Safe shortening of antibiotic treatment duration for complicated Staphylococcus aureus bacteraemia (SAFE trial): protocol for a randomised, controlled, open-label, non-inferiority trial comparing 4 and 6 weeks of antibiotic treatment.

INTRODUCTION: A major knowledge gap in the treatment of complicated Staphylococcus aureus bacteraemia (SAB) is the optimal duration of antibiotic therapy. Safe shortening of antibiotic therapy has the potential to reduce adverse drug events, length of hospital stay and costs. The objective of the SAFE trial is to evaluate whether 4 weeks of antibiotic therapy is non-inferior to 6 weeks in patients with complicated SAB. METHODS AND ANALYSIS: The SAFE-trial is a multicentre, non-inferiority, open-label, parallel group, randomised controlled trial evaluating 4 versus 6 weeks of antibiotic therapy for complicated SAB. The study is performed in 15 university hospitals and general hospitals in the Netherlands. Eligible patients are adults with methicillin-susceptible SAB with evidence of deep-seated or metastatic infection and/or predictors of complicated SAB. Only patients with a satisfactory clinical response to initial antibiotic treatment are included. Patients with infected prosthetic material or an undrained abscess of 5 cm or more at day 14 of adequate antibiotic treatment are excluded. Primary outcome is success of therapy after 180 days, a combined endpoint of survival without evidence of microbiologically confirmed disease relapse. Assuming a primary endpoint occurrence of 90% in the 6 weeks group, a non-inferiority margin of 7.5% is used. Enrolment of 396 patients in total is required to demonstrate non-inferiority of shorter antibiotic therapy with a power of 80%. Currently, 152 patients are enrolled in the study. ETHICS AND DISSEMINATION: This is the first randomised controlled trial evaluating duration of antibiotic therapy for complicated SAB. Non-inferiority of 4 weeks of treatment would allow shortening of treatment duration in selected patients with complicated SAB. This study is approved by the Medical Ethics Committee VUmc (Amsterdam, the Netherlands) and registered under NL8347 (the Netherlands Trial Register). Results of the study will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NL8347 (the Netherlands Trial Register).

Indwelling time of peripherally inserted central catheters and incidence of bloodstream infections in haematology patients: a cohort study.

BACKGROUND: We aimed to assess whether longer indwelling time of peripherally inserted central catheters (PICC) increases risk of central line associated bloodstream infections (CLABSI) in haematology patients. METHODS: Multicentre retrospective cohort study among haematology patients receiving PICCs between 2013 and 2015. Occurrence of CLABSI based on CDC definitions was assessed. We calculated incidence rates, determined risk factors for CLABSI and used Poisson regression models to assess the risk of developing CLABSI as a function of PICC dwell time. We compared diagnoses and treatment characteristics between 2013-2015 and 2015-2020. RESULTS: 455 PICCs placed in 370 patients were included, comprising 19,063 catheter days. Median indwelling time was 26 days (range 0-385) and CLABSI incidence was 4.0 per 1000 catheter days, with a median time to CLABSI of 33 days (range 18-158). Aplastic anaemia (AA) was associated with an increased risk of CLABSI; patients undergoing autologous stem cell transplantation (SCT) were less likely to develop CLABSI. In the unadjusted analysis, PICCs with an indwelling time of 15-28 days, 29-42 days, 43-56 days and > 56 days each had an increased CLABSI incidence rate ratio of 2.4 (1.2-4.8), 2.2 (0.95-5.0), 3.4 (1.6-7.5) and 1.7 (0.9-3.5), respectively, compared to PICCs in place for < 15 days. However, after adjusting for AA and SCT, there was no significant difference in incidence rates between dwell times (p 0.067). CONCLUSIONS: Our study shows that risk of CLABSI does not appear to increase with longer PICC indwelling time. Routine replacement of PICCs therefore is unlikely to prevent CLABSI in this population.

[Can furosemide mask the use of performance-enhancing drugs?] / Maskeert furosemide dopinggebruik?

