Subtherapeutic triazole concentrations as result of a drug-drug interaction with lumacaftor/ivacaftor.

Lumacaftor/ivacaftor (Orkambi®, LUM/IVA) is indicated for the treatment of cystic fibrosis (CF) patients aged ≥ 2 years with homozygous F580del mutation in the CFTR gene. Triazole fungal agents are used to treat fungal disease in CF. The use of triazoles is limited by pharmacokinetic challenges, such as drug-drug interactions. The most notable drug-drug interaction between triazoles and LUM/IVA is due to strong induction of CYP3A4 and UGT by LUM. In this real-world retrospective observational study, we described the effect of LUM/IVA on the trough concentration of triazoles. Concomitant use of LUM/IVA with itraconazole, posaconazole or voriconazole resulted in subtherapeutic triazole levels in 76% of the plasma samples. In comparison, in patients with triazole agents without LUM/IVA only 30.6% of the plasma samples resulted in subtherapeutic concentrations. Subtherapeutic plasma concentrations of triazoles should be considered in CF patients on LUM/IVA and further research is warranted for other dosing strategies and alternative antifungal therapy.

The development and implementation of a guideline-based clinical decision support system to improve empirical antibiotic prescribing.

BACKGROUND: To describe and evaluate a clinical decision support system (CDSS) for empirical antibiotic therapy using a systematic framework. METHODS: A reporting framework for behavior change intervention implementation was used, which includes several domains: development, evaluation and implementation. Within the development domain a description is given of the engagement of stakeholders, a rationale for how the CDSS may influence antibiotic prescribing and a detailed outline of how the system was developed. Within the evaluation domain a technical validation is performed and the interaction between potential users and the CDSS is analyzed. Within the domain of implementation a description is given on how the CDSS was tested in the real world and the strategies that were used for implementation and adoption of the CDSS. RESULTS: Development: a CDSS was developed, with the involvement of stakeholders, to assist empirical antibiotic prescribing by physicians. EVALUATION: Technical problems were determined during the validation process and corrected in a new CDSS version. A usability study was performed to assess problems in the system-user interaction. IMPLEMENTATION: In 114 patients the antibiotic advice that was generated by the CDSS was followed. For 54 patients the recommendations were not adhered to. CONCLUSIONS: This study describes the development and validation of a CDSS for empirical antibiotic therapy and shows the usefulness of the systematic framework for reporting CDSS interventions. In addition it shows that CDSS recommendations are not always adhered to which is associated with incorrect use of the system.

Clinically relevant potential drug-drug interactions in intensive care patients: A large retrospective observational multicenter study.

PURPOSE: Potential drug-drug interactions (pDDIs) may harm patients admitted to the Intensive Care Unit (ICU). Due to the patient's critical condition and continuous monitoring on the ICU, not all pDDIs are clinically relevant. Clinical decision support systems (CDSSs) warning for irrelevant pDDIs could result in alert fatigue and overlooking important signals. Therefore, our aim was to describe the frequency of clinically relevant pDDIs (crpDDIs) to enable tailoring of CDSSs to the ICU setting. MATERIALS & METHODS: In this multicenter retrospective observational study, we used medication administration data to identify pDDIs in ICU admissions from 13 ICUs. Clinical relevance was based on a Delphi study in which intensivists and hospital pharmacists assessed the clinical relevance of pDDIs for the ICU setting. RESULTS: The mean number of pDDIs per 1000 medication administrations was 70.1, dropping to 31.0 when considering only crpDDIs. Of 103,871 ICU patients, 38% was exposed to a crpDDI. The most frequently occurring crpDDIs involve QT-prolonging agents, digoxin, or NSAIDs. CONCLUSIONS: Considering clinical relevance of pDDIs in the ICU setting is important, as only half of the detected pDDIs were crpDDIs. Therefore, tailoring CDSSs to the ICU may reduce alert fatigue and improve medication safety in ICU patients.

A usability study to improve a clinical decision support system for the prescription of antibiotic drugs.

