The effect of a trAnSitional Pharmacist Intervention in geRiatric inpatients on hospital visits after dischargE (ASPIRE): Protocol for a randomized controlled trial.

BACKGROUND: Unplanned rehospitalizations occur frequently in older patients. Drug-related problems constitute a major and largely preventable cause with inappropriate prescribing being a substantial culprit. Solutions are needed to reduce this risk by targeting pharmacotherapy both during and after hospital stay. Therefore, we aim to perform a randomized controlled trial in geriatric inpatients to investigate the impact of a multifaceted clinical pharmacy intervention on health-related outcomes. METHODS/DESIGN: The study concerns a monocenter, non-blinded, randomized controlled trial that will take place at the acute geriatric wards of a large academic hospital. Patients being in a palliative stage with active therapy withdrawal or patients discharged to another ward within the same hospital or another hospital are excluded. In total, 828 patients will be randomized (1:1) to the usual care or intervention group. The multifaceted clinical pharmacy intervention comprises medication reconciliation at admission and discharge, medication review, patient/caregiver education, intensified communication with primary care providers and post-discharge follow-up, which also includes a telepharmacology service. The primary endpoint is defined as the time to an all-cause, unplanned hospital revisit within six months after discharge. Other health-related outcomes such as drug-related readmissions, quality of life and number of potentially inappropriate medications will be analyzed as secondary endpoints. Patient inclusion started in February 2021. DISCUSSION: This study will provide useful insights regarding the impact of clinical pharmacy interventions on geriatric wards with the goal to optimize health-related outcomes such as hospital revisits. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04617340.

Itraconazole for COVID-19: preclinical studies and a proof-of-concept randomized clinical trial.

BACKGROUND: The antifungal drug itraconazole exerts in vitro activity against SARS-CoV-2 in Vero and human Caco-2 cells. Preclinical and clinical studies are required to investigate if itraconazole is effective for the treatment and/or prevention of COVID-19. METHODS: Due to the initial absence of preclinical models, the effect of itraconazole was explored in a clinical, proof-of-concept, open-label, single-center study, in which hospitalized COVID-19 patients were randomly assigned to standard of care with or without itraconazole. Primary outcome was the cumulative score of the clinical status until day 15 based on the 7-point ordinal scale of the World Health Organization. In parallel, itraconazole was evaluated in a newly established hamster model of acute SARS-CoV-2 infection and transmission, as soon as the model was validated. FINDINGS: In the hamster acute infection model, itraconazole did not reduce viral load in lungs, stools or ileum, despite adequate plasma and lung drug concentrations. In the transmission model, itraconazole failed to prevent viral transmission. The clinical trial was prematurely discontinued after evaluation of the preclinical studies and because an interim analysis showed no signal for a more favorable outcome with itraconazole: mean cumulative score of the clinical status 49 vs 47, ratio of geometric means 1.01 (95% CI 0.85 to 1.19) for itraconazole vs standard of care. INTERPRETATION: Despite in vitro activity, itraconazole was not effective in a preclinical COVID-19 hamster model. This prompted the premature termination of the proof-of-concept clinical study. FUNDING: KU Leuven, Research Foundation - Flanders (FWO), Horizon 2020, Bill and Melinda Gates Foundation.

Favipiravir at high doses has potent antiviral activity in SARS-CoV-2-infected hamsters, whereas hydroxychloroquine lacks activity.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapidly spread around the globe after its emergence in Wuhan in December 2019. With no specific therapeutic and prophylactic options available, the virus has infected millions of people of which more than half a million succumbed to the viral disease, COVID-19. The urgent need for an effective treatment together with a lack of small animal infection models has led to clinical trials using repurposed drugs without preclinical evidence of their in vivo efficacy. We established an infection model in Syrian hamsters to evaluate the efficacy of small molecules on both infection and transmission. Treatment of SARS-CoV-2-infected hamsters with a low dose of favipiravir or hydroxychloroquine with(out) azithromycin resulted in, respectively, a mild or no reduction in virus levels. However, high doses of favipiravir significantly reduced infectious virus titers in the lungs and markedly improved lung histopathology. Moreover, a high dose of favipiravir decreased virus transmission by direct contact, whereas hydroxychloroquine failed as prophylaxis. Pharmacokinetic modeling of hydroxychloroquine suggested that the total lung exposure to the drug did not cause the failure. Our data on hydroxychloroquine (together with previous reports in macaques and ferrets) thus provide no scientific basis for the use of this drug in COVID-19 patients. In contrast, the results with favipiravir demonstrate that an antiviral drug at nontoxic doses exhibits a marked protective effect against SARS-CoV-2 in a small animal model. Clinical studies are required to assess whether a similar antiviral effect is achievable in humans without toxic effects.

Bacteriophage Application for Difficult-to-treat Musculoskeletal Infections: Development of a Standardized Multidisciplinary Treatment Protocol.

Bacteriophage therapy has recently attracted increased interest, particularly in difficult-to-treat infections. Although it is not a novel concept, standardized treatment guidelines are currently lacking. We present the first steps towards the establishment of a "multidisciplinary phage task force" (MPTF) and a standardized treatment pathway, based on our experience of four patients with severe musculoskeletal infections. After review of their medical history and current clinical status, a multidisciplinary team found four patients with musculoskeletal infections eligible for bacteriophage therapy within the scope of Article 37 of the Declaration of Helsinki. Treatment protocols were set up in collaboration with phage scientists and specialists. Based on the isolated pathogens, phage cocktails were selected and applied intraoperatively. A draining system allowed postoperative administration for a maximum of 10 days, 3 times per day. All patients received concomitant antibiotics and their clinical status was followed daily during phage therapy. No severe side-effects related to the phage application protocol were noted. After a single course of phage therapy with concomitant antibiotics, no recurrence of infection with the causative strains occurred, with follow-up periods ranging from 8 to 16 months. This study presents the successful outcome of bacteriophage therapy using a standardized treatment pathway for patients with severe musculoskeletal infection. A multidisciplinary team approach in the form of an MPTF is paramount in this process.

