RPEM: Randomized Monte Carlo parametric expectation maximization algorithm.

Inspired from quantum Monte Carlo, by sampling discrete and continuous variables at the same time using the Metropolis-Hastings algorithm, we present a novel, fast, and accurate high performance Monte Carlo Parametric Expectation Maximization (MCPEM) algorithm. We named it Randomized Parametric Expectation Maximization (RPEM). We compared RPEM with NONMEM's Importance Sampling Method (IMP), Monolix's Stochastic Approximation Expectation Maximization (SAEM), and Certara's Quasi-Random Parametric Expectation Maximization (QRPEM) for a realistic two-compartment voriconazole model with ordinary differential equations using simulated data. We show that RPEM is as fast and as accurate as the algorithms IMP, QRPEM, and SAEM for the voriconazole model in reconstructing the population parameters, for the normal and log-normal cases.

What are the available online resources targeting psychosocial burden among stroke survivors and their informal caregivers: A scoping review.

Background: After discharge home, stroke survivors and their informal caregivers face a significant lack of support and information which accentuates their psychosocial burden. Online resources might provide this support and address psychosocial needs, but existing online stroke programmes mainly target functional rehabilitation. We aimed to map the existing literature on online resources that have been evaluated in stroke rehabilitation and aimed at reducing psychosocial impact in stroke survivors and informal caregivers. Methods: MEDLINE was searched (2010-2024) to identify studies investigating online resources targeting psychosocial health. Studies were selected and extracted independently by two reviewers. We described the content, use, and psychosocial impact of these interventions using a narrative approach. Results: Eleven studies were included in the review, reporting 10 online resources (two studies relating to the same resource). Online resources were heterogeneous: eight information/resources websites, one mobile app, and one forum. Five online resources were dedicated to stroke survivors, four to stroke survivors and their informal caregivers, and one to informal caregivers. Two randomized controlled trials reported a significant decrease in depressive symptoms associated with the use of online resources. Stroke survivors and informal caregivers find online resources useful and acceptable to address their psychosocial needs. Conclusions: Few online stroke resources have been designed and evaluated to support post-stroke psychosocial rehabilitation. Further larger-scale research needs to study the impact of these interventions on psychosocial recovery over time.

Comparison of daptomycin and glycopeptide efficacy and safety for the treatment of Gram-positive infections: a systematic review and meta-analysis.

BACKGROUND: The indications of daptomycin have been extended to off-label indications including prosthesis-related infection, and bone and joint infection (BJI). However, efficacy and safety have not been thoroughly demonstrated compared with the standard of care. This systematic review and meta-analysis aimed to compare the treatment effect of daptomycin and glycopeptides for complicated infections. MATERIALS AND METHODS: MEDLINE, Embase and Web of Science were searched for randomized controlled trials (RCTs) comparing daptomycin and standard of care for Gram-positive infections, published until 30 June 2021. The primary outcome was defined as all-cause mortality. Secondary outcomes were clinical and microbiological success. The main safety outcome was any severe adverse event (SAE) (grade  ≥3). RESULTS: Overall, eight RCTs were included in the meta-analysis, totalling 1095 patients. Six (75%) were in complicated skin and soft-structure infections, one (12.5%) in bacteraemia and one (12.5%) in a BJI setting. Six RCTs used vancomycin as a comparator and two used either vancomycin or teicoplanin. All-cause mortality and clinical cure were not different between groups. The microbiological cure rate was superior in patients who received daptomycin [risk ratio (RR) = 1.17 (95% CI: 1.01-1.35)]. The risk of SAEs [RR = 0.57 (95% CI: 0.36-0.90)] was lower in the daptomycin arm. CONCLUSIONS: While daptomycin is associated with a significantly lower risk of SAEs and a better microbiological eradication, substantial uncertainty remains about the best treatment strategy in the absence of good-quality evidence, especially in bacteraemia and endocarditis where further RCTs should be conducted.

Daptomycin Exposure as a Risk Factor for Daptomycin-Induced Eosinophilic Pneumonia and Muscular Toxicity.

