Routine urinary detection of antihypertensive drugs for systematic evaluation of adherence to treatment in hypertensive patients

International audienceBackground: Nonadherence to antihypertensive therapy is an important cause of poor blood pressure control. However, to date, few effective and accurate tools exist to routinely evaluate drug nonadherence.Methods: In this observational study, performed under conditions of routine clinical practice, we included 174 patients (aged 67 ± 11 years) with treated essential hypertension who attended the outpatient hypertension clinic of a university hospital. Adherence to antihypertensive treatment was measured by using ultraperformance liquid chromatography-tandem mass spectrometry in spot urine at the time of clinical appointment and blood pressure measurement. Patients were also asked to report their adherence using a validated questionnaire (four-item Morisky Medication Adherence Scale).Results: The prevalence of directly measured nonadherence by urine drug detection was approximately 10%. Compared with adherent patients, those who did not adhere to their treatment (n = 15) had a higher number of antihypertensive pills and drugs (P = 0.02), cotreatment with cardiovascular drugs (P < 0.05), and total concurrent medications and pills (P < 0.01). After adjustment for age, SBP and DBP were higher in nonadherent than adherent group (SBP: 146 ± 18 vs. 131 ± 14, respectively, P < 0.01; and DBP: 77 ± 15 vs. 73 ± 9, respectively, P < 0.01). There was no significant association between four-item Morisky Medication Adherence Scale score and directly measured nonadherence. A longitudinal analysis, performed in a subpopulation of 105 patients after a median follow-up of 11 months, showed that the adherence status remained unchanged in 88% of patients.Conclusion: These results indicate a good adherence to antihypertensive drugs in patients attending the outpatient clinics of a university hospital. They suggest that urine detection of antihypertensive drugs by ultraperformance liquid chromatography-tandem mass spectrometry is an accurate and practical tool for directly monitoring adherence. This direct information is not overlapping with self-report questionnaire

Niveau de preuve pour le suivi thérapeutique pharmacologique de la vancomycine

La vancomycine est un antibiotique à usage hospitalier administré par voie intraveineuse dans le traitement des infections systémiques. Éliminé par voie rénale, il est potentiellement néphrotoxique. Le suivi thérapeutique pharmacologique (STP) de cet antibiotique temps-dépendant vise à assurer l’efficacité du traitement et éviter l’apparition de résistance en ciblant des concentrations résiduelles supérieures à la concentration minimale inhibitrice (CMI). Secondairement, le STP est indiqué chez les sujets à risque de néphrotoxicité notamment l’insuffisant rénal. Il doit être généralement réalisé à l’équilibre (2-3 jours après l’initiation du traitement) ou dans les 24 h pour les sujets à risque. L’administration en perfusion continue (PC) n’améliore pas le pronostic mais assure une moindre variabilité pharmacocinétique et un meilleur rapport coût-efficacité. Les concentrations plasmatiques cibles sont de 15 à 20 mg/L [25 à 30 mg/L pour les infections à souches de Staphylococcus aureus de sensibilité intermédiaire aux glycopeptides (GISA)] en administration discontinue et 25 à 40 mg/L pour la PC

Niveau de preuve du suivi thérapeutique pharmacologique du posaconazole

Le posaconazole, antifongique systémique, est commercialisé en France depuis 2006. Il est indiqué en deuxième ligne dans le traitement des infections fongiques invasives (IFI) [aspergilloses] et en prophylaxie des IFI chez le patient recevant une chimiothérapie ou une greffe de cellules souches hématopoïétiques. L’analyse de la littérature indique l’existence d’une relation concentration-efficacité mais à ce jour aucune étude n’a pu démontrer de relation concentration-toxicité en raison d’un profil de sécurité favorable et de la difficulté d’obtenir des concentrations élevées. En curatif, le maintien des concentrations plasmatiques résiduelles entre 0,5 et 1,5 mg/L semble être un facteur prédictif d’efficacité. En prophylaxie, le seuil de 0,5 mg/L correspondrait à une exposition minimale acceptable. Toutefois cette cible n’est pas encore définie. La saturation de l’absorption du posaconazole au-dessus de la dose per os de 800 mg est un facteur limitant à l’adaptation. À ce titre, le Suivi Thérapeutique Pharmacologique du posaconazole peut être « recommandé »

An ultra performance liquid chromatography-tandem mass spectrometry method for the therapeutic drug monitoring of isavuconazole and seven other antifungal compounds in plasma samples