Impact of an oral nutrition protocol in patients treated with elective radical cystectomy: a long term follow-up.

Background After radical cystectomy, delayed return of bowel function is relatively common. Although studies investigating on the best modality for delivering nutritional support to this patient group are limited, parenteral nutrition was standard of care in those patients at the urological ward of the University Hospitals Leuven. In 2015, we published the findings from our study conducted in patients undergoing elective regular radical cystectomy at the urological ward of the University Hospitals Leuven comparing the length of hospital stay in patients with early postoperative parenteral nutrition (n = 48) versus an immediate oral nutrition protocol (n = 46). It was demonstrated that the implementation of an oral nutrition protocol was associated with a significant reduced length of hospital stay (median [IQR] of 18 [15-22] to 14 [13-18] days (p < 0.001)). The sample size was however too small to investigate the impact of the oral nutrition protocol on the incidence of catheter-related bloodstream infection, a common parenteral nutrition related complication. Objective To investigate the long term impact of an oral nutrition protocol on the incidence of catheter-related bloodstream infection, duration of catheterization and the length of hospital stay. Method Retrospectively, before (parenteral nutrition group) and after the implementation of the oral nutrition protocol (since March 10th 2010), two cohorts of 549 patients who underwent an elective regular radical cystectomy were included. The incidence of a catheter-related bloodstream infection and the length of stay were compared. A central venous catheter was present in every patient, which is standard of care. Results Catheter-related bloodstream infection was reduced from 22 (4%) to 10 (1.8%) (p = 0.031). The median duration of catheterization was 10 [7-13] days for the parenteral nutrition versus 7 [7-7] days for the oral nutrition group (p < 0.001). The median length of stay between both groups, 20 [17-25] before versus 17 [14-21] days after the implementation of the oral nutrition protocol, also differed significantly (p < 0.001). Implementing the oral nutrition protocol resulted in a parenteral nutrition associated cost saving of €470 per patient. Conclusion This large follow-up study showed that the oral nutrition protocol is associated with a reduction in catheter-related bloodstream infection. Besides, postponing parenteral nutrition in favour of oral nutrition enhances recovery.

Higher versus standard amikacin single dose in emergency department patients with severe sepsis and septic shock: a randomised controlled trial.

Recent studies suggest that intensive care unit patients treated with amikacin frequently do not attain the desired pharmacokinetic/pharmacodynamic (PK/PD) target, i.e. peak amikacin concentration (Cpeak) to minimum inhibitory concentration (MIC) ratio of ≥8, when a single dose of 15 mg/kg is used. No data are available for patients admitted to the emergency department (ED). The aim of this prospective randomised controlled study was to determine PK/PD target attainment in ED patients presenting with severe sepsis or septic shock treated with 15 mg/kg versus 25 mg/kg amikacin. Patients were randomly assigned to receive amikacin 25 mg/kg or 15 mg/kg. Amikacin Cpeak values were determined. The primary outcome was target attainment defined as Cpeak/MIC ≥ 8 both using EUCAST susceptibility breakpoints and actually documented MICs as denominator. A total of 104 patients were included. The EUCAST-based target was attained in 76% vs. 40% of patients assigned to the 25 mg/kg vs. 15 mg/kg dose groups (P <0.0001). Target attainment using actual MICs (median of 2 mg/L, documented in 48 isolated Gram-negative pathogens) was achieved in 95% vs. 94% of patients in the 25 mg/kg vs. 15 mg/kg dose groups (P = 0.969). Risk factors associated with PK/PD target failure were identified in the multivariable analysis. At least 25 mg/kg amikacin as a single dose should be used in ED patients with severe sepsis and septic shock to attain the EUCAST-based PK/PD target. However, when using local epidemiology as denominator, 15 mg/kg appears to be sufficient. [ClinicalTrials.gov ID: NCT02365272.

A simple tool to improve medication reconciliation at the emergency department.

BACKGROUND: Medication histories acquired upon admission are often incomplete. Using a standardized approach warrants more complete medication reconciliation, however, this is too time consuming to be performed. Other strategies guaranteeing complete medication histories should be explored. We developed a limited list of standardized questions and assessed its impact on completeness of medication histories. METHODS: This prospective study enrolled adults presenting to a tertiary care emergency department. In the control group, medication histories were conducted by physicians of general internal medicine conform standard care. In the intervention group, the physicians were obliged to use, besides the standard care, the 'limited questions list' for medication history acquisition. The clinical pharmacist re-obtained medication histories of the patients in both groups using a standardized approach. The primary outcome was the impact of the use of a 'limited questions list' on the frequency of drug omissions in medication histories. RESULTS: 260 consecutive patients were enrolled: 130 in the intervention group and 130 in the control group. There was a significant reduction of 49.3% in drug omissions in the intervention group. The omission rate per medication history was 1.1 for the control group, which was significantly lower (0.6) in the intervention group. Antithrombotics were most frequently forgotten in the control care group as opposed to dietary supplements in the intervention group. CONCLUSION: Drug omission rate in medication histories can be significantly reduced if a limited list of simple questions is used during anamnesis. Widespread use of this tool should be considered to be implemented.