OBJECTIVE: A clinical decision support system (CDSS) for empirical antibiotic treatment has the potential to increase appropriate antibiotic use. Before using such a system on a broad scale, it needs to be tailored to the users preferred way of working. We have developed a CDSS for empirical antibiotic treatment in hospitalized adult patients. Here we determined in a usability study if the developed CDSS needed changes. METHODS: Four prespecified patient cases, based on real life clinical scenarios, were evaluated by 8 medical residents in the study. The "think-aloud" method was used, and sessions were recorded and analyzed afterwards. Usability was assessed by 3 evaluators using an augmented classification scheme, which combines the User Action Framework with severity rating of the usability problems and the assessment of the potential impact of these problems on the final task outcomes. RESULTS: In total 51 usability problems were identified, which could be grouped into 29 different categories. Most (n = 17/29) of the usability problems were cosmetic problems or minor problems. Eighteen (out of 29) of the usability categories could have an ordering error as a result. Classification of the problems showed that some of the problems would get a low priority based on their severity rating, but got a high priority for their impact on the task outcome. This effectively provided information to prioritize system redesign efforts. CONCLUSION: Usability studies improve lay-out and functionality of a CDSS for empirical antibiotic treatment, even after development by a multidisciplinary system.

The effect of ICU-tailored drug-drug interaction alerts on medication prescribing and monitoring: protocol for a cluster randomized stepped-wedge trial.

BACKGROUND: Drug-drug interactions (DDIs) can cause patient harm. Between 46 and 90% of patients admitted to the Intensive Care Unit (ICU) are exposed to potential DDIs (pDDIs). This rate is twice as high as patients on general wards. Clinical decision support systems (CDSSs) have shown their potential to prevent pDDIs. However, the literature shows that there is considerable room for improvement of CDSSs, in particular by increasing the clinical relevance of the pDDI alerts they generate and thereby reducing alert fatigue. However, consensus on which pDDIs are clinically relevant in the ICU setting is lacking. The primary aim of this study is to evaluate the effect of alerts based on only clinically relevant interactions for the ICU setting on the prevention of pDDIs among Dutch ICUs. METHODS: To define the clinically relevant pDDIs, we will follow a rigorous two-step Delphi procedure in which a national expert panel will assess which pDDIs are perceived clinically relevant for the Dutch ICU setting. The intervention is the CDSS that generates alerts based on the clinically relevant pDDIs. The intervention will be evaluated in a stepped-wedge trial. A total of 12 Dutch adult ICUs using the same patient data management system, in which the CDSS will operate, were invited to participate in the trial. Of the 12 ICUs, 9 agreed to participate and will be enrolled in the trial. Our primary outcome measure is the incidence of clinically relevant pDDIs per 1000 medication administrations. DISCUSSION: This study will identify pDDIs relevant for the ICU setting. It will also enhance our understanding of the effectiveness of alerts confined to clinically relevant pDDIs. Both of these contributions can facilitate the successful implementation of CDSSs in the ICU and in other domains as well. TRIAL REGISTRATION: Nederlands Trial register Identifier: NL6762 . Registered November 26, 2018.

A clinical decision support system algorithm for intravenous to oral antibiotic switch therapy: validity, clinical relevance and usefulness in a three-step evaluation study.

Objectives: To evaluate a clinical decision support system (CDSS) based on consensus-based intravenous to oral switch criteria, which identifies intravenous to oral switch candidates. Methods: A three-step evaluation study of a stand-alone CDSS with electronic health record interoperability was performed at the Erasmus University Medical Centre in the Netherlands. During the first step, we performed a technical validation. During the second step, we determined the sensitivity, specificity, negative predictive value and positive predictive value in a retrospective cohort of all hospitalized adult patients starting at least one therapeutic antibacterial drug between 1 and 16 May 2013. ICU, paediatric and psychiatric wards were excluded. During the last step the clinical relevance and usefulness was prospectively assessed by reports to infectious disease specialists. An alert was considered clinically relevant if antibiotics could be discontinued or switched to oral therapy at the time of the alert. Results: During the first step, one technical error was found. The second step yielded a positive predictive value of 76.6% and a negative predictive value of 99.1%. The third step showed that alerts were clinically relevant in 53.5% of patients. For 43.4% it had already been decided to discontinue or switch the intravenous antibiotics by the treating physician. In 10.1%, the alert resulted in advice to change antibiotic policy and was considered useful. Conclusions: This prospective cohort study shows that the alerts were clinically relevant in >50% (n = 449) and useful in 10% (n = 85). The CDSS needs to be evaluated in hospitals with varying activity of infectious disease consultancy services as this probably influences usefulness.

