Fluconazole dosing for the prevention or treatment of invasive candidiasis in young infants

Abstract

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 at 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 an AUC/minimum inhibitory concentration (MIC) >50 for Candida species with MIC <8 microg/mL in > or =90% 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 an AUC of 50 and 100 mg*hr/L, respectively, and maintains fluconazole concentrations > or =2 or 4 microg/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 serum creatinine > or =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 can provide adequate exposure when unit specific MICs are taken into account.

Conflict of interest statement

No potential conflict of interests relevant to this article was reported.

Figures

Figure 1

Treatment of empiric or proven invasive candidiasis. Predicted median and population variability range (10th–90th percentile) of fluconazole plasma concentrations from 100 simulated trials of preterm 23–29 week gestation infants (A) and 30–40 week gestation infants (B) treated with 12 mg/kg/day for 14 days. Closed circles in (A) and (B) represent the observed fluconazole plasma concentrations in six infants who were receiving 10–12 mg/kg/day in a previous PK trial. Predicted median fluconazole AUC is shown in (C) for 23–29 week and 30–40 week infants receiving 6 or 12 mg/kg/day. A loading dose of 25 mg/kg followed by 12 mg/kg/day is predicted to achieve target AUC by day 2 (C). Predicted median fluconazole AUC is shown for 23–29 week gestation infants receiving 12 mg/kg/day with renal insufficiency if creatinine improves to ≤ 1 mg/dl after 4 days (D).

Figure 2

Early prevention of invasive candidiasis in 23–29 week gestation infants. Predicted median and population variability range (10th–90th percentile) of fluconazole plasma concentrations from 100 simulated trials of preterm 23–29 week gestation infants treated with 3 mg/kg (A) or 6 mg/kg (B) twice weekly for 42 days starting in the first 5 days of life. Closed circles in (A) represent the observed fluconazole plasma concentrations in infants participating in a previous PK trial who received 3 mg/kgl. Dash line in B represents the median fluconazole concentration predicted in infants with serum creatinine of 1.2 mg/dl for first two weeks of therapy. (C) shows the predicted median fluconazole plasma concentrations in 23–29 week infants with renal insufficiency treated with 6 mg/kg weekly for first two weeks and then twice weekly beginning on day 14 when creatinine decreases to ≤1.0 mg/dl in simulation.

Figure 3

Fluconazole has been used for the late prevention of invasive candidiasis during broad spectrum antibiotic exposure or necrotizing enterocolitis in infants born at 23–29 weeks gestation. Predicted fluconazole plasma concentrations in 23–29 week gestation infants treated with 6 mg/kg every 72 hours in infants who are 7–42 days old (A) and every 48 hours if in infants who are 43–80 days old (B). Closed circles in (A) represent observed fluconazole plasma concentrations in a preterm infant who participated in a previous PK trial and received 6 mg/kg every 72 hours.