OBJECTIVES:Rilpivirine, a non-nucleoside reverse transcriptase inhibitor for preventing mother-to-child HIV transmission, may have reduced plasma exposure in the second and third trimesters due to increased metabolism/elimination in pregnant women, potentially compromising its efficacy. The study aimed to evaluate maternal rilpivirine plasma concentrations during pregnancy and postpartum. METHODS:A multicenter, cross-sectional, cohort was conducted from 2020 to 2023. Pregnant women living with HIV-1 receiving rilpivirine 25 mg once-daily containing regimen were enrolled. Plasma concentrations of rilpivirine were determined throughout pregnancy and postpartum. A population pharmacokinetic approach was performed to analyze the plasma concentrations. Rilpivirine trough plasma concentrations (C24h) were estimated using individual parameters and interpreted using an efficacy threshold of 48 ng/ml (# four-fold protein adjusted EC50). RESULTS:Seventy-two (97% sub-Saharan African) pregnant women were enrolled: median age 34 years old (interquartile range 25-75%; 28-38). All were receiving triple-therapy, including emtricitabine/tenofovir (as tenofovir disoproxil fumarate or tenofovir alafenamide fumarate)-associated nucleoside reverse transcriptase inhibitors. Overall, 222 plasma concentrations were determined. There was no effect of gestational age or trimester on pharmacokinetic parameters to improve the between-occasion variabilities. Median rilpivirine estimated C24h were 79 ng/ml (interquartile range 25-75%; 55-105). Among the 72 women, 14% of them presented C24h<48 ng/ml. Only one woman presented >200 copies/ml viral load during her pregnancy. CONCLUSIONS:In our study, no significant effect of pregnancy on rilpivirine pharmacokinetic parameters was reported. No dose adjustment for orally-administered rilpivirine should be recommended in this setting.

Objective: The randomized RADIANCE-HTN TRIO trial assessed the safety and efficacy of ultrasound renal denervation (uRDN) among patients with resistant hypertension (HTN), demonstrating a difference in daytime ambulatory systolic BP (DASBP) of -4.5 mmHg in favor of uRDN over a sham procedure at 2 months. Blood pressure results may be confounded by changes in anti-hypertensive medications (AHM). In this analysis, we assessed the BP-lowering efficacy of uRDN adjusted for detected AHM metabolites at baseline and 2 months. Design and method: Following standardization on a single triple combination antihypertensive pill, patients with daytime ambulatory blood pressure (DABP) 135/85 mmHg or greater were randomized 1:1 to uRDN or sham. Chemical adherence testing was used to detect AHM or their metabolites in spot urine samples under blinding to treatment assignment at baseline and 2 months. Analysis of covariance (ANCOVA) was utilized to assess the 2-month change in DASBP between groups, adjusting for DASBP at baseline and AHM detected at baseline and 2 months. Results: Both DABP and AHM urine metabolite data at baseline and 2 months were available in 100 patients (uRDN n=47; sham n=53). Mean age was 52.6±8.8 years, 23% were female, and 71% were white. At baseline, DASBP was 149±11 mmHg and 2.7±1.2 AHM metabolites were detected. No changes in number of detected drugs between baseline and 2 months were found in 72% of the patients. Between baseline and 2 months, the change in DASBP was -10.9 [95% CI: -15.5, -6.3] mmHg in the uRDN group and -4.0 [-8.0, 0.0] mmHg in the sham group (baseline-adjusted between-group difference: -6.9 [-12.8, -1.1] mmHg; p=0.007). Following additional adjustment for the number of detected AHM at baseline and 2M, the mean between-group difference in DASBP was -9.3 [-14.9, -3.7] mmHg (p=0.0003) in favor of uRDN. Conclusions: The blood pressure-lowering efficacy of uRDN in patients with resistant HTN was maintained and numerically more pronounced when adjusting for changes in detected AHM metabolites.

