Potentially inappropriate medications in nursing homes and the community older adults using the French health insurance databases.

PURPOSE: Potentially inappropriate medications (PIMs) have become a major issue in improving prescribing practices and reducing the risk of adverse drug events in older people. However, very few studies have compared exposition to PIMs controlling for differences in demographic and health between nursing home residents (NHRs) and community-dwelling older adults (CDOAs). This study aimed to assess the prescribing pattern of PIMs between NHRs and CDOAs. METHODS: We conducted a cross-sectional study over three months in 2019 using the French Health Insurance databases. The study population included 274 971 NHRs and 4 893 721 CDOAs aged 75 years or over. The prevalence ratio (PR) between NHRs and CDOAs of 17 PIM indicators, based on the Beers and STOPP criteria lists, was assessed using multivariable robust Poisson regression adjusted for age, sex, diseases, and polypharmacy. RESULTS: During the study period, 54% of NHRs and 29% of CDOAs received at least one PIM. After adjustment, the prevalence of PIMs was 33% higher among NHRs compared to CDOAs (aPR = 1.33; 95% CI [1.33-1.34]). NHRs received PIMs related to benzodiazepines (aPR = 1.43; 95% CI [1.42-1.43]), anticholinergic drugs (aPR = 1.29; 95% CI [1.27-1.31]), and at least three central nervous system-active drugs (aPR = 1.94; 95% CI [1.92-1.96]) more frequently. Prevalence of PIMs related to non-steroidal anti-inflammatory drugs (aPR = 0.50; 95% CI [0.48-0.52]) and long-acting benzodiazepines (aPR = 0.84; 95% CI [0.82-0.85]) was lower among NHRs. CONCLUSION: The NHRs were at greater risk for PIM than CDOAs, although differences exist according to the category of PIMs. As the population is aging, it is essential to promote and evaluate interventions in NHs and the community to enhance medication optimization.

Atropine-induced toxicity after off-label sublingual administration of eyedrop for sialorrhoea treatment in neurological disabled patients.

Sialorrhea is a troublesome and disabling symptom defined by the unintentional loss of saliva from the mouth, usually associated with swallowing disorders. Today there is no consensus about the management of sialorrhoea, but off-label use of ophthalmic atropine eyedrop administered sublingually may offer benefits, despite limited safety data. We report 2 cases of atropine overdose after sublingual administration illustrating that atropine can expose to severe adverse effects when administered sublingually. The noncompartmental pharmacokinetic study of atropine performed in 1 patient highlighted that systemic absorption of sublingual atropine was effective (Cmax [1 h] = 2.2 ng mL-1 ; approximately) after a single dose of 1 mg.

Bloodstream infections in older population: epidemiology, outcome, and impact of multidrug resistance.

Bloodstream infections (BSIs) among older patients are frequent with high rate of mortality. Infections with multidrug-resistant organisms (MDRO) are associated with higher mortality than with susceptible microorganisms. We aimed to evaluate the prevalence of MDRO infection during BSI in older population and the factors associated with unfavorable outcome. This study is a retrospective cohort of all BSI episodes occurring among older patients (> 65yo), from April 1, 2010, to December 31, 2016, in a French university hospital for geriatric medicine. A total of 255 BSI episodes were analyzed. Mean age was 86.3±6.5 years, and sex ratio (M/F) was 0.96. Main comorbidities were orthopedic device (26.7%), active neoplasia (24.3%), and diabetes mellitus (18.4%). Main primary sites of infection were urinary tract infections (56.9%), respiratory tract infections (10.6%), intra-abdominal infections (7.1%), and skin and soft tissue infections (4.7%). Main bacteria identified were Escherichia coli (45.1%), Staphylococcus aureus (14.1%), enterococci (10.7%), coagulase-negative staphylococci (CoNS) (5.5%), and streptococci (5.1%). MDROs were involved in 17.2% of BSI (gram-negative bacilli: 9.0%; CoNS: 4.3%; and methicillin-resistant S. aureus (MRSA): 3.9%). The main factor associated with MDRO BSI was colonization with MDRO (OR=6.29; 95%CI=2.9-14.32). Total mortality was 18.4% and significantly higher in case of initial severity (OR=3.83; 95%CI=1.75-8.38), healthcare-associated infection (OR=5.29; 95%CI=1.11-25.30), and MRSA BSI (OR=9.16; 95%CI=1.67-50.16). BSI due to MDRO is frequent in older population and is strongly associated with carriage of MDRO. Healthcare-associated BSI, severe episodes, and BSI due to MRSA are associated with unfavorable outcome. In these cases, a broad-spectrum antibiotic should be promptly initiated.

