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.

Continuous infusion of cefepime and neurotoxicity: a retrospective cohort study.

OBJECTIVES: Neurotoxicity related to cefepime is increasingly reported in the literature but specific data concerning continuous infusion (CI) of the drug are still lacking. Our primary objective was to evaluate the incidence of neurotoxicity related to CI of cefepime and the associated risk factors. Our secondary objectives were to analyse the plasma cefepime concentrations and to define the threshold above which neurotoxicity occurs. METHODS: In this single-centre retrospective cohort study, all adult patients who underwent at least one cefepime therapeutic drug monitoring (TDM) and were treated with CI of 4 g/day between January 2017 and June 2019 were included. Neurotoxicity was evaluated according to a strict definition and was correlated with steady-state concentration at the time of toxicity presentation. RESULTS: Ninety-eight patients with 201 cefepime TDM studies were included, with an incidence of neurotoxicity of 14.3% (14/98). Patients with neurotoxicity had more often underlying brain disease (35.7% (5/14) vs 11.9% (10/84), p = 0.030)) and higher steady-state concentrations (mean ± standard deviation 71.8 ± 32.9 mg/L vs 49.6 ± 30.6, p = 0.036) than the others. A receiver operating characteristic curve analysis yielded a cefepime steady-state concentration of 63.2 mg/L as the best cut-off point between patients with or without neurotoxicity. A mean steady-state concentration of 46.4 mg/L was achieved if the dosages of cefepime were adapted to renal function which was under our threshold concentration but above our highest pharmacokinetic/pharmacodynamic target of 32-40 mg/L. CONCLUSIONS: Our results suggest that 4 g/day of cefepime adapted to renal function and infused over 24 h is a trade-off for the risk/benefit ratio, when used empirically.

[Biological markers of alcohol consumption]. / Les marqueurs biologiques de la consommation d'alcool.

To recognize an alcoholic subject is a frequent request, in a medical or forensic setting. The reasons to determine the alcoholic status of an individual are many and various. Amongst the most frequent are : to decide on the origin of liver or neurological disease, put and maintain a liver transplantation candidate on a waiting list, identify the alcoholic worker to prevent work-related accidents, or evaluate the possible risk an alcoholic individual represents, for road safety or for parental custody. The specific alcohol consumption biological markers combined with clinical and psychological examinations are the best tools to identify the individuals with a problematic consumption. The use of markers belongs to the recommended actions to support patients undergoing treatment for alcoholism. It is mandatory in various situations to distinguish between the teetotaler, the moderate or problematic drinkers. Different biomarkers are described here to allow practitioners to adapt their prescriptions.

Reconnaître un sujet alcoolique est une requête fréquente, que ce soit dans un cadre médical ou médico-légal. Les besoins de connaître le statut alcoolique d'un individu sont multiples et variés. Parmi les plus fréquents, on peut citer : se prononcer sur l'origine d'une pathologie hépatique ou neurologique, inscrire et maintenir un candidat à une greffe hépatique sur une liste d'attente, identifier le travailleur alcoolique afin de prévenir les accidents de travail, ou encore apprécier le risque éventuel qu'un individu alcoolique représente, que ce soit derrière son volant ou dans le contexte d'une garde parentale. Les marqueurs biologiques spécifiques de la consommation d'alcool, combinés aux examens cliniques et psychologiques, constituent à ce jour les meilleurs outils pour identifier les individus à consommation problématique. L'utilisation de ces indicateurs fait également partie des mesures prônées pour l'accompagnement des sujets en cure de désintoxication. Distinguer le sujet abstinent, consommateur social (dit modéré) ou problématique peut, dès lors, s'avérer essentiel dans diverses situations. Les différents biomarqueurs disponibles à ce jour sont discutés dans cet article afin de permettre aux cliniciens une prescription adaptée aux investigations à mener.

Determination of blood concentration levels of psychotropic medications in Rwandan patients.

