Objectifs L’IC-26 ou méthiodone est un opioïde de synthèse peu documenté, identifié pour la première fois en France en 2025. Nous rapportons ici deux cas de poly-intoxication impliquant cette molécule. Méthode Cas no 1 : homme de 50 ans qui aurait consommé lors d’une soirée chemsex du GHB et du « noopept » par voie orale, ainsi que de la méthiodone par inhalation et injection intramusculaire. Il se serait endormi après l’injection. Onze heures plus tard, son partenaire contacte les secours devant l’absence de réveil et la présence de sécrétions mousseuses blanchâtres nasales. À leur arrivée, le patient est aréactif avec un score de Glasgow (GCS) à 3/15, il présente un myosis bilatéral aréactif, une tachycardie à 112 bpm, une fréquence respiratoire irrégulière, et une saturation en oxygène en air ambiant à 50 %. Il est sédaté, intubé et transféré en réanimation. Le bilan biologique retrouve une hyperleucocytose, une rhabdomyolyse, une cytolyse hépatique sans insuffisance hépatique, une insuffisance rénale aiguë et une hyperkaliémie. Une recherche de stupéfiants urinaires Drugscreen® (Nal Von Minden) rend un résultat positif pour la méthadone. L’administration de naloxone engendre des signes de réveil avec agitation psychomotrice. L’évolution initiale est sans complication, permettant une sortie au troisième jour d’hospitalisation. Dix-sept jours plus tard, l’apparition de troubles neurologiques s’aggravant progressivement motive une nouvelle hospitalisation, conduisant au diagnostic de leucoencéphalopathie toxico-hypoxique retardée, secondaire à l’épisode de coma sur intoxication à la méthiodione. Cas no 2 : femme 21 ans, expérimentatrice, admise au service des urgences puis de réanimation devant une défaillance neurologique après consommation de bromazolam, d’amphétamine et d’olanzapine. À l’admission, le GCS est évalué à 7/15, elle présente un myosis serré avec des pupilles intermédiaires réactives, un discret allongement du QT sur l’ECG, une acidose métabolique non compensée. Le myosis n’étant pas compatible avec les molécules supposément prises, deux bolus de naloxone induisent des signes de réveil. L’évolution clinique est rapidement favorable avec retour à l’état antérieur dans les heures suivantes. Dans ces 2 cas des prélèvements à visée toxicologique ont été réalisés et transmis au laboratoire de pharmacologie-toxicologie du CHU de Nantes. Résultats Dans le cas no 1, le criblage toxicologique par LC-HRMS retrouve la méthiodone à 59,4 et 8477ng/mL respectivement dans le sang et l’urine, ainsi que les médicaments administrés en réanimation. Il est également retrouvé dans l’urine de l’emtricitabine, 2-FDCK et 2-Oxo-PCE (métabolites non recherchés dans le sang). Dans le cas no 2, le criblage sanguin retrouve la présence d’amphétamine, d’olanzapine, de bromazolam et de méthiodone à 18,7ng/mL. Conclusion La méthiodone est un analogue structural de la méthadone et agoniste des récepteurs opioïdes, ce qui est cohérent avec l’efficacité observée de la naloxone. Les études humaines et animales lui suggèrent une puissance analgésique comparable à celle de la méthadone (Lednicer D, 1982. Central Analgetics. Wiley. 194), cependant aucune donnée n’existe actuellement concernant un seuil de toxicité de la méthiodone. Des données post-mortem sont disponibles et basées sur deux cas de poly-intoxication fatales, avec des concentrations à 590 et 800ng/mL dans le sang fémoral (EUDA), supérieures à celles retrouvées dans nos cas. Concernant le test DrugScreen® positif pour la méthadone, une réaction croisée liée à l’analogie structurale entre la méthiodone et la méthadone peut être envisagée. Concernant le diagnostic de leucoencéphalopathie toxico-hypoxique retardée, cette complication a déjà été décrite à la suite d’intoxication aiguë aux opioïdes (Munoz Musat E. 2018. Prat Neurol. Elsevier, 252). À notre connaissance, il s’agit des premiers cas documentés de poly-intoxication non-fatale impliquant la méthiodone en France. Ces cas rappellent la nécessité d’une meilleure connaissance clinique et analytique des nouveaux opioïdes de synthèse, afin d’améliorer leur détection et leur prise en charge en contexte d’intoxication.