Impact of a medication reconciliation care bundle at hospital discharge on continuity of care: A randomised controlled trial.

OBJECTIVE: To compare the impact of a care bundle including medication reconciliation at discharge by a pharmacist versus standard of care, on continuity of therapeutic changes between hospital and primary care and outcome of patients, within 1 month after discharge. METHODS: Randomised controlled trial in 120 adult patients with at least one chronic disease and three current medications before admission, hospitalised in an infectious disease department of a tertiary hospital and discharged home. Patients were randomly assigned (1:1) to receive a discharge care bundle including medication reconciliation, counselling session and documentation transfer to primary care physician (PCP) (intervention group) or standard of care (control group). Primary outcome was the proportion of in-hospital prescription changes, not maintained by the PCP, 1 month after discharge. Secondary outcome measures included the proportion of patients experiencing early PCP's consultation, hospital readmissions or adverse reactions within 1-month postdischarge and cost of discharge prescriptions. RESULTS: Baseline characteristics were comparable between the two groups. One month after discharge, the proportion of in-hospital prescription changes, not maintained by the PCP, was 11% in the intervention group versus 24% in the control group (P = .007). The median delay before PCP's consultation was longer in the intervention group (30.5 vs 19.5 days, P = .013), there were fewer patients readmitted to hospital (3.4% vs 20.7%, P = .009, odds ratio (OR) = 0.13 [0.02-0.53]) and fewer patients who suffered from adverse drug reaction (7.0% vs 22.8%, P = .04, OR = 0.26 [0.07-0.78]). CONCLUSION: This care bundle resulted in the reduction of treatment changes between hospital discharge and primary care.

[Automation of the medication circuit to ensure patient safety]. / Automatisation du circuit du médicament dans la sécurisation du patient.

The medication circuit is a complex, transversal and risky process. It involves interdependent clinical and logistical stages. Its automation and computerisation are real levers for securing the patient's medication management and optimising the organisation of care. It allows care staff to free up precious time to provide care, particularly in geriatrics.

Acceptability of oral liquid pharmaceutical products in older adults: palatability and swallowability issues.

BACKGROUND: In institutional care, oral liquid pharmaceutical products are widely prescribed for older patients, especially for those with swallowing disorders. As medicines acceptability is a key factor for compliance in the older population, this study investigated the acceptability of oral liquid pharmaceutical products in this targeted population. METHODS: An observational, multicenter, prospective study was conducted in eight geriatric hospitals and eight nursing homes in France. Observers reported several behaviours/events describing the many aspects of acceptability for various pharmaceutical products' uses in patients aged 65 and older. Acceptability scores of oral liquid pharmaceutical products were obtained using an acceptability reference framework (CAST - ClinSearch Acceptability Score Test®): a 3D-map summarizing the different users' behaviors, with two clusters defining the positively and negatively accepted profiles materialized by the green and red zones, respectively. RESULTS: Among 1288 patients included in the core study and supporting the acceptability reference framework, 340 assessments were related to the administration of an oral liquid pharmaceutical product. The mean age of these patients was 87 (Range [66-104y]; SD = 6.7), 68% were women and 16% had swallowing disorders. Globally, the oral liquid pharmaceutical products were classified as "positively accepted," the barycenter of the 340 assessments, along with the entire confidence ellipses surrounding it, were positioned on the green zone of the map. Sub-populations presenting a different acceptability profile have also been identified. For patients with swallowing disorders, the oral liquid pharmaceutical products were classified as "negatively accepted," the barycenter of the 53 assessments along with 87% of its confidence ellipses were associated with this profile. A gender difference was observed for unflavored oral liquids. In women, they were classified "negatively accepted," the barycenter of the 68 assessments with 75% of its confidence ellipses were located in the red zone, while they were classified "positively accepted" in men. CONCLUSION: This study showed that oral liquid pharmaceutical products are a suboptimal alternative to solid oral dosage forms in patients with swallowing disorders. To ensure an optimal acceptability, prescribers should also consider the presence of a taste-masker in these oral liquids. As highlighted herein, palatability remains crucial in older populations, especially for women.

