Time to initiation of antifungal therapy for neonatal candidiasis.

The effect of delayed antifungal therapy in critically ill infants with invasive candidiasis has not been studied. Our objective was to evaluate the effect of time to initiation of antifungal therapy (TIA) on mortality, disseminated disease, and postinfection hospital stay. We conducted a cohort study of critically ill infants with cultures positive for Candida from 1990 to 2008. TIA was defined as the number of hours from the collection of the first positive culture until the start of antifungal therapy. Of 96 infants, 57% were male, the median gestational age was 27 weeks (range, 23 to 41 weeks), and the median birth weight was 956 g (range, 415 to 6,191 g). Most subjects received amphotericin B deoxycholate. TIA was ≤ 24 h for 35% of infants, between 25 and 48 h for 42%, and >48 h for 23%. Eleven subjects died during hospitalization, and 22% had disseminated candidiasis. The median duration of hospital stay postinfection was 53 days (range, 6 to 217 days). Both univariate and multivariate analyses demonstrated that TIA was not associated with mortality, disseminated disease, or hospital stay postinfection. However, ventilator use for >60 days significantly increased the risk of death (odds ratio [OR], 9.5; 95% confidence interval [CI], 2.2 to 66.7; P = 0.002). Prolonged candidemia increased the risk of disseminated disease by 10% per day of positive culture (OR, 1.1; 95% CI, 1.08 to 1.2; P = 0.007), and low gestational age was associated with increased neonatal intensive care unit (NICU) stay after the first positive Candida culture by 0.94 weeks (95% CI, 0.70 to 0.98; P < 0.001). The TIA was not associated with all-cause mortality, disseminated candidiasis, and postinfection length of hospital stay.

Improved vancomycin dosing in children using area under the curve exposure.

BACKGROUND: : Our objectives were to (1) determine the pharmacokinetic indices of vancomycin in pediatric patients; and (2) compare attainment of 2 target exposures: area under curve (AUC) / minimum inhibitory concentration (MIC) ≥400 and trough concentration ≥15 mcg/mL. METHODS: : The population-based pharmacokinetic modeling was performed using NONMEM 7.2 for children ≥3 months old who received vancomycin for ≥48 hours from 2003 to 2011. A 1-compartment model with first-order kinetics was used to estimate clearance, volume of distribution and AUC. Empiric Bayesian post hoc individual parameters and Monte Carlo simulations (N = 11,000) were performed. RESULTS: : Analysis included 702 patients with 1660 vancomycin serum concentrations. Median age was 6.6 (interquartile range 2.2-13.4) years, weight 22.7 (12.6-46) kg and baseline serum creatinine 0.40 (0.30-0.60) mg/dL. Final model pharmacokinetic indices were clearance (L/h) = 0.248 * Wt * (0.48/serum creatinine) * (ln(age)/7.8) and volume of distribution (L) = 0.636 * Wt. Using these parameters and the observed MIC distribution, Monte Carlo simulation indicated that the initial median dose of 44 (39-52) mg/kg/day was inadequate in most subjects. Regimens of 60 mg/kg/day for subjects ≥12 years old and 70 mg/kg/day for those <12 years old achieved target AUC/MIC in ~75% and trough concentrations ≥15 in ~45% of virtual subjects. An AUC/MIC ~400 corresponded to trough concentration ~8 to 9 mcg/mL. CONCLUSIONS: : Targeted exposure using vancomycin AUC/MIC, compared with trough concentrations, is a more realistic target in children. Depending on age, serum creatinine and MIC distribution, vancomycin in a dosage of 60 to 70 mg/kg/day was necessary to achieve AUC/MIC ≥ 400 in 75% of patients.