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Purpose The use of two-dimensional (2D) printing technologies of drugs on orodispersible films (ODF) can promote dose individualization and facilitate drug delivery in vulnerable patients, including children. We investigated midazolam pharmacokinetics after the administration of 2D-printed ODF. Methods Midazolam doses of 0.03 and 3 mg were printed on an ODF using a 2D drug printer. We investigated the bioavailability of the two midazolam doses with ODF swallowed immediately (ODF-IS) or delayed after 2 min (ODF-DS) by comparing their pharmacokinetics with intravenous and oral midazolam solution in 12 healthy volunteers. Results The relative bioavailability of ODF-IS 0.03 mg was 102% (90% confidence interval: 89.4–116) compared to oral solution and for 3 mg 101% (86.8–116). Cmax of ODF-IS 0.03 mg was 95.5% (83.2–110) compared to oral solution and 94.3% (78.2–114) after 3 mg. Absolute bioavailability of ODF-IS 0.03 mg was 24.9% (21.2–29.2) and for 3 mg 28.1% (23.4–33.8) (oral solution: 0.03 mg: 24.4% (22.0–27.1); 3 mg: 28.0% (25.0–31.2)). Absolute bioavailability of ODF-DS was significantly larger than for ODF-IS (0.03 mg: 61.4%; 3 mg: 44.1%; both p Conclusion This trial demonstrates the tolerability and unchanged bioavailability of midazolam printed on ODF over a 100-fold dose range, proving the suitability of ODF for dose individualization. Midazolam ODF-IS AUC0–∞ in both doses was bioequivalent to the administration of an oral solution. However, Cmax of the therapeutic dose of ODF-IS missed bioequivalence by a clinically not relevant extent. Prolonged mucosal exposure increased bioavailability. (Trial Registration EudraCT: 2020–003984-24, August 10, 2020).

The objective of this study was to analyse the preoperative medication management within the cardiac surgery patient population and measure the effectiveness of an interprofessional intervention in routine care.A jointly developed preoperative medication management was implemented in routine care on multiple levels (inclusion in admission letter to primary care, hotline for inquiries, pocket cards for physicians and correspondence with referring centres). The effectiveness was evaluated by analysing preoperative management before and after implementation. The primary endpoint was the number of drugs managed correctly according to the guidelines after implementation. Secondary endpoints consisted amongst others of bleeding on the intensive care unit, re-thoracotomy, postoperative infarction and cerebrovascular complications. Additionally, possible associations between the correct management and different variables were investigated by multivariate analysis.After the implementation, the number of drugs managed correctly according to guidelines increased from 54.0 to 73.5% (P .001). The effect was more prominent for direct oral anticoagulants and prophylactic aspirin where the guideline adherence increased from 29.2 to 74.5% and from 78.6 to 95.1%, respectively. No difference was seen for sodium-glucose transporter-2 inhibitors, metformin, vitamin-K antagonists and dual-antiplatelet therapy. Secondary endpoints showed no safety signals with regard to bleeding or thrombotic events. In multivariate analysis, the intervention was effective (odds ratio 2.17, 95% confidence interval [1.32-3.62]) after adjusting for possible confounders.An interprofessional programme was effective to improve preoperative medication management in cardiac surgery patients. Sodium-glucose transporter-2 inhibitors, metformin and direct oral anticoagulants appear to be especially at risk for incorrect management before cardiac surgery with possible adverse events.

Background It is known that drug shortages represent a major challenge for all stakeholders involved in the process, but there is little evidence regarding insights into patients′ awareness and perspectives. This study aimed to investigate the patients-perceived drug shortages experience and their view on outcomes in different European hospital settings. Furthermore, we wanted to explore information preferences on drug shortages. Methods A retrospective, cross sectional, a mixed method study was conducted in six European hospital settings. One hospital (H) from each of this country agreed to participate: Bosnia and Herzegovina (H-BiH), Croatia (H-CR), Germany (H-GE), Greece (H-GR), Serbia (H-SE) and Poland (H-PO). Recruitment and data collection was conducted over 27 months from November 2017 until January 2020. Overall, we surveyed 607 patients which completed paper-based questionnaire. Questions related to: general information (demographic data), basic knowledge on drug shortages, drug shortages experienced during hospitalization and information preferences on drug shortage. Differences between hospital settings were analyzed using Chi-squared test or Fisher’s exact test. For more complex contingency tables, Monte Carlo simulations (N = 2000) were applied for Fisher’s test. Post-hoc hospital-wise analyses were performed using Fisher’s exact tests. False discovery rate was controlled using the Bonferroni method. Analyses were performed using R: a language and environment for statistical computing (v 3.6.3). Results 6 % of patients reported experiences with drug shortages while hospitalized which led to a deterioration of their health. The majority of affected patients were hospitalized at hematology and/or oncology wards in H-BiH, H-PO and H-GE. H-BiH had the highest number of affected patients (18.1 %, N = 19/105, p N = 1/100, p = 0.001). In addition, 82.5 %, (N = 501/607) of respondents wanted to be informed of alternative treatment options if there was a drug shortage without a generic substitute available. Majority of these patients (66.4 %, N = 386/501) prefer to be informed by a healthcare professional. Conclusions Although drug shortages led to serious medical consequences, our findings show that most of the patients did not perceive shortages as a problem. One possible interpretation is that good hospital management practices by healthcare professionals helped to mitigate the perceived impact of shortages. Our study highlights the importance of a good communication especially between patients and healthcare professionals in whom our patients have the greatest trust.

Structured analyses of hospital administrative data may detect potentially preventable adverse drug events (ADE) and therefore are considered promising sources to prevent future harm and estimate cost savings. Whether results of these analyses indeed correspond to ADE that may be preventable in clinical routines needs to be verified. We exemplarily screened all adult inpatients admitted to a German University Hospital (n = 54,032) for International Classification of Diseases-10th revision (ICD-10) diagnoses coding for drug-induced kidney injury (AKI). In a retrospective chart review, we checked the coded adverse events (AE) for inhospital occurrence, causality to drug exposure, and preventability in all identified cases and calculated positive predictive values (ppv). We identified 69 inpatient cases of whom 41 cases (59.4%) experienced the AE in the hospital (ppv-range 0.43–0.80). Causality assessment revealed a rather likely causal relationship between AE and drug exposure in 11 cases (15.9, 11/69, ppv-range 0.17–0.22) whereby preventability measures could be postulated for seven cases (10.1%, 7/69). Focusing on drug-induced AKI, this study exemplarily underlines that ICD-10-code-based ADE prevention efforts are quite limited due to the small identification rate and its high proportion of primarily outpatient events. Furthermore, causality assessment revealed that cases are often too complex to benefit from generic prevention strategies. Thus, ICD-10-code-based calculations might overestimate patient harm and economic losses.