Development of operationalized intravenous to oral antibiotic switch criteria.

OBJECTIVES: Despite huge overlap in suggested criteria for a safe intravenous (iv)-to-oral antibiotic switch, there is considerable variation in their operationalization. The objective of this study was to develop a set of measurable conditions that should be met in adult hospitalized patients for a safe iv-to-oral switch. METHODS: A RAND-modified Delphi procedure was performed to develop a set of operationalized iv-to-oral switch criteria. Switch criteria and their accompanying suggested measurable conditions were extracted from the literature and appraised by a multidisciplinary expert panel during two questionnaire rounds with a face-to-face meeting between these two rounds. In a final step, the experts could approve the set of developed operationalized switch criteria. RESULTS: Seven switch criteria and 41 accompanying measurable conditions extracted from the literature were appraised. Sixteen measurable conditions that operationalize six switch criteria were selected: (i) stable systolic blood pressure; and the absence of (ii) fever, (iii) temperature <36°C, (iv) malabsorption syndrome, (v) short bowel syndrome, (vi) severe gastroparesis, (vii) ileus, (viii) continuous nasogastric suction, (ix) vomiting, (x) (severe) sepsis, (xi) fasciitis necroticans, (xii) CNS infection, (xiii) Staphylococcus aureus bacteraemia, and (xiv) endovascular infection. In addition, (xv) the patient should be cooperative and (xvi) adequate antimicrobial concentration should be achievable at the site of infection by oral administration. CONCLUSIONS: These operationalized criteria can be used in daily clinical practice. Future use of these criteria in audits and as rules in clinical decision support systems will facilitate the performance and evaluation of iv-oral switch programmes.

Computerized provider order entry system--does it support the inter-professional medication process? Lessons from a Dutch academic hospital.

OBJECTIVES: To assess the effects of a CPOE system on inter-professional workflow in the medication process. METHODS: Twenty-three semi-structured interviews with physicians, nurses, and pharmacists were conducted in a Dutch academic hospital. In addition, the handwritten and system-generated documents used daily were collected for analysis. Data was analyzed on the basis of three conceptual themes in the inter-professional workflow: division of tasks, flow of information, and task coordination. RESULTS: The CPOE system reorganized the existing work procedures, affecting the workflow among the three professional groups both advantageously and disadvantageously. The system resulted in the reassignment of tasks and reallocation of areas of expertise in the medication process. Moreover, patients' medication-related information became fragmented in both the paper records and in the electronic records, as well as in different professional domains. The system provided limited support for professional groups to coordinate their tasks temporally. It also made it difficult to build mutual intelligibility upon new changes in the medication plan. To integrate tasks, the professional groups had to bypass the system or add new steps and extra coordinative tasks. CONCLUSION: We identified several workflow integration issues after the implementation of a CPOE system. Our insights into these issues can help ensure that the system design or redesign properly integrates all tasks, information, and areas of expertise of professional groups into those of the physicians.

Evaluation of the impact of a CPOE system on nurse-physician communication--a mixed method study.