BackgroundCocaine intoxication and abuse is a worldwide problem that can be the cause of numerous acute medical complications, including severe acute hepatitis. Although these cases are scarce, they are extremely serious and may lead to liver transplantation or death. Management of toxic hepatitis, once the causative agent has been discontinued, is essentially symptomatic, based on clinical and biological monitoring and prevention of complications related to acute hepatitis.Case detailsWe present a case of a 28-year-old woman admitted to the emergency department for acute hepatitis due to cocaine intoxication. In addition to a sharp rise in her liver enzymes, the patient also presented metabolic acidosis, renal failure, and rhabdomyolysis. Treatment consisted of administering N-acetylcysteine (NAC), dialysis, and additional supportive measures. An improvement in the liver function with a decrease in transaminases occurred after the NAC administration. The toxicokinetics of major cocaine metabolites and clinical chemistry concentrations were monitored.ConclusionIn addition to the usual management measures for acute hepatitis, the administration of N-acetylcysteine should be investigated further, although it is currently used only in cases of acetaminophen acute toxic hepatitis.

Introduction: Immunoassay (IA) is currently used at Nantes University Hospital to perform urine drug screening in the inpatient addiction unit. Given its numerous limitations, we aimed to assess the overall benefit of the Liquid-Chromatography-High-Resolution-Mass Spectrometry (LC-HRMS), and to identify the profiles of patients for whom its use provided a clinical benefit. Methods: All adult patients admitted to this unit between January and September 2023 were systematically included. A part of the urine sample routinely collected on admission was retained for subsequent analysis by LC-HRMS. For each active molecule, the analytical performance of LC-HRMS compared with IA was evaluated by biologists. Then unit's physicians assessed for each patient whether the new data provided by LC-HRMS would have had an impact on their management. A multivariate analysis was carried out to identify the profiles of these patients. Results: 154 patients were included with 293 non-prescribed molecules and 434 prescribed drugs. For 2/3 of all molecules, LC-HRMS performed better than IA. Most of these molecules were not detectable by IA but some were not detected even though they belonged to the panel of detectable substances. Physicians considered that the new results provided by LC-HRMS would have had an impact on the management of 1/4 of patients. A history of opiate abuse/dependence was associated with a clinical benefit of LC-HRMS in the multivariate analysis. Conclusion: These results confirm the benefit of LC-HRMS for urine drug screening in inpatient addiction units for patients with multiple substance use, especially those with a history of opioid use.

Objectifs Présentation d’un cas clinique d’intoxication sévère liée à l’ingestion massive de cocaïne dans un contexte de « body-packing ». Méthodes Une patiente de 46ans a été admise en soins intensifs après un arrêt cardiaque survenu dans un contexte de malaise aigu. À la suite de l’évaluation initiale clinique, biologique et radiologique, une laparotomie d’urgence a été réalisée pour retirer les corps étrangers présents (36 paquets de cocaïne, soit environ 400g) au sein du tractus gastro-intestinal. Le suivi biologique de la patiente a permis d’étudier les cinétiques plasmatiques de la cocaïne et de ses métabolites. Malgré des soins intensifs, la patiente a évolué vers une mort cérébrale confirmée à trois jours d’hospitalisation. La cinétique des concentrations plasmatiques de cocaïne, de benzoylecgonine (BZE) et d’ecgonine méthyl ester (EME) a été réalisée par chromatographie liquide couplé à la spectrométrie de masse en tandem (Sciex QTRAP 5500 LC-MS/MS system). Résultats Les analyses biologiques initiales de la patiente lors de son admission aux urgences ont révélé une acidose métabolique avec hyperlactatémie (24 mmol/L) associé à une insuffisance rénale (créatinine à 106μmol/L, débit de filtration glomérulaire à 55mL/min/1,73m2) et à une cytolyse hépatique (aspartate transaminase à 159,8 UI/L et alanine transaminase à 130,7 UI/L). Les concentrations de la créatine kinase et la troponine étaient de 117,9 UI/L et 44 ng/L, respectivement. Les analyses toxicologiques ont montré une concentration plasmatique en cocaïne trois heures après l’arrêt cardiaque à 1410 ng/mL, avec également des concentrations élevées de ses métabolites (BZE à 9670 ng/mL et EME à 7410 ng/mL). Les dosages ultérieurs ont révélé une cinétique décroissante des concentrations de cocaïne et de ses métabolites, suggérant que le pic de concentration de la cocaïne a eu lieu en amont du premier bilan sanguin. Au 7e jour d’hospitalisation, les concentrations de cocaïne, BZE et EME étaient respectivement de 4,2 ng/mL, 2350 ng/mL et 192 ng/mL. Conclusion Les cas de «body-packing» impliquant l’ingestion de paquets de cocaïne restent une cause majeure d’intoxication aiguë, souvent mortelle, en médecine d’urgence. Ces situations représentent des défis diagnostiques et thérapeutiques complexes, particulièrement lorsque des complications telles que la rupture des paquets survient. Les rares données pharmacocinétiques confirment que la rupture (ou l’administration orale) au niveau du tractus gastro-intestinal d’un ou plusieurs paquets entraîne une absorption massive et rapide de la cocaïne au niveau de l’estomac, dû à l’environnement acide de celui-ci, responsable de fortes concentrations plasmatiques de cocaïne. Au niveau intestinal, la cocaïne est également absorbée mais dans une moindre mesure puisque le milieu alcalin des intestins favorise la métabolisation de la cocaïne en ses métabolites inactifs. À cela s’ajoute l’existence d’une probable saturation métabolique hépatique et intestinale à des doses élevées de cocaïne, contribuant également à l’augmentation de sa concentration plasmatique. La persistance de concentrations plasmatiques élevées de cocaïne et de ses métabolites, malgré le retrait chirurgical des paquets, souligne la nécessité d’une surveillance clinique et biologique étroite dans les jours suivants l’intervention. Un examen d’imagerie suivi d’une éventuelle intervention chirurgicale rapides associés à un soutien en soins intensifs sont essentiels, bien que le pronostic demeure sombre dans les cas graves. Ce cas illustre également la nécessité de protocoles standardisés dans la gestion de patients « body-packers » et la prévention des complications fatales.Les intoxications par ingestion massive de cocaïne dans un contexte de «body-packing» représentent une urgence médicale et nécessitent une prise en charge multidisciplinaire rapide et coordonnée. La surveillance toxicologique détaillée de ces cas, comme illustrée ici, est essentielle pour comprendre la toxicodynamie, améliorer les stratégies thérapeutiques et développer des protocoles adaptés.