Patient safety in hospitals can be compromised by preventable adverse events (AE). Among the preventable AEs, hospital-acquired infections (HAIs) are one of the most burdensome, contributing to not only poorer patient outcomes but institutional burden through direct financial losses and increased patient length of stay. Technological innovations can enhance patient safety by automating tasks, introducing medication alerts, clinical reminders, improved diagnostic and consultation reports, facilitating information sharing, improving clinical decision-making, intercepting potential errors, reducing variation in practice, and managing workforce shortages as well as making complete patient data available. A multidisciplinary working group from three European countries was convened to discuss how to optimise the use of technology to reduce preventable AEs in acute care hospitals. The working group identified examples where they felt there were opportunities to streamline patient pathways, including antimicrobial stewardship, point of care testing, microbiology test reporting to streamline time from sample-taking to clinical decision and mobile automated dispensing systems, which can reduce the burden on overworked staff. The working group also discussed key factors that were critical to ensuring different stakeholders, both within and outside the hospital, could meaningfully contribute to improving patient safety. They agreed that technological approaches and advances would have limited impact without meaningful cultural changes at all levels of healthcare infrastructure to implement the benefits offered by current or future technologies.

At inpatient admission, the timeliness and completeness of the Germany-wide standardised medication list ("Bundeseinheitlicher Medikationsplan") often seems inappropriate. It is also unclear which characteristics of the lists increase the probability of discrepancies.A total of 100 medication lists of elective patients of a surgical clinic were retrospectively evaluated with regard to potential discrepancies compared to the standardised medication reconciliation. The discprepancies were assigned to 7 categories: drug taken is missing on the list, drug on the list is no longer taken, strength or dosage is missing at the list or is incorrect, or the documented dosage form is different. Advice on patient safety, involved drugs and dosage forms were also recorded. Multivariate analyses were used to investigate the influence of the timeliness, number of drugs and issuing medical specialty of the lists on the type and number of discrepancies.Compared to the medication reconciliation, 78 % (78/100) of the lists showed discrepancies. A total of 226 deviations (2.3 ± 0.6 deviations/list) were documented. Most often, a drug was missing from the list (n = 103). Of all recommendations, 64 % (83/177) concerned the perioperative management of anticoagulants (n = 55) and antidiabetics (n = 28), corresponding to 62 % (62/100) of the lists. In the multivariate analysis, only the risk of incorrect information on strength and dosage increased significantly with the age of the lists (p = 0.047) and was more than twice as high when the list was more than one month old.The timeliness, completeness and aspects of patient safety must be comprehensively validated. Medication lists that are older than 1 month should be checked particularly critically with regard to information on strength and dosage and the plan should be updated accordingly at regular intervals.Bei stationärer Aufnahme scheint die Aktualität und Vollständigkeit des Bundeseinheitlichen Medikationsplans häufig nicht gegeben. Ebenso ist unklar, welche Charakteristiken der Pläne die Wahrscheinlichkeit für Diskrepanzen erhöhen.Retrospektiv wurden deshalb 100 Pläne, die zur Arzneimittelanamnese elektiver Patienten einer chirurgischen Klinik mitgebracht wurden, geprüft, ob und welche Abweichungen bestanden. Die Abweichungen wurden 7 Kategorien zugeordnet: Arzneimittel, das in der Anamnese erfasst wurde, fehlt auf dem Plan, Arzneimittel auf dem Plan wird nicht mehr eingenommen, Stärke oder Dosierung fehlt auf dem Plan bzw. ist falsch oder die Darreichungsform ist falsch dokumentiert. Hinweise zur Arzneimitteltherapiesicherheit, involvierte Arzneimittel und -formen wurden ebenfalls erfasst. Mithilfe multivariater Analysen wurde der Einfluss der Aktualität, der Anzahl der Arzneimittel und der ausstellenden Facharztdisziplin der Pläne auf die Art und Anzahl an Diskrepanzen untersucht.Zur Arzneimittelanamnese wiesen 78 % (78/100) der Pläne Abweichungen auf. Insgesamt wurden 226 Abweichungen (2,3 ± 0,6 Abweichungen/Anamnese) dokumentiert. Am häufigsten fehlte ein Arzneimittel auf dem Plan (n = 103). Von allen Hinweisen und Empfehlungen betrafen 64 % (83/177) das perioperative Management von Antithrombotika (n = 55) und Antidiabetika (n = 28). In der multivariaten Analyse stieg nur das Risiko für fehlerhafte Angaben bei Stärke und Dosierung mit dem Alter der Pläne signifikant (p = 0,047) und war um mehr als das 2-fache erhöht, wenn der Plan älter als einen Monat war.Die Aktualität, Vollständigkeit und Aspekte der Arzneimitteltherapiesicherheit des Bundeseinheitlichen Medikationsplans sollten umfassend und gezielt im Anamnesegespräch validiert werden. In der Praxis sollten Pläne, die älter als 1 Monat sind, besonders kritisch hinsichtlich Angaben zu Stärke und Dosierung geprüft und der Plan entsprechend regelmäßig aktualisiert werden.

Background: In patients with intracerebral hemorrhage (ICH) and prevalent atrial fibrillation (AF), the optimal stroke prevention strategy is unclear. We sought to estimate the risk of cerebrovascular events among ICH survivors with AF. Methods: We used the Danish Stroke Registry to identify patients with incident ICH and prevalent AF between 2003 and 2018. Key inclusion/exclusion criteria of the PRESTIGE-AF (Prevention of Stroke in Intracerebral hemorrhage Survivors With Atrial Fibrillation) trial were applied. Cumulative incidence of recurrent ICH, cerebrovascular ischemic event, and all-cause death were investigated after one year. Results: A total of 1885 patients (median age 80.0 years; 47.6% females) were included in the study. We observed 191 cerebrovascular events and 650 all-cause deaths, and more cerebrovascular ischemic events (N=63) than recurrent ICH events (N=40). Risks of recurrent ICH, cerebrovascular ischemic event, and all-cause death were 1.5%, 3.2%, and 30.3%, respectively, among patients not exposed to OAC during follow-up. The cumulative incidences were 2.8% for recurrent ICH, 3.2% for cerebrovascular ischemic events, and 22.0% for all-cause death among patients initiating/resuming OAC during follow-up. Conclusions: We observed a high risk of cerebrovascular ischemic events and a very high risk of all-cause death at one year after the incident ICH. The results of ongoing clinical trials are warranted to determine optimal stroke prevention treatment among ICH survivors with concomitant AF.