BACKGROUND: High-dose daptomycin is increasingly used in patients with bone and joint infection (BJI). This raises concerns about a higher risk of adverse events (AEs), including daptomycin-induced eosinophilic pneumonia (DIEP) and myotoxicity. We aimed to examine pharmacokinetic and other potential determinants of DIEP and myotoxicity in patients with BJI receiving daptomycin. METHODS: All patients receiving daptomycin for BJI were identified in a prospective cohort study. Cases were matched at a 1:3 ratio, with controls randomly selected from the same cohort. Bayesian estimation of the daptomycin daily area under the concentration-time curve over 24 hours (AUC24h) was performed with the Monolix software based on therapeutic drug monitoring (TDM) data. Demographic and biological data were also collected. Risk factors of AEs were analyzed using Cox proportional hazards model. RESULTS: From 1130 patients followed over 7 years, 9 with DIEP, 26 with myotoxicity, and 106 controls were included in the final analysis. Daptomycin AUC24h, C-reactive protein, and serum protein levels were associated with the risk of AEs. The adjusted hazard ratio of DIEP or myotoxicity was 3.1 (95% confidence interval [CI], 1.48-6.5; P < .001) for daptomycin AUC24h > 939 mg/h/L, 9.8 (95% CI, 3.94-24.5; P < .001) for C-reactive protein > 21.6 mg/L, and 2.4 (95% CI, 1.02-5.65; P = .04) for serum protein <72 g/L. CONCLUSIONS: We identified common determinants of DIEP and myotoxicity in patients with BJI. Because the risk of AEs was associated with daptomycin exposure, daptomycin TDM and model-informed precision dosing may help optimize the efficacy and safety of daptomycin treatment in this setting. A target AUC24h range of 666 to 939 mg/h/L is suggested.

Seventeen Cases of Daptomycin-Induced Eosinophilic Pneumonia in a Cohort of Patients Treated for Bone and Joint Infections: Proposal for a New Algorithm.

Background: Daptomycin is increasingly used in the treatment of bone and joint infections (BJIs) and may be responsible for daptomycin-induced eosinophilic pneumonia (DIEP), a potentially severe adverse drug reaction. The aim of this study was to describe DIEP in patients treated at a referral center for the management of BJI, and to revisit current definitions of this disease. Methods: Patients treated from 1 January 2012 to 31 March 2021 were included in a prospective cohort (NCT02817711), in which all potential serious adverse events are prospectively recorded. Patients diagnosed with DIEP were retrospectively analyzed using different definitions. Results: In a total of 4664 patients included in the cohort during the study period, 1021 patients (21.9%) received daptomycin, of whom 17 (1.7%) were diagnosed with DIEP. Most patients were male (n = 11 [64.7%]), and periprosthetic joint infection was the commonest BJI (n = 12 [70.6%]). Only 1 patient had bronchoalveolar lavage (BAL) eosinophil count ≥25%, while most patients had peripheral blood eosinophilia (n = 15 [88.2%]). Chest computed tomography (CT) was compatible with eosinophilic pneumonia in 13 of 14 cases (92.9%). All patients recovered upon discontinuation of daptomycin. Using the different definitions available, only a minority of cases fulfilled existing criteria for DIEP. We propose a new algorithm that includes specific CT scan signs, and systemic instead of BAL eosinophilia. Conclusions: DIEP is a rare event that requires prompt discontinuation of the causative antibiotic. Current criteria to diagnose definite DIEP are too restrictive and not easily applicable in clinical practice. A new algorithm is proposed here (Lyon algorithm) to facilitate the early identification of DIEP.

Implementation of Model-Based Dose Adjustment of Tobramycin in Adult Patients with Cystic Fibrosis.

Therapeutic drug monitoring (TDM) of tobramycin is widely performed in patients with cystic fibrosis (CF), but little is known about the value of model-informed precision dosing (MIPD) in this setting. We aim at reporting our experience with tobramycin MIPD in adult patients with CF. We analyzed data from adult patients with CF who received IV tobramycin and had model-guided TDM during the first year of implementation of MIPD. The predictive performance of a pharmacokinetic (PK) model was assessed. Observed maximal (Cmax) and minimal (Cmin) concentrations after initial dosing were compared with target values. We compared the initial doses and adjusted doses after model-based TDM, as well as renal function at the beginning and end of therapy. A total of 78 tobramycin courses were administered in 61 patients. After initial dosing set by physicians (mean, 9.2 ± 1.4 mg/kg), 68.8% of patients did not achieve the target Cmax ≥ 30 mg/L. The PK model fit the data very well, with a median absolute percentage error of 4.9%. MIPD was associated with a significant increase in tobramycin doses (p < 0.001) without significant change in renal function. Model-based dose suggestions were wellaccepted by the physicians and the expected target attainment for Cmax was 83%. To conclude, the implementation of MIPD was effective in changing prescribing practice and was not associated with nephrotoxic events in adult patients with CF.