Background: About 50% of patients are nonadherent to antihypertensive medications (AHM), impairing blood pressure (BP) management. The RADIANCE-HTN TRIO trial screened patients with resistant hypertension by first placing them on a fixed-dose combination triple pill (ARB+amlodipine+HCTZ). Ambulatory BP measurement 4 weeks later found 43% had controlled BP and were thus ineligible for enrollment. A total of 136 patients with uncontrolled BP were randomized to ultrasound renal denervation (uRDN) or sham-control. This analysis assessed adherence characteristics among patients in the trial. Method: TRIO patients consented to have chemical adherence testing that detected AHM or their metabolites in spot urine samples at baseline, 2 and 6 months. Full adherence (FA) was defined by all prescribed drugs detected in the sample. Results: Adherence data were available at any timepoint for 129 and all timepoints for 91 patients. Among patients with data at all timepoints, 66% (60/91) were FA and 34% (31/91) were partially- or fully nonadherent (PA/NA) to any of their prescribed medications. Adherence rates did not differ between treatment groups or geographies. Women were less likely to be FA (p<0.001) (Table). PA/NA patients had higher rates of peripheral and cerebrovascular disease, and higher BP before and after triple pill. Adherence to triple pill was 81% at baseline, 85% at 2-months, and 83% at 6-months. Medications were titrated after 2-months. At 6-months, adherence to additional medication classes prescribed was: aldosterone antagonist 71%, beta blockers 62%, and centrally-acting alpha-2 agonists 60%. Conclusions: The stringent TRIO study design uncovered significant medication nonadherence that translated into a high rate of apparent resistant HTN. It also showed high adherence to a fixed-dose triple pill. One third of enrolled patients were not fully adherent to medications, and these patients had higher BP and higher rates of vascular disease. Understanding clinical features associated with medication adherence may improve hypertension management.

Journal Article Corrected proof Nirmatrelvir and Ritonavir Combination in COVID-19 Patients With Advanced Chronic Kidney Disease Get access Emmanuel Lafont, Emmanuel Lafont Department of Internal Medicine, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France Correspondence: E. Lafont, Internal Medicine Department, Hôpital Européen Georges Pompidou, Assistance Publique–Hôpitaux de Paris, 20 rue leblanc, 75015 Paris, France (emmanuel.lafont@aphp.fr). https://orcid.org/0000-0001-9931-4285 Search for other works by this author on: Oxford Academic PubMed Google Scholar Damien Blez, Damien Blez Bacteriology Laboratory, Microbiology Department, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France Search for other works by this author on: Oxford Academic PubMed Google Scholar Marc-Antoine Bildan, Marc-Antoine Bildan Pharmacology Department, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France Search for other works by this author on: Oxford Academic PubMed Google Scholar David Veyer, David Veyer Virology Laboratory, Microbiology Department, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, FranceUnité mixte de recherche 1137, Infections Antimicrobials Modelling Evolution, Université Paris Cité, Paris, FranceUniversité Paris Cité, Paris, France Search for other works by this author on: Oxford Academic PubMed Google Scholar Hélène Péré, Hélène Péré Virology Laboratory, Microbiology Department, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, FranceUnité mixte de recherche 1137, Infections Antimicrobials Modelling Evolution, Université Paris Cité, Paris, FranceUniversité Paris Cité, Paris, France Search for other works by this author on: Oxford Academic PubMed Google Scholar Julien Puech, Julien Puech Virology Laboratory, Microbiology Department, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France Search for other works by this author on: Oxford Academic PubMed Google Scholar Benjamin Kably, Benjamin Kably Pharmacology Unit and Departement Medicaux Universitaire BIOPHYGEN, Hôpital Européen Georges Pompidou, AP-HP, Paris, FranceInserm Paris Cardiovascular Research Center UMRS970, Paris, France Search for other works by this author on: Oxford Academic PubMed Google Scholar Geoffrey Cheminet, Geoffrey Cheminet Department of Internal Medicine, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France Search for other works by this author on: Oxford Academic PubMed Google Scholar Jacques Pouchot, Jacques Pouchot Department of Internal Medicine, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, FranceUniversité Paris Cité, Paris, France Search for other works by this author on: Oxford Academic PubMed Google Scholar Eric Thervet, Eric Thervet Université Paris Cité, Paris, FranceNephrology Department, Hôpital Européen Georges Pompidou, AP-HP, Paris, France Search for other works by this author on: Oxford Academic PubMed Google Scholar ... Show more Gilles Peytavin, Gilles Peytavin Université Paris Cité, Paris, FrancePharmacology Department, Hôpital Bichat-Claude Bernard, AP-HP, Paris, France https://orcid.org/0000-0002-4359-537X Search for other works by this author on: Oxford Academic PubMed Google Scholar Helene Lazareth Helene Lazareth Université Paris Cité, Paris, FranceNephrology Department, Hôpital Européen Georges Pompidou, AP-HP, Paris, France Correspondence: H. Lazareth, Nephrology Department, Hôpital Européen Georges Pompidou, Assistance Publique–Hôpitaux de Paris, 20 rue leblanc, 75015 Paris, France (helene.lazareth@aphp.fr) Search for other works by this author on: Oxford Academic PubMed Google Scholar Clinical Infectious Diseases, ciad785, https://doi.org/10.1093/cid/ciad785 Published: 30 December 2023 Article history Published: 30 December 2023 Corrected and typeset: 22 January 2024