Background and importance Fast dissolving orodispersible films (ODF) provide an alternative formulation for patients with swallowing difficulties. Preparing these films is not yet part of the training in pharmacy school and is learned by self-training. Aim and objectives ODFs were produced using a manual and a technical technique. These were then analysed. Material and methods All solutions contained hydroxypropylmethylcellulose, glycerol 85%, water and, for quantitative analysis, propranolol hydrochloride (P-HCl). The films were manufactured using two different techniques: (1) dropping the solution with a syringe onto a foil: volume 0.1–1 mL; (2) solvent casting: pouring solution into a frame of 1000 µm height; fabricating stripes with the help of a film layering machine (Erichsen, Germany); after drying film stripes were cut in 1 cm2 and 4 cm2 pieces. All ODFs were dried for 3 days at room temperature and analysed for: height with a micrometer screw (Erichsen, model 497) dissolving rates. The OFDs were exposed every 30 s to a drop of purified water put onto the film. Time was measured to when the film became permeable. their content of P–HCl via UV/Vis. Results Film strips were 50 µm in height. The smallest drops of 0.1 mL had 135 µm height; those of 1 mL had a gauge of 175 µm. Dissolving rates depended on the thickness and gauge of the film. Time ranged from 2 to 3.6 min. 98% of the expected amount of P-HCl content was in the 1 mL drops, with only 90% in the smaller 0.1 mL drops. The content of active ingredients was 0.34 mg P-HCl in the film pieces of 1 cm². It raised linearly to 1.38 mg P-HCl in 4 cm² pieces. Conclusion and relevance Both methods led to suitable films. All films showed short dissolution rates and active ingredients had been inserted during the manufacturing process. The solvent casting method led to flatter films and therefore less active ingredient per cm². To receive a dose of 5 mg P-HCl, about 15 cm² of film should be taken orally. Further investigations are needed to improve this. Nevertheless, the dropping method is an elegant and easy method. References and/or acknowledgements Conflict of interest No conflict of interest

Background: Despite numbers of prescriptions filled remaining constant, expenditures for drugs are rising. Among others, this is caused by high prices for orphan drugs and advanced therapy medicinal products (ATMPs). Despite attempts by policymakers to intervene, the increasing use of these therapies poses numerous challenges on the health care system.Results: Using data from the University Hospital Heidelberg, we found that the division of pediatric neurology is experiencing a strong increase in drug costs, caused by two pharmaceuticals for the treatment of spinal muscular atrophy (SMA), Nusinersen and Onasemnogene Abeparvovec. To put this finding in a broader context, we conducted a survey of 41 German SMA treatment centers revealing a general lack of human and infrastructure resources for therapy and follow-up care, which demonstrates insufficient reimbursement of treatment. To improve structural conditions, we propose that disease-independent registries for medication surveillance that comply with the rules of the European Union are needed as well as the development of a fair funding model.Conclusion: Innovative forms of therapy require a critical discussion and concise regulation of treatment application and follow-up reimbursement as well as international industry-independent registry work. Based on the previously described model of “evidence-based dynamic pricing” by the Techniker Krankenkasse, we propose a revised model which offers an internationally scalable solution to meet these challenges.

Background: Despite a constant number of prescriptions, the expenditures of the statutory health insurance funds for pharmaceuticals are rising sharply. This is due to high prices for orphan drugs and advanced therapy medicinal products (ATMPs). Despite attempts by policymakers to intervene, such as the 2011 German Pharmaceutical Market Restructuring Act (Arzneimittelmarktneuordnungsgesetz, AMNOG), the use of these therapies poses numerous challenges for the healthcare system, especially insurance companies and healthcare providers.Results: Using data from the University Hospital Heidelberg, we found that the division of pediatric neurology is experiencing a disproportionate increase in drug costs, caused by two drugs for the treatment of spinal muscular atrophy (SMA), Nusinersen and Onasemnogen Abeparvovec. A survey of 41 German SMA treatment centers revealed a lack of human and infrastructural resources to manage therapy and follow-up care, which currently is insufficiently reimbursed. Disease-independent registers that comply with the rules of the European Union for medication surveillance and which are not tied to the pharmaceutical industry are necessary.Conclusion: Innovative forms of therapy require a critical discussion and regulation of application, aftercare and reimbursement as well as (inter)national industry independent registry work. Based on the model of evidence-based dynamic pricing by the Techniker Krankenkasse, we propose a concept which offers an internationally scalable solution to combat these challenges.

The mortality of patients with sepsis and septic shock is still unacceptably high. An effective antibiotic treatment within 1 h of recognition of sepsis is an important target of sepsis treatment. Delays lead to an increase in mortality;therefore, structured treatment concepts form a rational foundation, taking relevant diagnostic and treatment steps into consideration. In addition to the assumed focus and individual risks of each patient, local resistance patterns and specific problem pathogens must be taken into account for selection of anti-infection treatment. Many pathophysiological alterations influence the pharmacokinetics of antibiotics during sepsis. The principle of standard dosing should be abandoned and replaced by an individual treatment approach with stronger weighting of the pharmacokinetics/pharmacodynamics (PK/PD) index of the substance groups. Although this is not yet the clinical standard, prolonged (or continuous) infusion of beta-lactam antibiotics and therapeutic drug monitoring (TDM) can help to achieve defined PK targets. Prolonged infusion is sufficient without TDM but for continuous infusion TDM is basically necessary. A further argument for individual PK/PD-oriented antibiotic approaches is the increasing number of infections due to multidrug resistant pathogens (MDR) in the intensive care unit. For effective treatment antibiotic stewardship teams (ABS team) are becoming more established. Interdisciplinary cooperation of the ABS team with infectiologists, microbiologists and clinical pharmacists leads not only to a rational administration of antibiotics but also has a positive influence on the outcome. The gold standards for pathogen detection are still culture-based detection and microbiological resistance testing for the various antibiotic groups. Despite the rapid investigation time, novel polymerase chain reaction (PCR)-based procedures for pathogen identification and resistance determination, are currently only an adjunct to routine sepsis diagnostics due to the limited number of studies, high costs and limited availability. In complicated septic courses with multiple anti-infective treatment or recurrent sepsis, PCR-based procedures can be used in addition to therapy monitoring and diagnostics. Novel antibiotics represent potent alternatives in the treatment of MDR infections. Due to the often defined spectrum of pathogens and the practically absent resistance, they are suitable for targeted treatment of severe MDR infections (therapy escalation).