BACKGROUND:Levofloxacin is a broad-spectrum fluoroquinolone with pharmacokinetic characteristics that facilitate its use in many types of infections. OBJECTIVES:To develop a population pharmacokinetics (PK) model of levofloxacin and to identify covariates influencing its PK, to determine the best dose regimens for pharmacodynamic target achievement. PATIENTS AND METHODS:Patients treated with levofloxacin were retrospectively included from December 2014 to February 2021. The population PK analysis was performed using Pmetrics. Multiple covariates were tested: age, height, weight, ideal weight, BMI, body surface area (BSA), plasma protein and creatinine levels, and absolute glomerular filtration rate (aGFR) calculated from the chronic kidney disease-epidemiology formula and BSA. Dosing simulations were performed for all combinations of covariates and MIC values. The AUC0-24/MIC ratio targets were 50 for Streptococcus pneumoniae and 125 for other bacterial species. RESULTS:A total of 39 patients were included, of which 23 patients were hospitalized in ICUs. The population PK analysis was performed on 175 plasma concentrations of levofloxacin. A two-compartment model best described levofloxacin PK with three covariates: aGFR for the elimination rate constant and both plasma protein level and BSA for the central compartment volume. Tables with proposed dose regimens according to patient covariates and pharmacodynamic targets values are provided. CONCLUSIONS:This study provided a priori dose regimen adaptation based on a population PK model for levofloxacin. For patients with increased renal function or infection by high MIC bacteria, the pharmacodynamic target could not be reliably achieved with standard dosages.

Inulin, an increasingly studied dietary fiber, alters intestinal microbiota. The aim of this study was to assess whether inulin decreases intestinal colonization by multidrug resistant E. coli and to investigate its potential mechanisms of action. Mice with amoxicillin-induced intestinal dysbiosis mice were inoculated with extended spectrum beta-lactamase producing E. coli (ESBL-E. coli). The combination of inulin and pantoprazole (IP) significantly reduced ESBL-E. coli fecal titers, whereas pantoprazole alone did not and inulin had a delayed and limited effect. Fecal microbiome was assessed using shotgun metagenomic sequencing and qPCR. The efficacy of IP was predicted by increased abundance of 74 taxa, including two species of Adlercreutzia. Preventive treatments with A. caecimuris or A. muris also reduced ESBL-E. coli fecal titers. Fecal microbiota of mice effectively treated by IP was enriched in genes involved in inulin catabolism, production of propionate and expression of beta-lactamases. They also had increased beta-lactamase activity and decreased amoxicillin concentration. These results suggest that IP act through production of propionate and degradation of amoxicillin by the microbiota. The combination of pantoprazole and inulin is a potential treatment of intestinal colonization by multidrug-resistant E. coli. The ability of prebiotics to promote propionate and/or beta-lactamase producing bacteria may be used as a screening tool to identify potential treatments of intestinal colonization by multidrug resistant Enterobacterales.