Daptomycin Physiology-Based Pharmacokinetic Modeling to Predict Drug Exposure and Pharmacodynamics in Skin and Bone Tissues.

BACKGROUND AND OBJECTIVE: Daptomycin has been recommended in the treatment of bone and joint infection. Previous work showed that the approved dosage of daptomycin may be insufficient to achieve optimal exposure in patients with bone and joint infection. However, those studies assumed that bone exposure was similar to steady-state daptomycin-free plasma concentrations. We sought to establish a physiologically based pharmacokinetic (PBPK) model of daptomycin to describe the dynamics of daptomycin disposition in bone and skin tissue. METHODS: A PBPK model of daptomycin was built using PK-Sim®. Daptomycin concentrations in plasma and bone were obtained from three previously published studies. Physicochemical drug characteristics, mass balance, anthropometrics, and experimental data were used to build and refine the PBPK model. Internal validation of the PBPK model was performed using the usual diagnostic plots. The final PBPK model was then used to run simulations with doses of 6, 8, 10, and 12 mg/kg/24 h. Pharmacokinetic profiles were simulated in 1000 subjects and the probabilities of target attainment for the area under the concentration-time curve over the bacterial minimum inhibitory concentration were computed in blood, skin, and bone compartments. RESULTS: The final model showed a good fit of all datasets with an absolute average fold error between 0.5 and 2 for all pharmacokinetic quantities in blood, skin and bone tissues. Results of dosing simulations showed that doses ≥10 mg/kg should be used in the case of bacteremia caused by Staphylococcus aureus with a minimum inhibitory concentration >0.5 mg/L or Enterococcus faecalis with a minimum inhibitory concentration >1 mg/L, while doses ≥12 mg/kg should be used in the case of bone and joint infection or complicated skin infection. When considering a lower minimum inhibitory concentration, doses of 6-8 mg/kg would likely achieve a sufficient success rate. However, in the case of infections caused by E. faecalis with a minimum inhibitory concentration >2 mg/L, a higher dosage and combination therapy would be necessary to maximize efficacy. CONCLUSIONS: We developed the first daptomycin PBPK/pharmacodynamic model for bone and joint infection, which confirmed that a higher daptomycin dosage is needed to optimize exposure in bone tissue. However, such higher dosages raise safety concerns. In this setting, therapeutic drug monitoring and model-informed precision dosing appear necessary to ensure the right exposure on an individual basis.

Population Pharmacokinetics and Dosing Simulation of Vancomycin Administered by Continuous Injection in Critically Ill Patient.

Background: Vancomycin is widely used for empirical antimicrobial therapy in critically ill patients with sepsis. Continuous infusion (CI) may provide more stable exposure than intermittent infusion, but optimal dosing remains challenging. The aims of this study were to perform population pharmacokinetic (PK) analysis of vancomycin administered by CI in intensive care unit (ICU) patients to identify optimal dosages. Methods: Patients who received vancomycin by CI with at least one measured concentration in our center over 16 months were included, including those under continuous renal replacement therapy (CRRT). Population PK was conducted and external validation of the final model was performed in a dataset from another center. Simulations were conducted with the final model to identify the optimal loading and maintenance doses for various stages of estimated creatinine clearance (CRCL) and in patients on CRRT. Target exposure was defined as daily AUC of 400-600 mg·h/L on the second day of therapy (AUC24-48 h). Results: A two-compartment model best described the data. Central volume of distribution was allometrically scaled to ideal body weight (IBW), whereas vancomycin clearance was influenced by CRRT and CRCL. Simulations performed with the final model suggested a loading dose of 27.5 mg/kg of IBW. The maintenance dose ranged from 17.5 to 30 mg/kg of IBW, depending on renal function. Overall, simulation showed that 55.8% (95% CI; 47-64%) of patients would achieve the target AUC with suggested dosages. Discussion: A PK model has been validated for vancomycin administered by CI in ICU patients, including patients under CRRT. Our model-informed precision dosing approach may help for early optimization of vancomycin exposure in such patients.