International audienceA new analytical method was developed for the routine Therapeutic Drug Monitoring of 8 antifungals compounds in 50 μL of plasma: isavuconazole (ISZ), voriconazole (VRZ), posaconazole (PSZ), fluconazole (FCZ), caspofungin (CSF), flucytosine (5FC), itraconazole (ITZ) and its metabolite OH-itraconazole (OH-ITZ). After adding 50 μL of the internal standard, which consisted in a mixture of the deuterated isotopes of the quantified compounds, the sample treatment consisted in a simple protein precipitation with 400 μL of acetonitrile. Five microliters of the supernatant were directly injected into the chromatographic system. The chromatographic separation was performed with a Waters C18-BEH column and a mobile phase consisting in a mixture of water and acetonitrile, both containing 0.1% of formic acid. The total run time was 3 min and the detection of the analytes was performed by electrospray ionization in a positive mode using selected reaction monitoring. Intra and inter-day precision and inaccuracy were < 15% over the calibration ranges that were determined according to their clinical relevance: 0.20–20.0 mg/L for ISZ, VRZ, PSZ, ITZ, and OH-ITZ; 0.50–50.0 mg/L for FCZ and CSF; 2.00–200 mg/L for 5FC. This simple and fast method was found suitable for routine therapeutic drug monitoring

In Vivo Efficacy of Voriconazole in a Galleria mellonella Model of Invasive Infection Due to Azole-Susceptible or Resistant Aspergillus fumigatus Isolates

International audienceAspergillus fumigatus is an environmental filamentous fungus responsible for life-threatening infections in humans and animals. Azoles are the first-line treatment for aspergillosis, but in recent years, the emergence of azole resistance in A. fumigatus has changed treatment recommendations. The objective of this study was to evaluate the efficacy of voriconazole (VRZ) in a Galleria mellonella model of invasive infection due to azole-susceptible or azole-resistant A. fumigatus isolates. We also sought to describe the pharmacokinetics of VRZ in the G. mellonella model. G. mellonella larvae were infected with conidial suspensions of azole-susceptible and azole-resistant isolates of A. fumigatus. Mortality curves were used to calculate the lethal dose. Assessment of the efficacy of VRZ or amphotericin B (AMB) treatment was based on mortality in the lethal model and histopathologic lesions. The pharmacokinetics of VRZ were determined in larval hemolymph. Invasive fungal infection was obtained after conidial inoculation. A dose-dependent reduction in mortality was observed after antifungal treatment with AMB and VRZ. VRZ was more effective at treating larvae inoculated with azole-susceptible A. fumigatus isolates than larvae inoculated with azole-resistant isolates. The concentration of VRZ was maximal at the beginning of treatment and gradually decreased in the hemolymph to reach a Cmin (24 h) between 0.11 and 11.30 mg/L, depending on the dose. In conclusion, G. mellonella is a suitable model for testing the efficacy of antifungal agents against A. fumigatus

An ultra performance liquid chromatography-tandem mass spectrometry method for the therapeutic drug monitoring of isavuconazole and seven other antifungal compounds in plasma samples

International audienceA new analytical method was developed for the routine Therapeutic Drug Monitoring of 8 antifungals compounds in 50 μL of plasma: isavuconazole (ISZ), voriconazole (VRZ), posaconazole (PSZ), fluconazole (FCZ), caspofungin (CSF), flucytosine (5FC), itraconazole (ITZ) and its metabolite OH-itraconazole (OH-ITZ). After adding 50 μL of the internal standard, which consisted in a mixture of the deuterated isotopes of the quantified compounds, the sample treatment consisted in a simple protein precipitation with 400 μL of acetonitrile. Five microliters of the supernatant were directly injected into the chromatographic system. The chromatographic separation was performed with a Waters C18-BEH column and a mobile phase consisting in a mixture of water and acetonitrile, both containing 0.1% of formic acid. The total run time was 3 min and the detection of the analytes was performed by electrospray ionization in a positive mode using selected reaction monitoring. Intra and inter-day precision and inaccuracy were < 15% over the calibration ranges that were determined according to their clinical relevance: 0.20–20.0 mg/L for ISZ, VRZ, PSZ, ITZ, and OH-ITZ; 0.50–50.0 mg/L for FCZ and CSF; 2.00–200 mg/L for 5FC. This simple and fast method was found suitable for routine therapeutic drug monitoring

Toxicité pulmonaire des inhibiteurs de mTOR. Comparaison de deux populations distinctes : les transplantés d'organe solide et les patients atteints de cancer RESUME

