Modelled Target Attainment after Temocillin Treatment in Severe Pneumonia: Systemic and Epithelial Lining Fluid Pharmacokinetics of Continuous versus Intermittent Infusions.

The objective of this article is to describe the population pharmacokinetics (PK) of temocillin administered via continuous infusion (CI) versus intermittent infusion (II) in critically ill patients with pneumonia. Secondary objectives included characterization of epithelial lining fluid (ELF)/plasma penetration ratios and determination of the probability of target attainment (PTA) for a range of MICs. Thirty-two mechanically ventilated patients who were treated for pneumonia with 6 g of temocillin daily for in vitro sensitive pathogens were assigned to either the II (2 g every 8 h over 0.5 h) or the CI (6 g over 24 h after a loading dose of 2 g) group. A population pharmacokinetic model was developed using unbound plasma, and total ELF concentrations of temocillin and related Monte Carlo simulations were performed to assess PTAs. The area under the concentration-time curve from 0 to 24 h (AUC0-24) ELF/plasma penetration ratio was 0.73, at steady state, for both modes of infusion and whatever the level of creatinine clearance. Monte Carlo simulations showed that for the minimal pharmacodynamic (PD) targets of 50% T > 1× MIC (II group) and 100% T > 1× MIC (CI group), PK/PD breakpoints were 4 mg/L in plasma and 2 mg/L in ELF and 4 mg/L in plasma and ELF, respectively. The breakpoint was 8 mg/L in ELF for both modes of infusion in patients with creatinine clearance (CLCR) < 60 mL/min/1.73 m2. While CI provides better PKPD indexes, the latter remain below available recommendations for systemic infections, except in the case of moderate renal impairment, thereby warranting future clinical studies in order to determine the efficacy of temocillin in severe pneumonia.

[Community-acquired Staphylococcus aureus pneumonia]. / Pneumonie communautaire à staphylocoque doré.

We report a clinical case of a patient hospitalized for community-acquired Staphylococcus aureus pneumonia. A 26-year-old patient with no medical history went to the emergency department for fever. He quickly developed acute respiratory failure and community-acquired Staphylococcus aureus pneumonia as well as bacteremia were confirmed. This pulmonary infection is rare but can affect all age groups and occur in a variety of ways. Patients with community-acquired Staphylococcus aureus pneumonia have more severe clinical outcomes than those with community-acquired pneumonia caused by other germs. The article discusses the main characteristics of community-acquired Staphylococcus aureus pneumonia and recalls the recommendations in case of bacteremia with Staphylococcus aureus.

Nous rapportons le cas clinique d'un patient de 26 ans, sans antécédents médicaux, se présentant au service des urgences pour cause de fièvre persistante depuis plusieurs jours. Dans le décours de son admission à l'hôpital, le patient développe une insuffisance respiratoire aiguë d'installation rapide. Une pneumonie communautaire associée à une bactériémie à staphylocoque doré est alors mise en évidence. Les pneumonies communautaires à staphylocoque doré sont rares, mais peuvent toucher toutes les tranches d'âge et se présenter de façon variée. Leur sévérité est plus importante que celle des pneumonies communautaires imputées à d'autres germes. Par le biais de ce cas clinique, les principales caractéristiques des pneumonies communautaires à staphylocoque doré sont discutées et les recommandations médicales associées sont abordées.

[High anion gap metabolic acidosis (pyroglutamic acidosis) induced by chronic acetaminophen use]. / Acidose métabolique à trou anionique élevé (acidose pyroglutamique) induite par une prise chronique de paracétamol.

Acetaminophen is the most consumable analgesic in the world in the form of medical prescription or self-medication. It is one of the active ingredients most often involved in voluntary poisoning. Lethal dose of acetaminophen classically induces acute hepatic failure on hepatic necrosis. Chronic intake of sub-lethal doses (i.e. near recommended therapeutic doses) of acetaminophen in the presence of certain risk factors may be responsible for another much less recognized pathological manifestation: severe metabolic acidosis with an increased anion gap due to the accumulation of 5-oxoproline or pyroglutamic acid.

Le paracétamol est l'analgésique le plus consommé au monde sous forme de prescription médicale ou en automédication. Il compte parmi les principes actifs les plus souvent impliqués dans les intoxications volontaires, induisant en cas de prise d'une dose létale une insuffisance hépatique aiguë sur nécrose hépatique. La prise chronique de doses proches des doses thérapeutiques recommandées de paracétamol en présence de facteurs de risque peut être responsable d'une autre manifestation pathologique beaucoup moins reconnue : une acidose métabolique sévère à trou anionique augmenté, due à l'accumulation de 5-oxoproline ou acide pyroglutamique.

[Chelating agents : alert to misuses!] / Les agents chélateurs : alerte à l'abus !

Exposure to heavy metals is a common phenomenon due to their prevalence in food and environment; their toxicity remains a major concern for public health. Chelating agents are drugs used to increase the elimination of metals present at abnormally high levels in the body. Their approved clinical indications are limited, particularly because of their potential adverse effects. Unfortunately, too often, chelating agents are used to test the body impregnation level by heavy metals. It is an inappropriate and abusive use. In order to attract attention to this problematic, the good and bad uses of metal chelators are reviewed.