Furosemide is included in the World Anti-Doping Agency's (WADA) list of prohibited substances because it can be used by athletes to mask the presence of performance-enhancing drugs in urine and/or excrete water for rapid weight loss. But how effective is furosemide in masking prohibited substances in urine? Based on the pharmacology and the available literature, we conclude that the masking effect of furosemide is limited. Furosemide is a doping agent that is mainly relevant for sports with weight categories.

The potential of training specialist oncology nurses in real-life reporting of adverse drug reactions.

Specialist oncology nurses (SONs) have the potential to play a major role in monitoring and reporting adverse drug reactions (ADRs); and reduce the level of underreporting by current healthcare professionals. The aim of this study was to investigate the long term clinical and educational effects of real-life pharmacovigilance education intervention for SONs on ADR reporting. This prospective cohort study, with a 2-year follow-up, was carried out in the three postgraduate schools in the Netherlands. In one of the schools, the prescribing qualification course was expanded to include a lecture on pharmacovigilance, an ADR reporting assignment, and group discussion of self-reported ADRs (intervention). The clinical value of the intervention was assessed by analyzing the quantity and quality of ADR-reports sent to the Netherlands Pharmacovigilance Center Lareb, up to 2 years after the course and by evaluating the competences regarding pharmacovigilance of SONs annually. Eighty-eight SONs (78% of all SONs with a prescribing qualification in the Netherlands) were included. During the study, 82 ADRs were reported by the intervention group and 0 by the control group. This made the intervention group 105 times more likely to report an ADR after the course than an average nurse in the Netherlands. This is the first study to show a significant and relevant increase in the number of well-documented ADR reports after a single educational intervention. The real-life pharmacovigilance educational intervention also resulted in a long-term increase in pharmacovigilance competence. We recommend implementing real-life, context- and problem-based pharmacovigilance learning assignments in all healthcare curricula.

Accelerated treatment with rtPA for pulmonary embolism induced circulatory arrest.

Patients with circulatory arrest due to pulmonary embolism (PE) should be treated with fibrinolytics. Current guidelines do not specify which regimen to apply, and it has been suggested that the regimen of 100 mg rtPA/2 h should be used, because this is recommended for hemodynamic instable PE in the ESC/ERS Guideline. This two hour regimen, however, is incompatible with key principles of cardiopulmonary resuscitation (CPR), such as employment of interventions that allow fast evaluation of effectiveness, and limitation of the total duration of CPR to avoid poor neurological outcomes. Additionally, the low flow-state during CPR has important consequences for the pharmacokinetic properties of rtPA. Arguably, the volume of distribution is lower, the metabolism reduced and the half life time longer. Therefore, these changes largely discard the rationale to use high dosages of rtPA over a prolonged period of time. More importantly, these changes highlight that the guideline recommendations, based on studies in patients without circulatory arrest, cannot be easily translated to the situation of circulatory arrest. An accelerated regimen of rtPA (0.6 mg/kg/15 min., max 50 mg) is mentioned by the 2019 ESC/ERS Guideline. However, empirical support or a rationale is not provided. Due to the rarity of the situation and ethical difficulties associated with randomizing unconscious patients, a randomized head-to-head comparison between the two regimens is unlikely to ever be performed. With this comprehensive overview of the pharmacokinetics of rtPA and current literature, a strong rationale is provided that the accelerated protocol is the regimen of choice for patients with PE-induced circulatory arrest.

Medical students as adverse drug event managers, learning about side effects while improving their reporting in clinical practice.