To rapidly achieve ceftazidime target concentrations, a 2 g loading dose (LD) is recommended before continuous infusion, but its adequacy in critically ill patients, given their unique pharmacokinetics, needs investigation. This study included patients from six ICUs in Saint-Etienne and Paris, France, who received continuous ceftazidime infusion with plasma concentration measurements. Using MONOLIX and R, a pharmacokinetic (PK) model was developed, and the literature on ICU patient PK models was reviewed. Simulations calculated the LD needed to reach a 60 mg/L target concentration and assessed ceftazidime exposure for various regimens. Among 86 patients with 223 samples, ceftazidime PK was best described by a one-compartment model with glomerular filtration rate explaining clearance variability. Typical clearance and volume of distribution were 4.45 L/h and 88 L, respectively. The literature median volume of distribution was 37.2 L. Simulations indicated that an LD higher than 2 g was needed to achieve 60 mg/L in 80% of patients, with a median LD of 4.9 g. Our model showed a 4 g LD followed by 6 g/day infusion reached effective concentrations within 1 h, while a 2 g LD caused an 18 h delay in achieving target steady state.

Major bleedings have been described with cefazolin. The objective was to determine the frequency of bleeding events in cefazolin-treated patients and to identify risk factors for these complications. Monocenter prospective observational study of all consecutive cefazolin-treated patients. Patients benefited from a daily clinical assessment of bleedings and a twice-a-week blood sampling including hemostasis. Bleedings were classified according to the International Society on Thrombosis and Hemostasis classification: major, clinically relevant non-major bleedings (CRNMB) and minor bleedings. From September 2019 to July 2020, 120 patients were included, with a mean age of 59.4 (± 20.7) years; 70

Cardiovascular pharmacological countermeasures will be required as a preventive measure of cardiovascular deconditioning and early vascular ageing for long term space travelers. Physiological changes during spaceflight could have severe implications on drug pharmacokinetics and pharmacodynamics (PK/PD). However, limitations exist for the implementation of drug studies due to the requirements and constraints of this extreme environ-ment. Therefore, we developed an easy sampling method on dried urine spot (DUS), for the simultaneous quantification of 5 antihypertensive drugs in human urine: irbesartan, valsartan, olmesartan, metoprolol and furosemide analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), considering spaceflight parameters. This assay was validated in terms of linearity, accuracy, and precision with satisfactory results. There were no relevant carry-over, matrix interferences. The targeted drugs were stable in urine collected by DUS until 6 months at +21 degrees C, +4 degrees C,-20 degrees C (with or without desiccants) and at 30 degrees C during 48 h. Irbesartan, valsartan and olmesartan were not stable at 50 degrees C during 48 h. This method was found to be eligible for space pharma-cology studies in terms of practicality, safety, robustness and energy costs. It has been successfully implemented in space tests programs led in 2022.