OBJECTIVES: In Rwanda, no therapeutic monitoring of psychotropic drugs is done. This results in difficult treatment optimisation and exposition to a high risk of toxicity and drug ineffectiveness for patients under treatment. This study aimed to determine blood concentration levels of psychotropic drugs in Rwandan patients and identify problems associated with the lack of therapeutic drug monitoring (TDM) of these drugs. METHODS: The analysis was performed on 1 ml of serum sample using prazepam as internal standard. Regarding the step of sample preparation, we used a liquid-liquid extraction with a mixture of organic solvents: diethyl ether/dichloromethane/hexane/n-amyl alcohol (50/30/20/0.5:V/V). A Waters Alliance 2695 was used for analysis. The chromatography was run on a Symmetry C8 column and as mobile phase acetonitrile and phosphate buffer (pH 3.8) were used. RESULTS: Concerning the results, serum samples from 128 patients were analysed. Twenty-one different psychotropic drugs belonging to various pharmacological classes were detected and quantified. Analytical results were put into three categories based upon therapeutic reference ranges (TRR) of various drugs: subtherapeutic, therapeutic and supratherapeutic. For a total of 237 analyses, results within TRR represented 46% while 47 and 8% of results were, respectively, below and above TRR. CONCLUSION: It was therefore concluded that patients under psychotropic treatment in Rwanda are exposed to both the risk of drug ineffectiveness and the risk of toxicity (54%) with only 46% of results within the TRR. Consequently, TDM is needed to optimise psychotropic treatment in Rwandan patients.

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.

Blood, urine, and hair kinetic analysis following an acute lead intoxication.

A case of lead exposure resulting from the accidental ingestion of a lead-containing solution is reported. Because of clinical management rapidly performed through chelation therapy by 2,3-dimercaptopropane sulfonate sodium and meso-2,3-dimercaptosuccinic acid, blood lead levels of this 51-year-old patient were moderate (412.9 µg/L) and no clinical symptoms were observed. Numerous blood and urine samples were collected for kinetic analysis of lead elimination. However, we report the first case in which hair samples were analyzed to determine the excretion level of lead after acute intoxication.

Quantification in postmortem blood and identification in urine of tramadol and its two main metabolites in two cases of lethal tramadol intoxication.

Tramadol is an opioid analgesic considered to induce fewer side effects than other compounds of this class. It has been extensively prescribed for two decades. However, serious complications may occur in case of intoxication. We report here two cases of fatal intoxication due to tramadol ingestion. Tramadol, O-desmethyltramadol (ODT), and N-desmethyltramadol (NDT) were quantitatively and qualitatively determined in postmortem blood and urine, respectively. An HPLC method coupled with fluorescence detection was validated using total error approach for the analysis of tramadol, ODT, and NDT in blood. In case 1, concentrations of tramadol and its metabolites were 7.7 mg/L (tramadol), 1.33 mg/L (ODT), and 0.6 mg/L (NDT). In case 2, concentrations found were 48.34 mg/L (tramadol), 2.43 mg/L (ODT), and 10.09 mg/L (NDT). The tramadol concentration found in case 2 is one of the highest ever described in the literature. Opposite ratios of ODT/NDT concentrations observed in different cases were suggested to be useful for the evaluation of the delay between ingestion and death. However, the changes in metabolites levels may also be explained by pharmacokinetic interactions and quantitative differences in the activity of the cytochrome-P450 2D6. Interestingly, norfluoxetine was detected in subtherapeutic levels in case 2. Most of these aspects in tramadol-related fatalities are reviewed in this paper, and an overview of fatal intoxications due to tramadol is presented.

[Sulfonylureas dosage: from therapeutic monitoring to differential diagnosis of hyperinsulinism]. / Intérêt du dosage des sulfamidés hypoglycémiants: de la vérification de la compliance au diagnostic différentiel des hyperinsulinismes.

More than fifty years after their marketing, sulfonylureas remain one of the most prescribed drugs for the treatment of non-insulino-dependent diabetes mellitus. However, these products are sometimes responsible of unexplained and severe hypoglycaemias observed in patient without diabetic pathology. These typical hypoglycemias, qualified as factious, are one of the clinical expressions of the Munchausen syndrome, a psychiatric disorder characterized by the need for the subject to simulate a pathology. The hypoglycemia is associated with an endogenous hyperinsulinism, also observed in a rare endocrine pathology, the insulinoma. This article aims to show the interest of the determination of sulfonylureas in blood for the differential diagnostic of endogenous hyperinsulinisms. The confirmation of a factious hypoglycemia is capital to avoid a partial or subtotal pancreatectomy, surgical treatment when an insulinoma is suspected. Ultra liquid chromatography coupled with the mass spectrometry tandem (UPLC-MS-MS) technique had been used. The technique allowed the identification and quantification of the most used sulfonylureas and repaglinide in blood, and will be a method of choice to confirm a non-appropriate consumption of sulfonylureas.