Managing adverse drug reactions (ADRs) is a challenge, especially because most healthcare professionals are insufficiently trained for this task. Since context-based clinical pharmacovigilance training has proven effective, we assessed the feasibility and effect of a creating a team of Junior-Adverse Drug Event Managers (J-ADEMs). The J-ADEM team consisted of medical students (1st-6th year) tasked with managing and reporting ADRs in hospitalized patients. Feasibility was evaluated using questionnaires. Student competence in reporting ADRs was evaluated using a case-control design and questionnaires before and after J-ADEM program participation. From Augustus 2018 to Augustus 2019, 41 students participated in a J-ADEM team and screened 136 patients and submitted 65 ADRs reports to the Netherlands Pharmacovigilance Center Lareb. Almost all patients (n = 61) found it important that "their" ADR was reported, and all (n = 62) patients felt they were taken seriously by the J-ADEM team. Although attending physicians agreed that the ADRs should have been reported, they did not do so themselves mainly because of a "lack of knowledge and attitudes" (50%) and "excuses made by healthcare professionals" (49%). J-ADEM team students were significantly more competent than control students in managing ADRs and correctly applying all steps for diagnosing ADRs (control group 38.5% vs. intervention group 83.3%, p < 0.001). The J-ADEM team is a feasible approach for detecting and managing ADRs in hospital. Patients were satisfied with the care provided, physicians were supported in their ADR reporting obligations, and students acquired relevant basic and clinical pharmacovigilance skills and knowledge, making it a win-win-win intervention.

[Which side effects should I inform patients about?] / Over welke bijwerkingen informeer ik de patiënt?

The law requires that healthcare professionals adequately inform patients about possible side effects when they prescribe new pharmacological treatments. There are several reasons (lack of time, fear of nocebo effect, patient and prescriber preferences) why informing patients in detail could be undesirable or even harmful. Prescribers should focus on two types of side effects: (a) common side effects with significant impact on the quality of life and (b) side effects that should be recognised in time to prevent further harm. During treatment, patients should be monitored regularly for efficacy and side effects in order to weigh benefits and risks and to stop or switch therapy when necessary.

[Can dental students and dental care providers in the Netherlands effectively and safely prescribe drugs?] / Serie: Onderwijs en de tandarts anno 2025. Kunnen tandheelkunde­studenten en mondzorgverleners in Nederland effectief en veilig geneesmiddelen voorschrijven?

Dentists and dental specialists are qualified to prescribe drugs. In this study, we assessed and compared the pharmacotherapeutic knowledge and skills of final year dental students, dentists and dental specialists in the Netherlands. In 2017, a random sample of these three groups was invited to complete an assessment. The knowledge assessment comprised 40 multiple choice questions covering often prescribed drugs. The skills assessment comprised three patient cases for which participants had to write a treatment plan. For the knowledge assessment, the response rates were 26 (20%) dental students, 28 (8%) dentists and 19 (19%) dental specialists, and for the skills assessment the response rates were 14 (11%) dental students, eight (2%) dentists, and eight (8%) dental specialists. On average, all three groups had inadequate knowledge scores (smaller 80%) and only a small proportion (smaller 30%) of their treatment plans was assessed as correct. These results suggest that dental students, dentists and dental specialists lack prescribing competence, which could be caused by poor pharmacotherapy education during under- and postgraduate dental training.

Antibiotic treatment for 6 days versus 12 days in patients with severe cellulitis: a multicentre randomized, double-blind, placebo-controlled, non-inferiority trial.

OBJECTIVES: To investigate whether antibiotic treatment of 6 days' duration is non-inferior to treatment for 12 days in patients hospitalized for cellulitis. METHODS: This multicentre, randomized, double-blind, placebo-controlled, non-inferiority trial enrolled adult patients hospitalized for severe cellulitis who were treated with intravenous flucloxacillin. At day 6 participants with symptom improvement who were afebrile were randomized between an additional 6 days of oral flucloxacillin or placebo in a 1:1 ratio, stratified for diabetes and hospital. The primary outcome was cure by day 14, without relapse by day 28. Secondary outcomes included a modified cure assessment and relapse rate by day 90. RESULTS: Between August 2014 and June 2017, 151 of 248 included participants were randomized. The intention-to-treat population consisted of 76 and 73 participants allocated to 12 and 6 days of antibiotic therapy, respectively (mean age 62 years, 67% males, 24% diabetics); 38/76 (50.0%) and 36/73 (49.3%) were cured in the 12- and 6-day groups respectively (ARR 0.7 percentage points, 95%CI: -15.0 to 16.3). Cure rates were 56/76 (73.7%) and 49/73 (67.1%) with the modified cure assessment (ARR 6.6, 95%CI: -8.0 to 20.8). After initial cure without relapse, day 90 relapse rates were higher in the 6-day group (6% versus 24%, p < 0.05). CONCLUSIONS: Given the wide confidence intervals, we can neither confirm nor refute our hypothesis that 6 days of therapy is non-inferior to 12 days of therapy. However, a 6-day course resulted in significantly more frequent relapses by day 90. These findings require confirmation in future studies.