AIMS The main objective of this study was to compare extended-spectrum β-lactamase (ESBL) Escherichia coli fecal titers during 12 days between two groups: mice who received proton pump inhibitors (PPIs) and those that did not. METHODS AND RESULTS We tested three different in vivo models: model 1, high inoculum (106 CFU.ml-1); model 2, low inoculum (102 CFU.ml-1); and model 3, low inoculum and 2-day amoxicillin wash-out. There was no significant difference between the two groups in fecal ESBL E. coli titers in models 1 and 2. The fecal titers of ESBL E. coli were probably too high to show differences in colonization related to PPI treatment. By introducing a 2-day wash-out period after stopping amoxicillin (model 3), the fecal ESBL E. coli titers were higher in the PPI-treated mice during 12 days (3 log versus 11 log day.CFU.g-1; p < 0.05). This result highlighted that PPIs promote stable ESBL E. coli digestive carriage in mice. Fecal quantitative PCR showed that mice with low ESBL E. coli fecal titers had a much higher concentration of equol-producing bacteria, Muribaculum sp., and Adlercreutzia caecimuris. CONCLUSIONS Pantoprazole treatment promotes sustained digestive carriage of ESBL E. coli in amoxicillin-treated mice.

Background Cloxacillin is the first-line treatment for methicillin-susceptible staphylococcal infective endocarditis (IE). The recommended dose is 12 g per day regardless of the patient characteristics, despite the importance of renal function on its pharmacokinetics. Objectives We sought to build a population pharmacokinetics model of continuous infusion cloxacillin in IE patients to evaluate the influence of multiple covariates and then develop a nomogram based on significant covariates for individual adaptation. Patients and methods We included patients of a local IE cohort who were treated with cloxacillin administered by continuous infusion, excluding those who received intermittent or continuous dialysis, extracorporeal membrane oxygenation or extracorporeal circulation. The population pharmacokinetic analysis was performed using Pmetrics. The influence of weight, ideal weight, height, body mass index, body surface area, glomerular filtration rate (GFR) calculated with the Chronic Kidney Disease Epidemiology Collaboration formula (both expressed in mL/min/1.73 m(2) and in mL/min) and serum protein level on cloxacillin pharmacokinetics was assessed. Accounting for relevant covariates, a dosing nomogram was developed to determine the optimal daily dose required to achieve a steady-state plasma concentration range of 20-50 mg/L with a probability >= 0.9. Results A total of 114 patients (331 plasma concentrations) were included. A one-compartment model including GFR expressed in mL/min as a covariate was chosen. Using the nomogram, achieving the cloxacillin concentration target requires a daily dose ranging from 3.5 to 13.1 g for a GFR ranging from 20 to 125 mL/min. Conclusions This work provided a practical tool for cloxacillin dose adjustment in IE according to renal function.

Background. We evaluated the safety and efficacy of XAV-19, an antispike glyco-humanized swine polyclonal neutralizing antibody in patients hospitalized with severe coronavirus disease 2019 (COVID-19).Methods. This phase 2b clinical trial enrolled adult patients from 34 hospitals in France. Eligible patients had a confirmed diagnosis of severe acute respiratory syndrome coronavirus 2 within 14 days of onset of symptoms that required hospitalization for low-flow oxygen therapy (<6 L/min of oxygen). Patients were randomly assigned to receive a single intravenous infusion of 2 mg/kg of XAV-19 or placebo. The primary end point was the occurrence of death or severe respiratory failure between baseline and day 15.Results. Between January 12, 2021, and April 16, 2021, 398 patients were enrolled in the study and randomly assigned to XAV-19 or placebo. The modified intention-to-treat population comprised 388 participants who received full perfusion of XAV-19 (199 patients) or placebo (189 patients). The mean (SD) age was 59.8 (12.4) years, 249 (64.2%) individuals were men, and the median time (interquartile range) from symptom onset to enrollment was 9 (7-10) days. There was no statistically significant decrease in the cumulative incidence of death or severe respiratory failure through day 15 in the XAV-19 group vs the placebo group (53/199 [26.6%] vs 48/189 [25.4%]; adjusted risk difference, 0.6%; 95% CI, -6% to 7%; hazard ratio, 1.03; 95% CI, 0.64-1.66; P = .90). In the safety population, adverse events were reported in 75.4% of 199 patients in the XAV-19 group and in 76.3% of 190 patients in the placebo group through D29.Conclusions. Among patients hospitalized with COVID-19 requiring low-flow oxygen therapy, treatment with a single intravenous dose of XAV-19, compared with placebo, did not show a significant difference in terms of disease progression at day 15.

