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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT? • It is well known that tobramycin given as an once daily dose according to the usual recommendations needs therapeutic drug monitoring by measurement of peak and trough concentrations. In the literature, there are only few published studies on the population pharmacokinetics of once daily tobramycin in critically ill patients. Glomerular filtration rate and bodyweight were identified as covariates contributing to the inter-individual variability in the disposition of aminoglycosides. The study, by Peris-Marti et al. [24], only evaluated the pharmacodynamic effectiveness of a 4 mg kg−1 dose of tobramycin given once daily in critically ill patients. The authors concluded with a simulation showing that for a theoretical MIC of 1 or 2 mg l−1, a 7 mg kg−1 dose was required. WHAT THIS STUDY ADDS? • Our results confirm the high variability of tobramycin disposition in intensive care patients and consequently the possible lack of effectiveness. • By using a population pharmacokinetic approach, two explicative covariates (height and Cockcroft creatinine clearance) added to a two-compartment model with proportional error, explained much of the inter-individual variability of tobramycin disposition in the critically ill patient population. • In a median ICU patient, simulations were performed at various dosage regimens and peak and AUC pharmacodynamic targets could not be reached simultaneously in more than 45% of the ICU patient population. Drug monitoring is required to manage efficacy and toxicity. AIM The aim of this study was to evaluate the disposition of tobramycin (TOB) in critically ill patients (ICU) by a population pharmacokinetic approach, to determine the covariates involved, and to simulate tobramycin dosage regimens. METHODS Forty-nine adult ICU patients received TOB (5 mg kg−1) once daily. NonMem modelling was performed on 32 patients. The 17 other patients were used for the qualification process by normalized prediction distribution error. Then Monte Carlo simulations (MCS) were performed. RESULTS A two-compartment model with a proportional error best fitted the data. TOB total clearance (CLTOB) was significantly correlated with Cockcroft creatinine clearance (COCK) and height. TOB clearance was 4.8 ± 1.9 l h−1 (range 1.22–8.95), the volume of distribution of the central compartment was 24.7 ± 3.7 l (range 17.34–32.83) and that of the peripheral compartment and the inter-compartmental clearance were 30.6 l and 4.74 l h−1, respectively. Only 29% of the patients presented a target AUC between 80 and 125 mg l–1 h and 61% were lower than 80 mg l−1 h. After considering COCK and height, MCS showed that only 50% of the population could achieve the target AUC for the 375 and 400 mg dosages. CONCLUSION Even after taking into account COCK and height, for strains with an MIC ≤ 1 mg l−1, MCS doses evidenced that peak and AUC pharmacodynamic targets could not be reached simultaneously in more than 45% of the ICU patient population. Combination therapy in addition to drug monitoring are required to manage efficacy and toxicity.

International audience; L-glutamate is the major excitatory neurotransmitter in the mammalian brain. Specific proteins, the Na+/K+-dependent high affinity excitatory amino acid transporters (EAATs), are involved in the extracellular clearance and recycling of this amino acid. Type I synapses of the Drosophila neuromuscular junction (NMJ) similarly use L-glutamate as an excitatory transmitter. However, the localization and function of the only high-affinity glutamate reuptake transporter in Drosophila, dEAAT1, at the NMJ was unknown. Using a specific antibody and transgenic strains, we observed that dEAAT1 is present at the adult, but surprisingly not at embryonic and larval NMJ, suggesting a physiological maturation of the junction during metamorphosis. We found that dEAAT1 is not localized in motor neurons but in glial extensions that closely follow motor axons to the adult NMJ. Inactivation of the dEAAT1 gene by RNA interference generated viable adult flies that were able to walk but were flight-defective. Electrophysiological recordings of the thoracic dorso-lateral NMJ were performed in adult dEAAT1-deficient flies. The lack of dEAAT1 prolonged the duration of the individual responses to motor nerve stimulation and this effect was progressively increased during physiological trains of stimulations. Therefore, glutamate reuptake by glial cells is required to ensure normal activity of the Drosophila NMJ, but only in adult flies.