The impact of laboratory closing times on delay of adequate therapy in blood stream infections.

BACKGROUND: Patients with bloodstream infections need early adequate antimicrobial treatment to reduce mortality. This raises the question of timing and logistics. How important is the time of day when a culture is flagged positive to the processing of blood cultures and optimisation of antimicrobial therapy? METHODS: We performed a retrospective study assessing the time delay of a positive blood culture result during and after office hours and its impact on adequate antimicrobial therapy. Process duration from the moment of culture positivity to Gram stain completion was compared at different timepoints during the day in a medium-sized hospital with an offsite microbiological laboratory. RESULTS: Ninety-four patients with positive, noncontaminated blood cultures were included. Sixty-six patients (70%) received adequate empirical therapy; this increased to 76 cases (82%) and to 88 cases (95%) after analysis of Gram stain results and complete determination, respectively (p < 0.05 for all comparisons). Median duration from culture positivity to Gram stain completion (including offsite culture transport) increased from a median of four to 12 hours if time of cultures turned positive after office hours (p < 0.05), irrespective of the adequacy of empirical coverage. This also resulted in a median 12-hour delay for the complete process from time of culture positivity to administration of the antimicrobial drug (p < 0.05). CONCLUSION: Processing blood cultures after office hours is often deferred, which can lead to a delay in adequate antimicrobial therapy for patients with bloodstream infections.

Essential diseases in prescribing: A national Delphi study towards a core curriculum in pharmacotherapy education.

AIMS: Prescribing is a core skill for junior doctors, yet 8-10% of their prescriptions contain errors. To ensure adequate training in prescribing, it is important to define the diseases for which junior doctors should be competent to prescribe. The aim of the present study was therefore to identify the essential diseases in prescribing for junior doctors. METHODS: A two-round Delphi consensus study was conducted among medical specialists, general practitioners, junior doctors, pharmacists and pharmacotherapy teachers from all eight academic hospitals in the Netherlands. Using a five-point Likert scale, the participants indicated for each item on an initial questionnaire whether it should be considered an essential disease for junior doctors. The items for which ≥80% of all respondents agreed or strongly agreed were accepted as essential diseases. RESULTS: Sixty-two participants completed the Delphi survey. In total, 63 of 220 items were considered to be essential diseases. CONCLUSION: This is the first Delphi consensus study identifying exact conditions that junior doctors must be able to prescribe for. The essential diseases can be used for training in prescribing and assessment of junior doctors' prescribing competence.

Urgent need to modernize pharmacovigilance education in healthcare curricula: review of the literature.