Objectives Limited pharmacokinetics data support dalbavancin long-term use in off-label indications and the optimal dosing regimen is debated. We aimed to describe dalbavancin concentrations in an observational retrospective multicentre study.Methods Patients from 13 French hospitals, treated with 1500 mg doses of dalbavancin and for whom therapeutic drug monitoring was performed from June 2018 to March 2021 were included. Dalbavancin plasma concentrations were described at peak and 1, 2, 3, 4, 6 and 8 weeks after the last 1500 mg dose. Concentrations in patients weighing more or less than 75 kg and with a GFR greater or less than 60 mL/min were compared. Microbiological data were collected and dalbavancin MIC was measured when possible.Results One hundred and thirty-three patients were included (69% treated for bone and joint infections, 16% for endocarditis). Thirty-five patients received a single dose of dalbavancin and 98 received several administrations. Two, 3 and 4 weeks after the last dose, median plasma concentrations were respectively 25.00, 14.80 and 9.24 mg/L for the first doses and 34.55, 22.60 and 19.20 mg/L for the second or subsequent doses. Weight and renal function had an impact on pharmacokinetics. Infection was documented in 105 patients (Staphylococcus spp. in 68% of cases). Staphylococcus aureus was isolated in 32.5% of cases (median MIC: 0.047 mg/L) and Staphylococcus epidermidis in 27% of cases (median MIC of 0.047 mg/L).Conclusions Plasma concentrations of dalbavancin were consistent with those described in clinical trials and those sought during the industrial development of the molecule.

Introduction. CNI, mostly tacrolimus, is the cornerstone of immunosuppressive regiment after SPK transplantation. Due to its narrow therapeutic window, and given the multiple inter and intra-individual variability (mainly among the diabetic population), close monitoring of the drug is mandatory. Indeed, diabetic patients often require higher dosages which could lead to kidney and pancreatic allograft dysfunctions. Moreover, this is exacerbated by a high peak level consecutive of the frequently observed autonomic digestive diabetic neuropathy. In this context we designed in our center a prospective PK study in order to determine if LCPT tacrolimus formulation (Meltdose®) could be a safe alternative in patients receiving a SPK transplantation. Methods. We conducted a phase 4 trial comparing a 24-hour PK profile of tacrolimus depending on the formulation (Immediate Release Tacrolimus – IR Tac - versus LCPT) in type 1 diabetic patients receiving a SPK transplantation. Patients who consented to participate in the study were started on IR-Tac after transplantation. Our standard immunosuppressive regimen included ATG, tacrolimus, MPA and 7-10 days steroids. PK profiles (AUC 0-24, Cmin, Cmax, Ke, t1/2 and percentage of fluctuation) were measured when a stable trough level was achieved after an initial 7-17 p.o. period. Patients were then switched to LCPT. After 7 to 14 days, a second 24-hour PK profile was measured. Biological and clinical tolerance, as well as safety, were monitored for 5.5 months after the switch. The research protocol was approved by the Research Ethics Committee and was in accordance with the Declaration of Helsinki. Expected Results and Perspectives. During the study period (09/2020 – 04/2023), the total number of designed patients were included. 24 patients had a complete follow-up (the last inclusion was on April, 2023). Final results will be available and examined on September 2023. Our study will provide new insights of tacrolimus PK among this high-risk patient transplant category. It could also allow to refine the immediate posttransplant immunosuppressive regimen in patients requiring SPK.