A Decision Support Tool Facilitating Medicine Design for Optimal Acceptability in The Older Population.

PURPOSE: Medicine acceptability, which is of the utmost importance for vulnerable patients' adherence, is driven by both user and product characteristics. Herein, a novel multivariate approach integrating the many aspects of acceptability is used to discriminate positively and negatively accepted medicines in the older population. METHODS: An observational study was carried out in eight hospitals and eight nursing homes to collect a large set of real-life data on medicines uses in older patients (≥65 years). Mapping and clustering explored these multiple observational measures and summarised the main information into an intelligible reference framework. Resampling statistics were used to validate the model's reliability. RESULTS: A three-dimensional map and two clusters defining acceptability profiles, as positive or negative, emerged from the 1079 evaluations. Factors of interest (medicines, user features…) were positioned on the map at the barycentre of their evaluations and assigned to an acceptability profile. Focusing on patients' ability to swallow, we have highlighted the tool's efficacy in demonstrating the impact of user features on medicine acceptability. CONCLUSIONS: This multivariate approach provides a relevant judgement criterion for this multi-dimensional concept. Facilitating the choice of the most appropriate dosage form to achieve optimal acceptability in a targeted population, this tool is of real potential to improve clinical decisions.

Do Proton Pump Inhibitors Reduce Upper Gastrointestinal Bleeding in Older Patients with Atrial Fibrillation Treated with Oral Anticoagulants? A Nationwide Cohort Study in France.

BACKGROUND: Proton pump inhibitors (PPIs) are largely used in older adults and data are needed in off-label indications, such as the prevention of upper gastrointestinal bleeding (UGIB) in patients receiving oral anticoagulants (OACs). This study aimed to assess whether PPIs reduce the risk of UGIB in patients initiating oral anticoagulation. METHODS: We conducted a longitudinal study based on the French national health database. The study population included 109,693 patients aged 75-110 years with a diagnosis of atrial fibrillation who initiated OACs [vitamin K antagonist (VKA) or direct OAC (DOAC)] between 2012 and 2016. We used multivariable Cox models weighted by inverse of probability of treatment to estimate the adjusted hazard ratio (aHR) of UGIB between PPI users and nonusers over a 6- and 12-month follow-up. RESULTS: PPI users represented 23% of the study population (28% among VKA initiators and 17% among DOAC initiators). The mean age (83 ± 5.3 years) and proportion of women (near 60%) were similar between groups. The risk of UGIB in the first 6 months after initiation of OAC decreased by 20% in PPI users compared with PPI nonusers [aHR6 months = 0.80, 95% confidence interval (CI) 0.65-0.98], but was not significantly modified when the follow-up was extended to 12 months (aHR12 months = 0.90, 95% CI 0.76-1.07), with a stronger effect among patients treated with vitamin K antagonists (aHR6 months = 0.73, 95% CI 0.58-0.93; aHR12 months = 0.81, 95% CI 0.67-0.99). CONCLUSIONS: This study suggests that PPIs were associated with reduced risk of gastrointestinal bleeding after initiation of oral anticoagulation in older patients with atrial fibrillation, particularly within 6 months after initiation of an antivitamin K antagonist.

Efficacy of Expired Antibiotics: A Real Debate in the Context of Repeated Drug Shortages.

This narrative review aims to discuss the main interest in and cautions associated with the use of expired antibiotics in the context of repeated shortages, notably in Europe. Articles concerning the topic of expiry dates related to antibiotic use were reviewed using keywords in the PubMed®/MEDLINE and Google Scholar databases to identify the most extensive evidence-based documentation. The present review evaluates the potential interest and efficacy of using expired drugs and their possible related adverse events. Overall, in the context of drug shortages, expiry dates could be safely extended for at least one year for most solid antibiotics (tablets or powder) used in daily clinical practice, as long as they are stored under the right conditions, in accordance with the summary of product characteristics.