The present review assessed the evidence on risk factors for the occurrence of adverse health outcomes after discharge (i.e. unplanned readmission or adverse drug event after discharge) that are potentially modifiable by clinical pharmacist interventions. The findings were compared with patient characteristics reported in guidelines that supposedly indicate a high risk of drug-related problems. First, guidelines and risk assessment tools were searched for patient characteristics indicating a high risk of drug-related problems. Second, a systematic PubMed search was conducted to identify risk factors significantly associated with adverse health outcomes after discharge that are potentially modifiable by a clinical pharmacist intervention. After the PubMed search, 37 studies were included, reporting 16 risk factors. Only seven of 34 patient characteristics mentioned in pertinent guidelines corresponded to one of these risk factors. Diabetes mellitus (n = 11), chronic obstructive lung disease (n = 9), obesity (n = 7), smoking (n = 5) and polypharmacy (n = 5) were the risk factors reported most frequently in the studies. Additionally, single studies also found associations of adverse health outcomes with different drug classes {e.g. warfarin [hazard ratio 1.50; odds ratio (OR) 3.52], furosemide [OR 2.25] or high beta-blocker starting doses [OR 3.10]}. Although several modifiable risk factors were found, many patient characteristics supposedly indicating a high risk of drug-related problems were not part of the assessed risk factors in the context of an increased risk of adverse health outcomes after discharge. Therefore, an obligatory set of modifiable patient characteristics should be created and implemented in future studies investigating the risk for adverse health outcomes after discharge.

Background In the context of the cholinergic anti-inflammatory pathway, the clinical trial Anticholium® per Se (EudraCT Number: 2012-001650-26, ClinicalTrials.gov NCT03013322) addressed the possibility of taking adjunctive physostigmine salicylate treatment in septic shock from bench to bedside. Pharmacokinetics (PK) are likely altered in critically ill patients; data on physostigmine PK and target concentrations are sparse, particularly for continuous infusion. Our objective was to build a population PK (popPK) model for physostigmine, and further evaluate pharmacodynamics (PD) and concentration-response relationship in this setting. Methods In the randomized, double-blind, placebo-controlled trial, 20 patients with perioperative septic shock either received an initial dose of 0.04 mg/kg physostigmine salicylate, followed by continuous infusion of 1 mg/h for up to 120 h, or equivalent volumes of 0.9% sodium chloride (placebo group). Physostigmine plasma concentrations and acetylcholinesterase (AChE) activity were measured; concentration-response associations were evaluated, and popPK and PD modeling was performed with NONMEM. Results Steady state physostigmine plasma concentrations reached 7.60 ± 2.81 ng/mL (mean ± standard deviation [SD]). PK was best described by a two-compartment model with linear clearance. Significant covariate effects were detected for body weight and age on clearance, as well as a high inter-individual variability of the central volume of distribution. AChE activity was significantly reduced to 30.5%–50.6% of baseline activity during physostigmine salicylate infusion. A sigmoidal direct effect PD model best described enzyme inhibition by physostigmine, with an estimated half maximal effective concentration (EC50) of 5.99 ng/mL. Conclusions PK of physostigmine in patients with septic shock displayed substantial inter-individual variability with body weight and age influencing the clearance. Physostigmine inhibited AChE activity with a sigmoidal concentration-response effect.

Objectives Clinical pharmacy services in German hospitals appear to be underdeveloped compared with other European countries. However, recent developments have increased the interest in expanding these services. Detailed data about the current state of clinical pharmacy services in Germany are lacking. This survey establishes the current level of pharmacy services in Germany and the barriers to implementation. Methods An online survey conducted in 2017 was distributed to directors of all 389 German hospital pharmacies. The survey contained 26 questions addressing hospital and pharmacy characteristics, clinical pharmacy services provided, the number of clinical pharmacists and the frequency as well as the quality assurance of these services. Results There were 133 responses (34%). Of these, 84 (63%) pharmacies provided some form of clinical pharmacy services. Based on the 389 contacted pharmacies, a clinical pharmacy service is available in at least 22% of hospital pharmacies in Germany. On average there are 2.4 full-time equivalent (FTE) clinical pharmacists per hospital employed, although there is a wide variation in numbers (0.3–22 FTE) and service provision between hospitals. Clinical pharmacy services are generally provided on a daily or weekly basis, with a principal focus on general surgery, critical care and general medicine wards. Conclusions This is the first survey providing a detailed picture of clinical pharmacy services in Germany. There is wide variation in clinical service provision among hospitals, with some hospitals having developed a comprehensive range of clinical services. Compared with other countries, particularly the UK where the focus has shifted to provision of 7-day clinical services, the gap in clinical pharmacy services remains large. The focus should be turned to refining clinical pharmacy services in hospital admissions and discharge planning while also improving Health IT, the opportunities for specialisation and aligning education in accordance with the EAHP common training framework.