OBJECTIVE:We assessed the efficacy of a quality improvement programme to optimize the delivery of antimicrobial therapy in critically ill patients with hospital-acquired infections (HAI).PATIENTS AND METHODS:Before-after trial in a university hospital in France. Consecutive adults receiving systemic antimicrobial therapy for HAI were included. Patients received standard care during the pre-intervention period (June 2017 to November 2017). The quality improvement programme was implemented in December 2017. During the intervention period (January 2018 to June 2019), clinicians were trained to dose adjustment based on therapeutic drug monitoring and continuous infusion of β-lactam antibiotics. The primary endpoint was the mortality rate at day 90.RESULTS:A total of 198 patients were included (58 pre-intervention, 140 intervention). The compliance with the therapeutic drug monitoring-dose adaptation increased from 20.3% to 59.3% after the intervention (P < 0.0001). The 90-day mortality rate was 27.6% in the pre-intervention period and 17.3% in the intervention group (adjusted relative risk 0.53, 95%CI 0.27-1.07, P = 0.08). Treatment failures were observed in 22 (37.9%) patients before and 36 (25.7%) patients after the intervention (P = 0.07).CONCLUSIONS:Recommendations for therapeutic drug monitoring-dose adaptation and continuous infusion of β-lactam antibiotics were not associated with a reduction in the 90-day mortality rate in patients with HAI.

French guidelines recommend reaching an amikacin concentration of ≥8 × MIC 1 h after beginning infusion (C1h), with MIC = 8 mg/L for probabilistic therapy. We aimed to elaborate a nomogram guiding clinicians in choosing the right first amikacin dose for ICU patients in septic shock. A total of 138 patients with 407 observations were prospectively recruited. A population pharmacokinetic model was built using a non-parametric, non-linear mixed-effects approach. The total body weight (TBW) influenced the central compartment volume, and the glomerular filtration rate (according to the CKD–EPI formula) influenced its clearance. A dosing nomogram was produced using Monte Carlo simulations of the amikacin amount needed to achieve a C1h ≥ 8 × MIC. The dosing nomogram recommended amikacin doses from 1700 mg to 4200 mg and from 28 mg/kg to 49 mg/kg depending on the patient’s TBW and renal clearance. However, a Cthrough ≤ 2.5 mg/L 24 h and 48 h after an optimal dose of amikacin was obtained with probabilities of 0.20 and 0.81, respectively. Doses ≥ 30 mg/kg are required to achieve a C1h ≥ 8 × MIC with MIC = 8 mg/L. Targeting a MIC = 8 mg/L should depend on local ecology.

ImportanceThe DRAMES (Décès en Relation avec l’Abus de Médicaments Et de Substances) register is a database of drug-related deaths with the aim of identifying the psychoactive substances associated with and estimating the trends in these deaths. Our novel approach is based on the collection of data on all deaths for which toxicology experts have performed analyses.ObjectiveTo describe drug-related deaths in France and report trends over an 11-year period.Design, Setting, and ParticipantsThis case series used a national register to assess 4460 drug-related deaths that occurred from 2011 to 2021 in France. Data analyses were performed from January 1, 2012, to December 31, 2022.Main Outcomes and MeasuresDemographic characteristics; medical and substance abuse history; forensic autopsy findings; and toxicology reports.ResultsAmong the 4460 deceased individuals (mean [SD] age, 37.8 [10.5] years), the mortality rate was highest among men (sex ratio, 4.4:1). Of the deaths involving a single or predominant drug, the legal substitution product, methadone, was the leading cause of death during the entire study period, ahead of heroin—44.7% and 35.9% for methadone vs 15.8% and 21.8% for heroin in 2011 and 2021, respectively. Between 2011 and 2021, most of the drug-related deaths shifted from licit to illicit drugs, and statistically significant variations were found for buprenorphine, cocaine, heroin, methadone, and other licit opioids. Deaths related to polydrug use increased from 23.2% in 2011 to 30.6% in 2021. In this context, opioids remained associated with most deaths, with at least 1 opioid being involved in approximately 9 of 10 cases (85.9%) in 2021. However, the main trend was the dramatic increase in drug combinations with cocaine, from less than one-third of cases in 2011 (30.8%) to more than half in 2021 (57.8%).Conclusions and RelevanceThis case series assessment of 4460 drug-related deaths found that opioids used alone or in combination were the main contributor to drug-related deaths, despite having a lower prevalence than other drugs. This finding is similar to that of other countries; however, in France licit methadone was the leading cause of opioid-related deaths (ahead of heroin) during the study period. Deaths associated with use of cannabis, new psychoactive substances, and stimulants (including amphetamine-type stimulants and cocaine, especially in combination) have increased and should be closely monitored.

