Pharmacokinetics and safety of fluconazole and micafungin in neonates with systemic candidiasis: a randomized, open-label clinical trial.

AIMS: The pharmacokinetics (PK) of fluconazole and micafungin differ in neonates compared with children and adults. Dosing instructions in product labels appear to be inconsistent with the emerging scientific evidence. Limited information is available on the safety profile of these agents in neonates. Our objective was to study the population PK and safety of both drugs, randomly administered in neonates with suspected or confirmed systemic candidiasis. METHODS: Neonates were randomized 1:1 to fluconazole (loading dose 25 mg kg-1 ; maintenance dose 12 mg kg-1 day-1 or 20 mg kg-1 day-1 , respectively, for infants <30 weeks or ≥30 weeks' corrected gestational age) or micafungin (loading dose 15 mg kg-1 day-1 ; maintenance dose 10 mg kg-1 day-1 ). PK samples were taken on treatment days 1 and 5. Population parameters were determined using NONMEM and Monte Carlo simulations performed to reach predefined targets. Clinical and laboratory data, and adverse events were collected up to 36 weeks' corrected gestational age or hospital discharge. RESULTS: Thirty-six neonates were enrolled. The median (range) gestational age was 28.2 (24.1-40.1) and 26.8 (23.5-40.0) weeks for fluconazole and micafungin, respectively. Based on 163 PK samples, the median population clearance (l h-1 kg-1 ) and volume of distribution (l kg-1 ) for fluconazole were: 0.015 [95% confidence interval (CI) 0.008, 0.039] and 0.913, and for micafungin were: 0.020 (95% CI 0.010, 0.023) and 0.354 (95% CI 0.225, 0.482), respectively. The loading dose was well tolerated. No adverse events associated with micafungin or fluconazole were reported. CONCLUSION: Based on Monte Carlo simulations, a loading dose for fluconazole and dosing higher than recommended for both drugs are required to increase the area under the plasma drug concentration-time curve target attainment rate in neonates.

Plasticity of neonatal neuronal networks in very premature infants: Source localization of temporal theta activity, the first endogenous neural biomarker, in temporoparietal areas.

Temporal theta slow-wave activity (TTA-SW) in premature infants is a specific signature of the early development of temporal networks, as it is observed at the turning point between non-sensory driven spontaneous local processing and cortical network functioning. The role in development and the precise location of TTA-SW remain unknown. Previous studies have demonstrated that preterms from 28 weeks of gestational age (wGA) are able to discriminate phonemes and voice, supporting the idea of a prior genetic structural or activity-dependent fingerprint that would prepare the auditory network to compute auditory information at the onset of thalamocortical connectivity. They recorded TTA-SW in 26-32 wGA preterms. The rate of TTA-SW in response to click stimuli was evaluated using low-density EEG in 30 preterms. The sources of TTA-SW were localized by high-density EEG using different tissues conductivities, head models and mathematical models. They observed that TTA-SW is not sensory driven. Regardless of age, conductivities, head models and mathematical models, sources of TTA-SW were located adjacent to auditory and temporal junction areas. These sources become situated closer to the surface during development. TTA-SW corresponds to spontaneous transient endogenous activities independent of sensory information at this period which might participate in the implementation of auditory, language, memory, attention and or social cognition convergent and does not simply represent a general interaction between the subplate and the cortical plate. Hum Brain Mapp 38:2345-2358, 2017. © 2017 Wiley Periodicals, Inc.

Haemodynamic changes during seizure-like activity in a neonate: a simultaneous AC EEG-SPIR and high-resolution DC EEG recording.

OBJECTIVE: We sought to define the interaction between neonatal epileptic discharges and the haemodynamic activities in a control situation (i.e. in the absence of cardiorespiratory perturbation or any interaction with normal, ongoing, synchronized neuronal activity). METHOD: Alternating-current electroencephalography (AC EEG), near-infrared spectroscopy (NIRS), and high-resolution direct-current (HR DC) EEG were performed in a curarized, ventilated neonate with a flat interictal EEG. The seizure-like discharges (SLD) first spike was used as a trigger for further averaging of NIRS, AC and DC EEG. Source localization was performed on the averaged spike and the averaged, negative DC shift. RESULTS: SLD were of maximal amplitude in centroparietal areas and induced a change in local haemodynamic parameters characterized by a first increase in [HHb] followed by an increase in [HbO(2)] and [HbT]. [HHb] returned to baseline at the end of the seizure and decreased thereafter. The negative DC shift started before the first spike and the increase in haemodynamic parameters. It then became positive and returned to baseline at the end of the seizure. Source localization revealed different positions for the first spike and the negative DC shift. DISCUSSION: Pure SLD in neonates might induce a negative blood oxygen level-dependent (BOLD) effect on the cortex, which occurs after the negative DC shift and which has a closer temporal relationship with the neuronal discharge than a positive BOLD effect.