Background Orodispersible films (ODF)are described in the European Pharmacopoeia. However only a few ODF products are on the market, of which most are not medicines. ODFs provide an alternative formulation for those with swallowing difficulties, for example, paediatric and geriatric patients. An advantage of this formulation is that when they come into contact with water they become sticky, making it difficult to spit out. Purpose The aim was to develop a basis formulation of ODF. The formulation at the beginning of the manufacturing process should be fluid enough for pouring, but then solidify quickly. The resulting ODFs also should dissolve fast on contact with water and maintain good mechanical strength in handling. Material and methods Three different solutions were created, consisting of water, glycerol and hypromellose (HM), differing in the hypromellose content of: solution I with 3% HM, solution II with 4% HM and solution III with 5% HM. Prepared solutions were degassed by ultrasound and films were formed with the help of a film-layering machine. All were dried at room temperature. The dried films were then cut into pieces of 4 cm2 with a scalpel and the backing film removed. The taste was tested and the dissolution observed. Consequently, a piece of the film was placed in a dish with 20 ml of distilled water, every 10 s the dish was slightly agitated and the time to dissolution recorded. Results Solutions were found to be easy to process: solution III was almost too viscous. After drying, all films were found to be clear and even. Solution I was found to be quite sticky on the surface. All were easy to peel off from the backing film. All were found to be tear-resistant enough to handle. All films tasted sweet, were sticky in the mouth and subsequently unable to be spat out. All dissolved within about 4 min. Solution II was found to be the optimal formulation. Conclusion ODFs are very interesting and could extend the spectrum of dosage forms. In the future, further variants in composition will be investigated and drugs will be incorporated. References and/or acknowledgements Thanks to the team of the IPMB for supporting the film production. No conflict of interest.

Purpose The cholinergic anti-inflammatory pathway has been shown to be accessible by physostigmine salicylate in animal models. However, the cholinesterase inhibitor is not approved for adjunctive therapy in sepsis, and tolerability and safety of high initial doses followed by continuous infusion have not been investigated. Materials and methods In this trial, 20 patients with perioperative septic shock due to intra-abdominal infection were eligible. The physostigmine group received an initial dose of 0.04 mg/kg physostigmine salicylate, followed by continuous infusion of 1 mg/h for 120 h; the placebo group was treated with 0.9% sodium chloride. Primary outcome was the mean Sequential Organ Failure Assessment (SOFA) score during treatment and up to 14 days. Results Administration of physostigmine salicylate was well tolerated. Mean SOFA scores were 8.9 ± 2.5 and 11.3 ± 3.6 (mean ± SD) for physostigmine and placebo group, respectively. Adjusted for age, difference between means was not statistically significant (−2.37, 95% CI: −5.43 to 0.70, p = 0.121). Norepinephrine doses required only appeared lower in the physostigmine group (p = 0.064), along with a more rapid reduction from an elevated heart rate possibly indicating less hemodynamic instability. Conclusions Treatment with physostigmine salicylate was feasible and safe. Further studies are justified to assess the effect on recovery from septic shock. Trial registration EudraCT Number 2012-001650-26, ClinicalTrials.gov identifier NCT03013322 .

Drug-related problems (DRPs) are a significant and often preventable cause for morbidity and mortality. Hospitalization is associated with a high risk for DRPs, especially due to a lack of information transfer at transitions of care. At the same time, interventions during inpatient treatment usually require a change in drug therapy and additionally increase the risk of DRPs. Thereby, DRPs can occur at all levels of the medication process and can be caused by different groups of professionals. One way to improve medication safety in hospitals is to integrate clinical pharmacists into the medication process.According to available data, the integration of a clinical pharmacist in multi-professional teams during admission, hospitalization and discharge can significantly reduce DRPs, costs and increases efficacy of drug therapy. In addition, drug supply with unit-dose systems in combination with digitalization of the medication process can achieve an improvement in medication safety. Improvement in continuity of medical care through a structured medication review and seamless transmission of medically relevant information upon discharge contribute to a significant reduction of hospital readmissions and emergency admissions due to ABPs, as well as health costs. With a university education, the hospital pharmacist specialized in clinical pharmacy is the only professional group that can comprehensively support the physician in the field of drug therapy.

OBJECTIVES: In 2013, the PharmaHelp device was introduced to daily patient care at the University Hospital of Heidelberg in order to improve process and staff safety and health. It is a semiautomated device located in a safety workbench for aseptic preparation with weight-and-visual-supported process check as well as radio-frequency identification of bags and vials. METHODS: After qualification and a training period, several high-admixture-volume drugs were chosen stepwise to be prepared by the device. During a reporting period of 6 months, the number of processed production runs and produced bags were assessed as well as the productivity per hour of the device based on the processed admixing volume and time consumption for manual preprocessing and postprocessing steps. RESULTS: Weight conformity tests of 246 processed bags in 11 admixing-volume ranges showed 99.19% with a deviation of

Epidemiologische Studien der letzten Jahre belegen sowohl eine steigende Inzidenz invasiver Pilzinfektionen als auch ein zunehmendes Problem mit Therapieversagen auf Intensivstationen. In bis zu 70 % der Falle zeigt sich ein Nichtansprechen der primaren antimykotischen Therapie abhangig von der auslosenden Spezies bzw. von vorliegenden Grunderkrankungen. Der vorliegende Review-Beitrag soll fur das Thema des Therapieversagens sensibilisieren, die klinischen Umstande des Therapieversagens beschreiben sowie ein systematisches Vorgehen bei Verdacht auf ein Scheitern der primaren antimykotischen Therapie vorschlagen.

Background Relevant inhospital adverse drug events (ADE) are often documented in clinical administrative data (CAD) using ICD-10 codes (International Classification of Diagnosis Related Diseases, 10th revision). In a previous propensity matched cohort study, we analysed the CAD of 48 072 inpatients of a university hospital for potentially preventable inpatient ADE affecting length of stay. From a hospital’s perspective, particularly ICD-10 codes coding for drug induced renal failure, appeared to be preventable. Purpose We aimed to evaluate causes and conditions leading to renal failure in hospital and develop prevention strategies. Material and methods We assessed the validity of such codes in patient records and evaluated whether acute renal failure occurred during the hospital stay. Using the updated causality score by Begaud et al , we currently assess, using 2 independent reviewers, whether acute renal failure was drug related. 1 Based on root cause analyses, preventive strategies will be developed. Results The records of 69 patients were analysed (mean age 62 years (range 23–94), 33% women). 26 cases (38%) had a known history of renal failure or were hospitalised because of acute renal failure. In 43 cases (62%), the adverse event occurred in hospital. Nearly half of these cases (n=20) had a known history of renal failure. The pilot results of four randomly selected cases of this ongoing assessment revealed 6 suspect drugs with a high imputability to the ADE (1 drug with level I4 and 5 drugs with level I6 out of 7 possible scores from I0 to I6). As conceivable prevention strategies, we identified a priori dose adjustment and/or longer intravenous application duration for nephrotoxic drugs (eg, aciclovir) in patients with a known history of renal failure. Conclusion Unless CAD do not explicitly flag inpatient ICD-10 codes, CAD based ADE identification is laborious, and adequate risk management by the hospital is challenging. Screening for (pre-existing) renal (dys)function at the stage of hospitalisation for appropriate dose adjustment could prove a promising preventive strategy for our hospital. References and/or acknowledgements 1. Arimone Y, et al. Updating the French method for the causality assessment of adverse drug reactions. Therapie2013;68:69–76. No conflict of interest