Bacterial diversity and specific taxa are associated with decolonization of carbapenemase-producing enterobacterales after fecal microbiota transplantation.

OBJECTIVES: We evaluated the effect of fecal microbiota transplantation (FMT) on the clearance of carbapenemase-producing Enterobacterales (CPE) carriage. METHODS: We performed a prospective, multi-center study, conducted among patients who received a single dose of FMT from one of four healthy donors. The primary endpoint was complete clearance of CPE carriage two weeks after FMT with a secondary endpoint at three months. Shotgun metagenomic sequencing was performed to assess gut microbiota composition of donors and recipients before and after FMT. RESULTS: Twenty CPE-colonized patients were included in the study, where post-FMT 20% (n = 4/20) of patients met the primary endpoint and 40% (n = 8/20) of patients met the secondary endpoint. Kaplan-Meier curves between patients with FMT intervention and the control group (n = 82) revealed a similar rate of decolonization between groups. Microbiota composition analyses revealed that response to FMT was not donor-dependent. Responders had a significantly lower relative abundance of CPE species pre-FMT than non-responders, and 14 days post-FMT responders had significantly higher bacterial species richness and alpha diversity compared to non-responders (p < 0.05). Responder fecal samples were also enriched in specific species, with significantly higher relative abundances of Faecalibacterium prausnitzii, Parabacteroides distasonis, Collinsella aerofaciens, Alistipes finegoldii and Blautia_A sp900066335 (q<0.01) compared to non-responders. CONCLUSION: FMT administration using the proposed regimen did not achieve statistical significance for complete CPE decolonization but was correlated with the relative abundance of specific bacterial taxa, including CPE species.

Real-life temocillin use in Greater Paris area, effectiveness and risk factors for failure in infections caused by ESBL-producing Enterobacterales: a multicentre retrospective study.

Background: Temocillin is a ß-lactam that is not hydrolysed by ESBLs. Objectives: To describe the real-life use of temocillin, to assess its effectiveness in infections caused by ESBL-producing Enterobacterales, and to identify risk factors for treatment failure. Methods: Retrospective multicentric study in eight tertiary care hospitals in the Greater Paris area, including patients who received at least one dose of temocillin for ESBL infections from 1 January to 31 December 2018. Failure was a composite criterion defined within 28 day follow-up by persistence or reappearance of signs of infection, and/or switch to suppressive antibiotic treatment and/or death from infection. A logistic regression with univariable and multivariable analysis was performed to identify risks associated with failure. Results: Data on 130 infection episodes were collected; 113 were due to ESBL-producing Enterobacterales. Mean age was 65.2 ±â€Š15.7 years and 68.1% patients were male. Indications were mostly urinary tract infections (UTIs) (85.8%), bloodstream infections (11.5%), respiratory tract infections (RTIs) (3.5%) and intra-abdominal infections (3.5%). Bacteria involved were Escherichia coli (49.6%), Klebsiella pneumoniae (44.2%) and Enterobacter cloacae (8.8%). Polymicrobial infections occurred in 23.0% of cases. Temocillin was mostly used in monotherapy (102/113, 90.3%). Failure was found in 13.3% of cases. Risk factors for failure in multivariable analysis were: RTI (aOR 23.3, 95% CI 1.5-358.2) and neurological disease (aOR 5.3, 95% CI 1.5-18.6). Conclusions: The main use of temocillin was UTI due to ESBL-producing E. coli and K. pneumoniae, with a favourable clinical outcome. The main risk factor for failure was neurological disease.

Subcutaneous pantoprazole in an elderly, palliative care patient.

Proton pump inhibitors (PPIs) have become the agents of choice for acid-related diseases. In some clinical situations, PPI therapy by oral or intravenous route may be difficult especially among elderly and patients in palliative care. Off-label PPI subcutaneous injection could be the last alternative to improve patient relief, despite limited published data. We report a case of linitis plastica, peritoneal carcinomatosis and occlusive syndrome who suffered from painful regurgitations which rapidly improved after subcutaneous pantoprazole. No related adverse effects were observed during PPI therapy. Despite some limitations, this report suggests that off-label subcutaneous pantoprazole could be an interesting alternative route when intravenous infusion may be difficult or harmful for elderly and patients in palliative care. Nevertheless, clinical safety and efficiency data on larger populations are needed to validate this use in such population.