International audienceIntroduction: Mammalian target of rapamycin (mTOR) inhibitors-associated pneumonitis (mTOR-IP) has long been described in solid organ recipients (T) patients but more recently in cancer (K) patients. Its overall characteristics have never been compared between these 2 populations. The aim of this study was to compare them in terms of presentation, severity and outcome in T and in K patients.Material and methods: We carried out a retrospective study in a single French tertiary center. Four databases were used to ensure the exhaustive collection of all mTOR-IP cases between 2001 and 2020. All clinical, biological, radiological, pathological and outcome data were reviewed.Results: Thirty-nine patients with mTOR-IP were diagnosed during this period, 24T and 15K patients. The average dosage of everolimus and sirolimus was 2,65mg (±1,78) and 2,75mg (±0,96) in T patients, respectively, versus 8,75mg (±2,26) for everolimus in K patients. The overall prevalence of mTOR-IP was 6.4% with a median time of occurrence of 7 months [IQR 3-35 months]. mTOR-IP were significantly more frequent (P<0.001) and occurred earlier (P<0.001) in cancer patients. No clinical, functional, radiological, pathological nor outcome differences were otherwise observed between the 2 groups. Average everolimus blood levels at the time of mTOR-IP diagnosis were in the range of recommended therapeutic values.Conclusion: Our study shows that mTOR-IP is comparable in terms of presentation in T and in K patients but that it occurs significantly earlier after drug introduction in the latter. This raises questions as to the potential role of the higher doses used in K patients as well as that of co-treatments in the pathogeny of the disease.Introduction : Les inhibiteurs de mTOR (mammalian target of rapamycin), initialement utilisés comme immunosuppresseurs en transplantation d’organe solide, ont vu leurs indications s’étendre au domaine de l’oncologie médicale en raison de leurs propriétés antitumorales. La toxicité pulmonaire des inhibiteurs de mTOR est rapportée dans les deux indications, mais peu d’études ont exploré les différences entre les pneumopathies aux inhibiteurs de mTOR (mTOR-PI) en transplantation (T) et en oncologie (K). L’objectif de notre étude est de comparer les mTOR-PI dans ces deux populations. Méthodes : Notre étude rétrospective monocentrique a été réalisée dans un centre expert en pneumopathies interstitielles, en transplantation et en oncologie (Hôpital Européen Georges Pompidou). Quatre bases de données ont été utilisées afin d'assurer la collecte exhaustive de tous les cas de mTOR-PI entre 2001 et 2020. Toutes les données cliniques, biologiques, radiologiques et pathologiques ainsi que les résultats ont été collectés et analysés.Résultats: Trente-neuf patients atteints de mTOR-PI ont été diagnostiqués pendant cette période, 24 en transplantation (T) et 15 en oncologie (K). La posologie moyenne de l’everolimus et du sirolimusétait respectivement de 2,65 mg (± 1,78) et 2,75mg (± 0,96) en T contre 8,75mg (± 2,26) pour l’everolimus en K. La prévalence globale de mTOR-PI était de 6,4 % avec un délai médian de survenue de 7 mois [IQR 3-35 mois]. Les mTOR-PI étaient significativement plus fréquentes (p < 0,001) et survenaient plus précocement (p < 0,001) chez les patients K. Aucune autre différence clinique, fonctionnelle, radiologique, pathologique ou de sévérité n'a été observée entre les deux groupes. Au moment du diagnostic de mTOR-PI, 14/18 (78%) des patients transplantés avaient un taux résiduel d’éverolimus dans les normes des valeurs thérapeutiques recommandées.Conclusion: Les pneumopathies aux inhibiteurs de mTOR sont comparables en termes de présentation chez les patients T et K, mais elles surviennent significativement plus tôt après l'introduction du médicament chez ces derniers. Cela pourrait être en partie lié aux différences de posologie utilisées dans ces deux populations

Influence of Renal Function and Age on the Pharmacokinetics of Levofloxacin in Patients with Bone and Joint Infections

Despite its efficacy and toxicity being exposure-related, levofloxacin pharmacokinetics in patients with bone and joint infections has been poorly described to date, so the possible need for a dose adjustment is unknown in this population. A prospective population pharmacokinetic study was conducted in 59 patients to answer this question. The final model consisted of a one-compartment model with first-order absorption and elimination. Mean parameter estimates (% interindividual variability) were 0.895 h&minus;1 for the absorption rate constant (Ka), 6.10 L/h (40%) for the apparent clearance (CL/F), 90.6 L (25%) for the apparent distribution volume (V/F). Age and glomerular filtration rate (GFR), estimated by the modification of diet in renal disease formula, were related to CL/F by power models, and CL/F was found to increase for increasing GFR and decreasing age. For a similar GFR, the simulated area under the curve (AUC) was 55% higher in 70 years-old patients compared to 30 year-old patients. Based on this model, a 750 mg dose should provide an optimal exposure (AUC/ minimum inhibitory concentration (MIC) &ge;100), with the possible exception of patients older than 60 years and with GFR &lt;70 mL/min/m&sup2; who may necessitate a dose reduction, and patients with infections caused by bacteria with MIC close to 1 mg/L who may need an increase in the dose