The present review assessed the evidence on risk factors for the occurrence of adverse health outcomes after discharge (i.e. unplanned readmission or adverse drug event after discharge) that are potentially modifiable by clinical pharmacist interventions. The findings were compared with patient characteristics reported in guidelines that supposedly indicate a high risk of drug‐related problems. First, guidelines and risk assessment tools were searched for patient characteristics indicating a high risk of drug‐related problems. Second, a systematic PubMed search was conducted to identify risk factors significantly associated with adverse health outcomes after discharge that are potentially modifiable by a clinical pharmacist intervention. After the PubMed search, 37 studies were included, reporting 16 risk factors. Only seven of 34 patient characteristics mentioned in pertinent guidelines corresponded to one of these risk factors. Diabetes mellitus (n = 11), chronic obstructive lung disease (n = 9), obesity (n = 7), smoking (n = 5) and polypharmacy (n = 5) were the risk factors reported most frequently in the studies. Additionally, single studies also found associations of adverse health outcomes with different drug classes {e.g. warfarin [hazard ratio 1.50; odds ratio (OR) 3.52], furosemide [OR 2.25] or high beta‐blocker starting doses [OR 3.10]}. Although several modifiable risk factors were found, many patient characteristics supposedly indicating a high risk of drug‐related problems were not part of the assessed risk factors in the context of an increased risk of adverse health outcomes after discharge. Therefore, an obligatory set of modifiable patient characteristics should be created and implemented in future studies investigating the risk for adverse health outcomes after discharge.

Introduction Therapeutic drug monitoring (TDM) is a useful tool to optimize antibiotic therapy. Increasing interest in alternative dosing strategies of beta-lactam antibiotics, e.g. continuous or prolonged infusion, require a feasible analytical method for quantification of these antimicrobial agents. However, pre-analytical issues including sample handling and stability are to be considered to provide valuable analytical results. Methods For the simultaneous determination of piperacillin, meropenem, ceftazidime and flucloxacillin, a high performance liquid chromatography (HPLC) method including protein precipitation was established utilizing ertapenem as internal standard. Long-term stability of stock solutions and plasma samples were monitored. Furthermore, whole blood stability of the analytes in heparinized blood tubes was investigated comparing storage under ambient conditions and 2–8 °C. Results A calibration range of 5–200 μg/ml (piperacillin, ceftazidime, flucloxacillin) and 2–200 μg/ml (meropenem) was linear with r 2 > 0.999, precision and inaccuracy were Conclusions The presented method is a rapid and simple option for routine TDM of piperacillin, meropenem, ceftazidime and flucloxacillin. Whereas long-term storage of beta-lactam samples at −80 °C is possible for at least 9 months, whole blood tubes are recommended to be kept refrigerated until analysis.

Background Inadequate drug monitoring of drug therapy after hospital discharge facilitates adverse drug events and preventable hospital readmissions. Objective This study aimed to analyze the structure and content of drug monitoring advices of a representative sample of discharge letters as a basis for future electronic information systems. Methods On 2 days in November 2016, all discharge letters of 3 departments of a university hospital were extracted from the hospital information system. The frequency, content, and structure of drug monitoring advices in discharge letters were investigated and compared with the theoretical monitoring requirements expressed in the corresponding summaries of product characteristics (SmPC). The quality of the drug monitoring advices in the discharge letters was rated with the domains of an adapted systematic instructions for monitoring (SIM) score. Results In total, 154 discharge letters were analyzed containing 1180 brands (240 active pharmaceutical substances), of which 50.42% (595/1180) could theoretically be amended with a monitoring advice according to the SmPC. In reality, 40 discharge letters (26.0%, 40/154) contained a total of 66 monitoring advices for 57 brands (4.83%, 57/1180), comprising 18 different monitoring parameters. Drug monitoring advices only addressed mean 1.9 (SD 0.8) of the 7 domains of the SIM score and frequently did not address reasons for monitoring (86%, 57/66), the timing of monitoring, that is, the start (76%, 50/66), the frequency (94%, 63/66), the stop (95%, 63/66), and how to react (83%, 55/66). Conclusions Drug monitoring advices were mostly absent in discharge letters and a gold standard for appropriate drug monitoring advices was lacking. Hence, more effort should be put in the development of tools that facilitate easy presentation of clinically meaningful drug monitoring advices at the point of care.

It is being increasingly recognised by clinicians and scientists that participants in randomised clinical trials (RCTs) of antibiotics of last resort do not represent the patients who will later be treated with these drugs. Data on this subject are limited and have not been investigated systematically. This observational study aimed to examine this hypothesis quantitatively, using the example of tigecycline. To evaluate the influence of recruitment, patients eligible for clinical trials were retrospectively compared with ineligible patients regarding baseline and clinical characteristics as well as outcome parameters, e.g. length of hospital stay, intensive care unit (ICU) stay, ventilation and mortality. The clinical characteristics of 187 patients illustrated differences in the nature and severity of disease, co-morbidities and outcome. Eligible and ineligible patients differed in a number of parameters, e.g. median APACHE II score (15.5 vs. 28.0), number of liver transplantations (5% vs. 18%; P = 0.048), septic shock (21% vs. 49%; P = 0.001), need for mechanical ventilation (30% vs. 79%; P < 0.001), mean length of ICU stay (19.3 days vs. 40.7 days) and death (19% vs. 46%; P = 0.001). Critically ill patients were under-represented in clinical trials. Moreover, only a minority of patients in clinical practice (13%) were potentially eligible for a pivotal RCT. The disparities likely result from strict exclusion criteria in RCTs and recruitment bias. These data emphasise the importance of including critically ill patients in RCTs of antibiotics against multiresistant bacteria in order to account for those who will later be treated.