Gamma-hydroxybutyric acid (GHB) measurement by GC-MS in blood, urine and gastric contents, following an acute intoxication in Belgium.

Gamma-hydroxybutyrate (GHB, sodium oxybate) is a compound related to neuromodulator gamma-aminobutyric acid (GABA), emerging as a recreational drug of abuse and as a rape drug. GHB-related emergencies have dramatically increased in the 1990s, but a decrease is observed since 2000. We describe the case of an acute GHB intoxication in a 28-year-old male who fell unconscious after ingestion of a mouthful of an unknown beverage, and required medical support for 2 days. A cocaine abuse was also detected by preliminary toxicological screening, but the clinical presentation was not typical of cocaine intoxication. A simple liquid-liquid extraction was used for quantitation of GHB, followed by disilyl-derivatization and analysis in selective ion monitoring (SIM) mode by gas chromatography-mass spectrometry (GC-MS), using GHB-d6 as internal standard. High concentrations of GHB were detected in urine (3020 mg/L) and gastric contents (71487 mg/L) at admission. After a 6-hours delay, GHB was still present in urine at 2324 mg/L and in blood at 43 mg/L. The clinical symptoms of cocaine intoxication were diminished by GHB consumption, and the cerebral scan was modified. Attention must thus be paid to acute intoxications with surprising clinical symptoms, and GHB has probably to be added to the preliminary toxicological screening. Data available regarding GHB are briefly reviewed, and our results are compared with previously published reports of non-fatal GHB intoxication.

[Fatal methadone poisoning: observations at the CHU of Liege]. / Revue des cas d'intoxication mortelle a la methadone: observations recensees au CHU de Liege.

All methadone-associated deaths from October 2002 to April 2005 are analysed. A regular increase in these fatal intoxications has been recorded, in Belgium as in other countries, due, in particular, to an intensified prescription of this product, of which illicit use as street dope becomes problematic. Over the 30 months period covered by the study, 26 deaths related to methadone were listed, of which 3 occurred in accidental circumstances. In the other 23 cases, methadone can be found, yet always associated with psychotropic substances, mainly benzodiazepines (18 cases), narcotics (15 cases) and finally alcohol (5 cases). Based upon the nature of the products combined with methadone, records have been divided in two groups: In the first group (17 observations), xenobiotics at (infra)therapeutic levels are detected. In the other group (6 observations), xenobiotics at high and toxic levels are detected. Blood methadone concentrations are not so different between the 2 groups of individuals since the median values and the extreme values are worth respectively 308, and 110-11300 microg/L, for the first group and 776 and 93-2080 microg/L for the second group. There is thus an important overlap between the therapeutic blood methadone concentrations (150-400 microg/L) and blood concentrations observed in fatalities.Thus, it is necessary that all information and post-mortem results must be examined in a critical way to identify and justify cause of the death.

[Analysis of two year heroin seizures in the Liege area]. / Deux ans d'analyse de saisies d'héroïne en région liégeoise.

The results of heroin analysis from seizures in the Liege area during the last two years are presented in this article. Between January 2003 and January 2005, 50 samples were analysed in the Laboratory of Clinical Toxicology and Forensic Toxicology of the University of Liege. Mean heroin concentration was 14,7%. Noscapine and papaverine, other opium alcaloïds, were simultaneously present with heroin. As diluents, we only identified caffein and acetaminophen.

[Dioxin, poisoning information or brainwashing? On Seveso's and Yushchenko's acne]. / La dioxine, info ou intox? A propos de l'acné de Seveso et de Yushchenko.

The generic term "dioxin" covers more than 400 chemicals of which less than 30 prove to be toxic. Such compounds are involved in environmental pollutions and in food contaminations. Some selected dioxins have also been used as a non-lethal chemical weapon. The assessment of the impact on health needs a precise toxicological identification. Without that basic assessment, a discrepancy may appear between the real risk linked to the exposure and the concerns and fear generated in the population, particularly because in animals the toxic concentrations of dioxins can interfere with some hormonal systems, alter immunity, induce chloracne, and participate in the development of sarcomas, lymphomas and some carcinomas. They may be responsible for some birth defects.