BackgroundMedication adherence plays a critical role in controlling the evolution of chronic disease, as low medication adherence may lead to worse health outcomes, higher mortality, and morbidity. Assessment of their patients' medication adherence by clinicians is essential for avoiding inappropriate therapeutic intensification, associated health care expenditures, and the inappropriate inclusion of patients in time- and resource-consuming educational interventions. In both research and clinical practices the most extensively used measures of medication adherence are patient-reported outcome measures (PROMs), because of their ability to capture subjective dimensions of nonadherence. Machine learning (ML), a subfield of artificial intelligence, uses computer algorithms that automatically improve through experience. In this context, ML tools could efficiently model the complexity of and interactions between multiple patient behaviors that lead to medication adherence. ObjectiveThis study aimed to create and validate a PROM on medication adherence interpreted using an ML approach. MethodsThis cross-sectional, single-center, observational study was carried out a French teaching hospital between 2021 and 2022. Eligible patients must have had at least 1 long-term treatment, medication adherence evaluation other than a questionnaire, the ability to read or understand French, an age older than 18 years, and provided their nonopposition. Included adults responded to an initial version of the PROM composed of 11 items, each item being presented using a 4-point Likert scale. The initial set of items was obtained using a Delphi consensus process. Patients were classified as poorly, moderately, or highly adherent based on the results of a medication adherence assessment standard used in the daily practice of each outpatient unit. An ML-derived decision tree was built by combining the medication adherence status and PROM responses. Sensitivity, specificity, positive and negative predictive values (NPVs), and global accuracy of the final 5-item PROM were evaluated. ResultsWe created an initial 11-item PROM with a 4-point Likert scale using the Delphi process. After item reduction, a decision tree derived from 218 patients including data obtained from the final 5-item PROM allowed patient classification into poorly, moderately, or highly adherent based on item responses. The psychometric properties were 78% (95% CI 40%-96%) sensitivity, 71% (95% CI 53%-85%) specificity, 41% (95% CI 19%-67%) positive predictive values, 93% (95% CI 74%-99%) NPV, and 70% (95% CI 55%-83%) accuracy. ConclusionsWe developed a medication adherence tool based on ML with an excellent NPV. This could allow prioritization processes to avoid referring highly adherent patients to time- and resource-consuming interventions. The decision tree can be easily implemented in computerized prescriber order-entry systems and digital tools in smartphones. External validation of this tool in a study including a larger number of patients with diseases associated with low medication adherence is required to confirm its use in analyzing and assessing the complexity of medication adherence.

BACKGROUND Despite its important drug-drug interaction, combined clindamycin/rifampicin therapy may achieve effective plasma clindamycin concentrations, provided clindamycin is administered by continuous infusion. However, the precise clindamycin dose remains unknown. OBJECTIVES This study was undertaken to determine the daily clindamycin dose to be administered by continuous infusion in combination with rifampicin to achieve effective plasma clindamycin concentrations. PATIENTS AND METHODS Two plasma clindamycin concentrations were determined prospectively for 124 patients with bone-and-joint infections treated with continuously infused clindamycin. Twenty patients received clindamycin monotherapy, 19 clindamycin combined with rifampicin and 85 received clindamycin successively without and with rifampicin. A population pharmacokinetic model was developed using NONMEM 7.5. Monte Carlo simulations were run to determine which regimens obtained clindamycin concentrations of at least 3 mg/L. RESULTS A linear one-compartment model with first-order elimination accurately described the data. Clindamycin distribution volume was not estimated. Mean clindamycin clearances with rifampicin and without, respectively, were 33.6 and 10.9 L/h, with 12.8% interindividual variability. The lowest daily clindamycin dose achieving plasma concentrations of at least 3 mg/L in >90% of the patients, when combined with rifampicin, was 4200 mg/24 h. CONCLUSIONS Our results support continuous infusion of 4200 mg of clindamycin/24 h, in combination with rifampicin. This high-dose regimen requires therapeutic drug monitoring-guided dose adaptation.