Model-Based Comparative Analysis of Rifampicin and Rifabutin Drug-Drug Interaction Profile.

Rifamycins are widely used for treating mycobacterial and staphylococcal infections. Drug-drug interactions (DDI) caused by rifampicin (RIF) are a major issue. We used a model-based approach to predict the magnitude of DDI with RIF and rifabutin (RBT) for 217 cytochrome P450 (CYP) substrates. On average, DDI caused by low-dose RIF were twice as potent as those caused by RBT. Contrary to RIF, RBT appears unlikely to cause severe DDI, even with sensitive CYP substrates.

Population pharmacokinetics of daptomycin in patients with bone and joint infection: minimal effect of rifampicin co-administration and confirmation of a sex difference.

BACKGROUND: Daptomycin is increasingly used in the treatment of bone and joint infection (BJI), but its pharmacokinetics (PK) and dosage requirements have not been thoroughly investigated in this indication. Daptomycin may be co-administered with rifampicin, which raises questions about a potential drug interaction. OBJECTIVES: To investigate the population PK and dosage requirements of daptomycin in patients with BJI, and examine the influence of rifampicin co-administration. METHODS: A population approach was used to analyse PK data from patients who received daptomycin in our regional reference for BJI. We examined the influence of available covariates, including rifampicin co-administration on daptomycin PK. Simulations performed with the final model investigated the influence of dosages and covariates on PTA for both efficacy and safety. RESULTS: A total of 1303 daptomycin concentrations from 183 patients were analysed. A two-compartment model best described the data. Significant intra-individual variability was observed. Daptomycin clearance was influenced by renal function and sex, with females having a 26% lower typical clearance than males. Central volume of distribution (V1) was influenced by body weight, age, sex and rifampicin co-administration. Typical V1 was 11% lower in patients who were co-administered rifampicin. In PK/PD simulations, sex influenced the probability of AUC24/MIC target attainment, while rifampicin had a marginal effect. CONCLUSIONS: A daptomycin dosage of 8 mg/kg/24 h in women and 10 mg/kg/24 h in men should optimize efficacy but may lead to excessive trough concentrations in many patients, especially in women. Therapeutic drug monitoring appears necessary for precision dosing of daptomycin.

Economic impact of clinical pharmaceutical activities in hospital wards: A systematic review.

BACKGROUND: The positive impact of clinical pharmacy services (CPS) in improving clinical outcomes such as reduction of drug related problems is well demonstrated. Despite these results, the deployment of these activities is not systematically observed in the hospital setting. OBJECTIVES: This systematic review first aimed to describe existing evidence regarding economic evaluation of ward-based CPS focusing on the entire treatment of a patient in a hospital setting. Secondly, the quality of economic evaluations of existing evidence was assessed. METHODS: A comprehensive literature search was performed in PubMed/Medline, Science Direct and the NHS Economic Evaluation databases from January 2000 to March 2019. English or French language articles describing an economic evaluation of ward-based CPS on inpatients in hospital settings were included. Articles not describing a single study, dealing with a CPS not considering the entire medication regimen of the patient or presenting both inpatient and outpatient CPS were excluded. Selected articles were analyzed according to Drummond's check-list for assessing economic evaluations. RESULTS: Forty-one studies were included. About one third were American publications. CPS implemented in ICU represented about half of the selected articles. Pharmacist-to-bed ratios varied according to countries and care unit type with the most favorable ratios in ICU and in American studies. Cost-avoidance was mostly used to express economic impact and ranged from €1579 to €3,089 328. Studies yielding the greater economic impact were conducted in the USA with implementation of full-time equivalents pharmacists or establishing of collaborative practice agreements. Only 6 articles dealt correctly with at least 7 of the 10 Drummond's checklist assessment criteria. CONCLUSION: This review suggests that the existing evidence is not sufficient to conclude to a positive economic impact of CPS conducted according to clinical pharmacy guidelines. Funding resources, remuneration of clinical pharmacy activities and provision of standardized national clinical and economic databases appear to be essential evolutions to improve CPS development.