Midazolam is a benzodiazepine frequently used for sedation in patients hospitalized in the intensive care unit (ICU) for coronavirus disease 2019 (COVID‐19). This drug is primarily metabolized by cytochrome P450 3A (CYP3A) isoenzymes. Several studies have suggested that inflammation, frequently observed in these patients, could modulate CYP3A activity. The objective of this work was to study the impact of inflammation on midazolam pharmacokinetics in patients with COVID‐19. Forty‐eight patients hospitalized in the ICU for COVID‐19 and treated with midazolam administered by continuous infusion were included in this study. Midazolam and α‐hydroxymidazolam concentrations were measured and patient data, including the use of CYP3A inhibitors, were collected. Total and unbound concentrations of midazolam and α‐hydroxymidazolam were measured in plasma using a validated liquid‐chromatography coupled with mass spectrometry method. Inflammatory condition was evaluated by C‐reactive protein (CRP) level measurement. Both drug concentrations and CRP measurements were performed on 354 plasma samples. CRP elevation was significantly associated with the α‐hydroxymidazolam/midazolam plasma ratio decrease, whether for the unbound fraction or for the total fraction. Conversely, inflammation was not associated with protein binding modifications. Logically, α‐hydroxymidazolam/midazolam plasma ratio was significantly reduced when patients were treated with CYP3A inhibitors. In this study, we showed that inflammation probably reduces the metabolism of midazolam by CYP3A. These results suggest that molecules with narrow therapeutic margins and metabolized by CYP3A should be administrated with care in case of massive inflammatory situations.

LC-HRMS has nowadays become the "gold standard" for identification of xenobiotics in clinical and forensic toxicology providing both high selectivity and specificity. Sample preparation and introduction nevertheless remain a key step and should be simple, universal, reproducible and sensitive for a broad range of analytes. Two types of sample introduction were tested for drugs spiked in biological samples: on-line extraction by turbulent flow chromatography (TurboFlow®) versus direct injection. Then, parameters of protein precipitation such as organic solvent, sample/organic solvent ratio and evaporation after precipitation were evaluated. In all, 62 compounds (drugs of abuse, pharmaceuticals and metabolites) were selected according to several criteria such as polarity, log P, retention time, occurrence in drug screening and divided in two groups regarding their therapeutic (A: n = 20) or regulatory (B: n = 42) concentrations. Plasma, blood and urine samples were prepared by spiking different concentrations (0.25 to 1000 μg/L, n = 6) into blank matrices. TurboFlow® and LC analyses were performed using a Transcend II TLX-1 and Vanquish systems. Data were acquired on an Exploris 120 Orbitrap Mass spectrometer and processed with TraceFinder 5.1 software (ThermoFisher Scientific®, San Jose, USA). The analytical workflow was based on previous publication (Helfer, J Chrom B, 2017, 1043, 138–149) with minor modifications: Phenyl replaced by Fluoro Turboflow column. 400 μL of sample was mixed with 600 μL of acetonitrile for precipitation. After shaking and centrifugation, the supernatant was injected. Several parameters were assessed for protein precipitation: – Sample/organic solvent ratio: 1:1,5; 1:2 and 1:3; – Organic solvent: acetonitrile, methanol, acetonitrile plus 0.1% formic acid, acetonitrile:methanol (50:50, v:v), methanol plus 0.2 M ZnSO4 (80:20, v:v) and acetonitrile with 80 mg QuEChERS extraction salts; – Concentration: direct injection or evaporation after precipitation. The performances were evaluated regarding the limits of identification (LOI), reproducibility at the respective LOI of each compound and linearity. Reproducibility gave satisfactory results for 59 and 56 compounds in direct injection and in TurboFlow® in all matrices (CV < 15%). Linearity was acceptable in both injection modes with no exception (R2 > 0.95). Finally, sensitivity appeared to be the most differentiating factor, direct injection showing lower limits for 29 (plasma), 31 (blood) and 28 (urine) compounds. For example, identification was possible at 10 μg/L in plasma for gabapentin, metformin and baclofen in direct injection and at 100 μg/L in TurboFlow®. For protein precipitation, 1:1.5 and 1:2 ratios were statistically equivalent in term of sensitivity regardless of the matrix, whereas 1:3 ratio showed an average decrease of 48%, 35% and 22% of pic areas in plasma, blood and urine samples respectively. The LOI obtained with different organic solvent were identical except for few compounds. Acetonitrile provided lower LOI for sufentanyl (0.25 vs. 1 μg/L for other solvents) whereas methanol in urine showed better results for zopiclone (1 μg/L vs. 5 μg/L). Finally, the addition of QuEChERS salt and evaporation after precipitation doubled at least the average signal intensity for all drugs. Despite some benefits such as large injection volume and automation, the sensitivity of the method including TurboFlow® extraction did not show improvements compared with direct injection. Indeed, small hydrophilic molecules had generally less retention on TurboFlow® column resulting in lower recovery and signal suppression can occur due to many matrix components. The addition of formic acid for protein precipitation does not improve the sensitivity, neither ZnSO4 nor mix of solvents. Simple and providing adequate sensitivity, the use of acetonitrile as organic solvent for protein precipitation with a ratio of 1:2 was chosen for the 3 matrices for routine. The addition of QuEChERS salts and evaporation after precipitation could be dedicated to specific cases where very low LOI has to be reached.

