Placing nebulizers within a HFT circuit upstream from the humidification chamber may enable to deliver clinically relevant masses of aerosol at the cannula outlet, but more importantly downstream of the nose and pharynx, even in case of high patients' inspiratory flow. This method of aerosol therapy is expected to produce a bronchodilatatory effect to be evaluated in the clinical settings.

Overall, the inhalation of mAbs for therapeutic purposes is both appropriate and feasible. The size and structure of the biotherapeutic molecule are important properties to be taken into account when trying to achieve long-term retention. Mesh nebulizers currently appear to be the most appropriate devices for the safe delivery of large amounts of active mAb into the lungs. mAbs should be formulated so as to prevent their degradation and possible immunogenicity. General guidelines can be given for mAb aerosolization, but the formulation and device combination should be adapted for each therapeutic and clinical application.

Drug delivery in the airways by inhalation can be used for local and/or systemic action, depending on the ability of the aerosolized drug to cross the air-blood barrier. For proteins, this is partly conditioned by the drug's molecular weight, as well as aerosol characteristics. This editorial focuses on protein inhalation for topical delivery purposes. Even though systemic applications (such as insulin inhalation) are not considered herein, it is worth noting that systemic diffusion following topical delivery may happen in some cases, and provide therapeutic benefit (as is the case for granulocyte-macrophage colony-stimulating factor (GM-CSF)).

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Intensive care unit patients exhibit altered pharmacokinetics for many drugs and suboptimal exposure may be detrimental. • Despite frequent use of ceftriaxone in critically ill patients, its pharmacokinetics have not been studied in large cohorts of critically ill patients. • Population pharmacokinetic analysis provides pharmacokinetic parameter estimates, estimates of inter-individual and intra-individual variability in these parameters and allows patient characteristics explaining inter-individual variability to be quantified. • Coupled with pharmacodynamic analysis, this approach can help in simulating an optimal dosing regimen based on individual characteristics. WHAT THIS STUDY ADDS • Our population model characterized the pharmacokinetic profile of ceftriaxone in patients with highly variable characteristics • Creatinine clearance was identified as the main covariate influencing ceftriaxone pharmacokinetics, particularly for high values. Haemofiltration had no effect. • Model-based simulations showed that the risk of being under threshold concentrations is low for infections due to common pathogens, but exists in patients with high glomerular filtration rates. AIMS To investigate the population pharmacokinetics of ceftriaxone in critically ill patients suffering from sepsis, severe sepsis or septic shock. METHODS Blood samples were collected at preselected times in 54 adult patients suffering from sepsis, severe sepsis or septic shock in order to determine ceftriaxone concentrations using high-performance liquid chromatography-ultraviolet detection. The pharmacokinetics of ceftriaxone were assessed on two separate occasions for each patient: on the second day of ceftriaxone therapy and 48 h after catecholamine withdrawal in patients with septic shock, or on the fifth day in patients with sepsis. The population pharmacokinetics of ceftriaxone were studied using nonlinear mixed effects modelling. RESULTS The population estimates (interindividual variability; coefficient of variation) for ceftriaxone pharmacokinetics were: a clearance of 0.88 l h-1 (49%), a mean half-life of 9.6 h (range 0.83-28.6 h) and a total volume of distribution of 19.5 l (range 6.48-35.2 l). The total volume of distribution was higher than that generally found in healthy individuals and increased with the severity of sepsis. However, the only covariate influencing the ceftriaxone pharmacokinetics was creatinine clearance. Dosage simulations showed that the risk of ceftriaxone concentrations dropping below the minimum inhibitory concentration threshold was low. CONCLUSIONS Despite the wide interpatient variability of ceftriaxone pharmacokinetic parameters, our results revealed that increasing the ceftriaxone dosage when treating critically ill patients is unnecessary. The risk of ceftriaxone concentrations dropping below the minimum inhibitory concentration threshold is limited to patients with high glomerular filtration rates or infections with high minimum inhibitory concentration pathogens (...

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Monitoring of changes in the concentrations of the low molecular weight constituents enhanced by abundant proteins depletion.

Vibrational spectroscopic techniques can detect small variations in molecular content, linked with disease, showing promise for screening and early diagnosis. Biological fluids, particularly blood serum, are potentially valuable for diagnosis purposes. The so-called Low Molecular Weight Fraction (LMWF) contains the associated peptidome and metabolome and has been identified as potentially the most relevant molecular population for disease-associated biomarker research. Although vibrational spectroscopy can deliver a specific chemical fingerprint of the samples, the High Molecular Weight Fraction (HMWF), composed of the most abundant serum proteins, strongly dominates the response and ultimately makes the detection of minor spectral variations a challenging task. Spectroscopic detection of potential serum biomarkers present at relatively low concentrations can be improved using pre-analytical depletion of the HMWF. In the present study, human serum fractionation by centrifugal filtration was used prior to analysis by Attenuated Total Reflection infrared spectroscopy. Using a model sample based on glycine spiked serum, it is demonstrated that the screening of the LMWF can be applied to quantify blinded concentrations up to 50 times lower. Moreover, the approach is easily transferable to different bodily fluids which would support the development of more efficient and suitable clinical protocols exploring vibrational spectroscopy based ex-vivo diagnostic tools

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