Background While evidence on implementation of medication safety strategies is increasing, reasons for selecting and relinquishing distinct strategies and details on implementation are typically not shared in published literature. Objective We aimed to collect and structure expert information resulting from implementing medication safety strategies to provide advice for decision-makers. Setting Medication safety experts with clinical expertise from thirteen hospitals throughout twelve European and North American countries shared their experience in workshop meetings, on-site-visits and remote structured interviews. Methods We performed an expert-based, in-depth assessment of implementation of best-practice strategies to improve drug prescribing and drug administration. Main outcome measures Workflow, variability and recommended medication safety strategies in drug prescribing and drug administration processes. Results According to the experts, institutions chose strategies that targeted process steps known to be particularly error-prone in the respective setting. Often, the selection was channeled by local constraints such as the e-health equipment and critically modulated by national context factors. In our study, the experts favored electronic prescribing with clinical decision support and medication reconciliation as most promising interventions. They agreed that self-assessment and introduction of medication safety boards were crucial to satisfy the setting-specific differences and foster successful implementation. Conclusion While general evidence for implementation of strategies to improve medication safety exists, successful selection and adaptation of a distinct strategy requires a thorough knowledge of the institute-specific constraints and an ongoing monitoring and adjustment of the implemented measures.

Invasive fungal disease (IFD) causes increasing morbidity and mortality in haematological cancer patients. Reliable cost data for treating IFD in German hospitals is not available. Objective of the study was to determine the institutional cost of treating the IFD. Data were obtained by retrospective chart review in German hospitals. Patients had either newly diagnosed or relapsed acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS). Direct medical cost was calculated from hospital provider's perspective. A total of 108 patients were enrolled at 5 tertiary care hospitals, 36 IFD patients and 72 controls. The vast majority of IFD patients (74%) were diagnosed with invasive aspergillosis. On average, the hospital stay for IFD patients was 12 days longer than in control patients. All patients in the IFD group and 89% of patients in the control group received antifungal drugs. Mean direct costs per patient were €51,517 in the IFD group and €30,454 in the control group. Incremental costs of €21,063 were dominated by cost for antifungal drugs (36%), hospital stay (32%) and blood products (23%). From the perspective of hospitals in Germany the economic burden of IFD in patients with AML or MDS is substantial. Therefore, prevention of IFD is necessary with respect to both clinical and economic reasons.

The authors describe two cases of successful and safe posaconazole use in patients of a surgical intensive care unit of a university hospital.

Objective of the study The purpose of this prospective intervention study was to assess the number of patients with Y-site incompatibilities before and after implementation of quality improvement measures to prevent incompatibilities consisting of a focused instruction for pantoprazole as a drug frequently involved in incompatible drug pairs and of a recommendation to use 4-lumen instead of 3-lumen catheters to increase the number of available central infusion lines. Setting Cardiovascular intensive care unit where several standard operating procedures (SOPs) dealing with compatibility were already in place. Method In a prospective intervention study, patients’ IV medication was assessed for potential incompatibilities using a database containing compatibility information on approximately 60,000 drug pairs. In a first period, routine administration was monitored in 53 consecutive patients (control group). Then, quality improvement measures were implemented recommending a purging procedure before and after bolus administration of pantoprazole as a drug frequently causing incompatibilities in this setting. Additionally, the use of 4-lumen instead of 3-lumen catheters was suggested whenever considered useful by the responsible physicians. The monitoring was repeated during a second period in another 58 patients consecutively admitted to the same unit (intervention group). Main outcome measure Overall number of patients with at least one incompatible drug pair and number of patients receiving incompatible pantoprazole combinations. Results The number of patients receiving incompatible pantoprazole combinations decreased from 15 of the 15 patients receiving pantoprazole (100.0%) in controls to 9/16 (56.2%) in the intervention group (P < 0.01). The overall number of patients with incompatibilities was not influenced by the intervention with 36/58 (62.1%) compared to controls with 38/53 (71.7%, P = 0.28). The fraction of central lines contributed by four lumen central catheters was larger due to the intervention (80/168 lines, 47.6%) compared to controls (16/184, 8.7%, P < 0.001). Only sporadically there were incompatible combinations of drugs governed by the already existing SOPs. Conclusion In an intensive care setting with good SOP adherence, purging before and after administration decreased the respective incompatibility rate whereas the use of 4-lumen instead of 3- lumen catheters had not the expected benefit on separating drug pairs.

Background. The demand for pharmacy cancer services is expected to at least double over the next 10 years, as the population ages and new treatments are introduced. Safe and efficient handling of cytotoxic products minimises risks to staff and reduces medication errors. Objectives. To identify and describe strategies for coping safely and effectively with heavier workloads in the hospital oncology pharmacy, currently and in the future. Methods. The PubMed database was searched for literature on approaches to safe handling of antineoplastic agents and to decreasing medication errors in the hospital pharmacy. Articles that were judged to be of prime importance to the hospital oncologist were reviewed. These safety concepts are put into the context of contemporary hospital oncology pharmacy practice through discussion of key issues, including increased demand, the role of the pharmacist in determining the hospital formulary, and growth in patient preferences for oral chemotherapy. Recommendations on best practices are also provided, based on relevant literature and author experience. Conclusions. Efficient, safe hospital pharmacy operations can be aided by capacity planning, dose banding, and knowledge of novel products and procedures that can reduce risks to health while increasing the number of patients who are safely treated. Consideration may also be given to the economic role of oncology pharmacists in formulary development. J Oncol Pharm Practice (2010) 16: 9—18.

