8 mu g/mL in >= 90%o of <30 week gestation infants and 80% of 30 to 40 week gestation infants. The more preterm infants achieve a higher median AUC (682 mg*hr/L) compared with more mature infants (520 mg*hr/L). For early Prevention of candidiasis in 23 to 29 week infants, a dose of 3 or 6 mg/kg twice weekly during the first 42 days of life is equivalent to all AUC of 50 and 100 mg*hr/L, respectively, and maintains fluconazole concentrations >= 2 or 4 mu g/mL, respectively, for half of the dosing interval. For late prevention, the 6 mg/kg dose every 72 hours provides similar exposure to 3 mg/kg daily dose. Infants with scrum creatinine >= 1.3 mg/dL have delayed drug clearance and dose adjustment is indicated if creatinine does not improve within 96 hours. Conclusions: A therapeutic concentration of fluconazole in premature infants with invasive candidiasis requires dosing substantially greater than commonly recommended in most reference texts. To prevent invasive candidiasis. twice weekly prophylaxis regimens, call provide adequate exposure when unit specific MICs are taken into account.