ABSTRACTBackgroundWe assessed the pharmacokinetics and safety of XAV-19, a swine glyco-humanized polyclonal antibody against SARS-CoV-2, in COVID-19-related moderate pneumonia. In vitro, 100% neutralization activity is seen with XAV-19 concentrations above 5 μg/mL.MethodsIn this phase 2a trial, adults with COVID-19-related moderate pneumonia of ≤10 days duration were randomized to infusion of XAV-19 0.5 mg/kg at day 1 and day 5 (group 1), 2 mg/kg at day 1 and day 5 (group 2), 2 mg/kg at day 1 (group 3) or placebo.ResultsEighteen patients (n=7 for group 1, n=1 for group 2, n=5 for group 3, and n=5 for placebo) were enrolled. Baseline characteristics were similar across groups, XAV-19 serum concentrations (μg/mL, median, range) at Cmaxand at day 8 were 9.1 (5.2-18.1) and 6.4 (2.8-11.9), 71.5 and 47.2, and 50.4 (29.1-55.0) and 20.3 (12.0-22.7) for groups 1, 2 and 3, respectively (p=0.012). Terminal half-life (median, range) was estimated at 11.4 (5.5-13.9) days for 2 mg/kg of XAV-19 at day 1. Serum XAV-19 concentrations were above the target concentration of 10 μg/mL (tow fold the in vitro 100% inhibitory concentration [IC100]) from the end of perfusion to more than 8 days for XAV-19 2 mg/kg at day 1. No hypersensitivity or infusion-related reactions were reported during treatment, there was no discontinuation for adverse events and no serious adverse events related to study drug.ConclusionsSingle intravenous dose of 2 mg/kg of XAV-19 demonstrated high serum concentrations, predictive of potent durable neutralizing activity with good tolerability.Trial registrationClinicalTrials.gov Identifier:NCT04453384Main pointIn this first-in-human trial including patients with COVID-19-related pneumonia, a single 2mg/kg dose of a swine glyco-humanized polyclonal anti-SARS-CoV-2 antibody, achieved serum concentrations above the target of neutralization threshold for 8 days in all patients, with good tolerability and safety.

BackgroundThe globally increasing resistance due to extended-spectrum beta-lactamase producing Enterobacteriaceae is a major concern. The objective of this work was to develop a murine model to study the gut bacteria parameters during complex antibiotics like cefotaxime and ceftriaxone treatment and to compare the fecal carriage of ESBL-producing Enterobacteriaceae.MethodsSWISS mice were treated either with ceftriaxone or with cefotaxime or with NaCl 0.9% as a control group from day 1 to day 5. We performed a gavage at day 4 with a Klebsiella pneumonia CTX-M9. We collected stools and performed pharmacological measurements, cultures and 16S rRNA gene amplification and sequencing during the 12 days of the stool collection.ResultsMice treated with ceftriaxone were more colonized than mice treated with cefotaxime after gavage (p-value = 0.008; Kruskal-Wallis test). Ceftriaxone and cefotaxime were both excreted in large quantity in gut lumen but they drove architecture of the gut microbiota in different trajectories. Highest levels of colonization were associated with particular microbiota composition using principal coordinate analysis (PCoA) which were more often achieved in ceftriaxone-treated mice and which were preceded by highest fecal antibiotics concentrations in both cefotaxime or ceftriaxone groups. Using LEfSe, we found that twelve taxa were significantly different between cefotaxime and ceftriaxone-treated mice. Using SplinectomeR, we found that relative abundances of Klebsiella were significantly higher in CRO than in CTX-treated mice (p-value = 0.01).ConclusionCeftriaxone selects a particular microbial community and its substitution for cefotaxime could prevent the selection of extended-spectrum beta-lactamase producing Enterobacteriaceae.