Off-label use of midazolam in older inpatients: analysis of prescribing practices in a French hospital (MIDnight study).

Midazolam is a short-acting benzodiazepine approved for sedation and anesthesia induction. Recent data suggested that midazolam may also be used in off-label indications such as treatment of behavioral and psychological disturbances in older people. Given the scarcity of published data and a lack of evidence in older people in such indications, midazolam raises concern because it may also cause serious-related adverse events. To provide a better understanding of its real-life use in geriatrics, we examined the prescribing practices of midazolam in French older inpatients. Of the 460 patients aged 65 years and over hospitalized at the time of the study, 21 had a prescription of midazolam (5%) which was mainly prescribed for anxiolysis (n = 12), premedication before painful procedures (n = 5), and agitation (n = 4). Midazolam was often prescribed "as required," and the median duration of prescription was 6 months. This work results in a better knowledge and information about the use of midazolam in older people. These prescribing practices, which are not anecdotal, also plead for age-specific guidelines for the treatment of behavioral and psychological disturbances.

Population Pharmacokinetic Model of Plasma and Cellular Mycophenolic Acid in Kidney Transplant Patients from the CIMTRE Study.

BACKGROUND AND OBJECTIVE: Mycophenolate mofetil is widely used in kidney transplant recipients. Mycophenolate mofetil is hydrolysed by blood esterases to mycophenolic acid (MPA), the active drug. Although MPA therapeutic drug monitoring has been recommended to optimise the treatment efficacy by the area under the plasma concentration vs time curve, little is known regarding MPA concentrations in peripheral blood mononuclear cells, where MPA inhibits inosine monophosphate dehydrogenase. This study aimed to build a pharmacokinetic model using a population approach to describe MPA total and unbound concentrations in plasma and into peripheral blood mononuclear cells in 78 adult kidney transplant recipients receiving mycophenolate mofetil therapy combined with tacrolimus and prednisone. METHODS: Total and unbound plasma concentrations and peripheral blood mononuclear cell concentrations were assayed. A three-compartment model, two for plasma MPA and one for peripheral blood mononuclear cell MPA, with a zero-order absorption and a first-order elimination was used to describe the data. RESULTS: Mycophenolic acid average concentrations in peripheral blood mononuclear cells were well above half-maximal effective concentration for inosine monophosphate dehydrogenase and no relationship was found with the occurrence of graft rejection. Three covariates affected unbound and intracellular MPA pharmacokinetics: creatinine clearance, which has an effect on unbound MPA clearance, human serum albumin, which influences fraction unbound MPA and the ABCB1 3435 C>T (rs1045642) genetic polymorphism, which has an effect on MPA efflux transport from peripheral blood mononuclear cells. CONCLUSION: This population pharmacokinetic model demonstrated the intracellular accumulation of MPA, the efflux of MPA out of the cells being dependent on P-glycoprotein transporters. Nevertheless, further studies are warranted to investigate the relevance of MPA concentrations in peripheral blood mononuclear cells to dosing regimen optimisation.

Efficacy and safety of subcutaneous administration of ceftazidime as a salvage therapy in geriatrics: a case report.

Ceftazidime is a third-generation cephalosporin used for the treatment of Gram-negative bacteria only approved for parenteral use by intravenous and intramuscular route. In some clinical situations, off-label subcutaneous injection could be a salvage route for the administration of antibiotics, especially in geriatrics, despite the paucity of evidence about efficacy and safety. We report a case of a successful and well-tolerated subcutaneous ceftazidime therapy in a 90-year-old woman for the treatment of an acute urinary tract infection caused by Pseudomonas aeruginosa with therapeutic drug monitoring data.

Acceptability in the Older Population: The Importance of an Appropriate Tablet Size.