OBJECTIVES: To assess the impact of a CPOE system on medication-related communication of nurses and physicians. METHODS: In six internal medicine wards of an academic medical center, two questionnaires were used to evaluate nurses' attitudes toward the impact of a paper-based medication system and then a CPOE system on their communication in medication-related-activities (medication work). The questionnaires were analyzed using t-tests, followed by Bonferroni correction. Nine nurses and six physicians in the same wards were interviewed after the implementation to determine how their communication and their work have been impacted by the system. RESULTS: The total response rates were 54% and 52% for pre- and post-implementation questionnaires. It was shown that after implementation, the legibility and completeness of prescriptions were significantly improved (P <.001) and the administration system had a more intelligible layout (P <.001), with a more reliable overview (P <.001). The analysis of the interviews supported and confirmed the findings of the surveys. Moreover, they showed communication problems that caused difficulties in integrating medication work of nurses into physicians'. To compensate for these, nurses and physicians devised informal interactions and practices (workarounds), which often represented risks for medication errors. CONCLUSION: The introduction of CPOE system with paper-based medication administration system improved prescription legibility and completeness but introduced many workflow impediments and as a result error-inducing conditions. In order to prevent such an effect, CPOE systems have to support the level of communication which is necessary to integrate the work of nurses and physicians.

Flucytosine: correlation between toxicity and pharmacokinetic parameters.

Flucytosine (5-fluorocytosine, 5-FC) is a systemic antimycotic drug the major toxicities of which are bone marrow depression and hepatotoxicity. The purpose of this observational and retrospective study was to assess a possible relationship between toxicity and 5-FC pharmacokinetics within a group of 53 intensive care unit patients. The presented results reveal that thrombocytopenia is associated with a decreased 5-FC clearance and that the thrombocyte nadir is linearly related to the 5-FC clearance. Furthermore, patients experiencing 5-FC levels exceeding 100 mg 5-FC/l were found to be at a higher risk of developing thrombocytopenia and hepatotoxicity as compared to those not exceeding this level.

An accelerated stability study of 5-flucytosine in intravenous solution.

The stability of the antimycotic drug flucytosine (5-FC) and the extent of 5-fluorouracil (5-FU) formation in 5-FC intravenous solution was studied in an accelerated stability experiment. 5-FC intravenous solution (10 mg/ml) was heated at 40, 60, 70, 80 and 90 degrees C for a maximum of 131 days. At appropriate time intervals samples were taken and the concentrations of 5-FC and 5-FU were determined using a newly developed, stability indicating HPLC-UV method. Heating the 5-FC intravenous solution at 40, 60, 70, 80 and 90 degrees C lead to 5-FC decomposition of respectively 0, 8.9, 14.4, 52.5 and 61.6%. The Arrhenius plot of the 5-FC decomposition is described by: Lnk5-FC decomposition = 80.1892 *1/T-0.2396 and the 5-FU formation is described by Lnk5-FU formation = -13087 *1/T + 34.4028. It is concluded that 5-FC is very stable in intravenous solution at regular storing temperatures and can therefore be stored at ambient temperatures for several years before the critical limit of 95% 5-FC is reached. However, the toxic and teratogen degradation product 5-FU may be present in considerable amounts in the product, due to both impurities in the raw material and the formation from 5-FC upon sterilisation and storage.

Oral calcium phosphate: a new therapy for Crigler-Najjar disease?

BACKGROUND & AIMS: Calcium phosphate binds unconjugated bilirubin in vitro, and dietary calcium phosphate supplementation reduces the serum bilirubin level in rats with hereditary unconjugated hyperbilirubinemia (Gunn rats). The aim of this study was to evaluate the effect of oral calcium phosphate supplementation on plasma bilirubin levels in patients with Crigler-Najjar disease. METHODS: A placebo-controlled, double-blind, crossover design was used. Eleven patients, 2-42 years of age, participated. The group included 5 patients with type I disease who were all treated with phototherapy and 6 patients with type II disease who were primarily treated with phenobarbital. In addition to plasma bilirubin levels, dietary intake and urinary and fecal excretion of calcium and phosphate were evaluated. RESULTS: A modest but significant decrease in serum bilirubin was observed in patients with type I disease (18% +/- 6%, P = 0.03) but not in patients with type II disease during treatment with calcium phosphate. Urinary output of calcium and phosphate did not change during the treatment period. CONCLUSIONS: Oral calcium phosphate may be a useful adjuvant to photo-therapy in Crigler-Najjar type I disease.