L'exposition aux métaux lourds est un phénomène courant en raison de leur prévalence dans l'alimentation et dans l'environnement; leur toxicité demeure une préoccupation importante pour la santé publique. Les agents chélateurs sont des substances chimiques utilisées pour augmenter l'élimination de certains métaux présents à des concentrations anormalement élevées dans l'organisme. Leurs indications cliniques approuvées sont limitées, particulièrement en raison des effets indésirables qu'ils peuvent induire. Malheureusement, trop souvent, les agents chélateurs sont utilisés avec pour objectif de vérifier le niveau d'imprégnation de l'organisme par les métaux lourds. Il s'agit d'un usage inapproprié et abusif. Afin d'attirer l'attention des praticiens sur cette problématique, les bons et les mauvais usages des chélateurs de métaux sont passés en revue.

[Production of monoclonal antibodies]. / Production des anticorps monoclonaux.

In contrast to a polyclonal antiserum, a monoclonal antibody is specific to a single epitope on the surface of a complex antigen. In 1975, Kohler and Milstein produced the first monoclonal antibodies by using a method which rapidly became a key technology in immunology. By fusing activated antibody-forming cells (B cells) with myeloma cells, they obtained hybrid cells--the so-called hydridomas--which combine the ability of the activated B cells to secrete a single species of antibody and the immortality of the myeloma cell. The selected hybridomas proliferate continuously, their clonal progeny providing an unending supply of antibody with a single specificity. These antibodies have found many applications in basic research and in vitro diagnosis. In the clinical laboratory, monoclonal antibodies are used as reagents in immunoassays, often replacing traditional antisera. Many years of development and innovation were needed to humanize monoclonal antibodies in order to make them usable in human therapy.

[Interest of monoclonal antibodies in biomedical laboratory analysis]. / Intérêt des anticorps monoclonaux dans le laboratoire d'analyses biomédicales.

Immunoassays, or assays with antibodies as reagents, are widely used in medical laboratories. These assays are used to identify and quantify various substances in biological fluids, such as specific proteins (various tissue markers, markers of inflammation, hormones, coagulation factors...) or immunoglobulins (viral or bacterial antibodies, auto-antibodies...) and even both viral antigens and antibodies (HIV virology). The use of monoclonal antibodies allowed, through their specificity for a single epitope of the target molecule, the development of increasingly sophisticated immunoassays. In particular, the use of monoclonal antibodies with microarrays permits the simultaneous determination of various proteins (inflammatory profile, cardiac profile, specifics IgE...) quickly and accurately. Very important tools in the clinical laboratory, immunoassays techniques are, however, subject to various analytical interferences which may be responsible for significant changes in the test results.

[Vitamin D2 or vitamin D3?]. / Vitamine D2 ou vitamine D3?

PURPOSE: Nearly one billion people around the world are deficient in vitamin D and need to be supplemented. Vitamin D is available in medicines and fortified foods. It is available in two forms: vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). KEY POINTS: The pharmacopeiae consider these steroid hormones as equivalent and interchangeable. However, several studies have showed that serum level of 25(OH)D is increased more effectively with vitamin D3 than vitamin D2. Vitamin D2 has shorter plasma half-life and a lower affinity for the vitamin D binding protein, the hepatic vitamin D hydroxylase and the vitamin D receptor. CONCLUSION: Vitamin D2 should not be regarded anymore as suitable for supplementation or fortification. Currently though, it is still the most used in some countries such as Portugal and Australia.

Simultaneous determination of seven azole antifungal drugs in serum by ultra-high pressure liquid chromatography and diode array detection.

Azole antifungals are a group of fungistatic agents that can be administered orally or parenterally. The determination of the concentrations of these antifungals (miconazole, fluconazole, ketoconazole, posaconazole, voriconazole, itraconazole, and its major active metabolite, hydroxy-itraconazole) in serum can be useful to adapt the doses to pharmacological ranges because of large variability in the absorption and metabolism of the drugs, multiple drug interactions, but also potential resistance or toxicity. A method was developed and validated for the simultaneous determination of these drugs in serum utilizing ultra-high pressure liquid chromatography and diode array detection (UHPLC-DAD). After a simple and rapid liquid-liquid extraction, the pre-treated sample was analysed on an UHPLC-DAD system (Waters Corporation(®)). The chromatographic separation was carried out on an Acquity BEH C18 column (Waters Corporation) with a gradient mode of mobile phase composed of acetonitrile and aqueous ammonium bicarbonate 10·0 M pH10. The flow rate was 0·4 ml/min and the injection volume was 5 µl. The identification wavelength varied according to the drug from 210 to 260 nm. The method was validated by the total error method approach by using an analytical validation software (e•noval V3·0 Arlenda(®)). The seven azole antifungals were identified by retention time and specific UV spectra, over a 13-minute run time. All calibration curves showed good linearity (r(2)>0·99) in ranges considered clinically adequate. The assay was linear from 0·05 to 10 mg/l for voriconazole, posaconazole, itraconazole, hydroxy-itraconazole, and ketoconazole, from 0·3 to 10 mg/l for fluconazole, and from 0·1 to 10 mg/l for miconazole. The bias and imprecision values for intra- and inter-assays were lower than 10% and than 15%, respectively. In conclusion, a simple, sensitive, and selective UHPLC-DAD method was developed and validated to determine seven azole antifungal drugs in human serum. This method is applicable to patient samples, and can be applied successfully to clinical applications and therapeutic drug monitoring.