Presenting many advantages, solid oral dosage forms (SODFs) are widely manufactured and frequently prescribed in older populations regardless of the specific characteristics of patients. Commonly, patients with dysphagia (swallowing disorders) experience difficulties taking SODFs, which may lead to non-adherence or misuse. SODF characteristics (e.g., size, shape, thickness) are likely to influence swallowability. Herein, we used the acceptability reference framework (the ClinSearch acceptability score test (CAST))-a 3D-map juxtaposing two acceptability profiles-to investigate the impact of tablet size on acceptability. We collected 938 observer reports on the tablet intake by patients ≥65 years in hospitals or care homes. As we might expect, tablets could be classified as accepted in older patients without dysphagia (n = 790), while not in those with swallowing disorders (n = 146). However, reducing the tablet size had a significant impact on acceptability in this subpopulation: tablets <6.5 mm appeared to be accepted by patients with swallowing disorders. Among the 309 distinct tablets assessed in this study, ranging in size from 4.7 to 21.5 mm, 83% are ≥6.5 mm and consequently may be poorly accepted by institutionalized older people and older inpatients suffering from dysphagia. This underlines the need to develop and prescribe medicines with the best adapted characteristics to reach an optimal acceptability in targeted users.

Eculizumab as an emergency treatment for adult patients with severe COVID-19 in the intensive care unit: A proof-of-concept study.

BACKGROUND: Complement pathway inhibition may provide benefit for severe acute respiratory illnesses caused by viral infections such as COVID-19. We present results from a nonrandomized proof-of-concept study of complement C5 inhibitor eculizumab for treatment of severe COVID-19. METHODS: All patients (N = 80) with confirmed SARS-CoV-2 infection and severe COVID-19 admitted to our intensive care unit between March 10 and May 5, 2020 were included. Forty-five patients were treated with standard care and 35 with standard care plus eculizumab through expanded-access emergency treatment. The prespecified primary outcome was day-15 survival. Clinical laboratory values and biomarkers, complement levels, and treatment-emergent serious adverse events (TESAEs) were also assessed. FINDINGS: At day 15, estimated survival was 82.9% (95% CI: 70.4%‒95.3%) with eculizumab and 62.2% (48.1%‒76.4%) without eculizumab (log-rank test, P = 0.04). Patients treated with eculizumab experienced a significantly more rapid decrease in lactate, blood urea nitrogen, total and conjugated bilirubin levels and a significantly more rapid increase in platelet count, prothrombin time, and in the ratio of arterial oxygen tension over fraction of inspired oxygen versus patients treated without eculizumab. Eculizumab-associated changes in complement levels, laboratory values, and biomarkers were consistent with terminal complement inhibition, reduced hypoxia, and decreased inflammation. TESAEs of special interest occurring in >5% of patients treated with/without eculizumab were ventilator-associated pneumonia (51%/24%), bacteremia (11%/2%), gastroduodenal hemorrhage (14%/16%), and hemolysis (3%/18%). INTERPRETATION: Findings from this proof-of-concept study suggest eculizumab may improve survival and reduce hypoxia in patients with severe COVID-19. Randomized studies evaluating the efficacy and safety of this treatment approach are needed. FUNDING: Programme d'Investissements d'Avenir: ANR-18-RHUS60004.

Sex Differences in Medicine Acceptability: A New Factor to Be Considered in Medicine Formulation.

Palatability is a recognized driver of medicine acceptability in pediatrics but deemed less relevant in older populations due to sensory decline. Preliminary findings from an observational study implicated palatability problems with one Alzheimer's medicine. Among 1517 observer reports combining multiple measures on medicines uses in patients aged over 64, we focused on two original formulations of memantine (Ebixa®, tablets (n = 25) and oral solution (n = 60)). Evaluations were scored with an acceptability reference framework (CAST), the rodent Brief Access Taste Aversion (BATA) model tested aversiveness. Focusing on women treated with Ebixa® (n = 54), the oral formulation sub-group was classified as "negatively accepted", while the coated tablet was associated with the "positively accepted" cluster. In men, both formulations belonged to the "positively accepted" profile. Using BATA, the original oral solution was categorized as highly aversive/untolerated while solutions of excipients only were well tolerated. Furthermore, the number of licks was significantly lower in female than in male rats. These results revealed that medicine palatability remains important for acceptability in older populations. Moreover, converging results from humans and animal models highlighted that palatability profiles can significantly vary between the sexes. These drivers should be closely considered during drug development to enhance acceptability in this population.