L'utilisation de l'association clindamycine-rifampicine reste discutée du fait de l'existence d'une interaction médicamenteuse importante, préalablement décrite dans la littérature. Dans notre expérience, l'association peut être envisagée dans le traitement des infections ostéoarticulaires (IOAs) lorsque la clindamycine est administrée en perfusion IV continue et en contrôlant que les concentrations plasmatiques de clindamycine sont situées en zone thérapeutique. Cependant la posologie de clindamycine à utiliser en tenant compte de cette interaction est mal définie. L'objectif de cette étude était de développer un modèle de pharmacocinétique (PK) de population de la clindamycine administrée en perfusion IV continue et ainsi déterminer la posologie optimale quotidienne à administrer en cas d'association avec la rifampicine. Les données ont été obtenues à partir de 2 études prospectives portant sur cette interaction et incluant un total de 124 patients traités pour des IOAs par de la clindamycine en perfusion continue. Deux concentrations de clindamycine ont été mesurées pour chaque patient. Parmi ces patients, 20 recevaient de la clindamycine sans rifampicine, 19 l'association clindamycine-rifampicine, et 85 patients recevaient successivement la clindamycine sans puis avec rifampicine. Pour ces derniers, un dosage de clindamycine a été réalisé avant et après au moins une semaine de l'association. Un modèle PK de population a été développé en utilisant NONMEM 7.5. Par la suite, des simulations de Monte-Carlo ont été réalisées afin de déterminer la posologie optimale de clindamycine IV permettant d'obtenir des concentrations cibles de 3 à 10mg/L. Mille patients ont été simulés pour chaque posologie testée. Un modèle linéaire à un compartiment décrivait le mieux les données. Le volume de distribution (VD) n'a pas été estimé. Les clairances moyennes de clindamycine avec et sans rifampicine étaient respectivement de 33,6 et 10,9 L/h avec une variabilité interindividuelle (%CV) de 12,8%. Les courbes de résidus et le Bootstrap n'ont pas montré de biais. En l'absence de rifampicine, la probabilité la plus élevée d'atteindre la zone cible parmi les posologies testées était obtenue avec 1800mg/24h (85%). En présence de rifampicine, ce sont les posologies de 4200mg/24h et de 4800mg/24h qui permettent d'atteindre la zone cible avec les probabilités les plus élevées (89% et 90%, respectivement). En cas d'association à la rifampicine, des posologies initiales de clindamycine en perfusion IV continue très élevées de 4200mg/24h ou 4800mg/24h doivent être envisagées. Ces posologies sont à contrôler et au besoin à adapter par le suivi thérapeutique pharmacologique (STP). Les modalités pratiques d'administration de telles posologies (délai d'augmentation des posologies de clindamycine par rapport au début de la rifampicine et délai du STP) sont à définir. En cas d'utilisation de clindamycine sans rifampicine, des posologies plus faibles, de 1800mg/24h sont suffisantes pour atteindre les zones cibles. Aucun lien d'intérêt

OBJECTIVES:Treating patients with infective endocarditis (IE) due to streptococci and enterococci currently involves high-dosage antibiotics. Recent literature suggests a 30%-70% diffusion rate could be extrapolated to human heart valve tissue. The objective of this study was to evaluate the diffusion coefficient of amoxicillin in heart valve tissue of patients operated for IE.METHODS:Adult patients were prospectively included that underwent surgery at the European Hospital Georges Pompidou for IE due to streptococci and enterococci and had previous IV amoxicillin treatment. Plasma (taken 48 h preoperatively) and heart valve tissue amoxicillin concentrations were measured with a validated LC-MS/MS method. The MIC values of amoxicillin were measured for all available isolates.RESULTS:Seventeen patients were included. Eleven (64.7%) patients had native valve IE and six (35.3%) had prosthetic valve IE. Fourteen IE cases (82.4%) were due to streptococci, one (5.9%) was due to enterococci and two (11.8%) were Haemophilus spp, Aggregatibacter actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella kingae group infections. Median (IQR) amoxicillin dose administered was 10.5 (8.0-12.0) g/day corresponding to 138.2 (112.5-160.0) mg/kg/day. The median amoxicillin plasma concentrations pre-surgery and intra-tissular weighted concentrations were 31.9 (25.9-51.9) mg/L and 19.0 (7.9-31.4) µg/g, respectively. Median tissue/plasma concentration ratio was 0.47 (0.24-0.67), with a median amoxicillin plasma/MIC ratio of 487 (179-745), and median amoxicillin tissue/MIC ratio of 42 (14-116).CONCLUSIONS:With a significant diffusion coefficient, amoxicillin dosage in heart valve tissues showed a concentration/MIC ratio well above current recommendations for bactericidal activity. Our study suggests that lower doses can be considered for susceptible bacteria.