OBJECTIVES: Pharmacovigilance education is essential since adverse drug reactions (ADRs) are a serious health problem and contribute to unnecessary patient burden and hospital admissions. Healthcare professionals have little awareness of pharmacovigilance and ADR reporting, and only few educational interventions had durable effects on this awareness. Our future healthcare providers should therefore acquire an adequate set of pharmacovigilance competencies to rationally prescribe, distribute, and monitor drugs. We investigated the pharmacovigilance and ADR-reporting competencies of healthcare students to identify educational interventions that are effective in promoting pharmacovigilance. METHODS: The PubMed, EMBASE, Cochrane, CINAHL, PsycINFO, and ERIC databases were searched using the terms "pharmacovigilance," "students," and "education.". RESULTS: Twenty-five cross-sectional and 14 intervention studies describing mostly medical and pharmacy students were included. Intentions and attitudes on ADR reporting were overall positive, although most students felt inadequately prepared, missed the training on this topic, and lacked basic knowledge. Although nearly all students observed ADRs during clinical rounds, only a few had actually been involved in reporting an ADR. Educational interventions were predominately lectures, sometimes accompanied by small interactive working groups. Most interventions resulted in a direct increase in knowledge with an unknown long-term effect. Real-life learning initiatives have shown that healthcare students are capable of contributing to patient care while increasing their ADR-reporting skills and knowledge. CONCLUSIONS: There is an urgent need to improve and innovate current pharmacovigilance education for undergraduate healthcare students. By offering real-life pharmacovigilance training, students will increase their knowledge and awareness but can also assist current healthcare professionals to meet their pharmacovigilance obligations.

Nudging to improve hand hygiene.

BACKGROUND: Hand hygiene is paramount to prevent healthcare-associated infections, but improving compliance is challenging. When healthcare workers seldom encounter healthcare-associated infections, they will consider the odds of causing infections through poor hand hygiene negligible. Cognitive biases such as these may induce non-compliance. Nudging, 'a friendly push to encourage desired behaviour', could provide an easily implemented, inexpensive measure to address cognitive biases and thus support hand hygiene interventions. AIM: To investigate whether behavioural nudges, displayed as posters, can increase the use of alcohol-based hand rub. METHODS: We developed nudges based on a systematic review of previously described cognitive biases, and tested these through a cross-sectional survey among the target audience. We then conducted a controlled before-after trial on two hospital wards, to assess the effect of these nudges on the use of alcohol-based hand rub, measured with electronic dispensers. FINDINGS: Poisson regression analyses adjusted for workload showed that nudges displayed next to dispensers increased their overall use on one ward [poster 1: relative risk: 1.6 (95% confidence interval: 1.2-2.2); poster 2: 1.7 (1.2-2.5)] and during doctor's rounds on both wards [poster 1: ward A: 1.7 (1.1-2.6); ward B: 2.2 (1.3-3.8)]. Use of dispensers without adjacent nudges did not increase. CONCLUSION: Nudges based on cognitive biases that play a role in hand hygiene, and displayed as posters, could provide an easy, inexpensive measure to increase use of alcohol-based hand rub. When applying nudges to change behaviour, it is important to identify the right nudge for the right audience.

Pharmacology and Therapeutics Education in the European Union Needs Harmonization and Modernization: A Cross-sectional Survey Among 185 Medical Schools in 27 Countries.

Effective teaching in pharmacology and clinical pharmacology and therapeutics (CPT) is necessary to make medical students competent prescribers. However, the current structure, delivery, and assessment of CPT education in the European Union (EU) is unknown. We sent an online questionnaire to teachers with overall responsibility for CPT education in EU medical schools. Questions focused on undergraduate teaching and assessment of CPT, and students' preparedness for prescribing. In all, 185 medical schools (64%) from 27 EU countries responded. Traditional learning methods were mainly used. The majority of respondents did not provide students with the opportunity to practice real-life prescribing and believed that their students were not well prepared for prescribing. There is a marked difference in the quality and quantity of CPT education within and between EU countries, suggesting that there is considerable scope for improvement. A collaborative approach should be adopted to harmonize and modernize the undergraduate CPT education across the EU.

[Thiamine in patients with alcohol use disorder and Wernicke's encephalopathy]. / Thiamine bij een alcoholstoornis en Wernicke-encefalopathie.