Given the high incidence (1.5%–10%) of invasive aspergillosis (IA) after liver transplantation and the associated mortality, prophylaxis according to the patients’ circumstances is a reasonable approach. The purpose of this investigation was to determine the effect and significance of risk factors for IA in a specialized transplantation center. We collected data from patients who underwent liver transplantation at the Transplantation Center of the University Hospital Heidelberg (Germany) between December 2001 and December 2004 in a specifically designed database for retrospective analysis. Invasive aspergillosiswas defined according to the European Organization for Research and Treatment of Cancer classifications. Univariate analysis and logistic regression were performed to assess the influence of each assumed risk factor. A total of 195 liver transplantationswere performed in 170 patients, with two patients (1.2%) developing a proven IA, seven (4.1%) developing a probable IA, and five developing a possible IA (2.9%). All patients received oral itraconazole prophylaxis. Of these 14 patients with proven, probable or possible IA, 13 died within 4 weeks after the initial diagnosis; this represents 33.3% of all patients with a fatal outcome. Univariate significant factors were retransplantation (p = 0.004), cytomegalovirus (CMV) infection (p = 0.024), dialysis (p < 0.001), renal insufficiency (p = 0.05), thrombocytopenia (p = 0.001), and leukocytopenia (p = 0.002). Multivariate analysis showed an independent influence of CMV infection (OR 6.032, 95% CI 1.446–25.163) and dialysis (OR 14.985, 95%CI 2.936–76.486). The rate of IA found in this investigation is within the range reported in published studies. Based on our data, extended antifungal prophylaxis should be given to liver transplant patients with specific risk factors, such as renal insufficiency, requirement for dialysis, CMV infection, or thrombocytopenia. Additional focus should be on the prevention of CMV infections.

Incompatibility of drug solutions administered through a common line may jeopardize the safety and effectiveness of i.v. drug therapies.[1][1] We recently reported that, in the absence of dedicated preventive strategies, incompatibilities are alarmingly frequent in an intensive care setting.[2][2]

Background: Considering the complexity of diagnosis, high costs of therapy and high morbidity and mortality of systemic fungal infections, antifungal therapy of intensive care patients should follow clearly defined guidelines. We outline the impact of a standardised practice of antifungal treatment in an interdisciplinary surgical intensive care unit of a university hospital. Methods: Therapy was intended to be optimised by implementation of standardised practice guidelines supported by the clinical pharmacist. Costs for antifungal agents during a period of 18 months before and after implementation of the practice guidelines were compared, respectively. Results: The intervention was associated with a significant decrease in use of antifungal agents. Analysis of data revealed a reduction in costs by 50%. This could substantially be attributed to the implementation of the practice guidelines. Conclusion: The implementation of standardised practice guidelines for antifungal therapy in intensive care units decreased the use of selected antifungal agents and resulted in substantial reduction in expenditure on antifungal agents.

Aging-associated nitro-oxidative stress causes tissue injury and activates proinflammatory pathways that play an important role in the pathogenesis of aging-associated cardiovascular dysfunction. It has been recently reported, that the copper(II)-aspirinate complex (CuAsp) exerts not only the well-known anti-inflammatory and platelet antiaggregating effects of aspirin, but, due to its superoxide dismutase mimetic activity, it acts as a potent antioxidant as well. In this study we investigated the effects of CuAsp on aging-associated myocardial and endothelial dysfunction.Aging and young rats were treated for 3 weeks with vehicle, or with CuAsp (200 mg/kg per day per os). Left ventricular pressure-volume relations were measured by using a microtip pressure-volume conductance catheter, and indexes of contractility (e.g., slope of end-systolic pressure-volume relationships [ESPVR] [E(es)], and dP/dt(max) - end-diastolic volume [EDV]) were calculated. In organ bath experiments for isometric tension with isolated aortic rings, endothelium-dependent and -independent vasorelaxation were investigated by using acetylcholine and sodium nitroprusside. When compared to the young controls, aging rats showed impaired left ventricular contractility (E(es), 0.51 +/- 0.04 vs. 2.16 +/- 0.28 mmHg/microL; dP/dt(max) - EDV, 10.71 +/- 2.02 vs. 37.23 +/- 4.18 mmHg/sec per microL; p0.05) and a marked endothelial dysfunction (maximal relaxation to acetylcholine: 66.66 +/- 1.30 vs. 87.09 +/- 1.35%; p0.05). Treatment with CuAsp resulted in reduced nitro-oxidative stress, improved cardiac function (E(es), 1.21 +/- 0.17 vs. 0.51 +/- 0.04 mmHg/microL; dP/dt(max) - EDV, 23.40 +/- 3.34 vs. 10.71 +/- 2.02 mmHg/sec per microL; p0.05) and higher vasorelaxation to acetylcholine in aging animals (94.83 +/- 0.73 vs. 66.66 +/- 1.30%; p0.05). The treatment did not influence the cardiovascular functions of young rats.Our results demonstrate that oxidative stress and inflammatory pathways contribute to the pathogenesis of cardiovascular dysfunction in the aging organism, which can be reversed by CuAsp.

Objective Medication errors are frequent in a hospital setting and often caused by inappropriate drug handling. Systematic strategies for their prevention however are still lacking. We developed and applied a classification model to categorise medication handling errors and defined the urgency of correction on the basis of these findings. Setting Nurses on medical wards (including intensive and intermediate care units) of a 1,680-bed teaching hospital. Method In a prospective observational study we evaluated the prevalence of 20 predefined medication handling errors on the ward. In a concurrent questionnaire survey, we assessed the knowledge of the nurses on medication handling. The severity of errors observed in individual areas was scored considering prevalence, potential risk of an error, and the involved drug. These scores and the prevalence of corresponding knowledge deficits were used to define the urgency of preventive strategies according to a four-field decision matrix. Main outcome measure Prevalence and potential risk of medication handling errors, corresponding knowledge deficits in nurses committing the errors, and priority of quality improvement. Results In 1,376 observed processes 833 medication handling errors were detected. Errors concerning preparation (mean 0.88 errors per observed process [95% CI: 0.81–0.96], N = 645) were more frequent than administration errors (0.36 [0.32–0.41], N = 701, P

Candida species constitute the majority of nosocomial fungal pathogens in non-neutropenic patients. Candida infections are still connected with substantial mortality. Recent epidemiological observations indicate a shift to non-albicans species, especially because of a rise of infections caused by C. glabrata, which frequently shows fluconazole-resistance. New therapeutic options like caspofungin, as the first licensed echinocandin, new broad-spectrum azoles, and lipid preparations of amphotericin B emerged in the last decade as efficient alternatives to fluconazole and amphotercin B deoxycholate. In invasive candidiasis, a delayed treatment initiation is associated with an increased mortality, thus risk stratification and empirical therapy strategies become vitally important. This review reflects the efficacy of caspofungin in the treatment of Candida infections, especially in the setting of empirical therapy in critically ill patients, and considers the option of de-escalation to fluconazole.