ImportanceAlthough early trials of endovascular renal denervation (RDN) for patients with resistant hypertension (RHTN) reported inconsistent results, ultrasound RDN (uRDN) was found to decrease blood pressure (BP) vs sham at 2 months in patients with RHTN taking stable background medications in the Study of the ReCor Medical Paradise System in Clinical Hypertension (RADIANCE-HTN TRIO) trial.ObjectivesTo report the prespecified analysis of the persistence of the BP effects and safety of uRDN vs sham at 6 months in conjunction with escalating antihypertensive medications.Design, Setting, and ParticipantsThis randomized, sham-controlled, clinical trial with outcome assessors and patients blinded to treatment assignment, enrolled patients from March 11, 2016, to March 13, 2020. This was an international, multicenter study conducted in the US and Europe. Participants with daytime ambulatory BP of 135/85 mm Hg or higher after 4 weeks of single-pill triple-combination treatment (angiotensin-receptor blocker, calcium channel blocker, and thiazide diuretic) with estimated glomerular filtration rate (eGFR) of 40 mL/min/1.73 m2 or greater were randomly assigned to uRDN or sham with medications unchanged through 2 months. From 2 to 5 months, if monthly home BP was 135/85 mm Hg or higher, standardized stepped-care antihypertensive treatment starting with aldosterone antagonists was initiated under blinding to treatment assignment.InterventionsuRDN vs sham procedure in conjunction with added medications to target BP control.Main Outcomes and MeasuresSix-month change in medications, change in daytime ambulatory systolic BP, change in home systolic BP adjusted for baseline BP and medications, and safety.ResultsA total of 65 of 69 participants in the uRDN group and 64 of 67 participants in the sham group (mean [SD] age, 52.4 [8.3] years; 104 male [80.6%]) with a mean (SD) eGFR of 81.5 (22.8) mL/min/1.73 m2 had 6-month daytime ambulatory BP measurements. Fewer medications were added in the uRDN group (mean [SD], 0.7 [1.0] medications) vs sham (mean [SD], 1.1 [1.1] medications; P = .045) and fewer patients in the uRDN group received aldosterone antagonists at 6 months (26 of 65 [40.0%] vs 39 of 64 [60.9%]; P = .02). Despite less intensive standardized stepped-care antihypertensive treatment, mean (SD) daytime ambulatory BP at 6 months was 138.3 (15.1) mm Hg with uRDN vs 139.0 (14.3) mm Hg with sham (additional decreases of −2.4 [16.6] vs −7.0 [16.7] mm Hg from month 2, respectively), whereas home SBP was lowered to a greater extent with uRDN by 4.3 mm Hg (95% CI, 0.5-8.1 mm Hg; P = .03) in a mixed model adjusting for baseline and number of medications. Adverse events were infrequent and similar between groups.Conclusions and RelevanceIn this study, in patients with RHTN initially randomly assigned to uRDN or a sham procedure and who had persistent elevation of BP at 2 months after the procedure, standardized stepped-care antihypertensive treatment escalation resulted in similar BP reduction in both groups at 6 months, with fewer additional medications required in the uRDN group.Trial RegistrationClinicalTrials.gov Identifier: NCT02649426

BACKGROUND:Poor adherence to treatment is a major health issue in hypertension. The large number of drugs to be detected limits the implementation of chemical adherence testing by liquid chromatography/mass spectrometry (LC-MS/MS). AcSDKP, a peptide accumulating in the presence of angiotensin-converting-enzyme inhibitor (ACEI) treatment, has been validated as a proven marker of adherence by enzyme-linked immunosorbent assay. Our aim was to validate urine measurements of AcSDKP compared with active metabolites of various ACEI, measured simultaneously by LC-MS/MS.METHOD:We first studied the time-dependent relationships between urinary perindoprilat and AcSDKP in a pharmacokinetic/pharmacodynamic study in healthy volunteers. We then compared the sensitivity and specificity of urinary AcSDKP vs. three ACEI active metabolites (enalaprilat, perindoprilat, ramiprilat) taken as reference to detect nonadherence in spot urine samples from a prospective cohort of hypertensive outpatients.RESULTS:The urinary excretion profiles of AcSDKP and perindoprilat were similar, exhibited a significant correlation, and showed excellent agreement in healthy volunteers. In patients, we found a similar agreement between AcSDKP and the three ACEI metabolites urinary concentrations. The sensitivity and specificity for adherence assessment of urine AcSDKP was 92.2 and 100%, respectively. We observed a difference in the evaluation of good adherence between ACEI metabolites (85.7%) and AcSDKP (79.0%) because of discrepancies in samples where AcSDKP reached undetectability quicker than ACEI metabolites. This characteristic of AcSDKP is of particular interest and could better reflect the true adherence status of patients.CONCLUSION:Overall, spot urine AcSDKP measurement by LC-MS/MS is a reliable marker of the intake of ACEI treatment and could substitute ACEI metabolites detection.