- Patients with alcohol use disorder frequently have a thiamine deficiency.- A potential life-threatening complication of thiamine deficiency is Wernicke's encephalopathy.- Since it is clinically difficult to recognize Wernicke's encephalopathy, this condition is often treated inadequately. - Early supplementation of thiamine is important to avoid irreversible neurological damage. - There are differences between the Dutch guidelines regarding the supplementation of thiamine for the treatment of alcoholic use disorder, and those for Wernicke's encephalopathy. - There are no solid evidence-based recommendations about the best dosage, route of administration and duration of thiamine supplementation for the treatment of alcohol use disorder and Wernicke's encephalopathy. - Based on the pharmacokinetic properties of thiamine, it is more appropriate to give patients with alcohol use disorder 25 mg four times a day rather than 50 mg twice a day. - Patients at high risk of Wernicke's encephalopathy should immediately receive an intravenous or intramuscular dose of thiamine; patients with suspected Wernicke's encephalopathy should preferably receive an intravenous dose.- Reports of anaphylactic reaction to parenteral administration of thiamine are rare and are not a reason to refrain from parenteral treatment.

Effect of an antibiotic checklist on length of hospital stay and appropriate antibiotic use in adult patients treated with intravenous antibiotics: a stepped wedge cluster randomized trial.

OBJECTIVES: Quality indicators (QIs) have been developed to define appropriate antibiotic use in hospitalized patients. We evaluated whether a checklist based on these QIs affects appropriate antibiotic use and length of hospital stay. METHODS: An antibiotic checklist for patients treated with intravenous antibiotics was introduced in nine Dutch hospitals in a stepped wedge cluster randomized trial. Prophylaxis was excluded. We included a random sample before (baseline), and all eligible patients after (intervention) checklist introduction. Baseline and intervention outcomes were compared. Primary endpoint was length of stay (LOS), analysed by intention to treat. Secondary endpoints, including QI performances, QI sum score (performance on all QIs per patient), and quality of checklist use, were analysed per protocol. RESULTS: Between 1 November 2014 and 1 October 2015 we included 853 baseline and 5354 intervention patients, of whom 993 (19%) had a completed checklist. The LOS did not change (baseline geometric mean 10.0 days (95% CI 8.6-11.5) versus intervention 10.1 days (95% CI 8.9-11.5), p 0.8). QI performances increased between +3.0% and +23.9% per QI, and the percentage of patients with a QI sum score above 50% increased significantly (OR 2.4 (95% CI 2.0-3.0), p<0.001). Higher QI sum scores were significantly associated with shorter LOS. Discordance existed between checklist-answers and actual performance. CONCLUSIONS: Use of an antibiotic checklist resulted in a significant increase in appropriateness of antibiotic use, but not in a reduction of LOS. Low overall checklist completion rates and discordance between checklist-answers and actual provided care might have attenuated the impact of the checklist.

The prescribing performance and confidence of final-year medical students.

It is widely believed that medical students are not as well prepared or as sufficiently skilled in prescribing as they should be at the outset of their careers. However, a preclinical context-learning pharmacotherapy program has been found to improve students' therapeutic skills during an ensuing clinical clerkship in internal medicine.(1) In this Commentary, we argue that a similar approach during a clinical clerkship may further enhance therapeutic skills at the end of the clerkship.

5-Oxoproline as a cause of high anion gap metabolic acidosis: an uncommon cause with common risk factors.

High anion gap metabolic acidosis might be caused by 5-oxoproline (pyroglutamic acid). As it is very easy to treat, it might be worth drawing attention to this uncommon and probably often overlooked diagnosis. We present three cases of high anion gap metabolic acidosis due to 5-oxoproline seen within a period of six months.

[TNF-blocking drugs and infection; recommendations for daily practice]. / TNF-blokkerende geneesmiddelen en infecties; adviezen voor de dagelijkse praktijk.

Anti-tumour necrosis factor (TNF) therapy is associated with an increased risk of infection. There are sparse data and no evidence-based guidelines on how to deal with this problem in daily practice. However, recommendations can be made based on theoretical considerations and by extrapolating from recommendations for other types ofimmunodeficiency. Before starting anti-TNF therapy, screening for tuberculosis and other possible infections is indicated. During therapy, alertness is required to the increased risk of infection, infections with a more serious clinical course or unusual manifestations and opportunistic infections. Flu vaccination during anti-TNF therapy is indicated. Travel vaccinations with live microbial inocula should not be given.