PURPOSE:The increasing burden of invasive fungal infections results in growing challenges to antifungal (AF) therapeutic drug monitoring (TDM). This review aims to provide an overview of recent advances in AF TDM. METHODS:We conducted a PubMed search for articles during 2016-2020 using "TDM" or "pharmacokinetics" or "drug-drug-interaction" with "antifungal," consolidated for each AF. Selection was limited to English language articles with human data on drug exposure. RESULTS:More than 1000 articles matched the search terms. We selected 566 publications. The latest findings tend to confirm previous observations in real-life clinical settings. The pharmacokinetic variability related to special populations is not specific but must be considered. AF benefit-to-risk ratio, drug-drug interaction (DDI) profiles, and minimal inhibitory concentrations for pathogens must be known to manage at-risk situations and patients. Itraconazole has replaced ketoconazole in healthy volunteers DDI studies. Physiologically based pharmacokinetic modeling is widely used to assess metabolic azole DDI. AF prophylactic use was studied more for Aspergillus spp. and Mucorales in oncohematology and solid organ transplantation than for Candida (already studied). Emergence of central nervous system infection and severe infections in immunocompetent individuals both merit special attention. TDM is more challenging for azoles than amphotericin B and echinocandins. Fewer TDM requirements exist for fluconazole and isavuconazole (ISZ); however, ISZ is frequently used in clinical situations in which TDM is recommended. Voriconazole remains the most challenging of the AF, with toxicity limiting high-dose treatments. Moreover, alternative treatments (posaconazole tablets, ISZ) are now available. CONCLUSIONS:TDM seems to be crucial for curative and/or long-term maintenance treatment in highly variable patients. TDM poses fewer cost issues than the drugs themselves or subsequent treatment issues. The integration of clinical pharmacology into multidisciplinary management is now increasingly seen as a part of patient care.

Introduction Ceftazidime is used for the treatment of many bacterial infections, including severe P. aeruginosa infections. Like other beta-lactams, inter-individual variability in ceftazidime pharmacokinetics has been described. Due to its related pathophysiological modifications, obesity might influence ceftazidime pharmacokinetics. Areas covered The objective of this review is to assess the current state of knowledge about the impact of obesity on ceftazidime treatment. A literature search was conducted on PubMed-MEDLINE (2016-2021) to retrieve pharmacokinetic studies published in English, matching the terms 'ceftazidime' AND 'pharmacokinetics.' Expert opinion The impact of obesity on pharmacokinetics is generally poorly known, mainly because obese patients are often excluded from clinical studies. However, the published literature clearly shows that obese patients have significantly lower ceftazidime concentrations. This could be explained by increased volume of distribution and clearance. This low exposure represents a major factor of therapeutic failure, potentially fatal for critically ill patients. While further studies would be useful to better assess the magnitude and understanding of this variability, the use of higher doses of ceftazidime is needed in obese patients. Moreover, therapeutic drug monitoring for dose adaptation is of major interest for these patients, as the efficacy of ceftazidime seems to be directly related to its plasma concentration.

A population PK model of clindamycin orally administered to patients with prosthetic joint infections (PJIs) was developed using NONMEM 7.5. Monte-Carlo simulations were run to determine the probability of obtaining bone clindamycin concentrations equal to at least the MIC or four times the MIC for several MIC values and dosing regimens. One hundred and forty plasma concentrations prospectively obtained from 20 patients with PJIs were used. A one-compartment model with first-order absorption and elimination appropriately described the data. Mean PK-parameter estimates (F being the bioavailability) were: apparent clearance, CL/F = 23 L/h, apparent distribution volume, V/F = 103 l and absorption rate constant, Ka = 3.53/h, with respective interindividual variabilities (coefficients of variation) of 14.4%, 8.2% and 59.6%. Neither goodness-of-fit curves nor visual predictive checks indicated bias. The currently recommended 600 mg q8h regimen provided a high probability of obtaining concentrations equal to at least the MIC, except for MIC ≥ the clinical breakpoint for Staphylococcus spp. (0.25 mg/L). For such MIC values, higher daily doses and q6h regimens could be considered.